NANO-01028; No of Pages 26

Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx – xxx nanomedjournal.com

3 4

5 6 7

8

Jun Li, MD a, 1 , Yujue Wang, MD a, 1 , Ruijing Liang b , Xiangjie An, MD a , Ke Wang b , Guanxin Shen, MD c , Yating Tu, MD a , Jintao Zhu, PhD b,⁎, Juan Tao, MD a,⁎

F

Q22Q1

Recent advances in targeted nanoparticles drug delivery to melanoma, a

Department of Dermatology, Affiliated Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan 430022, PR China b School of Chemistry and Chemical Engineering and National Engineering Center for Nanomedicine, HUST, Wuhan 430074, PR China c Department of Immunology, Tongji Medical College, HUST, Wuhan 430022, PR China Received 6 August 2014; accepted 15 November 2014

R O O

1

Abstract

10

18

Melanoma is one of the most aggressive skin cancers, notorious for its high multidrug resistance and low survival rate. Conventional therapies approved by the FDA for melanoma treatment (e.g., dacarbazine, interferon-alpha-2b and interleukin-2) are limited by low response rate and demonstrate no overall survival benefit. Novel targeted therapies (e.g., vemurafenib, dabrafenib, and trametinib) have higher initial response rate and clear impact on the overall survival, but relapse usually occurs within 6 to 9 months. Although immunotherapy (e.g., ipilimumab) can achieve long-term and durable response, rate of adverse events is extremely high. With the development of nanotechnology, the applications of nanocarriers are widely expected to change the landscape of melanoma therapy for foreseeable future. In this review, we will relate recent advances in the application of multifunctional nanocarriers for targeted drug delivery to melanoma, in melanoma nanotheranostics and combination therapy, and nanopharmaceutical associated melanoma clinical trials, followed by challenges and perspectives. © 2015 Published by Elsevier Inc.

19

Key words: Nanoparticles; Melanoma; Drug delivery; Targeting; Nanotheranostics

20 21 Q4

Introduction

22 23 24 25 26 27 28 29 30

D

E

T

Q3

C

E

17

R

16

Melanoma, originated from the malignant transformation of melanocytes, is one of the most aggressive skin cancers, notorious for its high multidrug resistance (MDR), easy to relapse and low survival rate. Nearly 76,100 newly diagnosed cases of melanoma were reported in the United States in 2014 with an estimated 9710 expected deaths. 1 The statistical data collected from the National Cancer Institute of America quote melanoma as the fifth and seventh most commonly diagnosed malignancies among men and women, respectively. 2 The

R

15

O

14

C

13

N

12

U

11

P

9

Financial support: We gratefully acknowledge funding for this work provided by the National Basic Research Program of China (973 Program, 2012CB932500), National Natural Science Foundation of China (81271751), and Excellent Youth Foundation of Hubei Scientific Committee (2012FFA008). Conflict of interest: The authors declare no competing interests. ⁎Corresponding authors. E-mail addresses: [email protected] (J. Zhu), [email protected] (J. Tao). 1 These authors contributed equally to this work.

median survival time for metastatic melanoma patients is about 8-9 months with a 3-year overall survival rate of less than 15%. 3 As a highly heterogeneous malignancy, melanoma resulted from the interplay of genetic, host, and environmental factors. 4 The mutations of oncogenes and tumor suppressors thought to be the drivers of melanomagenesis include BRAF (~ 50% mutation frequency), NRAS (~ 30%), KIT (~ 1%), p53 (~ 5%), PTEN (~ 50%) and so on. 4 Furthermore, the higher somatic mutation load in melanoma than in other cancer types is believed to be attributable to the preponderance of cytosine-to-thymine nucleotide substitutions as a result of UV radiation exposure. 5 Also, melanoma is one of the most immunogenic tumors in which immune evasion and immune suppression play an important role. 6 The abnormal and down-regulated expression of MHC-I molecules on melanoma cell surface was due to the loss of transporters associated with antigen processing (TAP) function and loss of β2m within the endoplasmic reticulum, which resulted in the loss of recognition by tumor infiltrated T lymphocytes (TILs). 7 Up-regulation of programmed death ligand-1 (PD-L1) expression on the surface of melanoma cells led to the loss of effector function of TILs. 8 Also myeloidderived suppressor cells (MDSCs) such as tumor associated

http://dx.doi.org/10.1016/j.nano.2014.11.006 1549-9634/© 2015 Published by Elsevier Inc. Please cite this article as: Li J., et al., Recent advances in targeted nanoparticles drug delivery to melanoma. Nanomedicine: NBM 2015;xx:1-26, http://dx. doi.org/10.1016/j.nano.2014.11.006

31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52

64 65 66

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110

F

63

111 112 113 114 115 116 117 118 119 120 121

Targeted NPs drug delivery to melanoma

122

Targeting in nanotechnology refers to the spatial localization of the NP within the intentional sites and is distinct from molecularly targeted drugs. Targeted drug means blocking essential biochemical pathways or mutant proteins that are required for tumor cell growth. 17,18 The aforementioned vemurafenib and dafrafenib are targeted drugs for melanoma patients with mutant BRAF V600E. 14 There are many other therapeutic drugs which can target different signaling pathways of melanoma such as KIT and extracellular regulated protein kinases (ERK) inhibitors. 4 By contrast, targeted drug delivery refers to the preferential accumulation of a drug within a target site that is independent of the method and route of drug administration. 17 Targeted drug delivery to melanoma with the aid of nanocarriers allows therapeutic drugs to accumulate in tumor tissues with a high concentration, facilitates the uptake and internalization of the drug-loaded NPs by tumor cells, and avoids off-target distribution which may lead to severe adverse effects. In addition, the incorporation of therapeutic agents such as chemotherapeutic drugs, metals or magnetic particles, proteins, nucleic acids and vaccines, creates an ideal delivery system for the clinical treatment for metastatic melanoma. The principles of drug targeting to tumors can be divided into three categories: passive targeting, active targeting and triggered drug delivery responsive to different internal/external stimuli. Passive targeting is based on the EPR effect, whereby the vasculature leakiness and poor lymphatic drainage of the tumors enable the drug-loaded NPs to accumulate in the tumor areas. 19 As opposed to passive targeting, active targeting refers to the specific interactions between the drug-loaded NPs and the targeted tumors by modifying the NPs with targeting ligands, such as antibodies, peptides, nucleic acid based ligands or small molecules, which specifically bind to the receptors or molecules highly expressed at the targeted site. 20 Active targeting thus enables an enhanced interaction between the NPs and targeted tumor lesions and an increased internalization of drugs through specific receptor-mediated endocytosis. Also, by combining bioresponsive NPs with internal or external stimuli (such as pH gradient, hyperthermia, alternating magnetic field, light and acoustic), stimuli-triggered drug release can be successfully achieved. These stimuli-responsive NPs are designed to only release the encapsulated therapeutic drugs upon applying locally confined triggers, thereby maximizing drug release at the pathological sites of tumors. Inorganic NPs, polymeric micelles,

123

R O O

62

P

61

D

60

E

59

influence on the efficacy of both passive and active targeting. And the difficulties in achieving reproducible and controlled synthesis of NPs, lack of universal standard for evaluating the potent cytotoxicity of NPs and surfactants etc, are unavoidable problems before the NPs reach commercialization. Only by minimizing these pitfalls can we see the most immediate clinical translation. In this review, we will mainly focus on the targeted drug delivery to melanoma, associated theranostic strategies and combination therapy, and nanopharmaceutical associated melanoma clinical trials, followed by the current status, challenges and perspectives of this field.

C

58

E

57

R

56

R

55

macrophages (TAM) as well as the suppressive tumor microenvironment repress the host immune responses and promote the tumorigenesis. 9,10 Surgery offers a good chance of recovery at the early stage of melanoma. However, for advanced metastatic melanoma, only modest results are obtained with DTIC (1975), recombinant interferon α-2b (1995) and high-dose interleukin 2 (HD IL-2) (1998), the only three conventional therapeutic agents approved by the Food and Drug Administration (FDA) for metastatic melanoma. 11–13 All of these drugs are limited by low response rates (~ 15%) and show no clear impact on the overall survival, followed by severe toxicity. 11–13 Small targeted molecules such as selective mutant BRAFV600E inhibitors vemurafenib (2011) and dabrafenib (2013), MEK inhibitor trametinib (2013), 14,15 and immune checkpoint inhibitor ipilimumab (2011), an anti-cytotoxic T lymphocyteassociated antigen-4 (anti-CTLA-4) monoclonal antibody, 16 which have been newly approved by the FDA, marked a major breakthrough in clinical metastatic melanoma treatment. Although improved clinical response rate, clear benefits of progression-free survival (PFS) and the overall survival have been achieved by the clinical application of these novel therapeutic agents, some long-term obstacles and major challenges in melanoma therapy still need to be conquered. First of all, although many chemotherapeutic agents (e.g., nitrosoreas, vinca alkaloids and taxanes, platinums, etc.) are potentially effective anti-melanoma drugs with comparable response rate to that of DTIC, poor solubility and/or stability as well as serious toxicity limit their applications in clinical melanoma treatment. Thus, how to improve the pharmaceutical and pharmacological properties of these chemotherapeutic agents without changing the drug molecules is of great concern. Secondly, how to deliver these chemotherapeutics more efficiently to tumor tissues and further increase the efficacy of these agents by enhancing the intracellular concentrations in melanoma cells? Thirdly, how to exert melanoma killing effect while monitoring the biodistribution of the therapeutic agents but with smaller systemic dosing and less administration frequency? Last but not least, how to make a rational combination plan to overcome the resistance caused by single drug usage? Fortunately, the development of nanotechnology and the application of nanocarriers in medicine make it possible to get over the above mentioned hurdles. For example, multifunctional nanoparticles (NPs) have been developed to elongate the circulation time and improve the accumulation of drugs in the tumor tissues based on the surface modification (e.g., PEGylation) and enhanced permeation and retention (EPR) effect, to enhance the uptake of the drugs by tumor cells and avoid the adverse effect through both specific and enhanced interactions between the targeted tumors cells and ligand-modified NPs, and to overcome MDR by co-encapsulating rational combination of different therapeutic agents. Furthermore, nanotheranostics, by incorporation of therapeutic and diagnostic agents in the same NP, is a brand new protocol with the capability of detecting while treating tumors simultaneously. Besides all these opportunities and advantages, the challenges are not insignificant. For example, the complexicity of the EPR effect due to the interpatient variability and tumor heterogeneity will have great

N C O

54

U

53

J. Li et al / Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx–xxx

T

2

124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165

3

R O O

F

J. Li et al / Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx–xxx

P

Figure 1. Illustration of the classification of various nanocarriers for drug delivery and release.

172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198

E

D

inhibition in vitro, which suggested that good clinical efficacy would still be achieved if the intratumoral concentration could reach the minimum tumor killing threshold even though tumor cells can decrease the intracellular concentration of the drug by increasing drug efflux pumps on their membrane. In addition, the poor solubility/stability and severe toxicity to normal tissues also limited their clinical use not only in melanoma but also in other malignancies. Therefore, the development of nanoplatforms is essential to overcome these problems of low delivery efficiency and formulation for the improvement of pharmacokinetic parameters and the toxic adverse effects to normal tissues. The discovery of EPR effect was a milestone made by Maeda et al, who postulate that the enhanced accumulation of the colloidal particles in the tumor was attributed to the tumor structures features such as leaky vasculature and absent lymphatic vessels. 21 Further studies indicated that EPR effect was also observed in proteins, polymer bioconjugates, micelles, liposomes and many other types of NPs. Abraxane (based on the NP albumin-bound (nab) platform, nab–paclitaxel) approved by the FDA in 2005, and Geneol-PM (a paclitaxel loaded polymeric micelle) approved in Korea in 2007, have been clinically used for the treatment of metastatic breast cancer. 21 The application of nab-platform removed the need for the use of the toxic excipient Cremophor EL and led to an increase of PTX maximum tolerated dose. Also, both nanomedicines demonstrated significantly higher tumor response rate and longer times to tumor progression among the patients who did not respond to conventional therapy, 21 which ignite the quest for the further investigation of the anti-tumor effects of a variety of nanomedicines in patients with metastatic melanoma. And this will be discussed in more detail in the following section of clinical trials in melanoma with the use of NPs. Polymer bioconjugates or block copolymer micelles are commonly used nanocarriers for the delivery of these

T

Although DTIC has been the only chemotherapeutics approved by the FDA for clinical malignant melanoma treatment since 1975, its efficacy is very disappointing. But this cannot change the generally accepted opinion that chemotherapy is still one of the most important clinical strategies for metastatic tumors including melanoma. Although no significant improvement on response rate was obtained and not having demonstrated an overall survival benefit, chemotherapy has a clear role for palliation of patients with metastatic melanoma. Also, there are almost half of the melanoma patients who do not harbor a BRAF V600E mutation or who are ineligible for treatment with ipilimumab. Additionally, even if eligible for treatment, many patients treated with ipilimumab obtained no benefit and most of the patients treated with targeted small molecule kinase inhibitors eventually relapse from therapy, even in some countries where targeted therapy or immunotherapy is inaccessible which forced the clinicians turn to the conventional therapies. That is why chemotherapy remains an essential treatment option even in the era of CTLA-4 blockade and targeted therapies. Multiple chemotherapeutics have been evaluated in the treatment of advanced melanoma. For other highly effective antitumor agents such as docetaxel (DTX), paclitaxel (PTX) and doxorubicin (DOX), etc, their clinical application in melanoma treatment is largely hampered because clinical melanoma patients are not sensitive to all these chemotherapeutics with an objective response rate usually no more than 15%. But all these chemotherapeutics showed significant melanoma growth

C

171

E

170

Passive targeting to increase drug accumulation in melanoma site

R

169

R

168

liposomes, nanogels, polymer–drug conjugates and dendrimers are commonly used nanocarriers for drug delivery and release in melanoma (see Figure 1).

N C O

167

U

166

199 200 201 202 203 204 205 206 207 208 209 210 Q5 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233

245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291

F

244

R O O

243

P

242

D

241

E

240

NP accumulated in murine melanoma tissues in vivo by EPR effect and led to a dramatic reduction in tumor growth without any apparent signs of toxicity. 32 Huang et al 33 designed α-melittin-based lipid NP (α-melittin-NP) with reduced cytotoxicity and a widened safe dosage range compared to free melittin. This α-melittin-loaded NP efficiently suppressed tumor growth in melanoma-bearing mice with no side effects. Although passive targeting based on EPR effect enables the increased accumulation and retention of NPs in the tumor site, physical aspects such as size, shape, charge and PEGylation are all critical parameters affecting the pharmacokinetic and pharmacodynamic profiles of NP therapeutic agents. This topic has been reviewed elsewhere and interested readers can refer to the excellent review of Morachis et al 34 and Albanese et al 35 In addition, the EPR effect does not mean that NPs go only to the tumors. Actually, more than 90% of the injected NPs end up in or near normal tissues and organs such as liver, kidney and spleen. 36 Most importantly, the EPR effect only affects the distribution pattern of the NPs but does not increase the ability of the NP to reach its target—which means that it still cannot improve the NP uptake efficiency by tumor cells and increase the intracellular drug concentration. Active targeting mediated by specific interactions of ligands-receptors may complement the main defect of passive targeting or provide an alternative delivery system since it not only enhances the affinity between nanocarriers and tumor cells, but also facilitates the uptake of NPs by tumor cells via receptor-mediated endocytosis.

C

239

E

238

R

237

R

236

chemotherapeutic agents to melanoma. For instance, DTX was attached to carboxymethyl chitosan (CMCS) via a biodegradable linker to form CMCS–DTX conjugates. CMCS–DTX conjugates displayed better antitumor effect than DTX by inhibiting tumor growth and prolonging the survival time of B16 melanoma bearing mice more effectively. 22 Zhang et al 23 synthesized PTXloaded polymeric micelles (PF-PTX) consisting of Pluronic P123 and F127 block copolymers, and found that PF-PTX significantly prevented tumor growth and increased the survival time in subcutaneous or pulmonary B16-F10 melanoma model than Taxol. DOX loaded monomethoxy poly (ethylene glycol)-poly (epsilon-caprolactone) (DOX/MPEG-PCL) micelles improved the cytotoxicity of DOX and enhanced its cellular uptake in B16 melanoma cells. Compared to free DOX group, more significant antitumor efficacy and prolonged survival but less system toxicity were observed in melanoma xenograft treated with the DOX/MPEG-PCL micelles. 24 Besides chemotherapeutics, micelles can also be used for siRNA and plasmid DNA delivery to melanoma cells. Yang et al 25 successfully delivered VEGF-siRNA to melanoma cells by using chitosan (CTS/siRNA) NPs. These CTS/siRNA NPs displayed not only improved transfection efficacy but also greater VEGF gene silencing efficiency in B16-F10 melanoma cells without apparent cytotoxicity. Cationic micelles formed from PEG–poly(propylene sulfide)–poly(ethylene imine) (PEG–PPS–PEI) and from mixtures of PEG-PPS with PEG– PPS–PEI were used for the delivery of antigen plasmid DNA (pDNA) to melanoma cells. Both micelle formulations showed improved transfection efficiency compared with naked pDNA and with lower cytotoxicity. Tumor growth suppression and increased intratumoral infiltration of cytotoxic T lymphocytes were also observed in a melanoma animal model. 26 Liposomes, another important nanocarrier, have also been widely used for passive targeting to melanoma. Polycation liposomes containing dicetylphosphate-tetraethylenepentamine (DCP-TEPA) were formulated for luciferase 2 siRNA delivery to B16-F10-luc2 melanoma cells. The complex decorated with cyclic Arg–Gly–Asp peptide (RGD) (RGD–PEG–PCL/siLuc2) exhibited high luc2 gene-silencing efficacy against melanoma cells in the lung metastatic mice modal. 27 Cytochalasin D and N, N,N-trimethylphytosphingosine-iodide (TMP) are both effective cytotoxic drugs but the severe side effects limit their use in cancer therapy. Cytochalasin D encapsulated in polyethylene liposomes could significantly inhibit melanoma growth and prolong the survival time with less side effects in mice models compared with natural cytochalasin D. 28 TMP liposomes also efficiently suppressed melanoma growth and angiogenesis with reduced side effects. 29 Besides cytotoxic drugs, cytolytic peptides are also of high potential for cancer therapy. However, their clinical applications are greatly hampered by toxicity, nonspecificity, and degradation. Melittin, derived from the venom of the honeybee Apis mellifera, is a water-soluble cationic cytolytic peptide that nonselectively attacks all lipid membranes with significant toxicity, thereby limiting its therapeutic benefit. Soman et al 30,31 synthesized a nanoscale delivery vehicle for melittin by incorporating this nonspecific cytolytic peptide into the outer lipid monolayer of a perfluorocarbon NP. This melittin-loaded

N C O

235

U

234

J. Li et al / Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx–xxx

T

4

292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318

Active targeting to increase uptake and internalization of drugs

319

Targeted drug delivery to melanoma cells Compared with small molecular targeted drugs which can be given orally and reach cytoplasmic targets by diffusion across the plasma membrane, the most effective targeted therapies may be the use of biotherapeutics (usually antibodies) that modulate the target molecules expressed at the cancer cell surface. 37 There are currently 13 antibodies approved by the FDA for cancer treatment since the introduction of the first effective therapeutic antibodies in cancer, the CD20 antibody rituximab and the HER2 antagonist trastuzumab. 38 Therapeutic agent loaded NP conjugated with antibody for tumor specific antigen is one of the most promising strategies for cancer therapy. For example, BIND-014, a DTX loaded polymeric NP targeting the PSMA (prostate specific membrane antigen) expressed on a variety of tumors, is currently being evaluated in clinical trials with 1 complete response, 3 partial response and 5 stable disease over 12 weeks in 28 cancer patients. 39 The success of BIND-014 brought the hope of designing antibodies with high specificity and a broad selection for melanoma surface molecules targeting. However, inflammation-driven phenotypic plasticity is a source of tumor heterogeneity which alters the antigenic landscape of melanoma cells. 40 And high antigenic diversity could also result from the much higher frequency of somatic mutations caused by UV radiation exposure than other tumors. 5 In addition, some of the melanoma biomarkers with high specificity are usually intracytoplasmic proteins with very low expression on the melanoma cell surface. 41 All these may explain the variability and lack of

320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347

5

E

D

P

R O O

F

J. Li et al / Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx–xxx

352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372

R

351

R

350

specificity of melanoma surface antigen in different individuals, and this might also explain why the antigenic profile of metastatic lesions does not always reflect that of the primary tumor. And these may partly be the reasons why few antibodies targeting molecules expressed on melanoma cell surface have been introduced till now. Although identifying and targeting the melanoma specific antigens are difficult, pre-clinical investigations with great efforts still have been made to verify the improved therapeutic efficacy in melanoma animal model. For example, monoclonal antibody Ep1 to the human melanomaspecific antigen CSPG4 was conjugated to a single cisplatinencapsulated ferritin cage (HFt–Pt–Ep1). HFt–Pt–Ep1 demonstrated specific binding to a CSPG4 (+) melanoma cell line, but not to a CSPG (−) breast carcinoma cell line. Also, the HFt–Pt– Ep1 showed significant antitumor growth effect in melanoma Colo 38 mice model. 42 As an alternative option, receptors that are over-expressed on the surface of melanoma can be used for specific and efficient targeted drug delivery. Even though these receptors can also be expressed on normal tissues, their high density distribution and expression on tumor cells make them possible targets for drug delivery with relatively higher specificity and affinity compared with normal tissues. For example, transferrin receptors (TfR) and folic acid receptors (FR) are often over-expressed on the surface of a wide variety of solid tumors including melanoma. 43 The

N C O

349

U

348

E

C

T

Figure 2. Transferrin conjugated nanocarriers for gene delivery to melanoma. (A) RRM2 mRNA and protein expression in samples from malignant melanoma patients A, B and C2 before and after dosing. (B) Nova Red chromagen staining in immunohistochemically treated slides (RRM2 (a, d) and TFR (b, e)) and haematoxylin and eosin staining (c, f) from malignant melanoma patients before and after dosing. (C) Bioluminescence imaging of the tumoricidal activity of transferrin-bearing DAB dendriplex carrying plasmid DNA encoding p73 in a mouse B16-F10-luc tumor model. Controls: non-targeted DAB dendriplex, uncomplexed DAB-Tf, naked DNA and untreated tumors. Reprinted from Davis et al 45 and Lemarié et al. 46

large quantity and relatively low cost of transferrin and folic acid, as well as their low antigenicity to avoid RES capture and clearance make them a favorable option for targeted drug delivery. Nearly all the targeted nanomedicines that are now in early clinical trials for solid tumors (e.g., ovarian cancer, breast cancer, etc) utilize transferrin as the targeting ligand. 44 Davis et al 45 conducted the first siRNA clinical trial in 2008 by using a targeted NP-delivery system to treat patients with solid tumors refractory to standard-of-care therapies. The NPs (denoted as CALAA-01 in clinical version) contain a linear, cyclodextrinbased polymer (CDP), transferrin ligand, a hydrophilic polymer (PEG), and siRNA of ribonucleotide reductase M2 subunit (RRM2). Tumor biopsies from melanoma patients after NPs intravenous infusion treatment showed a specific inhibition of RRM2 gene expression (Figure 2). Transferrin-bearing polypropylenimine dendrimers loaded with a plasmid DNA encoding p73 enhanced anti-proliferative activity in vitro by up to 120-fold in A431 and rapidly inhibited tumor growth in A431 and B16-F10 melanoma bearing mice without apparent toxicity (Figure 2). 46 Folic acid-targeted NPs containing IL-2 plasmid suppressed the growth of melanoma and prolonged the survival in B16-F1 melanoma mice model more efficiently compared to the non-targeted control group. 47 Even though antitumor effects have been achieved to a certain extent by modifying nanocarriers with transferrin and folate, the wide distribution of the TfR and

373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397

409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455

Targeting melanoma vasculature associated endothelial cells Tumor stromal tissue, especially tumor vasculature, is not a passive bystander but an active participant with the utmost importance in the development and progression of solid tumors including melanoma. 62 Rapid proliferation and metastasis are based on having a sufficient blood supply which brings oxygen and nutrients to tumor tissues. As essential cell adhesion receptors expressed on the tumor vasculature, the transmembrane glycoprotein integrins are very important in mediating tumor growth, invasion, metastasis and angiogenesis. 63 Tumor growth retardation and metastasis elimination can be obtained through specific and efficient tumor vessel targeting and antiangiogenesis therapy. A wide variety of integrins such as αvβ3, αvβ5 and α5β1 are usually highly expressed on melanoma vasculature associated endothelial cells. Over-expression of these integrins is often associated with the transition to a metastatic phenotype in malignant melanoma. 64 Therefore, integrins have become

495

F

408

R O O

407

P

406

456

D

405

antagonist-conjugated NPs exhibited significantly higher tumor uptake than non-targeted one and were more quickly dispersed from tumor vessels via receptor-mediated endocytosis and subsequent transcytosis. 56 Therefore, better understanding of functions and mechanisms of these receptors on melanoma cells can guide us to synthesize more effective targeted nanocarriers with significantly enhanced delivery efficiency and endocytosis ability. Although all the above mentioned in vivo experiments demonstrated increased drug delivery efficiency to melanoma and enhanced melanoma growth inhibition, they all carried out in animal models. The variations and diversities of genetic, antigenic and immunogenic patterns between mice model and melanoma patient are the top priorities need to be taken into consideration. For example, the xenograft mice lack a functional immune system, the transplanted tumors in syngeneic mice that have normal immune systems often lack specific mutations which can be targeted, and many genetically engineered mouse models lack the antigenic diversity seen in most human cancers, especially in melanoma, one of the most immunogenic cancers. 57 In addition, the expression level of the receptors on the surface of melanoma cells varies widely among different individuals even in the same individual but under different pathological conditions or tumor stages. And over-expression means that these receptors also expressed on normal cells. The unspecific “off-target” may greatly affect the targeting efficiency. Thus, more preclinical experiments need to be carried out and more specific tumor surface molecules need to be exploited before evaluating the real efficacy of actively-targeted NPs in melanoma patient. Fortunately, besides BIND-014 and CALAA01, anti-EGFR-Ils-dox using cetuximab for EGFR targeting, 58 DOX loaded liposomes MM-302 and MCC-465 for HER2 and gastric cancer antigens targeting, 59,60 and both MBP-426 and SGT53 for TfR targeting, 61 are actively-targeted NPs currently evaluated in clinical trials. Although no actively-targeted NPs are commercially available right now, the promising result obtained in the phase I/II clinical trials of these targeted NPs will offer the opportunity to carry out further pre-clinical and clinical investigations in melanoma targeting.

E

404

C

403

E

402

R

401

R

400

FR on normal tissues and cells will pose the danger of off-target (yet specific) binding and effects. Receptors with relatively higher expression on melanoma but lower expression on normal cells and tissues than TfR and FR may offer greater choice for clinical advanced melanoma treatment with more specificity and efficiency. Melanocortin receptor-1 (MCR-1), fibroblast growth factor receptor (FGFR), laminin receptor, somatostatin receptor (SSTR) and sigma receptor etc. are among the receptors that can be conjugated with NPs for active melanoma targeting. PTX or DOX-loaded truncated FGF fragment-targeted PEGylated liposomes showed higher accumulation in tumor tissues and internalization by melanoma cells but less concentration in other organs such as heart, lung and kidney compared with non-targeted liposomes or free PTX and DOX. 48,49 Octreotide is verified to be the ligand of SSTRs which are highly expressed on the surface of pancreas and melanoma cells. DOX-loaded liposomes modified with octreotide–PEG–phosphatidylethanolamine (Oct–PEG–PE) showed a remarkable accumulation of DOX in melanoma and the pancreas, and enhanced drug cytotoxicity to melanoma cells. 50 Tyr–Ile–Gly– Ser–Arg (YIGSR) peptide anchored pegylated nanospheres (YIGSR-SN) loaded with 5-fluorouracil (5-FU) could specifically target laminin receptors and showed significant efficacy in the prevention of tumor growth and lung metastasis in B16-F10 melanoma bearing mice compared to free 5-FU and nontargeted liposomes. 51 Etoposide loaded polymeric micelles targeting laminin receptor also showed higher cytotoxicity to B16-F10 melanoma cells and a marked increase in inhibition in lung metastasis compared to non-conjugated micelles. 52 In addition to the aforementioned CALAA-01, the first TfR targeted NP to reach clinical trials for siRNA delivery, other ligand-modified nanocarriers loaded with DNA/siRNA can also cause a significantly enhanced antitumor effect in melanoma animal models and are bound to be of great benefit to clinical advanced melanoma therapy. For example, sigma receptortargeted N,N-distearyl-N-methyl-N-2-(N′-arginyl) aminoethyl ammonium chloride (DSAA) NPs and lipid/calcium/phosphate (LCP) NP were synthesized for c-Myc or c-Myc/MDM2/VEGF siRNA delivery. Both sigma receptor-targeted NPs showed significantly enhanced anti-melanoma effect compared to nontargeted control in mice model. 53,54 The MCR-1 targeted polyplexes carrying herpes simplex virus thymidine kinase suicide gene (HSVtk) exhibited more efficient melanoma growth inhibition and prolonged the lifespan of melanoma bearing mice more than the non-targeted ones. 55 Besides the enhanced interactions between the NPs and tumor cells, the true value of active targeting may lie in its ability to be internalized upon receptor-mediated endocytosis. The internalization process is of great importance because many drug-loaded NPs need to release the drug intracellularly before it can act on its intracellular target. Many of the above mentioned targeting ligands can facilitate receptor-mediated endocytosis and help to control the intracellular trafficking and destination. However, significant differences in the efficiency of endocytosis and transcytosis from different ligand–receptor interactions can be observed, even those different ligands targeting the same receptor. For example, MCR-1 agonist- but not MCR-1

N C O

399

U

398

J. Li et al / Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx–xxx

T

6

457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494

496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512

7

R

E

C

T

E

D

P

R O O

F

J. Li et al / Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx–xxx

514 515 516 517 518 519 520 521 522 523 524 525 526 527 528

important targets in clinical melanoma treatment. RGD-peptides have a high affinity to integrin αvβ3. Many studies indicated that activated endothelial cells could bind and internalize PEGliposomes modified with cyclic RGD-peptides on their surfaces. Cyclic RGDyK-modified dual-drug system (encapsulating both DOX and antivascular agent combretastatin A4 (CA4) exhibited an optimal anti-tumor vasculature and anti-proliferation effect compared to non-targeted control (Figure 3). 65 The cRGDfK peptide conjugated NPs co-encapsulating PTX and CA4 also showed dramatic tumor vasculature disruption and significant tumor growth suppression. 66 Integrin α5β1 antagonist with DOX-loaded stealth liposomes exhibited enhanced intracellular uptake and much stronger tumor inhibition compared with nontargeted control in B16-F10 melanoma bearing mice. 67 Although mono-targeting exhibited good anti-tumor effect, dual targeting brought more significant tumor inhibition effect

U

513

N C O

R

Figure 3. cRGDfK peptide conjugated NPs for drug delivery to melanoma (B16-F10) and vasculature endothelial cells (HUVEC). (A) Confocal laser scanning microscopy (CLSM) images of B16-F10 and HUVECs. Red signal represents fluorescence of DOX while blue signal represents nuclear fluorescence of Hoechst 33258. (B) Effect of various treatments on the apoptosis of tumor cells from B16-F10 melanoma mice model. Tumor apoptotic cells were detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL). Reprinted from Wang et al. 65

than mono target. A 12-amino acid synthetic peptide C16Y, derived from the globular domain of the laminin γ1 chain, binds to the integrins αvβ3 and α5β1 on the tumor vasculature associated endothelial cells and tumor cells in B16 melanoma bearing mice. The intracellular uptake of C16Y modified PEGylated liposomes was higher than that of non-targeted control and significantly enhanced antitumor effect was observed in melanoma mice. 68 Two angiogenesis-specific ligands (galectin-1-specific anginex [Anx] and αvβ3 integrin-specific RGD) conjugated liposomes produced significantly enhanced synergistic targeting effect and the specificity on the tumor vasculature in B16-F10 melanoma bearing mice compared to either Anx or RGD-targeted liposomes. 69 Interestingly, in a recent study a newly synthesized TH10 peptide (TAASGVRSMH) conjugated NPs loading DTX (TH10-DTX-NP) exhibited specific targeting ability to NG2, a highly expressed proteoglycan receptor on

529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544

8

557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600

F

556

R O O

555

P

554

Immune targeting for melanoma treatment It has long intrigued biologist and oncologist that immune system could be activated to generate anticancer responses. With the development of our knowledge concerning the function of immune system and the interaction between the tumor immunosuppression and host immune response, a shift of dogma has been made that melanoma is not only a genetic disease, but also an immunological disorder. As mentioned at the beginning of this review, melanoma is one of the most immunogenic tumors and can easily evade immune surveillance, which is not common in other malignant tumors. With great success achieved in melanoma clinical trials, immune checkpoint inhibitors such as ipilimumab and tremulimumab (an antibody against CTLA-4), nivolumab (BMS-936558) and lambronlizumab (MK-3475) (an antibody against PD-1) marked a great breakthrough in melanoma therapy. PD-1 contributes to T-cell exhaustion in peripheral tissues, CTLA-4 inhibits at earlier points in T-cell activation. Blockade of PD-1 and CTLA-4 achieved significant antitumor activity in metastatic melanoma. 71,72 Even though great achievements have been made, serious adverse events related to the treatment were reported in 49% of patients in the concurrent-regimen group. 73 The pursuit for new immune targeting strategies with more efficiency but less adverse effect is becoming increasingly important. For example, specific targeting to immune cells and lymphoid organs such as dendritic cells (DCs), tumor-specific T lymphocytes and lymph nodes (LNs) attracts more and more attention.

D

553

E

552

Targeting dendritic cells. DCs serve as a bridge between innate and adaptive immune system. As potent antigenpresenting cells, DCs initiate primary immune response and further stimulate T cells differentiation and activation. DCs play an important role in the immune regulation and surveillance of most kinds of tumors including melanoma, and the great success of melanoma vaccines in clinical trials provide a promising strategy in melanoma treatment. For example, gp100 as a melanoma vaccine is now in its phase III clinical trial and showed significant higher response rate and PFS in combination group than treated with IL-2 alone. 74 Also, Allovectin-7 and GVAX melenoma are in their phase III and phase I study, respectively. 75,76 Even though some exciting clinical results have been obtained, the pursuit of more efficient and specific DC targeting in melanoma treatment has never ceased. 77 With the development of nanotechnology, a great variety of NPs as biomaterial vehicles for DC targeting have been widely used in vaccines and cancer immunotherapy. 78 NPs encapsulated with antigen or peptide can be protected from degradation of seral protease and enhance the efficiency of phagocytosis or

macropinocytosis by DC. Ligand modified NPs can be recognized by specific receptors expressed on the surface of DC. Also, as labeled vehicles, metallic and magnetic NPs can be recognized by specific receptor for effective tracking and realtime monitoring the migration and distribution of DCs. The biodegradable poly (D,L-lactide-co-glycolide) (PLGA) NPs were synthesized for the delivery of murine melanoma antigenic peptides human gp100 (hgp100) and tyrosinase-related protein 2 (TRP2). When injected into melanoma bearing mice, these peptide-loaded PLGA-NPs showed increased uptake efficiency by DCs and induced antigen-specific T cell responses more strongly than the peptides mixed with Freund's adjuvant. 79 But the relatively low efficiency of antigen delivery to DCs and non-specific uptake and endocytosis of NPs by mononuclear phagocyte system (e.g., macrophages) can be significantly improved by surface modification with DC specific or positive receptors/biomarkers. DC-specific intercellular adhesion molecule-3-grabbing nonintergrin (DC-SIGN), CD11c and DEC-205 are among these receptors/biomarkers which can be utilized to improve the delivery efficiency, facilitate the uptake and internalization and enhance the antigen presentation capability to T lymphocytes. 80 For example, DC-SIGN-targeted liposomes loaded with melanoma antigen recognized by T-cells 1 (MART1) provided more efficient antigen presentation to T cells than non-targeted control. 81 B16-OVA is a tumor antigen from the highly metastatic murine melanoma. B16-OVA-loaded stealth liposomes, targeting DCs by single chain antibody fragments to DC surface molecules CD11c and DEC-205, induced dramatic B16-OVA-specific cytotoxic T lymphocytes (CTLs) responses, significant protection against tumor growth and prolonged melanoma-free survival (Figure 4). 82 MART-1 mRNA-loaded Man (11)-LPR100 (mannosylated and histidylated lipopolyplexes) could efficiently bind the mannose receptors on splenic DCs, deliver melanoma antigen mRNA to splenic DCs in B16F10 melanoma bearing mice and induce significant antimelanoma immune responses and tumor growth inhibition. 83 The above-mentioned research indicated that potential DCtargeting vaccinations based on nanocarriers may offer new options for melanoma treatment. Furthermore, targeted NPs have been designed for both multimodal imaging of NPs-DC interactions and tracking the distribution of DCs from the subcellular to the organism level. For example, NP harboring superparamagnetic iron oxide particles (SPIO) and fluorescentlylabeled DC-SIGN could not only track NPs at subcellular organel level, but also quantify specific versus nonspecific uptake of targeted NPs by DCs. This study demonstrated that incorporation of two imaging agents within a single carrier allowed tracking of targeted nanovaccines on a subcellular, cellular and possibly organism level, thereby facilitating the rational design of in vivo targeted vaccination strategies. 84 Specific melanomas targeting through different ligand–receptor mediated interactions are listed in Table 1. Despite of the great advantages of DC targeting, some factors such as the toxicity, formulation, especially the particle size should be also taken into consideration. Among them, size of NP is a key question whether the NPs with targeting agents are too large to freely diffuse through the extracellular matrix for substantial DC targeting, since macrophages in the tissue environment will readily engulf

T

551

C

550

E

549

R

548

R

547

tumor vascular pericytes, leading to the DTX-induced pericyte apoptosis with decreased microvessel density in lung metastasis and enhanced antitumor effect in B16F10-luc-G5 melanoma mice model. 70 Despite some encouraging clinical success achieved, there is still a long way to go to explore more specific targeted nanocarriers for the delivery of anti-angiogenesis agents to melanoma vasculature associated endothelial cells and pericytes.

N C O

546

U

545

J. Li et al / Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx–xxx 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658

9

R O O

F

J. Li et al / Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx–xxx

Figure 4. Schematic illustration of the stimuli-triggered drug release from the NPs.

667 668 Q6 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688

689 690 691 692 693 694

P

D

E

666

receptors (CAR). 90 Besides ACT, immune modulators for the purpose of up-regulating the activity of tumor-specific T lymphocytes are of the same importance. Either inhibiting its exhaustion/inactivation or enhancing its activation is important strategy to promote T lymphocyte responses in tumor immunotherapy. Ipilimumab and nivolumab are characteristic and successful examples of the former in clinical melanoma treatment. And for the latter, significantly enhanced T lymphocytes activation and responses could be observed in the clinical application of Urelumab (BMS-663513, anti-4-1-BB) (antiCD137 monoclonal antibody) for cancer treatment. 91 Besides targeting co-stimulatory or inhibitory molecules on the surface of T lymphocyte, other attempts to activate T lymphocytes are also of great value. As aforementioned, cytokines such as HD IL-2 can be used to stimulate the activation of tumor specific T lymphocytes for clinical anti-melanoma treatment. But the serious adverse events to normal tissues limited its clinical application. However, with the aid of NPs, cytokines can be delivered to the tumor area and activate the tumor specific T lymphocytes more efficiently but less harmful to normal tissues. For example, IL-15 and IL-21 are two cytokines which can cooperatively promote T lymphocytes expansion and anti-tumor function. IL-15 and IL-21 co-encapsulated NP enables the delivery of both cytokines to melanoma tissues and promote in vivo Pmel-1 melanoma-specific T-cells activation and expansion, which further prevented tumor growth and disseminated B16F10 melanoma lung and bone marrow metastases more efficiently and with less systemic adverse effects compared to no cytokine modified control. 92 However, all of the above mentioned strategies are nonspecific for tumor specific T lymphocytes. When administered systemically, the activation of “unwanted” T lymphocyte will undoubtedly bring severe adverse events. Therefore, how to overcome this “pan-activation pitfall” by only targeting tumor specific T Lymphocytes is an urgent need. Moreover, it is worth noting that MDSCs recruited to the melanoma lesion from bone marrow could induce an immunosuppressive state. Tumor cells under this suppressive microenvironment could upregulate antiapoptotic and proliferative genes and produce ROS, NO and

T

665

C

664

Targeting lymph nodes (LNs). Draining LNs are the second lymphoid organs where adjuvant or antigen loaded NPs can directly reach the antigen-presenting cells (APCs) such as LNresident DCs. Also, NPs can be drained through these LNs into the systemic circulation and access APCs in distal tissues and organs. Jeanbart et al 87 found that NPs conjugated with CpG-B or CpG-C oligonucleotides led to better dual-targeting of adjuvant and antigen to the LNs and enhanced cross-presenting ability of DCs compared with the control group, which further induced the maturation of DCs and led to an increased anti-tumor immunity and efficient tumor growth inhibition in E.G7-OVA or the more aggressive B16-F10-OVA mice model. Liu et al 88 immunized mice with synthesized CpG-DNA/peptide amphvaccines which resulted in significant increases in LN accumulation and decreased systemic dissemination compared with the control, leading to 30-fold increases in T-cell priming and slowed melanoma tumor growth while greatly reducing systemic toxicity. Also, the CpG-NP and PTX-NP could accumulate within the tumor draining LNs (TDLNs) after intradermal administration and induce DC maturation in the TDLNs, further led to an increased antigen specific CD8 + T cell activation and suppressed tumor growth in B16-F10 melanoma bearing mice. 89 Taken together, as an efficient antigen and other potential vaccine components delivery strategy, LN targeting has a bright future in the immunotherapy for melanoma and other malignant tumors.

E

663

R

662

R

661

N C O

660

these NPs in a non-specific manner before the targeting happens. 85,86 It is for these reasons that lymph node targeting seems to be an alternative or even better choice for more efficient antigen presenting to DCs.

U

659

Targeting T lymphocytes. Tumor-specific T lymphocyte plays an important role in antitumor therapy. Adoptive T cell therapy (ACT) is a promising and advancing strategy to enhance the antitumor immune responses by tumor specific T lymphocytes, including expanded and activated TILs, T cells with an ex-vivo modified specific TCR, and T cells with chimeric antigen

695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733

10

J. Li et al / Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx–xxx

t1:1 t1:2

Table 1 Specifically targeting melanoma cells/melanoma vasculature associated endothelial cells/dendritic cells through ligand–receptor mediated interactions.

t1:3

Specific ligand–receptor interactions

t1:4 t1:5

Targeting melanoma cells Tf/TfR

t1:16 t1:17 t1:18 t1:19 t1:20 t1:21 t1:22 t1:23 t1:24 t1:25

t1:26 t1:27

t1:28

Ref.

F

R O O

P

D

t1:14 t1:15

E

t1:13

T

t1:12

C

t1:11

E

t1:10

Effect

Specific RRM2 gene expression inhibition and tumor growth suppression P73 plasmid DNA Enhanced anti-proliferative activity and tumor growth inhibition Folate/FR IL-2 plasmid DNA Tumor growth suppression and prolonged survival tbFGF/FGFR DOX and PTX Significant inhibition in tumor growth and improvement in survival rate PTX tbFGF-PEG-LPs Higher drug accumulation in tumor tissues and prolonged drug half-life time Oct/SSTR DOX Oct–PEG–PE Remarkable accumulation of DOX in melanoma tumors and the pancreas and more significant cytotoxicity to melanoma cells YIGSR/laminin 5-FU YIGSR-SN Significant efficacy in the prevention of receptor tumor growth and lung metastasis Etoposide YIGSR peptide conjugated micelles Higher cytotoxicity to melanoma cells and a markedly inhibition in lung metastasis AA/sigma receptor MDM2, c-myc, and VEGF siRNA LCP NP grafted with PEG and AA Efficient tumor growth inhibition and metastasis suppression c-Myc siRNA AA-targeted NPs Partially inhibited tumor growth MC1SP-peptide/ HSVtk PEI-PEG-based polyplexes containing Efficient melanoma growth inhibition and MCR-1 MC1SP-peptide prolonged the lifespan Targeting melanoma vasculature associated endothelial cells RGD-base peptide/ DOX and CA4 RFPMs modified with PEG-PLA Anti-tumor vasculature and antiαvβ3 integrin proliferation effect cRGDfK peptide/αvβ3 PTX and CA4 cRGDfK peptide conjugated with PLGA Anti-tumor vasculature and anti-proliferation integrin modified solid NPs effect Ac-PHSCN-NH(2)/ DOX Ac-PHSCNK-NH(2) (PHSCNK) Enhanced intracellular uptake and much α5β1 integrin conjugated with stealth liposomes stronger tumor inhibition C16Y peptide/αvβ3 C16Y-L Higher intracellular uptake and enhanced andα5β1 integrin antitumor effect Anx and RGD/galectinAnx/RGD-L Significantly enhanced synergistic targeting 1 andαvβ3 integrin effect and specificity on the tumor vasculature than single target TH10 peptide/NG2 DTX TH10-DTX-NPs Pericyte apoptosis with decreased microvessel density in lung metastasis and enhanced antitumor effect Targeting dendritic cells DC-SIGN-binding MART-1 DC-SIGN-binding glycans modified More efficient antigen presentation to T cells glycans/DC-SIGN liposomes and drive CD8(+) T cells differentiation CD11c and DEC-205 OVA or OVA peptide antigen CD11c and DEC-205 single chain antibody Induction of dramatic B16-OVA-specific single chain antibody fragments conjugated stealth liposomes CTL responses, significant protection fragments/CD11c against tumor growth and prolonged and DEC-205 melanoma-free survival Mannose/mannose MART-1 mRNA Man(11)-LPR100 Significant anti-melanoma immune receptor responses and tumor growth inhibition DC-SIGN antibody/ Fluorescently labeled antigen SPION coated with antibodies Two imaging agents within a single carrier DC-SIGN recognizing DC-SIGN allows tracking of targeted nanovaccines on a subcellular, cellular and possibly organism level

R

t1:9

Transferrin-bearing pegylated cyclodextrinbased polymer (CALAA-01) Transferrin-bearing polypropylenimine dendrimer Polyethylenimine linked by beta-cyclodextrin and conjugated with folate (named H1) tbFGF-LPs

R

t1:8

siRNA of RRM2 subunit

N C O

t1:7

Nanocarriers

U

t1:6

Therapeutic agents

45

46

47

48

49

50

51

52

54

53 55

65

66

67

68

69

70

81

82

83

84

Abbreviations: Tf, transferrin; TfR, transferrin receptor; FR, folate receptor; tbFGF, truncated human basic fibroblast growth factor; FGFR, fibroblast growth factor receptor; tbFGF-LPs, tbFGF-modified liposomes; DOX, doxorubicin; PTX, paclitaxel; tbFGF-PEG-LPs, tbFGF-modified PEGylated liposomes; Oct, octreotide; SSTR, somatostatin receptor; Oct–PEG–PE, octreotide–polyethylene glycol–phosphatidylethanolamine; YIGSR, Tyr–Ile–Gly–Ser–Arg; YIGSR-SN, YIGSR peptide anchored pegylated nanospheres; RRM2, ribonucleotide reductase M2 subunit; 5-FU, 5-fluorouracil; AA, anisamide; LCP NP, Lipid/calcium/phosphate nanoparticle; MCR-1, melanocortin receptor-1; HSVtk, herpes simplex virus thymidine kinase suicide gene; RGD, arginine–glycine–aspartic acid; CA4, combretastatin A4; RFPMs, RGD functionalized polymeric micelles; Ac-PHSCN-NH(2), N-acetyl-proline-histidine-serine-cysteine-asparagine-amide; C16Y-L, C16Y peptide-modified liposomes; Anx, galectin-1-specific anginex; Anx/RGD-L, Anx and RGD dual-conjugated liposomes; TH10, 10 peptides with sequence of TAASGVRSMH; CTL, cytotoxic T lymphocyte; MART-1, melanoma antigen recognized by T-cells 1; Man(11)-LPR100, mannosylated and histidylated lipopolyplexes; SPION, superparamagnetic iron oxide nanoparticle; DC-SIGN, DC-specific intercellular adhesion molecule-3-grabbing nonintergrin.

J. Li et al / Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx–xxx

Stimuli-responsive delivery is another “smart” targeted drug delivery system which is designed to react on certain stimuli. Some unique properties of tumors, for example, the more acidic intratumoral microenvironment (lower pH value) and higher sensitivity to hyperthermia than normal tissues, can act as internal stimuli and trigger localized drug release at the tumor site. Meanwhile, when exposed to certain external stimuli such as light and acoustic, the temporally and spatially controlled release can be obtained at the exposed site (Figure 4). 93

746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780 781 782 783 784 785 786 787 788 789

pH value The more acidic tumor microenvironment than surrounding normal tissues makes it possible to deliver drugs either conjugated with NPs through acid-sensitive bonds or encapsulated inside the acid-sensitive biomaterial shells more efficiently. The lower pH at the tumor site may trigger the breaking of the acid-sensitive bonds or degradation of the acid-sensitive biomaterial shell and finally the drug can be released. Gemcitabine bound to C18 (a hydrophobic stearic acid derivative) modified micelles (GemC18) through an acidsensitive hydrazone bond (PHC). GemC18 in the acid-sensitive micelles was more cytotoxic than in the acid-insensitive micelles under acidic tumor microenvironment. 94 DOX methacrylamide derivative (DOX-MA) encapsulated micelles were susceptible to pH-sensitive hydrolysis and demonstrated higher cytotoxicity and better antitumor activity in B16-F10 melanoma mice model compared to free DOX-MA control. 95 pH-responsive PEGchitosan modified nanogels loaded with 5-FU can release the drug under significantly increased acidity in subcellular compartments (pH value of ~5.0). Moreover, its pH response can also be modulated remotely by external cooling/heating. And the combination of chemo-thermal treatment showed enhanced antitumor effect but reduced toxicity in melanoma mice model. 96 Cisplatin was conjugated with thermal-sensitive poly-N-isopropylacrylamide (PNIPAM) modified AuNPs. The acidic intracellular environment in A875 melanoma cells could efficiently trigger the release of cisplatin and enhanced cytotoxicity against melanoma was detected as compared to free cisplatin. 97 pH-sensitive cationic biomaterial modified NP is also effective for nucleic acid delivery because it can protect DNA/ RNA from degradation by serum nuclease, enhance the capability of crossing cell membrane and facilitate the escape of NPs from endosomes. For example, pH-sensitive carboxymethyl poly (L-histidine) (CM-PLH) modified CM-PLH/poly (β-amino ester) (PbAE)/DNA core–shell ternary complexes exhibited significant improvement in transfection efficiency in comparison with non-coated PbAE/DNA in B16-F10 tumorbearing mice, which resulted from the enhanced endosomal escape of the DNA-loaded NPs. 98 Tao and coworkers 99 found that the expression of HIF-1a was up-regulated in A375 melanoma bearing mice under hypoxic microenvironment. The enhanced HIF-1a expression subsequently up-regulated TfR expression on melanoma cells.

Temperature Under alternating magnetic field (e.g., for SPIO NPs) or heating with shortwave radio-frequency fields (e.g., for gold NPs), the electromagnetic energy may be converted into heat. The heat can kill melanoma cells directly, and the heat can also trigger drug release from thermal-responsive polymers which can further kill tumor cells. For example, heat shock protein (Hsp) 90 inhibitor exerts an antitumor effect by increasing the cells' susceptibility to hyperthermia and reducing Akt expression in B16 melanoma cells. The thermal-sensitive NP combining GA (geldanamycin; Hsp 90 inhibitor) with thermo-sensitive ferromagnetic particles (FMP) was synthesized. When exposed to a magnetic field, GAloaded FMP showed an increased antitumor effect compared to the control without FMP. 101 DOX-loaded stealth thermosensitive liposomes (DOX-TSL) showed efficient intratumoral DOX release, improved tumor growth inhibition and enhanced survival compared to DOX-loaded low-thermo-sensitive liposomes (DOX-LTSL). 102

798

T

745

C

744

E

743

R

742

R

741

N C O

740

U

739

F

738

R O O

Stimuli-responsive delivery

790

P

737

Hypoxia can lead to the accumulation of acid metabolites (e.g., lactic acid) in the tumor area. 100 The acidic extracellular environment and increased expression of TfR on melanoma cells may offer dual-modal therapies for melanoma by either targeting over-expressed TfR or responding to the reduced pH in the tumor microenvironment, or a synergistic function of both of them, which will be discussed in the following section concerning combination therapy.

D

736

ARG-1 (arginase 1) to suppress T lymphocytes immunity. Thus, targeting the MDSCs such as TAM and leukocytes is undoubtedly the future hotspot for melanoma therapy.

735

E

734

11

Light Light-responsive NPs for drug delivery are also an attractive strategy because it can be remotely applied with extremely high spatial and temporal precision. In addition, experimental parameters, such as wavelength, light intensity and exposure time, can easily be adjusted to modulate the drug release. 29 By combining optically active substances (e.g., functional dyes, metals, and photo-sensitive materials) with nanocarriers we can synthesize light-responsive polymers. These NPs are capable of changing the light energy into heat and further release their loaded drugs when irradiated by ultraviolet (UV), visible light or near-infrared (NIR) light. 103 CdTe and CdSe QDs can rapidly convert light energy into heat after irradiation. CdTe QDs coated with a silica shell significantly inhibited melanoma growth after laser irradiation compared to the tissues without laser irradiation. 104 Hollow gold nanospheres modified with alpha-melanocyte-stimulating hormone analog could be specifically taken up by melanoma cells and induce significant photo-thermal ablation of melanoma after NIR irradiation in animal model. 105 Photodynamic therapy (PDT) is a form of phototherapy using non-toxic light-sensitive compounds that are exposed selectively to light, whereupon they react with oxygen and become toxic to targeted malignant and other diseased cells. Since it has no longterm side effects and is less invasive than surgery, PDT is now considered as one of the most promising treatment methods of skin cancers including melanoma. Aminolevulinic acid derivatives as photosensitizers were conjugated to chitosan NPs. The complex exhibited enhanced

791 792 793 794 795 796 797

799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845

J. Li et al / Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx–xxx

N C O

R

R

E

C

T

E

D

P

R O O

F

12

U

Figure 5. Mesoporous-silica-coated NaYF4:Yb,Er upconversion fluorescent nanoparticle (UCN) as an agent of PDT for melanoma. (A) Transmission electron microscopy (TEM) images of the mesoporous-silica-coated UCNs at high magnification (scale bar, 50 nm). (B, C) The fluorescence emission spectrum and schematic of the UCN under 980-nm NIR laser excitation and the absorption spectra of ZnPc and MC540 photosensitizers. (D, E) Representative gross photos of a mouse showing tumors at 14 days after treatment with the conditions described for groups 1-4 (scale bars: 10 mm) (D) and tumor volumes after treatment to determine the effectiveness of the treatment in terms of tumor cell growth inhibition (E). (F) Schematic diagram showing UCN-based targeted PDT in a mouse model of melanoma intravenously injected with UCNs surface modified with folic acid and PEG moieties (Scale bar, 10 mm). (G) Change in tumor size as a function of time after treatment to assess the effectiveness of UCN-based mediated targeted PDT in tumor-bearing mice intravenously injected with FA-PEGUCNs. Reprinted from Idris et al. 107

846 847 848 849 850 851

permeation of photosensitizers through the skin and improved the efficiency of PDT for melanoma and other skin cancers after visible light irradiation. 106 However, the application of these visible light photosensitizers is limited to superficial tumor treatment and is less effective for large and deep-seated tumors. NIR light in PDT can afford greater penetration

depths than that of visible light. Mesoporous-silica-coated upconversion fluorescent NPs were used as a nanotransducer and a carrier of the dual-photosensitizers to convert deeply penetrating NIR light to visible wavelengths and showed significant tumor growth inhibition (Figure 5), 107 providing a new approach for future noninvasive deep-cancer therapy.

852 853 854 855 856 857

J. Li et al / Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx–xxx t2:1 t2:2

Table 2 NPs mediated stimuli-responsive drug delivery to melanoma.

t2:3

Therapeutic agents

t2:4 t2:5

pH Gemcitabine

t2:6 t2:7 t2:8

DOX-MA 5-FU Cisplatin

PEG and C18 (a hydrophobic stearic acid derivative) modified micelles

Gemcitabine in the acid-sensitive micelles was more cytotoxic than in the acid-insensitive micelles under acidic tumor microenvironment Higher cytotoxicity and better antitumor activity Enhanced antitumor effect but reduced toxicity Enhanced cytotoxicity against melanoma than free cisplatin Significant improvement in transfection efficiency

94

mPEG-b-p (HPMAm-Lac(n)) polymeric micelles PEG-chitosan based nanogel PNIPAM modified AuNPs

pGL3-promoter DNA

Carboxymethyl poly (L-histidine) coated poly (beta-amino ester)

Temperature DOX

Stealth TSL

GA

FMP

Light CdTe(710) QDs

QDs coated with a silica shell

t2:17

HAuNS

NDP–MSH–PEG–HAuNS

t2:18

Dual-photosensitizers

Mesoporous-silica-coated upconversion fluorescent NPs

Ultrasound Melanoma antigen

Erfluoropropane gas-entrapping liposomes (Bubble liposomes)

Plasmid DNA of gp100 and TRP-2

Man-PEG(2000) bubble lipoplexes

t2:23

DOX

Microbubbles

860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878

96 97

98

Improved tumor growth inhibition and enhanced survival Better antitumor effects

101

Significant inhibition of melanoma growth after laser irradiation Significant photo-thermal ablation of melanoma after laser irradiation Convert NIR light to visible wavelengths and showed significant tumor growth inhibition

104

Activate melanoma specific cytotoxic T lymphocytes and prevent the melanoma lung metastasis Enhanced melanoma growth inhibition and metastatic prevention Elevated tumor cell killing efficiency

108

102

105

107

109

110

C

E R

Other stimuli-responsive release Other external stimuli, such as ultrasound, can also be used for effective antigen, gene and drug delivery. Directly delivering antigens extracted from melanoma cells into the cytosol of DCs using perfluoropropane gas-entrapping liposomes (bubble liposomes) and ultrasound can activate melanoma specific cytotoxic T lymphocytes and prevent the melanoma lung metastasis. 108 Moreover, efficient DNA vaccination can be achieved by delivering plasmid DNA of melanoma-specific antigens (gp100 and TRP-2) to DCs under ultrasound using Man-PEG (2000) bubble lipoplexes. Enhanced melanoma growth inhibition and metastatic prevention can be observed. 109 Furthermore, DOX liposome-loaded microbubbles for ultrasound responsive drug delivery to melanoma tissues led to elevated tumor cell killing efficiency even at very low doses of DOX. 110 Different types of stimuli-triggered drug delivery to melanoma can be found in Table 2.

R

859

N C O

858

95

Abbreviations: DOX-MA, DOX methacrylamide derivative; TSL, thermosensitive liposome; GA, geldanamycin; PNIPAM, poly-N-isopropylacrylamide; FMP, thermosensitive ferromagnetic particle; HAuNS, hollow gold nanosphere; QD, quantum dot; NDP–MSH–PEG–HAuNS, HAuNS modified with PEG and alpha-melanocyte-stimulating hormone analog.

U

t2:24

T

t2:22

E

t2:19 t2:20 t2:21

F

Ref.

R O O

t2:13 t2:14 t2:15 t2:16

Effect

P

t2:10 t2:11 t2:12

Nanocarriers

D

t2:9

13

Nanotheranostics to detect tumor, track the distribution of therapeutic drugs and evaluate the pharmacokinetic efficiency It is well-known that melanoma is a highly malignant tumor with early metastatic potential. The earlier the detection of the metastasis, the better the therapeutic effect is. Therefore, the real-

time tracking of the therapeutic drugs distribution can provide us with an evaluation of the therapeutic efficiency. By combining therapeutic and diagnostic capability into the same NP, nanotheranostics has become a new strategy of more specific and efficient therapy. 111,112 Theranostic NPs can be designed to image the localization of early metastatic melanoma, to detect the NPs' distribution, to deliver the therapeutic agents to melanoma cells and tissues, and to monitor the real-time pharmacokinetic efficiency of drugs. It is worth noting that nanotheranostics has already been and will become a more promising strategy for personalized melanoma management. 113 Temozolomide-loaded nanogel was formulated by combining Ag–Au bimetallic NP core with PEG-based hydrogel shell. The Ag–Au NP core can emit strong visible fluorescence for melanoma imaging, and thermo-triggered temozolomide release from the hydrogel shell can kill melanoma cells more efficiently. 114 Wang et al 115 synthesized multifunctional polyDL-lactic acid (PLA) NPs (encapsulated with PTX, oleylaminecoated QDs, and oleylamine-coated magnetite NPs (MNPs)). The PTX–QDs–MNPs-loaded PLA NPs induced a higher inhibition ratio of A875 melanoma cells than neat PTX. Meanwhile, QDs and MNPs could be used in melanoma bioimaging. A biocompatible polymeric NPs co-encapsulated two

879 880 881 882 883 884 885 886 887 888 889 890 891 892 893 894 895 896 897 898 899 900 901

J. Li et al / Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx–xxx

R

R

E

C

T

E

D

P

R O O

F

14

903 904 905 906 907 908 909 910 911 912 913 914 915 916

different chromo-fluorogenic components achieved both bimodal phototherapeutic performance (inducing amplified cell mortality due to the simultaneous photogeneration of singlet oxygen and nitric oxide) and dual-color fluorescence imaging capacity (Figure 6). 116 Curcumin and DOX loaded magneticbased core–shell particles produced a dark contrast signal in magnetic resonance imaging (MRI) in melanoma tissues and inhibited melanoma growth with reduced side effects in melanoma mice modal (Figure 7). 117 Due to their great photostability and a wide range of excitation/emission wavelengths, QDs in bio-imaging have now become a growing field of interest. Chromosome segregation 1-like (CSE1L) antibody can suppress melanoma metastasis. The NPs encapsulated with anti-CSE1L antibody and QDs exhibited both capabilities of melanoma imaging and

U

902

N C O

Figure 6. Biocompatible polymeric NPs for dual-color imaging and bimodal PDT for melanoma. (A) Schematic illustration of the multifunctional photoresponsive NPs. (B-E) CLSM images of melanoma cells incubated with DAPI for 4 h, blue, green and red image for excitation at 405, 457 and 640 nm collecting fluorescence in the range 425-475, 500-550, and 660-730 nm, respectively. (F-H) From top to bottom: the confocal spectra forlexc = 405 (the region of interest in the nucleus), 457 and 640 nm (the region of interest in the cytoplasm). Reprinted from Fraix et al. 116

metastasis suppression. 118 QDs–liposomes with cisplatin exhibited significant fluorescent signal in melanoma tissues and higher cytotoxic activity compared to an equal dose of free cisplatin. 119 The applications of NPs in melanoma theranostics are listed in Table 3.

917

Combination therapy

922

Quick relapse due to the MDR and severe adverse effects following high dose administration are two major barriers which we are now facing in melanoma treatment. None of the current strategies, including chemotherapy, immune modulation and targeted therapy, are capable of achieving good clinical therapeutic effect when used alone. Recently, combination

923

918 919 920 921

924 925 926 927 928

15

R

E

C

T

E

D

P

R O O

F

J. Li et al / Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx–xxx

930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946

therapy is attracting more and more attention because of the synergistic anticancer effects, reduction of drug-related toxicity and MDR suppression through different mechanisms of action. 120 The investigation of the clinical trials showed that targeted therapies such as BRAF inhibitors exhibited high initial RR, but long-lasting responses appeared to be rare because of acquired secondary resistance, mostly through reactivation of mitogenactivated protein kinase (MAPK) pathway. Conversely, the immunotherapies such as anti-CTLA-4 or anti-PD-1 monoclonal antibodies showed long-term and durable effects both in RR and adverse effects. Combining immunotherapies with small inhibitor targeted therapies seems to have double bonus effect of BRAF inhibitors to specifically target driver mutations in melanoma cells and sensitize the immune system to target tumors, leading to more durable and long-lasting responses but with less adverse effects. When BRAF-mutant melanoma cells exposed to BRAF inhibitors, the expressions of melanocyte

U

929

N C O

R

Figure 7. Multifunctional magnetic NPs (MSCSP) for melanoma imaging and therapy. (A, B) Schematic and TEM image of MBCSP; inset shows core–shell structure of MBCSP. (C) Cytotoxicity of particles after 24 h of exposure on B16-F10 cells. (D) In vivo detection of GRGDS-conjugated MBCSP targeted to melanoma. Reprinted from Wadajkar et al. 117

differentiation antigens such as MART-1, gp100 and tyrosinase et al are up-regulated, which leads to improved antigen-specific T lymphocytes recognition. 121 Furthermore, the increased number of TILs was induced by treatment with vemurafenib. 121 All these observations and results provide strong support for conducting trials that combine BRAF inhibitors with immunotherapy in the hope of prolonging clinical responses. For example, vemurafenib 960 mg for 6 weeks followed by 4 doses of ipilimumab every three weeks has entered its phase II clinical trial in metastatic melanoma patients. 122 The combination of dabrafenib with ipilimumab is also in its phase I clinical trial. 122 Also, patients with metastatic melanoma were enrolled in the phase I clinical trial with the treatment of vemurafenib plus anti-PDL1 antibody (MPDL3280A). 122 Although we still wait for the clinical results, we can foresee the bright future of the combination treatment in advanced metastatic melanoma patients. Meanwhile, we have to face the unavoidable difficulties that conventional drug delivery system could not significantly

947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964

16

J. Li et al / Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx–xxx

t3:1 t3:2

Table 3 The applications of nanotheranostics in melanoma.

t3:3

Imaging agents

Therapeutic agents

Nanocarriers

t3:4

Ag–Au bimetallic NP

Temozolomide

Nanogel consists of Ag–Au bimetallic NP core and PEG-based hydrogel shell PTX–QDs–MNPs-loaded PLA NPs Polymeric NPs

Effect

Ref.

t3:10

Abbreviation: GRGDS, Gly–Arg–Gly–Asp–Ser; MNP, magnetic nanoparticle; MBCSP, magnetic-based core–shell particle.

Chemotherapy with immunotherapy

979

Chemo-immunotherapy combination could be one of the most effective multidimensional modes of therapy in curing melanoma aiming at both the metabolism and the immunoregulation of tumors with higher anticancer activity, less toxicity and ease of delivery. Ipilimumab plus DTIC showed significantly longer overall survival, and higher survival rate than control group in a phase III study involving patients with previously treated metastatic melanoma is a very good example of this combined therapy. 124 Although grade 3 or 4 adverse events occurred in 56.3% of patients treated with ipilimumab plus DTIC, as compared with 27.5% treated with DTIC and placebo, at least we can see the hope of this combination based on immunotherapy. The combination of nanomedicine with immunotherapy could be the future of metastatic melanoma treatment if we can make full use of the aforementioned advantages of NPs. Some studies have already demonstrated the enhanced antitumor effect through the chemo–immuno combination therapy with the aid of nanomedicine. The conjugation of potent immunostimulant soluble lipopolysaccharides (SP-LPS) with PTX assembled into a single NP, and the complex showed significantly higher antitumor activity and a higher percentage of activated immune cells infiltration in melanoma mice modal as compared to PTX-treated control. 125 IL-12 has shown remarkable antitumor properties by enhancing the interaction between APCs and T lymphocytes via inducing IFN-γ production and promoting CTLs maturation. PTX and adenovirus vector

973 974 975 976

980 981 982 983 984 985 986 987 988 989 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004

E

972

R

971

R

970

N C O

969

U

968

119

R O O

978

967

C

977

reduce the adverse effects and MDR caused by the unspecific biodistribution of the therapeutic agents. Very recently, the approval of Abraxane in combination with gemcitabine as the first-line treatment of advanced pancreatic cancer changed the picture that no clinically-validated nanomedicines have become the first-line treatment of cancer. 123 And this great success indicates the true potential of nanomedicines in combination therapy for solid tumors including melanoma. In the following part, we will briefly review the common combination strategies with the aid of NPs and the improved efficacy achieved in these preclinical melanoma experiments may encourage us to make an intensive study of their further applications in clinical melanoma patients.

966

118

encoding for IL-12 (Ad5-mIL-12) were incorporated into anionic liposomes (AL). The significantly enhanced antitumor effect of this complex was observed in B16 melanoma-bearing mice compared with those treated with either AL/Ad5-mIL-12 or AL/PTX (Figure 8). 126 For melanoma patients with unresectable brain metastases, selective small molecular kinase inhibitor such as vemurafenib does not work because it cannot pass through the blood–brain barrier (BBB). However, the BBB does not prevent ipilimumab from entering the cerebral tissues. In the meantime, some nanocarriers are able to overcome the problem of passing the BBB as they can be administered directly to the brain. For example, by modifying the transferrin molecules on their surface, the newly developed fourth-generation poly(amido amine) (PAMAM) dendrimers encapsulating DOX could efficiently pass through the BBB and target the tumor cells. 127 Therefore, the combination of more effective NPs capable of passing through the BBB with ipilimumab would be a promising option for melanoma patients with brain metastases considering that ipilimumab takes a relatively slower effect.

1005

Different therapeutic drugs combination

1025

PTX and CA4 as the respective anticancer and antiangiogenesis agent were co-encapsulated into biocompatible PLGA NPs with a cRGDfK targeting peptide. This targeted dual drug NPs showed dramatic tumor growth inhibition and tumor vasculature disruption in melanoma-bearing mice. 66 Interstitial fluid pressure (IFP) is one of the great obstacles for chemotherapeutic drugs delivery because it is much higher in tumor than in normal tissues. 128 Imatinib-loaded sterically stabilized liposomes (SSL-IMA) could reduce the tumor IFP. The combination of SSL-IMA and SSL-DOX significantly inhibited tumor growth at a low dose in which neither SSL-DOX nor SSL-IMA showed obvious antitumor efficacy. 129

1026

Different gene combination therapy

1038

P

965

117

D

t3:8

116

E

t3:7

115

T

t3:5 t3:6

114

F

t3:9

Strong visible fluorescence for melanoma imaging and thermo-triggered temozolomide release QDs and MNPs PTX Melanoma growth inhibition and melanoma imaging Two different chromoDual-color fluorescence imaging and bimodal fluorogenic components phototherapeutic performance MBCSP Curcumin and DOX MBCSP conjugated with GRGDS peptides Tumor imaging under MRI and synergistical melanoma growth inhibition QDs Anti-CSE1L Anti-CSE1L antibody conjugated NPs Both capabilities of melanoma imaging and metastasis antibody suppression Cisplatin QDs–liposomes Melanoma imaging and higher cytotoxic activity

130

Tran et al developed a nanoliposomal-ultrasound-mediated approach for delivering (V600E)B-Raf and Akt3 siRNA into melanoma cells. This siRNA combination targeting both (V600E)B-Raf and Akt3 led to an approximately 65% decrease

1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024

1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037

1039 1040 1041 1042

17

N C O

R

R

E

C

T

E

D

P

R O O

F

J. Li et al / Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx–xxx

U

Figure 8. Application of NPs in the combination therapy for melanoma. (A, B) TEM images of naked Ad5 and AL/Ad5/PTX. (C, D) Therapeutic effect of B16 melanoma tumor-bearing mice after treatment with various formulations. Growth in tumor volume (C) and survival (D) were monitored on a regular basis (n = 10). AL/Ad5-mIL-12/PTX showed the most robust anticancer effect compared with the other groups. Reprinted from Cao et al. 126

1043 1044 1045 1046 1047 1048 1049 1050

in early or invasive cutaneous melanoma compared with inhibition of each individual with negligible associated systemic toxicity. Bcl-2, VEGF, c-Myc, MDM2 and others are also important (onco) genes involved in the proliferation, differentiation, DNA transcription, angiogenesis and metastasis of melanoma. The combination of siRNAs corresponding to these genes such as the aforementioned Bcl-2/VEGF/c-Myc and MDM2/c-Myc/VEGF cocktail therapy can efficiently inhibit

melanoma growth and overcome MDR with less systemic toxicity. 54,131,132 Despite the great benefit of the combination therapy, coencapsulation of drugs with different physicochemical properties, accurate control of drug loading, and temporal sequencing on drug release are very important features which need to be taken into careful consideration. 133 Generally, the difficulty of co-encapsulating hydrophobic and hydrophilic drugs in the same

1051 1052 1053 1054 1055 1056 1057 1058

18

J. Li et al / Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx–xxx

t4:1 t4:2

Table 4 NPs for melanoma combination therapy.

t4:3

Combinational therapeutic agents

t4:4 t4:5 t4:6 t4:7 t4:8 t4:9

Chemotherapeutics combination therapy PTX and CA4 PLGA NPs conjugated with cRGDfK peptide Imatinib and DOX SSL

Nanocarrier

Effect

Ref.

Dramatic tumor vasculature disruption and tumor growth inhibition Significant tumor growth inhibition at a low dose

66

125

AL

Higher antitumor activity and a higher percentage of activated immune cells infiltration Significant enhanced antitumor effect

Liposome ABP LCP NP, LPH

Cooperative tumor growth inhibition and metastasis suppression Effective regression of advanced stage tumors Efficient tumor growth inhibition with less systemic toxicity

130

Chemotherapy with immunotherapy PTX and SP-LPS Self-assembled NPs

129

Gene combination therapy BRAF V600E and AKT3 siRNA Bcl-2/VEGF/c-Myc siRNA MDM2/c-Myc/VEGF siRNA

t4:16

Abbreviations: SP-LPS, soluble lipopolysaccharides; Ad5-mIL-12, adenovirus encoding for interleukin-12; AL, anionic liposome; SSL, sterically stabilized liposome; ABP, arginine-grafted bioreducible poly (disulfide amine) polymer; VEGF, vascular endothelial growth factor; LPH, liposome–polycation– hyaluronic acid.

1064 1065 1066 1067 1068 1069

Clinical trials in melanoma with the use of NPs

1071

Although promising results with the aid of NPs have been obtained in melanoma experimental animal models with a myriad of publications, efficacy and safety of nanomedicine in melanoma patients rather than in animal models have always been the issue of greatest concern. As of September 2014, totally 1584 studies were listed on the clinicaltrials.gov Web site for melanoma. About 70 (~4.4%) nanopharmaceutical associated studies were screened out from all these melanoma clinical trials. And the efficacy and safety profiles of a wide variety of nanopharmaceuticals, such as Abraxane, Taxoprexin (docosahexaenoic acid–paclitaxel, DHA– paclitaxel, Protarga), Marqibo (vincristine sulfate liposomes injection, VSLI, Talon Therapeutics), Caelyx (pegylated liposomal doxorubicin, Janssen Pharm), ADI-PEG-20 (pegylated arginine deiminase, Polaris Group), Allovectin-7 (HLA-B7/beta-2 microglobulin plasmid DNA/lipid complex, Vical), CR011-vcMMAE (human IgG2 monoclonal antibody glembatumumab (CR011) linked to monomethyl auristatin E (MMAE), CuraGen), IMCgp100 (melanoma gp100 peptide fused to an anti-CD3 antibody fragment, Immunocore), ALT-801 (IL-2/T-cell receptor fusion protein targeting human p53 antigen peptide epitope (aa264-272), Altor Bioscience), hu14.18-IL2 (humanized antidisialoganglioside (GD2) antibody (hu14.18)-IL-2 fusion protein, EMD Serono), L19IL2 (anti-ED-B fibronectin domain antibody-

1076 1077 1078 1079 1080 1081 1082 1083 1084 1085 1086 1087 1088 1089 1090 1091 1092 1093

R

1075

N C O

1074

U

1073

R

1070

1072

R O O

P

D

1063

E

1062

126

131 54,132

IL-2 fusion protein, Philogen S.p.a.), AS1409 (humanized antiBC1 antibody-IL-12 fusion protein, Antisoma Research), ANG1005 (Angiopep-2 paclitaxel conjugate targeting lipoprotein receptor-related protein 1 (LRP-1), AngioChem), PEG–Intron (peginterferon-α-2b, Schering-Plough), and others have been investigated in patients with metastatic melanoma in these clinical trials. Representative clinical trials in melanoma with the use of NPs are listed in Table 5 and will be discussed in more details in the following part. Abraxane (also named ABI-007), approved by the FDA, showed efficacy in the patients with metastatic breast cancer and pancreatic cancer. Also, its therapeutic efficacy and safety have been investigated in patients with metastatic melanoma. In a phase 2 trial (NCT00093119), ABI-007 as monotherapy achieved an objective response rate of 21.6%, along with a median PFS of 4.5 months and median survival of 9.6 months in the chemotherapy-naive group of patients with metastatic melanoma. Twenty-two percent of the patients in this group discontinued therapy due to the toxicity. 137 In addition, the effect of ABI-007 in combination therapy with other conventional drugs was investigated. In another phase 2 study (NCT00404235), the weekly combination of ABI-007 and carboplatin appeared to be moderately well tolerated, with promising clinical activity as therapy in chemotherapy-naive patients with stage IV melanoma (25.6% response rate and a median overall survival of 11.1 months) and with modest antitumor activity in those previously treated (8.8% response rate and a median overall survival of 10.9 months). 138 Moreover, the combination of abraxane and bevacizumab (NCT00462423) also seemed to be effective in melanoma patients with a response rate of 36%, a median PFS of 7.63 months and overall survival of 16.8 months, and could be moderately well tolerated with a 26% of serious adverse events. In a recent phase 3 clinical trial (NCT00864253) with 529 patients enrolled, the comparison study of the efficacy and safety of ABI-007 and DTIC has completed. Patients with metastatic melanoma who received ABI-007 had longer PFS than those who received DTIC (hazard ratio [HR] 0.792; p = 0.044):

T

1061

C

1060

NP limits the efficiency of combination therapy. 134 In addition, chemical modifications may need to be employed to overcome the unfavorable interactions between the drugs and nanocarriers. 135 Furthermore, improper release sequencing of co-encapsulated chemotherapeutics which are most potent in specific cell cycles could lead to unintended cell cycle arrest and diminish the response to the subsequent drug release. 136 In spite of so many difficulties, the advances in understanding drug synergism and the development of nanotechnology will bring about an improvement in combination therapy. Different combinations for melanoma therapy are listed below in Table 4.

E

1059

PTX and Ad5-mIL-12

F

t4:10 t4:11 t4:12 t4:13 t4:14 t4:15

1094 1095 1096 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 1108 1109 1110 1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 1121 1122 1123 1124 1125 1126 1127 1128 1129 1130 1131

J. Li et al / Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx–xxx

1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 1161 1162 1163 1164 1165 1166 1167 1168 1169 1170 1171 1172 1173 1174 1175 1176 1177 1178 1179 1180 1181 1182 1183 1184 1185 1186 1187 1188 1189

F

1143

R O O

1142

1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201

Current status, challenges and perspectives

1202

Although the rapid development of nanotechnology and increased knowledge on nanomedicine have accelerated the progress in NP targeted delivery and therapy, we still have to face the fact that NP therapies actually have revealed no more promise than have myriad other non-particulate agents in animal trials which have been published. Within the past two decades, less than ten non-targeted anticancer nanomedicines, including Doxil (Doxorubicin; Ortho Biotech), DaunoXome (Daunorubicin; Gilead Sciences), Mepact (Muramyl tripeptide; IDM Pharma SAS), DepoCyt (Cytarabine; SkyePharma) and Abraxane (Paclitaxl; Abraxia BioScience, AstraZeneca), have been approved by the FDA with Myocet (Doxorubicin; Enzon) approved in Europe and Canada, and Genexol-PM (Paclitaxel; Samyang) approved in Korea. Although an increasing number of targeted nanopharmaceuticals is now undergoing clinical trials, e.g., EndoTAG-1 (Paclitaxel; MediGene), MBP-426 (Oxaliplatin; MebioPharm), CRLX101 (Campthotecin; Cerulean), NC-6004 (Cisplatin; Nanocarrier), BIND-014 (Doxetaxel; BIND Biosciences), etc., none of them has been approved by the FDA till now. In addition, the current status of very limited number of nanomedicine associated clinical trials, especially the unsatisfactory efficacy and safety issues revealed that the future of nanomedicine is not as optimistic as we expected. Thus, how best to design nanomedicines to improve efficacy while minimizing safety issues is of the top priority. To achieve this goal, the following problems require serious consideration. Given the heterogeneous nature of nanomaterials, the wide diversity of nanomaterial platforms, as well as the limited knowledge and experience with both formulation development and nanomedicine manufacturing compared to conventional therapeutics, unique challenges of tracking the distinct toxicological property, the in vivo absorption, distribution, metabolism and excretion (ADME) patterns and interactions with the immune and/or hematological systems need to be conquered. In addition, release kinetics of a drug payload varies among different NPs and is not well understood, followed by its unknown impact on efficacy and safety. Furthermore, vacuolation induced by PEG may present toxicological concerns. 145 Also, detectable antibodies against PEG appeared in an increasing number of patients due to the wide use of PEG in the food and pharmaceutical industry may also raise concerns. 145 Finally, the variety of parameters such as molecular weight,

1203

P

1141

D

1140

E

1139

between the two arms for the primary outcome of disease-free survival (hazard ratio [HR] 0.91; 95% CI 0.73-1.15) or the secondary outcomes of distant metastasis-free survival (HR 1.02; 95% CI 0.80-1.32) and overall survival (HR 1.09; 95% CI 0.821.45). In addition, PEG–Intron was associated with higher rates of grade 3-4 adverse events (47.3% versus 25.2%; p b 0.0001) and discontinuations (54.3% versus 30.4%) compared with Intron-A. 144 In view of the very limited number of nanopharmaceutical associated clinical trials as well as some unsatisfactory study results, we can conclude that nowadays it is too early to say a new era of NP therapy for melanoma arrives.

T

1138

C

1137

E

1136

R

1135

R

1134

median PFS was 4.8 months (95% confidence interval [CI] 3.7-5.5) for patients in the ABI-007 group and 2.5 months (95% CI 2.0-3.6) for patients in DTIC group. Yet, no significant difference in participant survival (p = 0.094) was observed between the ABI-007 group (12.8 months) and DTIC group (10.7 months). In addition, the rates of serious adverse events were 24.12% and 20.93% in the ABI-007 and DTIC groups, respectively. Meanwhile, a phase 2 open-label study (NCT00249262) of weekly taxoprexin (another paclitaxel conjugate (DHA–paclitaxel)) in 30 patients with cutaneous and mucosal metastatic melanoma showed that 3 patients (10%) had partial responses and 15 patients (50%) had stable disease. And the median survival was 14.8 months. Although taxoprexin was proved to be effective and well-tolerated in metastatic melanoma patients, its efficacy as a first-line therapy for metastatic melanoma did not exceed that seen with other single-agent chemotherapies such as DTIC. 139 The result of another study (NCT00087776) of taxoprexin versus DTIC in 393 chemotherapy-naive patients with metastatic malignant melanoma also showed that taxoprexin was not superior to DTIC, as evidenced by no significant difference in overall survival, response rate, duration of response, time to progression, and time to treatment failure between the two drugs. 140 Although the above nanopharmaceuticals proved effective in patients with malignant melanoma, not all the chemotherapeutic nanomedicines could produce effects on melanoma patients. A phase 2 study of pegylated liposomal doxorubicin (PLD) as second-line treatment in patients with disseminated melanoma indicated that PLD as monotherapy was well tolerated while with limited clinical efficacy. 141 Another phase 2, open label, monotherapy study of PLD in patients with metastatic malignant melanoma showed no positive response in the evaluable patients and enrollment was stopped as per protocol, due to lack of activity. 142 Besides chemotherapeutic nanomedicine, the efficacy and safety of tumor vaccines with the use of NPs have also been evaluated in melanoma clinical trials. Allovectin-7 is a bicistronic plasmid encoding human leukocyte antigen-B7 and beta-2 microglobulin formulated with a cationic lipid system. The results of its phase 2 trial (NCT00044356) indicated that high-dose allovectin-7 seemed to be an active, well-tolerated treatment for selected stage III/IV metastatic melanoma patients with injectable cutaneous, subcutaneous, or nodal lesions. 143 A phase 3 pivotal trial (NCT00395070) to compare the safety and efficacy of allovectin-7 versus DTIC or temozolomide in subjects with recurrent stage 3 or stage 4 melanoma has completed, and we still wait for their clinical trial results. Intron-A (recombinant interferon-α-2b, Schering-Plough) and PEG–Intron have been approved by the FDA for the treatment of melanoma in 1995 and 2011, respectively. Both have been shown to be superior to the observation in the adjuvant treatment of melanoma without macrometastatic nodes, but have never been directly compared. A multicenter, open-label, randomized, phase 3 trial (NCT00221702) compared standard low-dose Intron-A and prolonged treatment with PEG–Intron showed no superiority for adjuvant PEG–Intron over conventional low-dose Intron-A in melanoma patients without clinically detectable nodes, as evidenced by no statistical differences

N C O

1133

U

1132

19

1204 1205 1206 1207 1208 1209 1210 1211 1212 1213 1214 1215 1216 1217 1218 1219 1220 1221 1222 1223 1224 1225 1226 1227 1228 1229 1230 1231 1232 1233 1234 1235 1236 1237 1238 1239 1240 1241 1242 1243 1244

20

Table 5 Clinical trials in melanoma with the use of NPs.

t5:3

NCT no.

t5:4 t5:5

Chemotherapy NCT00864253

t5:6

NCT00462423

t5:7

NCT00626405

t5:8

NCT00404235

t5:9

NCT00093119

U

Sponsor/Collaborators

Phase

N

Celgene Corporation; University of Arizona

Number NP formulated agents enrolled

C

Phase 3 529

O

R

Nab–paclitaxel (Abraxane, ABI-007)

Lynn E.Spitler, MD; Celgene Corporation; Genentech North Central Cancer Treatment Group; National Cancer Institute (NCI)

Phase 2 50

North Central Cancer Treatment Group; National Cancer Institute (NCI)

Phase 2 76

Celgene Corporation

Phase 2 74

Phase 2 93

Study

Nab–paclitaxel

R

Nab–paclitaxel

E

C

Nab–paclitaxel

Result

Ref.

A trial of ABI-007 versus dacarbazine In ABI-007 group: median PFS in previously untreated patients with (4.8m), OS (12.8 m), SAEs (24.12%) metastatic MM In dacarbazine group: median PFS (2.5 m), OS (10.7%), SAEs (20.93%) Abraxane and avastin as therapy for Objective response rate (36%), PFS patients with MM (7.63m), OS (16.8 m), SAEs (26%) A trial of temozolomide and For TB group: median PFS (3.8 m), bevacizumab (TB) or ABI-007, OS (12.3 m), PFS rate (32.8%); bevacizumab and carboplatin (ABC) For ABC group: median PFS (6.7 m), in patients with unresectable stage IV OS (13.9 m), PFS rate (56.1%) MM Carboplatin and ABI-007 in treating In chemotherapy naive group: patients with stage IV melanoma that response rate (25.6%), median PFS cannot be removed by surgery (4.5 m), OS (11.1 m); In previously treated group: response rate (8.8%), median PFS (4.1 m), OS (10.9 m) A trial of ABI-007 in previously In chemotherapy naive group: treated patients with metastatic response rate (21.6%), median PFS (4.5 m), median survival (9.6 m), free melanoma of disease progression at 6 months (34%), 22% discontinued therapy because of toxicities in previously treated group: response rate (2.7%), median PFS (3.5 m), median survival (12.1 m), free of disease progression at 6 months (27%) Taxoprexin injection vs. dacarbazine No significant difference in response in patients with metastatic MM rate, duration of response, time to progression and OS between taxoprexin and dacarbazine Study of weekly taxoprexin injection PR (5%), SD (32%), median duration as treatment of patients with of response (3 m), median OS (9.8 m) metastatic uveal (choroidal) MM Study of weekly taxoprexin injection PR (10%), SD (50%), median survival as 1st line treatment of patients with (14.8 m) metastatic non-choroidal melanoma

Results available from clinicaltrials.gov Web site

Results available from clinicaltrials.gov Web site 147

138

T

Nab–paclitaxel

E

D

137

P

R O

t5:10

NCT00087776

Luitpold Pharmaceuticals

Phase 3 575

DHA–paclitaxel (Taxoprexin)

t5:11

NCT00244816

Luitpold Pharmaceuticals

Phase 2 22

DHA–paclitaxel

t5:12

NCT00249262

Luitpold Pharmaceuticals

Phase 2 30

DHA–paclitaxel

t5:13

O

F

140

148

139

J. Li et al / Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx–xxx

t5:1 t5:2

t5:15 t5:16 t5:17

Immunotherapy Vaccine NCT00044356

t5:18 t5:19

Pegylated interferon NCT00221702 University Hospital, Bordeaux; Phase 3 898 Schering-Plough

Vical

Phase 2 133

U

N

European Organisation for Research and Treatment of Cancer—EORTC

O

Phase 3 1258

R

E

C

t5:21

t5:22

NCT00623402

University of SchleswigHolstein; Dermatologic Cooperative Oncology Group

Phase 2 55

144

Comparing adjuvant treatment With PEG–Intron over 36 months versus reference treatment with intron A (interferon-α-2b) over 18 months in cutaneous melanoma patients AJCC stage II

Peginterferon-α-2b

R

No statistical difference between the two arms for DFS or DMFS. PEG-IFN was associated with higher rates of grade 3-4 AEs (47.3% versus 25.2%; p b 0.0001) and discontinuations (54.3% versus 30.4%) compared with IFN. PEG–Intron observation after At 7.6 years median follow-up, 384 regional lymph node dissection in recurrences or deaths had occurred AJCC stage III (TxN1-2MO) with PEG-IFN-α-2b versus 406 in the observation group (p = 0.055); 7-year melanoma patients RFS rate 39.1% versus 34.6%. No difference in OS. In stage III-N1 ulcerated melanoma, RFS (p = 0.06), DMFS (p = 0.006) were prolonged with PEG-IFN-α-2b. PEG-IFN-α-2b was discontinued for toxicity in 37% of patients Combined treatment of sorafenib and Forty-one patients (74.5 %) peginterferon-α-2b in stage IV developed cutaneous side effects, dose reductions were required in 10 metastatic MM patients, interruption of therapy in 10 cases and permanent discontinuation of therapy

Peginterferon-α-2b (PEG–Intron)

Peginterferon-α-2b

T

E

149

150

D

P

Abbreviations: AEs, adverse events; DFS, disease-free survival; DHA–paclitaxel, docosahexaenoic acid–paclitaxel; DMFS, distant metastasis-free survival; MM, malignant melanoma; Nab–paclitaxel, nanoparticle albumin-bound paclitaxel; OS, overall survival; PFS, progression-free survival; PR, partial response; RFS, recurrence-free survival; SAEs, serious adverse events; SD, stable disease.

R O

O

J. Li et al / Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx–xxx

NCT00006249

143

Study of high-dose allovectin-7 in patients with advanced metastatic MM

C

t5:20

Objective response rate (11.8%), median duration of response (13.8 m), median time-to-progression (1.6 m)

Allovectin-7 (HLA-B7/ beta-2 microglobulin plasmid DNA/lipid complex)

F 21

1294 1295 1296 1297 1298 1299 1300 1301 1302 1303 1304 1305 1306 1307 1308 1309 1310 1311 1312 1313 1314 1315 1316 1317 1318 1319 1320 1321 1322 1323 1324 1325 1326 1327 1328 1329 1330 1331 1332 1333 1334 1335 1336 1337 1338 1339 1340

References

1348

1342 1343 1344 1345 1346 1347

1. http://www.cancer.gov/cancertopics/pdq/treatment/melanoma/patient. 1349 2. http://www.cancer.gov/researchandfunding/snapshots/melanoma. 1350 3. Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, 1351 Byrd DR, et al. Final version of 2009 AJCC melanoma staging and 1352 classification. J Clin Oncol 2009;36:6199-206. 1353 4. Flaherty KT, Hodi FS, Fisher DE. From genes to drugs: targeted 1354 strategies for melanoma. Nat Rev Cancer 2012;12(5):349-61. 1355 5. Hill VK, Gartner JJ, Samuels Y, Goldstein AM. The genetics of 1356 melanoma: recent advances. Annu Rev Genomics Hum Genet 1357 2013;14:257-79. 1358 6. Jacobs JF, Nierkens S, Figdor CG, de Vries IJ, Adema GJ. Regulatory T 1359 cells in melanoma: the final hurdle towards effective immunotherapy? 1360 Lancet Oncol 2012;13(1):e32-42. 1361 7. Hinrichs CS, Restifo NP. Reassessing target antigens for adoptive T- 1362 cell therapy. Nat Biotechnol 2013;31(11):999-1008. 1363 8. Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, et al. PD- 1364 L1/B7H-1 inhibits the effector phase of tumor rejection by T cell 1365 receptor (TCR) transgenic CD8 + T cells. Cancer Res 2004;64 1366 (3):1140-5. 1367 9. Tüting T. T cell immunotherapy for melanoma from bedside to bench to 1368 barn and back: how conceptual advances in experimental mouse 1369 models can be translated into clinical benefit for patients. Pigment Cell 1370 Melanoma Res 2013;26(4):441-56. 1371 10. Van den Boorn JG, Hartmann G. Turning tumors into vaccines: co- 1372 opting the innate immune system. Immunity 2013;39(1):27-37. 1373 11. Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, et 1374 al. High-dose recombinant interleukin 2 therapy for patients with 1375 metastatic melanoma: analysis of 270 patients treated between 1985 1376 and 1993. J Clin Oncol 1999;17(7):2105-16. 1377 12. Hill II GJ, Krementz ET, Hill HZ. Dimethyl triazeno imidazole 1378 carboxamide and combination therapy for melanoma. IV. Late results 1379 after complete response to chemotherapy (Central Oncology Group 1380 protocols 7130, 7131, and 7131A). Cancer 1984;53(6):1299-305. 1381 13. Phan GQ, Attia P, Steinberg SM, White DE, Rosenberg SA. Factors 1382 associated with response to high-dose interleukin-2 in patients with 1383 metastatic melanoma. J Clin Oncol 2001;19(15):3477-82. 1384 14. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, 1385 et al. Improved survival with vemurafenib in melanoma with BRAF 1386 V600E mutation. N Engl J Med 2011;364(26):2507-16. 1387 15. Falchook GS, Lewis KD, Infante JR, Gordon MS, Vogelzang NJ, 1388 DeMarini DJ, et al. Activity of the oral MEK inhibitor trametinib in 1389 patients with advanced melanoma: a phase 1 dose-escalation trial. 1390 Lancet Oncol 2012;13(8):782-9. 1391 16. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen 1392 JB, et al. Improved survival with ipilimumab in patients with metastatic 1393 melanoma. N Engl J Med 2010;363(8):711-23. 1394 17. Torchilin VP. Drug targeting. Eur J Pharm Sci 2000;11(Suppl 2): 1395 S81-91. 1396 18. Strebhardt K, Ullrich A. Paul Ehrlich's magic bullet concept: 100 years 1397 of progress. Nat Rev Cancer 2008;8(6):473-80. 1398 19. Matsumura Y, Maeda H. A new concept for macromolecular 1399 therapeutics in cancer chemotherapy: mechanism of tumoritropic 1400 accumulation of proteins and the antitumor agent smancs. Cancer 1401 Res 1986;46(12 Pt 1):6387-92. 1402

F

1293

R O O

1292

P

1291

1341

D

1290

drug delivery system – and the understanding of melanoma tumorigenesis are of the same importance. How to further actively harness the EPR effect instead of passive obedience to it, and how to combine nanotechnology with recently highlighted clinical progress in melanoma are also great challenges. Only in this way can targeted NPs yield the greatest returns for clinical melanoma therapy.

E

1289

C

1288

E

1287

R

1286

R

1285

thickness of coating and density of PEG among diverse NPs, may also impose a potential impact on the toxicological property. Besides, the EPR effect is always the key element of NP targeted delivery system which brings not only great success in the development of nanomedicine but also a puzzle perplexing us for decades. A wide range of vascularization phenotypes displayed in tumors can affect the extravasation, diffusion and accumulation of NPs in tumor tissues. It is still not well known if and how the heterogeneity of EPR effect occurs. Thus, an indepth understanding of the mechanism of the EPR effect is crucial to understand the delivery and efficacy of NPs in animal and human tumors. In addition, whether active targeted NPs are more efficient than non-targeted NPs has long been debated because the only thing that the antibody or ligand on the NP surface presents is the higher chance of binding and/or internalizing into tumor cells while the antibody or ligand itself has no propulsive force leading to the target. Thus, to acclerate the translation from academic research to the clinic, the general batch to batch inconsistency of the nanomedicine must be taken into careful consideration. Also, it would be desirable to establish the rational baseline pharmacokinetic profile, bioavailability, and other pharmacologic or metabolic endpoints. Most importantly, more preclinical studies to evaluate the toxicity and ADME patterns of nanomedicines are required to support safe clinical development and product registration. On the other hand, the crosstalk of genetic mutations and epigenetic changes in melanoma results in the phenotypical plasticity. 146 This phenotypic plasticity is a source of melanoma heterogeneity which alters the antigenic landscape of melanoma cells. Thus, it seems not possible to design and prepare a specific antibody-based nanomedicine which is applicable to all subsets of melanoma. Furthermore, nanocarrier modified with specific ligands targeting the receptors over-expressed on melanoma cells is a commonly used strategy for drug delivery. Unfortunately, the density of these receptors may also change in different individuals or at different stages of melanoma. In addition, these receptors are not only unique to melanoma but also with a wide expression on normal tissues. That is why an “off-target” effect may still happen despite the use of high affinity ligands binding these receptors. The “off-target” effect not only leads to low drug delivery efficiency but also can cause toxicity to normal cells and tissues. This non-specific targeting also reduces the sensitivity of imaging of metastatic melanoma at the early stage. For theranostics, the reduced encapsulation coefficiency of the therapeutic drugs and the unfavorable interaction between drugs and imaging agents should also be taken into careful consideration. In conclusion, the top priority is not synthesizing more targeted multifunctional NPs, but developing a greater understanding of the basis of targeted drug delivery system, the mechanisms involved in melanoma tumorigenesis (e.g., gene mutation and phenotypical plasticity) as well as the importance of immunological functions during its development and metastasis. The importance of melanoma targeting with the aid of NPs for a better therapeutic efficacy is self-evident, but it is only one side of the coin. As another side of the coin, an in-depth understanding of the EPR effect – the theory basis of the targeted

N C O

1284

U

1283 1282 1281 1280 1279 1278 1277 1276 1275 1274 1273 1272 1271 1270 1269 1268 1267 1266

J. Li et al / Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx–xxx

T

22

J. Li et al / Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx–xxx

E

D

P

R O O

F

40. Hölzel M, Bovier A, Tüting T. Plasticity of tumour and immune cells: a source of heterogeneity and a cause for therapy resistance? Nat Rev Cancer 2013;13(5):365-76. 41. Ordóñez NG. Value of melanocytic-associated immunohistochemical markers in the diagnosis of malignant melanoma: a review and update. Hum Pathol 2014;45(2):191-205. 42. Falvo E, Tremante E, Fraioli R, Leonetti C, Zamparelli C, Boffi A, et al. Antibody-drug conjugates: targeting melanoma with cisplatin encapsulated in protein-cage nanoparticles based on human ferritin. Nanoscale 2013;5(24):12278-85. 43. Sutherland R, Delia D, Schneider C, Newman R, Kemshead J, Greaves M. Ubiquitous cell-surface glycoprotein on tumor cells is proliferationassociated receptor for transferrin. Proc Natl Acad Sci U S A 1981;78 (7):4515-9. 44. Cheng Z, Al Zaki A, Hui JZ, Muzykantov VR, Tsourkas A. Multifunctional nanoparticles: cost versus benefit of adding targeting and imaging capabilities. Science 2012;338(6109):903-10. 45. Davis ME, Zuckerman JE, Choi CH, Seligson D, Tolcher A, Alabi CA, et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 2010;464 (7291):1067-70. 46. Lemarié F, Croft DR, Tate RJ, Ryan KM, Dufès C. Tumor regression following intravenous administration of a tumor-targeted p73 gene delivery system. Biomaterials 2012;33(9):2701-9. 47. Yao H, Ng SS, Huo LF, Chow BK, Shen Z, Yang M, et al. Effective melanoma immunotherapy with interleukin-2 delivered by a novel polymeric nanoparticle. Mol Cancer Ther 2011;10(6):1082-92. 48. Cai L, Wang X, Wang W, Qiu N, Wen J, Duan X, et al. Peptide ligand and PEG-mediated long-circulating liposome targeted to FGFR overexpressing tumor in vivo. Int J Nanomedicine 2012;7:4499-510. 49. Chen X, Wang X, Wang Y, Yang L, Hu J, Xiao W, et al. Improved tumor-targeting drug delivery and therapeutic efficacy by cationic liposome modified with truncated bFGF peptide. J Control Release 2010;145(1):17-25. 50. Sun M, Wang Y, Shen J, Xiao Y, Su Z, Ping Q. Octreotidemodification enhances the delivery and targeting of doxorubicin-loaded liposomes to somatostatin receptors expressing tumor in vitro and in vivo. Nanotechnology 2010;21(47):475101. 51. Dubey PK, Singodia D, Vyas SP. Polymeric nanospheres modified with YIGSR peptide for tumor targeting. Drug Deliv 2010;17 (7):541-51. 52. Ukawala M, Chaudhari K, Rajyaguru T, Manjappa AS, Murthy RS, Gude R. Laminin receptor-targeted etoposide loaded polymeric micelles: a novel approach for the effective treatment of tumor metastasis. J Drug Target 2012;20(1):55-66. 53. Chen Y, Bathula SR, Yang Q, Huang L. Targeted nanoparticles deliver siRNA to melanoma. J Invest Dermatol 2010;130(12):2790-8. 54. Yang Y, Li J, Liu F, Huang L. Systemic delivery of siRNA via LCP nanoparticle efficiently inhibits lung metastasis. Mol Ther 2012;20 (3):609-15. 55. Durymanov MO, Beletkaia EA, Ulasov AV, Khramtsov YV, Trusov GA, Rodichenko NS, et al. Subcellular trafficking and transfection efficacy of polyethylenimine–polyethylene glycol polyplex nanoparticles with a ligand to melanocortin receptor-1. J Control Release 2012;163(2):211-9. 56. Lu W, Xiong C, Zhang R, Shi L, Huang M, Zhang G, et al. Receptormediated transcytosis: a mechanism for active extravascular transport of nanoparticles in solid tumors. J Control Release 2012;161 (3):959-66. 57. Lizée G, Overwijk WW, Radvanyi L, Gao J, Sharma P, Hwu P. Harnessing the power of the immune system to target cancer. Annu Rev Med 2013;64:71-90. 58. Mamot C, Ritschard R, Wicki A, Stehle G, Dieterle T, Bubendorf L, et al. Tolerability, safety, pharmacokinetics, and efficacy of doxorubicinloaded anti-EGFR immunoliposomes in advanced solid tumours: a phase 1 dose-escalation study. Lancet Oncol 2012;13(12):1234-41.

N C O

R

R

E

C

T

20. Yu B, Tai HC, Xue W, Lee LJ, Lee RJ. Receptor-targeted nanocarriers for therapeutic delivery to cancer. Mol Membr Biol 2010;27(7):286-98. 21. Kamaly N, Xiao Z, Valencia PM, Radovic-Moreno AF, Farokhzad OC. Targeted polymeric therapeutic nanoparticles: design, development and clinical translation. Chem Soc Rev 2012;41(7):2971-3010. 22. Liu F, Feng L, Zhang L, Zhang X, Zhang N. Synthesis, characterization and antitumor evaluation of CMCS–DTX conjugates as novel delivery platform for docetaxel. Int J Pharm 2013;451(1–2):41-9. 23. Zhang W, Shi Y, Chen Y, Hao J, Sha X, Fang X. The potential of Pluronic polymeric micelles encapsulated with paclitaxel for the treatment of melanoma using subcutaneous and pulmonary metastatic mice models. Biomaterials 2011;32(25):5934-44. 24. Zheng L, Gou M, Zhou S, Yi T, Zhong Q, Li Z, et al. Antitumor activity of monomethoxy poly(ethylene glycol)–poly (epsilon-caprolactone) micelle-encapsulated doxorubicin against mouse melanoma. Oncol Rep 2011;25(6):1557-64. 25. Yang Y, Liu X, Zhang D, Yu W, Lv G, Xie H, et al. Chitosan/VEGFsIRNA nanoparticle for gene silencing. J Control Release 2011;152 (Suppl 1):e160-1. 26. Velluto D, Thomas SN, Simeoni E, Swartz MA, Hubbell JA. PEG-b– PPS-b–PEI micelles and PEG-b–PPS/PEG-b–PPS-b–PEI mixed micelles as non-viral vectors for plasmid DNA: tumor immunotoxicity in B16F10 melanoma. Biomaterials 2011;32(36):9839-47. 27. Yonenaga N, Kenjo E, Asai T, Tsuruta A, Shimizu K, Dewa T, et al. RGD-based active targeting of novel polycation liposomes bearing siRNA for cancer treatment. J Control Release 2012;160(2):177-81. 28. Huang FY, Mei WL, Li YN, Tan GH, Dai HF, Guo JL, et al. The antitumour activities induced by pegylated liposomal cytochalasin D in murine models. Eur J Cancer 2012;48(14):2260-9. 29. Song CK, Lee JH, Jahn A, Choi MJ, Namgoong SK, Hong SS, et al. In vitro and in vivo evaluation of N,N,N-trimethylphytosphingosineiodide (TMP) in liposomes for the treatment of angiogenesis and metastasis. Int J Pharm 2012;434(1–2):191-8. 30. Soman N, Marsh J, Lanza G, Wickline S. New mechanisms for nonporative ultrasound stimulation of cargo delivery to cell cytosol with targeted perfluorocarbon nanoparticles. Nanotechnology 2008;19 (18):185102. 31. Soman NR, Baldwin SL, Hu G, Marsh JN, Lanza GM, Heuser JE, et al. Molecularly targeted nanocarriers deliver the cytolytic peptide melittin specifically to tumor cells in mice, reducing tumor growth. J Clin Invest 2009;119(9):2830-42. 32. Soman NR, Lanza GM, Heuser JM, Schlesinger PH, Wickline SA. Synthesis and characterization of stable fluorocarbon nanostructures as drug delivery vehicles for cytolytic peptides. Nano Lett 2008;8 (4):1131-6. 33. Huang C, Jin HL, Qian Y, Qi SH, Luo HM, Luo QM, et al. Hybrid melittin cytolytic peptide-driven ultrasmall lipid nanoparticles block melanoma growth in vivo. ACS Nano 2013;7(7):5791-800. 34. Morachis JM, Mahmoud EA, Almutairi A. Physical and chemical strategies for therapeutic delivery by using polymeric nanoparticles. Pharmacol Rev 2012;64(3):505-19. 35. Albanese A, Tang PS, Chan WC. The effect of nanoparticle size, shape, and surface chemistry on biological systems. Annu Rev Biomed Eng 2012;14:1-16. 36. Bae YH, Park K. Targeted drug delivery to tumors: myths, reality, and possibility. J Control Release 2011;153(3):198-205. 37. Sliwkowski MX, Mellman I. Antibody therapeutics in cancer. Science 2013;341(6151):1192-8. 38. Maloney DG, Grillo-López AJ, White CA, Bodkin D, Schilder RJ, Neidhart JA, et al. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood 1997;90(6):2188-95. 39. Hrkach J, Von Hoff D, Mukkaram Ali M, Andrianova E, Auer J, Campbell T, et al. Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile. Sci Transl Med 2012;4(128):128ra39.

U

1403 1404 1405 1406 1407 1408 1409 1410 1411 1412 1413 1414 1415 1416 1417 1418 1419 1420 1421 1422 1423 1424 1425 1426 1427 1428 1429 1430 1431 1432 1433 1434 1435 1436 1437 1438 1439 1440 1441 1442 1443 1444 1445 1446 1447 1448 1449 1450 1451 1452 1453 1454 1455 1456 1457 1458 1459 1460 1461 1462 1463 1464 1465 1466 1467 1468

23 1469 1470 1471 1472 1473 1474 1475 1476 1477 1478 1479 1480 1481 1482 1483 1484 1485 1486 1487 1488 1489 1490 1491 1492 1493 1494 1495 1496 1497 1498 1499 1500 1501 1502 1503 1504 1505 1506 1507 1508 1509 1510 1511 1512 1513 1514 1515 1516 1517 1518 1519 1520 1521 1522 1523 1524 1525 1526 1527 1528 1529 1530 1531 1532 1533 1534

84.

85. 86. 87.

E

88.

E

R

R

N C O

F

83.

R O O

82.

P

81.

nanoparticle mediated antigen delivery. Biomaterials 2011;32 (14):3666-78. Zhang Z, Guo Y, Feng SS. Nanoimmunotherapy: application of nanotechnology for sustained and targeted delivery of antigens to dendritic cells. Nanomedicine (Lond) 2012;7(1):1-4. Unger WW, van Beelen AJ, Bruijns SC, Joshi M, Fehres CM, van Bloois L, et al. Glycan-modified liposomes boost CD4 + and CD8 + Tcell responses by targeting DC-SIGN on dendritic cells. J Control Release 2012;160(1):88-95. Van Broekhoven CL, Parish CR, Demangel C, Britton WJ, Altin JG. Targeting dendritic cells with antigen-containing liposomes: a highly effective procedure for induction of antitumor immunity and for tumor immunotherapy. Cancer Res 2004;64(12):4357-65. Perche F, Benvegnu T, Berchel M, Lebegue L, Pichon C, Jaffrès PA, et al. Enhancement of dendritic cells transfection in vivo and of vaccination against B16F10 melanoma with mannosylated histidylated lipopolyplexes loaded with tumor antigen messenger RNA. Nanomedicine 2011;7 (4):445-53. Cruz LJ, Tacken PJ, Bonetto F, Buschow SI, Croes HJ, Wijers M, et al. Multimodal imaging of nanovaccine carriers targeted to human dendritic cells. Mol Pharm 2011;8(2):520-31. Moon JJ, Huang B, Irvine DJ. Engineering nano- and microparticles to tune immunity. Adv Mater 2012;24(28):3724-46. Swartz MA, Hirosue S, Hubbell JA. Engineering approaches to immunotherapy. Sci Transl Med 2012;4(148):148rv9. Jeanbart L, Ballester M, de Titta A, Corthésy P, Romero P, Hubbell JA, et al. Enhancing efficacy of anticancer vaccines by targeted delivery to tumor-draining lymph nodes. Cancer Immunol Res 2014;2(5):436-47. Liu H, Moynihan KD, Zheng Y, Szeto GL, Li AV, Huang B, et al. Structure-based programming of lymph-node targeting in molecular vaccines. Nature 2014;507(7493):519-22. Thomas SN, Vokali E, Lund AW, Hubbell JA, Swartz MA. Targeting the tumor-draining lymph node with adjuvanted nanoparticles reshapes the anti-tumor immune response. Biomaterials 2014;35 (2):814-24. Itzhaki O, Levy D, Zikich D, Treves AJ, Markel G, Schachter J, et al. Adoptive T-cell transfer in melanoma. Immunotherapy 2013;5 (1):79-90. Li SY, Liu Y. Immunotherapy of melanoma with the immune costimulatory monoclonal antibodies targeting CD137. Clin Pharmacol 2013;5(Suppl 1):47-53. Stephan MT, Moon JJ, Um SH, Bershteyn A, Irvine DJ. Therapeutic cell engineering with surface-conjugated synthetic nanoparticles. Nat Med 2010;16(9):1035-41. Fleige E, Quadir MA, Haag R. Stimuli-responsive polymeric nanocarriers for the controlled transport of active compounds: concepts and applications. Adv Drug Deliv Rev 2012;64(9):866-84. Zhu S, Lansakara-P DS, Li X, Cui Z. Lysosomal delivery of a lipophilic gemcitabine prodrug using novel acid-sensitive micelles improved its antitumor activity. Bioconjug Chem 2012;23(5):966-80. Talelli M, Iman M, Varkouhi AK, Rijcken CJ, Schiffelers RM, Etrych T, et al. Core-crosslinked polymeric micelles with controlled release of covalently entrapped doxorubicin. Biomaterials 2010;31 (30):7797-804. Zhou T, Xiao C, Fan J, Chen S, Shen J, Wu W, et al. A nanogel of onsite tunable pH-response for efficient anticancer drug delivery. Acta Biomater 2013;9(1):4546-57. Xiao M, Liang R, Deng R, Dong L, Yi S, Zhu J, et al. pH-Sensitive cisplatin-loaded gold nanoparticles for potential melanoma therapy. J Control Release 2013;172:e44. Gu J, Wang X, Jiang X, Chen Y, Chen L, Fang X, et al. Self-assembled carboxymethyl poly (L-histidine) coated poly (beta-amino ester)/DNA complexes for gene transfection. Biomaterials 2012;33(2):644-58. Tao J, Liu YQ, Li Y, Peng JL, Li L, Liu J, et al. Hypoxia: dual effect on the expression of transferrin receptor in human melanoma A375 cell line. Exp Dermatol 2007;16(11):899-904.

D

80.

89.

C

59. Wickham T, Futch K. A phase I study of MM-302, a HER2-targeted liposomal doxorubicin, patients with advanced, HER2-positive breast cancer, Suppl. 3. Cancer Research, San Antonio, TX; 2012 [P5-18-09]. 60. Matsumura Y, Gotoh M, Muro K, Yamada Y, Shirao K, Shimada Y, et al. Phase I and pharmacokinetic study of MCC-465, a doxorubicin (DXR) encapsulated in PEG immunoliposome, in patients with metastatic stomach cancer. Ann Oncol 2004;15(3):517-25. 61. Senzer N, Nemunaitis J, Nemunaitis D, Bedell C, Edelman G, Barve M, et al. Phase I study of a systemically delivered p53 nanoparticle in advanced solid tumors. Mol Ther 2013;21(5):1096-103. 62. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer 2003;3(6):401-10. 63. Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 2010;10 (1):9-22. 64. Kuphal S, Bauer R, Bosserhoff AK. Integrin signaling in malignant melanoma. Cancer Metastasis Rev 2005;24(2):195-222. 65. Wang Y, Yang T, Wang X, Dai W, Wang J, Zhang X, et al. Materializing sequential killing of tumor vasculature and tumor cells via targeted polymeric micelle system. J Control Release 2011;149 (3):299-306. 66. Wang Z, Chui WK, Ho PC. Nanoparticulate delivery system targeted to tumor neovasculature for combined anticancer and antiangiogenesis therapy. Pharm Res 2011;28(3):585-96. 67. Dai W, Yang T, Wang Y, Wang X, Wang J, Zhang X, et al. Peptide PHSCNK as an integrin alpha5beta1 antagonist targets stealth liposomes to integrin-overexpressing melanoma. Nanomedicine 2012;8(7):1152-61. 68. Hamano N, Negishi Y, Fujisawa A, Manandhar M, Sato H, Katagiri F, et al. Modification of the C16Y peptide on nanoparticles is an effective approach to target endothelial and cancer cells via the integrin receptor. Int J Pharm 2012;428(1–2):114-7. 69. Kluza E, Jacobs I, Hectors SJ, Mayo KH, Griffioen AW, Strijkers GJ, et al. Dual-targeting of alphavbeta3 and galectin-1 improves the specificity of paramagnetic/fluorescent liposomes to tumor endothelium in vivo. J Control Release 2012;158(2):207-14. 70. Guan YY, Luan X, Xu JR, Liu YR, Lu Q, Wang C, et al. Selective eradication of tumor vascular pericytes by peptide-conjugated nanoparticles for antiangiogenic therapy of melanoma lung metastasis. Biomaterials 2014;35(9):3060-70. 71. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A 2010;107(9):4275-80. 72. McArthur GA, Ribas A. Targeting oncogenic drivers and the immune system in melanoma. J Clin Oncol 2013;31(4):499-506. 73. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013;369(2):122-33. 74. Schwartzentruber DJ, Lawson DH, Richards JM, Conry RM, Miller DM, Treisman J, et al. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med 2011;364 (22):2119-27. 75. Gonzalez R, Hutchins L, Nemunaitis J, Atkins M, Schwarzenberger PO. Phase 2 trial of Allovectin-7 in advanced metastatic melanoma. Melanoma Res 2006;16(6):521-6. 76. Nemunaitis J. Vaccines in cancer: GVAX, a GM-CSF gene vaccine. Expert Rev Vaccines 2005;4(3):259-74. 77. Tacken PJ, de Vries IJ, Torensma R, Figdor CG. Dendritic-cell immunotherapy: from ex vivo loading to in vivo targeting. Nat Rev Immunol 2007;7(10):790-802. 78. Reddy ST, Swartz MA, Hubbell JA. Targeting dendritic cells with biomaterials: developing the next generation of vaccines. Trends Immunol 2006;27(12):573-9. 79. Zhang Z, Tongchusak S, Mizukami Y, Kang YJ, Ioji T, Touma M, et al. Induction of anti-tumor cytotoxic T cell responses through PLGA-

U

1535 1536 1537 1538 1539 1540 1541 1542 1543 1544 1545 1546 1547 1548 1549 1550 1551 1552 1553 1554 1555 1556 1557 1558 1559 1560 1561 1562 1563 1564 1565 1566 1567 1568 1569 1570 1571 1572 1573 1574 1575 1576 1577 1578 1579 1580 1581 1582 1583 1584 1585 1586 1587 1588 1589 1590 1591 1592 1593 1594 1595 1596 1597 1598 1599 1600

J. Li et al / Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx–xxx

T

24

90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

1601 1602 1603 1604 1605 1606 1607 1608 1609 1610 1611 1612 1613 1614 1615 1616 1617 1618 1619 1620 1621 1622 1623 1624 1625 1626 1627 1628 1629 1630 1631 1632 1633 1634 1635 1636 1637 1638 1639 1640 1641 1642 1643 1644 1645 1646 1647 1648 1649 1650 1651 1652 1653 1654 1655 1656 1657 1658 1659 1660 1661 1662 1663 1664 1665 1666

J. Li et al / Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx–xxx

123.

124.

125.

126.

D

127.

E

128.

129.

C

E

R

R

N C O

130.

131.

132.

133.

134.

135.

136.

137.

138.

F

122.

R O O

121.

riers for theranostic use in brain and skin. J Nanoparticle Res 2012;14:1-18. Parhi P, Mohanty C, Sahoo SK. Nanotechnology-based combinational drug delivery: an emerging approach for cancer therapy. Drug Discov Today 2012;17(17–18):1044-52. Hu-Lieskovan S, Robert L, Homet Moreno B, Ribas A. Combining targeted therapy with immunotherapy in BRAFmutant melanoma: promise and challenges. J Clin Oncol 2014;32(21):2248-54. Salama AK, Flaherty KT. BRAF in melanoma: current strategies and future directions. Clin Cancer Res 2013;19(16):4326-34. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab–paclitaxel plus gemcitabine. N Engl J Med 2013;369(18):1691-703. Robert C, Thomas L, Bondarenko I, O'Day S, M D JW, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;364(26):2517-26. Roy A, Chandra S, Mamilapally S, Upadhyay P, Bhaskar S. Anticancer and immunostimulatory activity by conjugate of paclitaxel and nontoxic derivative of LPS for combined chemo-immunotherapy. Pharm Res 2012;29(8):2294-309. Cao L, Zeng Q, Xu C, Shi S, Zhang Z, Sun X. Enhanced antitumor response mediated by the codelivery of paclitaxel and adenoviral vector expressing IL-12. Mol Pharm 2013;10(5):1804-14. Li Y, He H, Jia X, Lu WL, Lou J, Wei Y. A dual-targeting nanocarrier based on poly(amidoamine) dendrimers conjugated with transferrin and tamoxifen for treating brain gliomas. Biomaterials 2012;33 (15):3899-908. Boucher Y, Baxter LT, Jain RK. Interstitial pressure gradients in tissueisolated and subcutaneous tumors: implications for therapy. Cancer Res 1990;50(15):4478-84. Fan Y, Du W, He B, Fu F, Yuan L, Wu H, et al. The reduction of tumor interstitial fluid pressure by liposomal imatinib and its effect on combination therapy with liposomal doxorubicin. Biomaterials 2013;34(9):2277-88. Tran MA, Gowda R, Sharma A, Park EJ, Adair J, Kester M, et al. Targeting V600EB-Raf and Akt3 using nanoliposomal-small interfering RNA inhibits cutaneous melanocytic lesion development. Cancer Res 2008;68(18):7638-49. Beloor J, Choi CS, Nam HY, Park M, Kim SH, Jackson A, et al. Arginine-engrafted biodegradable polymer for the systemic delivery of therapeutic siRNA. Biomaterials 2012;33(5):1640-50. Kenjo E, Asai T, Yonenaga N, Ando H, Ishii T, Hatanaka K, et al. Systemic delivery of small interfering RNA by use of targeted polycation liposomes for cancer therapy. Biol Pharm Bull 2013;36 (2):287-91. Hu CM, Zhang L. Nanoparticle-based combination therapy toward overcoming drug resistance in cancer. Biochem Pharmacol 2012;83 (8):1104-11. Zhang L, Radovic-Moreno AF, Alexis F, Gu FX, Basto PA, Bagalkot V, et al. Co-delivery of hydrophobic and hydrophilic drugs from nanoparticle–aptamer bioconjugates. ChemMedChem 2007;2 (9):1268-71. Aryal S, Hu CM, Zhang L. Polymeric nanoparticles with precise ratiometric control over drug loading for combination therapy. Mol Pharm 2011;8(4):1401-7. Wang Z, Ho PC. A nanocapsular combinatorial sequential drug delivery system for antiangiogenesis and anticancer activities. Biomaterials 2010;31(27):7115-23. Hersh EM, O'Day SJ, Ribas A, Samlowski WE, Gordon MS, Shechter DE, et al. A phase 2 clinical trial of nab–paclitaxel in previously treated and chemotherapy-naive patients with metastatic melanoma. Cancer 2010;116(1):155-63. Kottschade LA, Suman VJ, Amatruda III T, McWilliams RR, Mattar BI, Nikcevich DA, et al. A phase II trial of nab–paclitaxel (ABI-007) and carboplatin in patients with unresectable stage IV melanoma: a

P

120.

T

100. Brahimi-Horn MC, Bellot G, Pouysségur J. Hypoxia and energetic tumour metabolism. Curr Opin Genet Dev 2011;21(1):67-72. 101. Ito A, Saito H, Mitobe K, Minamiya Y, Takahashi N, Maruyama K, et al. Inhibition of heat shock protein 90 sensitizes melanoma cells to thermosensitive ferromagnetic particle-mediated hyperthermia with low Curie temperature. Cancer Sci 2009;100(3):558-64. 102. Li L, ten Hagen TL, Hossann M, Süss R, van Rhoon GC, Eggermont AM, et al. Mild hyperthermia triggered doxorubicin release from optimized stealth thermosensitive liposomes improves intratumoral drug delivery and efficacy. J Control Release 2013;168(2):142-50. 103. Bédard MF, De Geest BG, Skirtach AG, Möhwald H, Sukhorukov GB. Polymeric microcapsules with light responsive properties for encapsulation and release. Adv Colloid Interface Sci 2010;158(1–2):2-14. 104. Chu M, Pan X, Zhang D, Wu Q, Peng J, Hai W. The therapeutic efficacy of CdTe and CdSe quantum dots for photothermal cancer therapy. Biomaterials 2012;33(29):7071-83. 105. Lu W, Xiong C, Zhang G, Huang Q, Zhang R, Zhang JZ, et al. Targeted photothermal ablation of murine melanomas with melanocyte-stimulating hormone analog conjugated hollow gold nanospheres. Clin Cancer Res 2009;15(3):876-86. 106. Ferreira DM, Saga YY, Aluicio-Sarduy E, Tedesco AC. Chitosan nanoparticles for melanoma cancer treatment by photodynamic therapy and electrochemotherapy using aminolevulinic acid derivatives. Curr Med Chem 2013;20(14):1904-11. 107. Idris NM, Gnanasammandhan MK, Zhang J, Ho PC, Mahendran R, Zhang Y. In vivo photodynamic therapy using upconversion nanoparticles as remote-controlled nanotransducers. Nat Med 2012;18 (10):1580-5. 108. Oda Y, Suzuki R, Otake S, Nishiie N, Hirata K, Koshima R, et al. Prophylactic immunization with Bubble liposomes and ultrasoundtreated dendritic cells provided a four-fold decrease in the frequency of melanoma lung metastasis. J Control Release 2012;160(2):362-6. 109. Un K, Kawakami S, Suzuki R, Maruyama K, Yamashita F, Hashida M. Suppression of melanoma growth and metastasis by DNA vaccination using an ultrasound-responsive and mannose-modified gene carrier. Mol Pharm 2011;8(2):543-54. 110. Lentacker I, Geers B, Demeester J, De Smedt SC, Sanders NN. Tumor cell killing efficiency of doxorubicin loaded microbubbles after ultrasound exposure. J Control Release 2010;148(1):e113-4. 111. Lammers T, Kiessling F, Hennink WE, Storm G. Nanotheranostics and image-guided drug delivery: current concepts and future directions. Mol Pharm 2010;7(6):1899-912. 112. Xie J, Lee S, Chen X. Nanoparticle-based theranostic agents. Adv Drug Deliv Rev 2010;62(11):1064-79. 113. Mura S, Couvreur P. Nanotheranostics for personalized medicine. Adv Drug Deliv Rev 2012;64(13):1394-416. 114. Zhu H, Li Y, Qiu R, Shi L, Wu W, Zhou S. Responsive fluorescent Bi (2)O(3)@PVA hybrid nanogels for temperature-sensing, dual-modal imaging, and drug delivery. Biomaterials 2012;33(10):3058-69. 115. Wang J, Liang R, Jiang H, Zhu J, Tu Y, Tao J. A simple route to prepare multifunctional PLA nanoparticles against melanoma. J Control Release 2013;172:e43. 116. Fraix A, Kandoth N, Manet I, Cardile V, Graziano AC, Gref R, et al. An engineered nanoplatform for bimodal anticancer phototherapy with dual-color fluorescence detection of sensitizers. Chem Commun (Camb) 2013;49(40):4459-61. 117. Wadajkar AS, Bhavsar Z, Ko CY, Koppolu B, Cui W, Tang L, et al. Multifunctional particles for melanoma-targeted drug delivery. Acta Biomater 2012;8(8):2996-3004. 118. Liao CF, Lin SH, Chen HC, Tai CJ, Chang CC, Li LT, et al. CSE1L, a novel microvesicle membrane protein, mediates Ras-triggered microvesicle generation and metastasis of tumor cells. Mol Med 2012;18:1269-80. 119. Zhang LW, Wen CJ, Al-Suwayeh SA, Yen TC, Fang JY. Cisplatin and quantum dots encapsulated in liposomes as multifunctional nanocar-

U

1667 1668 1669 1670 1671 1672 1673 1674 1675 1676 1677 1678 1679 1680 1681 1682 1683 1684 1685 1686 1687 1688 1689 1690 1691 1692 1693 1694 1695 1696 1697 1698 1699 1700 1701 1702 1703 1704 1705 1706 1707 1708 1709 1710 1711 1712 1713 1714 1715 1716 1717 1718 1719 1720 1721 1722 1723 1724 1725 1726 1727 1728 1729 1730 1731 1732

25 1733 1734 1735 1736 1737 1738 1739 1740 1741 1742 1743 1744 1745 1746 1747 Q7 1748 1749 1750 1751 1752 1753 1754 1755 1756 1757 1758 1759 1760 1761 1762 1763 1764 1765 1766 1767 1768 1769 1770 1771 1772 1773 1774 1775 1776 1777 1778 1779 1780 1781 1782 1783 1784 1785 1786 1787 1788 1789 1790 1791 1792 1793 1794 1795 1796 1797 1798

26

141.

142.

143.

144.

F

140.

145. Rudmann DG, Alston JT, Hanson JC, Heidel S. High molecular weight polyethylene glycol cellular distribution and PEGassociated cytoplasmic vacuolation is molecular weight dependent and does not require conjugation to proteins. Toxicol Pathol 2013;41(7):970-83. 146. Burgess DJ. Epigenetics: melanoma insights written in the DNA. Nat Rev Cancer 2012;12(11):738-9. 147. Kottschade LA, Suman VJ, Perez DG, McWilliams RR, Kaur JS, Amatruda III TT, et al. A randomized phase 2 study of temozolomide and bevacizumab or nab–paclitaxel, carboplatin, and bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N0775. Cancer 2013;119(3):586-92. 148. Homsi J, Bedikian AY, Papadopoulos NE, Kim KB, Hwu WJ, Mahoney SL, et al. Phase 2 open-label study of weekly docosahexaenoic acid–paclitaxel in patients with metastatic uveal melanoma. Melanoma Res 2010;20(6):507-10. 149. Eggermont AM, Suciu S, Testori A, Santinami M, Kruit WH, Marsden J, et al. Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. J Clin Oncol 2012;30 (31):3810-8. 150. Degen A, Weichenthal M, Ugurel S, Trefzer U, Kilian K, Garbe C, et al. Cutaneous side effects of combined therapy with sorafenib and pegylated interferon alpha-2b in metastatic melanoma (phase II DeCOG trial). J Dtsch Dermatol Ges 2013;11(9):846-53.

R O O

139.

North Central Cancer Treatment Group study, N057E (1). Cancer 2011;117(8):1704-10. Homsi J, Bedikian AY, Kim KB, Papadopoulos NE, Hwu WJ, Mahoney SL, et al. Phase 2 open-label study of weekly docosahexaenoic acid–paclitaxel in cutaneous and mucosal metastatic melanoma patients. Melanoma Res 2009;19(4):238-42. Bedikian AY, DeConti RC, Conry R, Agarwala S, Papadopoulos N, Kim KB, et al. Phase 3 study of docosahexaenoic acid–paclitaxel versus dacarbazine in patients with metastatic malignant melanoma. Melanoma Res 2009;19(4):238-42. Fink W, Zimpfer-Rechner C, Thoelke A, Figl R, Kaatz M, Ugurel S, et al. Clinical phase II study of pegylated liposomal doxorubicin as second-line treatment in disseminated melanoma. Onkologie 2004;27(6):540-4. Smylie MG, Wong R, Mihalcioiu C, Lee C, Pouliot JF. A phase II, open label, monotherapy study of liposomal doxorubicin in patients with metastatic malignant melanoma. Invest New Drugs 2007;25(2):155-9. Bedikian AY, Richards J, Kharkevitch D, Atkins MB, Whitman E, Gonzalez R. A phase 2 study of high-dose Allovectin-7 in patients with advanced metastatic melanoma. Melanoma Res 2010;20(3):218-26. Grob JJ, Jouary T, Dréno B, Asselineau J, Gutzmer R, Hauschild A, et al. Adjuvant therapy with pegylated interferon alfa-2b (36 months) versus low-dose interferon alfa-2b (18 months) in melanoma patients without macrometastatic nodes: an open-label, randomised, phase 3 European Association for Dermato-Oncology (EADO) study. Eur J Cancer 2013;49(1):166-74.

P

1799 1800 1801 1802 1803 1804 1805 1806 1807 1808 1809 1810 1811 1812 1813 1814 1815 1816 1817 1818 1819 1820 1821 1822 1823

J. Li et al / Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx–xxx

U

N C O

R

R

E

C

T

E

D

1850

1824 1825 1826 1827 1828 1829 1830 1831 1832 1833 1834 1835 1836 1837 1838 1839 1840 1841 1842 1843 1844 1845 1846 1847 1848 1849

Nanomedicine: Nanotechnology, Biology, and Medicine xx (2015) xxx – xxx nanomedjournal.com

Graphical Abstract

2 5

Recent advances in targeted nanoparticles drug delivery to melanoma

6 7 8

Jun Li, MD a, Yujue Wang, MD a, Ruijing Liang b, Xiangjie An, MD a, Ke Wang b, Guanxin Shen, MD c, Yating Tu, MD a, Jintao Zhu, PhD b,⁎, Juan Tao, MD a,⁎

Nanomedicine: Nanotechnology, Biology, and Medicine xxx (2015) xxx –xxx

F

1

9

14

15 16 17 18 19 20 21 22

Due to its high multidrug resistance and low survival rate, melanoma is one of the most aggressive skin cancers. Fortunately, the applications of nanocarriers are widely expected to change the landscape of melanoma therapy for foreseeable future. We will demonstrate recent development in the application of multifunctional nanoparticles for targeted drug delivery (active and passive targeting) to melanoma, in melanoma nanotheranostics and combination therapy, and nanopharmaceutical associated melanoma clinical trials. Moreover, we will discuss current status, challenges, and perspectives of the targeted NPs drug delivery to melanoma.

12

13

D

423

U

N

C

O

R

R

E

C

T

E

24

R O O

a

Department of Dermatology, Affiliated Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan 430022, PR China b School of Chemistry and Chemical Engineering and National Engineering Center for Nanomedicine, HUST, Wuhan 430074, PR China c Department of Immunology, Tongji Medical College, HUST, Wuhan 430022, PR China1

11

P

10

Recent advances in targeted nanoparticles drug delivery to melanoma.

Melanoma is one of the most aggressive skin cancers, notorious for its high multidrug resistance and low survival rate. Conventional therapies (e.g., ...
4MB Sizes 4 Downloads 10 Views