http://informahealthcare.com/drt ISSN: 1061-186X (print), 1029-2330 (electronic) J Drug Target, Early Online: 1–13 ! 2015 Informa UK Ltd. DOI: 10.3109/1061186X.2015.1051049

REVIEW ARTICLE

Nanocarriers for cancer-targeted drug delivery Preeti Kumari, Balaram Ghosh, and Swati Biswas

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Department of Pharmacy, Birla Institute of Technology and Science – Pilani, Hyderabad Campus, Hyderabad, Andhra Pradesh, India

Abstract

Keywords

Nanoparticles as drug delivery system have received much attention in recent years, especially for cancer treatment. In addition to improving the pharmacokinetics of the loaded poorly soluble hydrophobic drugs by solubilizing them in the hydrophobic compartments, nanoparticles allowed cancer specific drug delivery by inherent passive targeting phenomena and adopted active targeting strategies. For this reason, nanoparticles-drug formulations are capable of enhancing the safety, pharmacokinetic profiles and bioavailability of the administered drugs leading to improved therapeutic efficacy compared to conventional therapy. The focus of this review is to provide an overview of various nanoparticle formulations in both research and clinical applications with a focus on various chemotherapeutic drug delivery systems for the treatment of cancer. The use of various nanoparticles, including liposomes, polymeric nanoparticles, dendrimers, magnetic and other inorganic nanoparticles for targeted drug delivery in cancer is detailed.

Liposomes, targeted drug delivery, targeted polymers, tumor targeting

Introduction Cancer remains a leading cause of mortality worldwide, accounting for 8.2 million cancer related deaths in 2012. According to the statistics reported by World Health Organization (WHO), annual cancer cases are expected to rise from 14 million in 2012 to 22 within the next two decades [1]. Cancer is a pathophysiologically heterogeneous disease that rapidly progresses to an uncontrollable stage after onset [2]. Even though various treatment modalities, including immuno, photothermal, photodynamic, gene and hormone therapy display promising cancer eradicating potential in preclinical studies, however, surgery, radiation and chemotherapy continue to be the first line treatment option for most cancers [3]. However, these focused treatment strategies fail to control metastatic tumors that have reached in distant organs. Conventional chemotherapy, the next major strategy for cancer treatment is highly non-specific in targeting the drugs to the cancer cells causing undesirable side-effects to the healthy tissues [4]. Even though cytotoxic agents are commonly utilized for the whole-body treatment in recurrent cancers, however, conventional anticancer drugs encounters several drawbacks, including poor aqueous solubility, nonspecific biodistribution, severe toxicity to normal cells, inadequate drug concentrations at tumors or cancerous cells and the development of multiple drug resistance [5,6].

Address for correspondence: Swati Biswas, PhD, Assistant Professor, Department of Pharmacy, Room A-006, BITS – Pilani, Hyderabad Campus, Shameerpet, Hyderabad 500078, Andhra Pradesh, India. Tel: 040-6630-3630. Fax: 040-6630-3998. E-mail: swati.biswas@ hyderabad.bits-pilani.ac.in

History Received 9 February 2015 Revised 3 May 2015 Accepted 3 May 2015 Published online 10 June 2015

Therefore, quest for alternate therapeutic approaches remains as unmet necessity. Use of nanotechnology in various biomedical applications, including drug delivery has attracted increasing interest due to their ability to alter the drug’s pharmacokinetics [7]. Nanomedicines render improved solubility of poorly soluble drugs and reduced metabolism by dissolving them in their hydrophobic or hydrophilic compartment. Nanomedicines have prolonged plasma half life and different biodistribution profile compared to conventional chemotherapy. Moreover, nanomedicines reach tumor tissues by evading circulation and passing through the discontinuous fenestrations in the endothelial layer in the tumor microenvironment that ranges from 300 to 4700 nm in diameter. In addition to the leaky tumor vasculature, poor lymphatic drainage is encountered in the tumors due to the dysfunctional lymph angiogenesis and compression of lymphatic vessels by proliferating cancer cells. As a result, nanomedicines get preferentially accumulated in the interstitial fluid of tumor compared to other normal tissues surrounded by endothelial cells with tight junctions and functional lymphatic drainage, which reduced the toxicity to the normal tissues. The phenomena of eventual accumulation of nanomedicines to the tumor are referred to as enhanced permeability and retention (EPR) effect [8–11]. Even though nanocarriers can be passively targeted to tumor via EPR effect, still, there is potential to improve the tumor targetability of the nanocarriers by adopting various active targeting strategies. This review discusses the challenges associated with EPR effect and various active targeting strategies adopted to improve tumor targeting of the nanocarriers. Cancer targeted nanocarriers loaded with small molecule chemotherapeutics with proven therapeutic

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efficacy in pre-clinical and clinical studies are discussed with emphasis on the strategies adopted for their active tumor targeting.

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Limitations of conventional chemotherapy The treatment of localized and metastasized cancers with the use of chemical antineoplastic drugs, mostly administered through IV regimens, referred to as chemotherapy is the primary therapeutic approach. Although widely used in cancer treatment, chemotherapeutic drugs possess limitations as follows.  The lack of specificity toward neoplastic tissues causes significant damage to non-cancerous cells leading to severe surplus side effects such as mucositis, suppression of bone marrow activity (immuno and myelosuppression), nausea, secondary neoplasms and infertility. In addition, the high distribution volume of chemotherapeutics makes the drug delivery non-specific to tumors resulting in an abnormal concentration of the antineoplastic drugs in healthy tissues [12].  The lack of selectivity in mechanism of action is prominent drawback in conventional chemotherapy. Most chemotherapeutic drugs do not act on intracellular mechanisms unique to malignant cells but on common pathways shared by both neoplastic and normal cells. Thus, cytotoxic and cytostatic mechanisms induced by these drugs hit healthy non-cancerous tissues as well. Epirubicin (EPI), an Anthracycline derivative, used for Hepatocellular carcinoma (HCC) causes DNA damage by disrupting the cleavage-religation equilibrium and increasing the concentration of DNA topoisomerase II covalent complexes. As a result, apoptosis mediated by p53 DNA-damage sensor and activated caspases (proteases) occurs [13]. However, long-term clinical use of EPI is limited due to serious non-specific toxicity to normal tissues, particularly cardiac toxicity associated to intramyocardial production of reactive oxygen species (ROS). The rate of rapid clearance by the reticuloendothelial system (RES) reduces the extravasation of EPI into tumor site and thus weakens drug efficacy [14]. Thus, there is an unmet need to develop non-toxic and more efficacious therapeutic approach for hepatocellular carcinoma (HCC). Chemotherapeutic agents induce cytotoxicity due to high pharmacokinetic volume of distribution for low molecular weight drugs. Chemicals of low molecular weight are excreted quickly. For this reason, a higher concentration is required to achieve a therapeutic effect that leads to toxicity. The low therapeutic index of chemotherapeutic drugs implies that the needed concentration for the effective treatment is often high leading to systemic dose-dependent side effects [15].  Formulating chemotherapeutic drugs is challenging due to their poor aqueous solubility. The low solubility makes preparation of drugs difficult [16]. Due to high hydrophobicity and poor solubility in water (50.5 mg/L), the chemotherapeutic application of paclitaxel has been limited. Other chemotherapeutic agents have poor solubility due to the inclusion of lipophilic groups that show affinity toward the target receptor [17,18]. In addition, high degradation susceptibility mostly at the





reticuloendothelial system allows avoiding the use of the formulation for oral drug administration and implies administration regimens, not in compliance with the patients such as IV, transdermal and intraperitoneal. Thus, the modification could be done in routes of administration of available chemotherapeutic agents by optimizing drug delivery systems [19]. The poorly soluble drugs may cause embolization of blood vessels upon intravenous injection due to aggregation of the insoluble drugs, and often cause local toxicity as a result of high drug concentrations at the site of deposition. The currently available formulation paclitaxel comprises of Cremophor EL (polyethoxylated castor oil) and dehydrated ethanol. Though, Cremophor EL is known to be toxic and causes serious side effects, including hypersensitivity reactions, nephrotoxicity and cardiotoxicity [20]. Alternatively, surfactants may be employed in the formulation to solubilize the drug, but this may cause the drug to precipitate in vivo, because their critical micelle concentrations in physiological fluids are too low to hold micellar structures capable of maintaining the drugs in solubilized state. Currently, thermodynamically stable polymeric micelles composed of a hydrophobic core surrounded by a hydrophilic shell have been investigated and tested as an effective delivery system for poorly soluble drugs [21,22]. Chemotherapy experience limited efficacy of anticancer drugs due to strong innate or acquired chemoresistance mechanisms [23]. The interstitium of a tumor tissue is characterized by high hydrostatic pressure, leading to an outward convective interstitial flow that can remove the drug away from the tumor unlike from normal tissues. Moreover, even if the drug is successfully delivered to the tumoral interstitium, its efficacy may be limited if the cancer cells have acquired multidrug resistance (MDR) [24]. The characteristic feature of MDR is over-expression of the plasma membrane P-glycoprotein (P-gp), which is capable of keeping drugs away from the cell. Several strategies have been proposed to avoid P-gp-mediated MDR, including the encapsulation of anticancer drugs in nanoparticles and the coadministration of P-gp inhibitors [25]. Efflux of many lipophilic drugs via drug efflux transporters leading to suboptimal therapeutic drug concentration at the site of action is considered to be one of the barriers behind the success of chemotherapy [26]. Conventional chemotherapy encounters challenge during transport of the drugs to the tumor. Physicochemical properties of the drug, including size, surface composition, charge plays major role in the transport [27]. Further hurdles consist in the pathophysiological tumor heterogeneity, which inhibit a uniform drug delivery into the whole tumoral mass. In addition, acidic tumor microenvironment causes degradation of the acid-sensitive drugs [28].

Advantages of nanotechnological drug delivery systems Nanotechnology is an emerging therapeutic platform that uses nanoparticles (NPs) for the diagnosis and treatment of cancer

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DOI: 10.3109/1061186X.2015.1051049

[29,30]. NPs are utilized in cancer therapy due to their unique size, i.e. in general 1–1000 nm, or preferably in the range of 5–200 nm suitable for drug delivery applications. The nanoranged size, large surface-to-volume ratios and the ability for surface functionalization play a crucial role in its biodistribution in vivo. The most common examples of nanocarriers for the delivery of chemotherapeutics include liposomes, polymeric nanoparticles, dendrimers, nano-shells, inorganic, nucleic acid based and magnetic nanoparticles (Figure 1) [31]. Nanoparticular drug delivery systems offer distinct advantages for cancer therapy over free drug administration since NPs:  improve the therapeutic index of the loaded chemotherapeutic agents compared to the drugs delivered via conventional dosage forms.  increase drug efficacy by achieving steady state therapeutic levels of drugs over an extended period.  lower drug toxicity due to controlled drug release and improve drug’s pharmacokinetics by increasing drug’s solubility and stability. Improvement in drug’s pharmacokinetic parameters by the development of nanotechnology based formulations allows resuming investigation of potentially productive new chemical entities that have been hindered during the pre-clinical or clinical development due to their suboptimal pharmacokinetic or biochemical properties. In addition, targeted delivery of the chemotherapeutic agent can be achieved by developing multifunctional nanocarrier systems [32,33]. The engineered nanocarriers offer various other advantages compared to free drug administration, such as (i) nanometer size range suitable for tumor targeting via EPR effect, (ii) protective insulation of drug molecules to enhance their stability and minimize their systemic clearance, (iii) ability for surface functionalization, (iv) possibility of multiple drug delivery to achieve synergistic therapeutic response, (v) opportunity for the application of combination therapy by utilizing chemotherapeutic and photothermal effects, or creating magnetic nanostructures

Figure 1. Commonly utilized nanomaterials for biomedical applications. (A) Liposomes, (B) Polymer Conjugate, (C) Micelles, (D) Dendrimers, (E) Carbon nanoparticles and (F) Inorganic (metal) nanoparticles.

Nanocarriers for cancer-targeted drug delivery

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making delivery of NPs easier with the application of an external magnetic field [34]. The parameters such as size, conformation, non-covalent interactions and surface adsorption would have remarkable effects and variations on the interaction between the nanocarrier and the biological environment [35,36]. For example, size of the NPs is critical for their renal and liver excretion: kidney filters particles smaller than 10 nm (about 70 kDa) and the liver can capture particles of diameter larger than 50 nm. For this reason, the size of an ideal nanocarrier must be in the range of 10–50 nm [37]. In addition, surface characteristics of NPs influence their uptake and clearance in vivo. NP clearance occurs mainly via opsonization and phagocytosis by macrophages following the mechanism of receptor-mediated endocytosis [26,38]. To delay degradation, surface of the NPs has been decorated using a biocompatible and non-immunogenic hydrophilic polymer, poly(ethylene glycol) (PEG) that reduces nanoparticle binding to opsonins, avoiding reticuloendothelial degradation [39]. Furthermore, nanoparticles incorporating anticancer agents can minimize chemoresistance to drug action, increasing the selectivity of drugs toward cancer cells and reducing their toxicity toward normal cells [26]. In addition, the selectivity of nanocarriers toward cancer cells increases by functionalizing their surface with specific antibodies or Ab-fragments, which recognize specific epitopes of tumor-associated antigens (TAA) and tumor-specific antigens (TSA) [40]. After eventual accumulation to the tumor tissues, nanocarriers are retained into the tumor interstitium due to their compromised lymphatic clearance at the tumor site [41]. Drug release into the tumoral interstitium can be controlled by modulating the nanoparticulate structure, e.g. polymer used and the thickness of polymer wall coating the nanoparticle.

EPR effect and its limitations The EPR effect mediated delivery of nanocarriers has been considered to be the greatest breakthrough leading to

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the targeted anticancer therapy [11]. EPR effect was first reported by Matsumura and Maeda and illustrated in following articles by Maeda et al. [42–45] The group showed that most of the solid tumors have blood vessels with defective architecture and exhibit enhanced vascular permeability to ensure sufficient supply of nutrients and oxygen to tumor tissues for rapid proliferation. EPR effect enables extravasation of macromolecules larger than 40 kDa from the tumor vessel into the interstitial space resulting in accumulation of macromolecules. However, tight junctions in the normal endothelial cells do not allow such extravasation. Therefore, EPR effect offers tumor targeted drug delivery, which is considered to be a promising paradigm for anticancer drug development. One such passive targeted doxorubicin loaded liposomal formulation, DoxilÕ is in the clinic for the treatment of Kaposi sarcoma and many more nanomedicines relying only on EPR effect for their tumor targeting are in clinical trials and in pre-clinical studies [11,45–47]. Even though EPR effect-based anticancer drug delivery has shown some effect in nanocarrier mediated targeted delivery of chemotherapeutic agents, however, this strategy faces several challenges in delivering drugs to the tumor. First, interstitial fluid pressure poses a significant barrier that prevents the penetration of nanocarriers inside the tissues. Fluid pressure develops with the growth of tumor as the plasma fluids and proteins leak out from the capillaries. High protein content in the interstitial space causes colloidal pressure to develop that prevents the entry of any macromolecules from the blood flow. Second, rapidly growing tumor cells compresses the lymphatic vessels causing reduction of interstitial fluid drainage with a net gain of fluid pressure. Third, factor arises from the heterogeneity of the tumor tissues. Central part of the tumor comprised of tumor stem cells show less accumulation of nanocarriers compared to other parts of the tumor. Entry of drug to this necrotic, central part of the tumor is poor via EPR effect as the central part is hypo-vascularized with the consequence of less vascular leakage.

Targeted delivery of nanocarriers to tumors The systemically delivered nanoparticles would reach the desired tumor tissues overcoming the barriers with minimal loss of volume or activity. After reaching the tumor tissue, drugs should translocate into the cancer cells and produce cytotoxicity [48–50]. Delivery of NPs to the tumor tissue via systemic circulation has been performed by two targeting strategies, including passive and active targeting. As stated earlier, in passive targeting, NPs take advantage of the leaky tumor vasculature resulting in enhanced permeability and retention (EPR) responses that facilitate greater accumulation of nanoparticles compared to individual soluble molecules or drugs in the perivascular tumor microenvironment [11]. A cartoon representation of passive and active targeting of nano-sized drug delivery vehicles has been shown in Figure 2. The EPR effect varies depending on the size and surface properties of the nanocarriers, and hence, nanoparticles must be designed to achieve maximum targeting and therapeutic efficacy. Nanocarriers in the size range of 20–200 nm can

J Drug Target, Early Online: 1–13

easily extravasate through the walls of poorly formed microvessels in the angiogenic tumor. The other targeting strategy, active targeting has additional advantages for directing NPs to tumor compared to passive targeting. Based on molecular recognition processes, the attachment of a homing moiety, such as a ligand or a monoclonal antibody, to deliver a drug to pathological sites or to cross biological barriers can be achieved through active targeting [24,51,52]. Targeted drug delivery involves ligand-mediated, or antibody (Ab)-mediated targeting of the nanocarriers to the cancer cells [47]. Ligand mediated targeting of nanocarriers improves the therapeutic index of the drug by increasing the drug’s efficacy and reduces the non-specific toxicity [53,54]. A wide range of targeting ligands as nanocarriersurface modifier, including proteins (antibody or antibody fragments), peptides (arginine–glycine–aspartic acid or RGD), vitamin (folic acid), nucleic acid (aptamer) and glycoprotein (transferrin) are currently being exploited extensively for the development of cancer targeted nanocarriers [55–59]. The epidermal growth-factor receptor (EGFR) overexpressed in a variety of solid tumors plays a significant role in the progression of several human malignancies. Activation of this receptor stimulates critical tumor promoting processes including cell proliferation, angiogenesis, invasion and metastasis. Human epidermal receptor-2 (HER-2) is over-expressed in a majority of patients with breast cancer [60–62]. AntiEGFR or anti-HER-2 monoclonal antibody-grafted nano preparations, mainly as immuno-liposomes have been studied extensively as anticancer therapeutic [63–65]. The transferrin receptor (TfR) plays an active role in transporting iron intracellularly through its interaction with transferrin. TfR is an attractive molecular target for cancer therapy since it is upregulated on the surface of many cancer types and efficiently internalized by receptor-mediated endocytosis. This receptor can be approached in two ways to obtain cytotoxic response: (i) for the delivery of therapeutic molecules into cancer cells or (ii) to block the natural function of the receptor leading directly to cancer cell death. In a recent study, a dual-targeted solid lipid nanoparticle (SLN) gene delivery system was developed as an anti-cancer therapy which was modified with an amphiphilic polymer transferrinPEG-PE and a synthetic glucocorticoid dexamethasone for enhancing cellular and nuclear uptake of the genetic materials [66]. Pro-apoptotic ceramide loaded liposome were targeted to cancer cells by anchoring transferrin to the liposomal surface [67]. The overexpression of folate receptors occurs in many human malignancies particularly in ovarian cancer. Various approaches have been carried out to target nanopreparations actively to tumor by conjugating folic acid (FA) to the NPsurface [68–71]. In a related study, folate-polymer coated liposome’s were developed for targeted chemotherapy using doxorubicin [72]. Targeting vascular endothelial growth factor receptor (VEGFR) inhibits neovascularization, resulting in tumor cell death due to lack of oxygen and nutrients. For targeting nanocarriers to the tumor, the human recombinant VEGF isoform VEGF121 was conjugated to a carrier surface [73].

Nanocarriers for cancer-targeted drug delivery

DOI: 10.3109/1061186X.2015.1051049

Figure 2. Schematic of (A) passive (via the EPR effect) and (B) active (receptor-mediated) targeting utilized for targeting nanopreparations to tumors.

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(A) Leaky capillary vasculature

Blood flow

Endothelial cell

Tumor cell

Nanocarrier

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(B)

Normal cells

Targeted Nanocarrier

Anti-VEGFR-2 mAb-labeled NPs were more efficient in delaying tumor growth than Anti-VEGFR-2 mAb alone [74]. avb3-Integrin is over-expressed in neovascular tumor endothelial cells and mediates their migration in the tumor microenvironment. Targeting avb3 integrin is usually done by anchoring the RGD sequence in peptides and mimetic nonpeptides [75]. An RGD-anchored cationic NP was reported to deliver genes selectively to angiogenic blood vessels that resulted in apoptosis leading to regression of primary and metastatic tumors [76]. Vascular cell adhesion molecules (VCAM) are overexpressed on the surface of the endothelial cells during inflammation. This signaling molecule is absent in the normal human vasculature, but readily inducible by inflammation and angiogenesis [77]. An anti-VCAM-1 monoclonal antibody (M/ K-271) is anchored to the nanocarrier to achieve active targeting of the nanopreparations to cancer cells [78]. This VCAM-1 targeted nanopreparation actively targeted angiogenic tumor blood vessels. For this reason, VCAM-1 targeted nanocarriers can be further developed for the purpose of modifying the endothelial functions in tumor. Lipid-based nanoparticles (liposomes) Liposomes are self-assembled, uni-lamellar or multi-lamellar spherical vesicles primarily composed of phospholipids from either plant or animal origins [79]. The size of liposomes ranges from 20 nm to more than 1 mm [80]. Each microscopic vesicle has a hydrophilic core and a hydrophobic phospholipid bilayer, which enable entrapment of both the hydrophilic and the hydrophobic drugs [81]. Liposomes encapsulate hydrophilic drugs within the aqueous core and hydrophobic

Tumor cells

Receptor

Ligand

Encapsulated drug

drugs in the lipid bilayer, which protect the drugs from the environmental degradation during systemic circulation [82]. Even though nanocarriers improve the pharmacokinetics and bioavailability of the loaded drugs and decrease nonspecific toxicity via passive targeting compared to conventional formulations for poorly soluble chemotherapeutics, however, nanocarriers face challenges in demonstrating optimum therapeutic efficacy due to their decreased retention in tumors due to high interstitial fluid pressure, slow accumulation and low rate of release of encapsulated drugs, which leads to the development of drug resistance [83]. Liposomal formulations of several chemotherapeutic agents, currently in pre-clinical and clinical trials with promising results have been listed in Tables 1 and 2, respectively. One of the approaches to eliminate Cremophor EL and ethanol was by the inclusion of paclitaxel in liposomal formulations, which improved the drug’s antitumor efficacy. Zhang et al. developed a lyophilized liposome-based paclitaxel (LEP-ETU) with a mean particle size of 150 nm which increases the solubility (0.25 mg/ml) without drug precipitation or change in particle size. In vitro drug release study of LEP-ETU in phosphate-buffered saline (pH 7.4) showed that less than 6% of the entrapped paclitaxel was released after 120 h confirming the stability of the drug in entrapped form at physiologic temperature. Stability data indicated that the lyophilized LEP-ETU was physically and chemically stable for at least 12 months at 2–8  C as well as 25  C [84]. Polymer/lipid-based nanoparticles and micelles The strategy of utilizing polymer-based nanoparticles have been recognised as a promising prospect for diagnosis and

Celator Pharmaceuticals (USA) Celator Pharmaceuticals (USA) Galen (United Kingdom) DepoTech Corporation (USA) Yakult Honsha Co., Ltd (Japan) Inex Pharm (Canada) Janseen Pharmaceutical K.K. (Japan) University of New Mexico (USA) Insys Therapeutics Inc. (USA) Alliance for Clinical Trials in Oncology (USA) Regulon (Greece) Regulon (Greece) Taiwan Liposome Company (China)

CPX-1

CPX-351

DaunoXomeÕ (Non-PEGylated liposomes) DepoCytÔ IHL-305 INX-0125 JNS002

L9NC

LEM LE-SN38

S-CKD602

Pharma Engine (China) Memorial Sloan-Kettering Cancer Center and National Cancer Institute (NCI) (USA) University of Pittsburgh (USA)

University of California, San Francisco (USA) Inex Pharmaceuticals Corporation (Canada) OSI Pharmaceuticals (USA) OSI Pharmaceuticals (USA)

Ovarian cancer Gastric or Gastroesophageal (GEJ) Cancer

Lurtotecan (S-2-[-5-[[[1,2-dihydro-3-methyl-1-oxobenzo[f]-quinazolin-9-yl] methyl] amino]-1-oxo-2-isoinso-linyl] glutaric acid) [Thymidylate synthase Inhibitor] Irinotecan Irinotecan Paclitaxel CKD-602 [semi-synthetic analogue of camptothecin]

Non-Hodgkin’s lymphoma

Vincristine

Advanced Malignancies

Metastatic Pancreatic Cancer Locally Advanced or Metastatic Cancer of the Esophagus

Recurrent High-Grade Glioma Ovarian

Colon cancer, gastric tumor Colorectal cancer Kaposi’s sarcoma, breast and ovarian cancer Sarcoma, neuroblastoma, Wilms tumor, leukemia, lymphoma, brain tumors Metastatic breast cancer

Lymphomatous meningitis Treat Advanced Solid Tumors Advanced breast cancer Epithelial ovarian carcinoma, primary carcinoma of fallopian tube, peritoneal carcinoma Metastatic or Recurrent Cancer of the Endometrium or the Lung Advanced Cancer Advanced colorectal cancer

Advanced Kaposi’s sarcoma

Advanced Hematologic cancer

Completed

II II

II II

Approved

I

III

I/II

Completed Completed Approved

I II

Completed

Approved I I I

Approved

Completed

Completed

Completed

Advanced solid malignancies, B-cell lymphoma Advanced colorectal cancer

Phase

Disease

CPT-11

Doxorubicin

Vincristine

Cisplatin Oxaliplatin Doxorubicin

Mitoxantrone SN-38 active metabolite of irinotecan

9-nitro-20 (S)-Camptothecin

Cytarabine Irinotecan Vinorelbine Doxorubicin

cis-bis-Neodeca-noato-trans-R,R-1,2-diaminocyclohexane platinum(II) [Analogue of oxaliplatin] Fixed combination of Irinotecan and Floxuridine Fixed combination of Cytarabine and Daunorubicin Daunorubicin

Drug

P. Kumari et al.

PEP02 PNU-93914

MyocetÕ (Non-PEGylated liposomal DOX) NL CPT-11 (PEGylated liposomes) Onco TCSÕ (Non-PEGylated liposomes) OSI-211 OSI-7904L

MarqiboÔ

Spectrum Pharmaceuticals, Inc., National Cancer Institute (NCI) (USA) Cephalon/Sopherion therapeutics (USA)

Agenus Inc. (USA)

Aroplatin

LipoplatinÔ LipoxalÔ Lipo-Dox

Company

Products

Table 1. Examples of non-targeted liposomes undergoing clinical trial for anticancer therapy.

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Nanocarriers for cancer-targeted drug delivery

I/II

I

I

To-BBB (Netherlands) 2B3-101

US Food and Drug Administration website (http://www.accessdata.fda.gov) – US Clinical trials website (http://clinicaltrials.gov/).

Spectrum Pharmaceuticals, Inc. (USA) VLI

Doxorubicin

Topotecan Spectrum Pharmaceuticals, Inc. (USA)

Vinorelbine

Doxorubicin Celsion Corporation (USA)

TelcytaÕ

ThermoDoxÕ (PEGylated liposomes) TLI

Small Cell Lung Cancer (SCLC), Ovarian Cancer and Other Advanced Solid Tumors Advanced Solid Tumors, Non-Hodgkin’s Lymphoma or Hodgkin’s Disease Brain and breast cancer

I

II

Advanced ovarian, non-small cell lung, colon and breast cancers Hepatocellular carcinoma Canfosfamide HCl

Recurrent Ovarian Cancer Cisplatin

New York University School of Medicine and National Cancer Institute (NCI) (USA) Telik, Inc. (USA) SPI-77 (PEGylated liposomes)

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Completed

DOI: 10.3109/1061186X.2015.1051049

7

cancer treatment due to the noteworthy properties of the nanocarriers, including nano-size, excellent biocompatibility, biodegradability, prolonged circulation time in the bloodstream, enhanced drug loading capacity and easy surface functionalization using targeting ligands. Polymeric micelles are self-assembled, monolayer system formed spontaneously under suitable conditions, including the concentrations of amphiphilic surfactants, pH, temperatures and ionic strength with a hydrophobic core and a hydrophilic shell in the nanometer range. Avoidance of uptake by mononuclear phagocyte system (MPS) due to the presence of hydrophilic corona and evasion of renal excretion due to the high molecular weight provide polymeric micelles with the property of passive targeting to the cancer [85]. Attachment of ligands such as small organic molecules, DNA/RNA aptamers, peptides, carbohydrates and monoclonal antibodies to the surface of the micelles not only increases the accumulation to the tumor sites, but also increases the cellular uptake in cancer cells via receptor-mediated endocytosis [86]. The polymer-based nanomedicine could be broadly divided into three classes based on the drug incorporation mechanisms such as polymer–drug conjugates by covalent conjugation, polymeric micelles by hydrophobic interactions and polyplexes or polymersomes by encapsulation. Various examples of nanoparticles clinically approved or at different stages of development for cancer therapy are listed in Table 3. Polymer–drug conjugates covalently link poorly water soluble drugs to water-soluble natural or synthetic polymeric carriers via bio-degradable linkage, which could passively accumulate to the tumor microenvironment via EPR effect [87]. Polymer–drug conjugates had several advantages such as enhanced therapeutic efficiency, fewer side effects, flexible drug administration and increased patient compliance. They still face challenges related to design of novel polymers with modulated drug loading, release, stability at circulation and degradation characteristics, polymerization methods for controlling the weight distribution and conjugation techniques for site-specific attachment of chemotherapeutic agents. Amphiphilic block copolymers can self-assemble into different kinds of mesoscopic structures (micelles and vesicles) based on the volume ratio of hydrophilic to hydrophobic domains [88]. Unlike liposomes that are formed by amphiphilic phospholipids, polymersomes are self-assembled polymer vesicles formed by synthetic, amphiphilic block co-polymers. The hydrophilic interior structure is appropriate for encapsulating water-soluble agents such as DNAs or proteins while the hydrophobic exterior bilayer membrane can be simultaneously conjugated to poorly water-soluble drugs. Slow diffusion releases the drug through the vesicle membrane or following degradation of the vesicle [89]. Polymersomes exhibit higher loading capabilities, greater stabilities and longer circulation time compared to conventional liposomes [90]. 1,2-[bis (1,2-Benzisoselenazol-3(2H)-one)] (BBSKE) is an organic selenium compound with significant antitumor activity. However, BBSKE is poorly soluble in water (2.57 lg/mL) with considerably low oral bioavailability. Li et al. prepared a series of monomethoxy poly (ethylene glycol)-poly (lactide) (mPEG-PLA) diblock copolymers and fabricated with mPEGPLA micelle. BBSKE was efficiently encapsulated into the

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Table 2. Actively targeted liposomes currently in clinical trials. Products Õ

Õ

Doxil /Caelyx (Pegylated liposomal DOX) MBP-426 MCC-465 MM-302 SGT-53-01

Company

Target (ligand)

Drug

Disease

Phase

Johnson&Johnson (USA)

EGFR (Ab, cetuximab)

Doxorubicin

Mebiopharm Co., Ltd (Japan) National Cancer Centre, (Japan) Merimack Pharmaceuticals (USA) Synergene therapeutics (USA)

Her2 (Ab scFv)

Oxaliplatin

Ab fragment

Doxorubicin

Metastatic ovarian cancer and advanced Kaposi’s sarcoma Gastroesophageal adenocarcinoma Gastric cancer

I

Tf-Receptor (Tf)

Doxorubicin

Breast cancer

I

Tf-Receptor (Tf) (Ab scFv)

pDNA with p53 gene

Solid tumors

I

Approved I/II

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US Food and Drug Administration website (http://www.accessdata.fda.gov) – US Clinical trials website (http://clinicaltrials.gov/).

micelles by the dialysis method, and the solubility of BBSKE in water was increased up to 82 lg/mL. BBSKE-loaded polymeric micelle demonstrated enhanced antitumor efficacy and reduced toxic effect compared with BBSKE-HP-b-CD inclusion at the same dose in H22 human liver cancer cell bearing mouse models. These results suggested that mPEGPLA polymeric micelles had great potential as nanocarriers for effective solubilization of poorly soluble BBSKE [91]. Dendrimers Dendrimers, a hyperbranched polymer with defined architectures, have attracted a great deal of interest in various biomedical applications [92–94]. Unique properties of dendrimers such as uniform size and size distribution, globular design high degree of branching, defined molecular weight and functionalize surface make them an attractive vehicle for drug delivery application [93,95,96]. Core of the dendrimer is composed of monomers possessing two or more functional groups capable of attaching additional moieties to generate dendrimers with increasing generation numbers. In general, dendrimers are synthesized by following two approaches: divergent method, where the repeating layers are added around a central core, and convergent method, where individual segments of dendrimers are prepared and linked together at the final step [97]. Particular generation numbers and surface functionalization of dendrimers could be achieved using these approaches. Among many polymers possessing dendritic architectures, poly(amidoamine) (PAMAM) and poly(propyleneimine) (PPI) dendrimers are the most widely studied dendrimers for biomedical applications. However, other dendritic structures such as polyester and polypeptide scaffolds have been developed with improved biodegradability [98]. The size and surface charge density of a given dendrimer are controlled by varying the number of generations. Dendrimer complexes with DNA in a manner similar to that of other cationic polymers, with the nature of the polyplex being dependent on the stoichiometry and concentration of DNA phosphates and dendrimer amines, as well as solution properties such as pH and salt concentration. Among the different versions of dendrimers, the one most commonly used as a gene carrier is polyamidoamine (PAMAM), which has both secondary and tertiary amines. The PAMAM dendrimers are composed of an ethylenediamine or ammonia

core with four and three branching points, respectively. Dendrimer-based polyplexes have shown promising potential for gene delivery because the numerous cationic charges on their surfaces enhance the interaction with target cells, and their functional groups may be used for further modifications [94,99]. Carbon-based nanoparticles Carbon nanotubes (CNTs) can enter cells using ‘‘needle-like penetration’’ technique and deliver molecules into the cytoplasm. The application of CNTs as nanocarriers for drug delivery was marked immediately after the first demonstration of the capacity of this material to penetrate into the cells. Structurally, CNTs could be viewed as a tube rolled from layers of graphene sheets. Depending on the number of graphene layers, CNTs is classified as single-walled carbon nanotubes (SWNTs) or multi-walled carbon nanotubes (MWNTs). Besides, CNTs easily penetrate all types of cells, including hard-to-transfect types of cells [100]. CNTs are widely explored for potential biological applications because of its size, unique shape and structure, as well as its attractive physical properties. As a new type of nanomaterial, the potential toxicity of CNT has been intensively investigated in vitro and in vivo. It has been shown that appropriately functionalized CNTs, e.g. PEG functionalized CNTs do not cause noticeable toxicity [101]. Biodistribution of the lipid– polymer, phospholipid-PEG (PL-PEG) functionalized SWNT indicated that suitably functionalized CNTs are safe as it could be excreted via the biliary and renal pathways after intravenous injection [102,103]. More importantly, a high tumor accumulation of PL-PEG functionalized SWNTs could be achieved by conjugation of targeting ligands to SWNTs [104]. These results have paved the way for the application of CNTs in cancer therapy. In recent years, SWNTs have been applied in a variety of biomedical applications ranging from cancer drug delivery, tumor imaging and diagnosis [105]. Adsorption of doxorubicin on SWNTs has been reported in a study, where high loading of drug has been observed (400% by weight). When the drugs are loaded directly to CNT, the CNT-coating polymers are freed for conjugation with other functionalities, e.g. targeting molecules, antibodies, fluorescence molecule or other drugs for multifunctional delivery [106]. However, for drugs with bulky structures, e.g.

Cerulean pharma Inc. (England) Samyang Corporation (South Korea)

CRLX101 GenexolÕ -PM NK105 BIND-014 Lupron Depot Oncaspar NK911 SP1049C XyotaxÕ Mylotarg Zevalin Kadcyla

Polymeric Nanoparticles (Cyclodextrin)

Polymeric micelles (PEG-poly-D,L-lactide)

Polymeric micelles (PEG-poly aspartate) Polymeric micelles (PEG-PLGA) Polymeric microparticles Polymeric conjugates Polymeric micelles (PEG-poly aspartate) Polymeric micelles (Glycoproteins) Polymer–drug conjugate (PGA-Taxol) Polymer–drug conjugate (Monoclonal antibody) Polymer–drug conjugate (Monoclonal antibody) Polymer–drug conjugate (Monoclonal antibody)

US Food and Drug Administration website (http://www.accessdata.fda.gov) – US Clinical trials website (http://clinicaltrials.gov/).

Nippon Co. Ltd (Japan) BIND Therapeutics Cambridge, (England) Abbvie pharmaceuticals, North Chicago (USA) Merck & Co. (USA) Nippon Kayaku Co., Ltd., Tokyo (Japan) Supratek Pharma Inc. (Canada) Cell Therapeutics, Inc. (UK) Wyeth (USA) M.D. Anderson Cancer Center (USA) Hoffmann-La Roche (Switzerland)

Cell therapeutics Inc. (USA)

OPAXIOÔ

Polymeric conjugates (Poly-L-glutamic acid)

Company

Product

Formulation

Table 3. Polymer based nanoformulations on the market and under clinical evaluation.

Paclitaxel Docetaxel Leuprolid Asparaginase Doxorubicin Doxorubicin Paclitaxel Ozogamacin Yttrium-90 Emtansine

Paclitaxel

Camptothecin

Paclitaxel

Drug

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Non-small cell lung cancer in woman Advanced ovarian or primary peritoneal or fallopian tube cancer Head and neck cancer Glioblastoma multiform Solid tumor Non-small cell lung cancer Renal cell carcinoma Breast cancer Ovarian cancer Head and neck cancer Breast cancer Various cancers Prostate and breast cancer Leukaemia Various cancers Various cancers Lung cancer, ovarian cancer Leukaemia Non-Hodgkin’s lymphoma Breast cancer

Disease

I/II II I III I/II II III I Approved Approved I II III Approved Approved Approved

III III I/II II

Phase

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Nanocarriers for cancer-targeted drug delivery 9

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Table 4. Examples of metal-based nanoparticles approved and under clinical trials.

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Products

Company

Drug

Aurimmune

Cyt-immune Sciences (Maryland)

Auroshell Combidex Feridex GastroMARK

Nanospectra Biosciences (USA) Advanced magnetics (USA) Advanced Magnetics (USA) Advanced Magnetics (USA)

Colloidal gold nanoparticles coupled to TNF-a and PEG-thiol Gold coated silicon nanoparticles Iron oxide nanoparticles Superparamagnetic iron-oxide Superparamagnetic iron-oxide

paclitaxel, the absorption of the drugs on nanotube is not satisfactory resulting in unstable system. Therefore, bulky drugs are usually conjugated to CNT-dispersing polymers at their distal ends for CNTs-surface functionalization [107]. Drug delivery via conjugation of drug on the surface limit attachment site, therefore, development of multifunctional drug delivery system with the attachment of active targeting ligands is limited due to lack of surface area for insertion of other functional groups. Metallic and magnetic nanoparticles Since the discovery of metallic nanoparticles in 1971, various metal-based nanoparticles have found their way to clinical trials. Metal nanoparticles have been used in different biomedical applications, including probes for electron microscopy to visualize cellular components, as vehicle for delivering drugs, proteins and peptides [108]. Metallic nanoparticles such as gold or silver have optical and electronic properties derived from their size and composition. Gold nanoparticles act as a chemical senor when conjugated with specific oligonucleotides to sense complementary DNA strands as detected by color change [109]. Gold nanoparticles can be readily functionalized with drugs as well as with probe molecules such as antibodies, enzymes and nucleotides [110]. Currently, magnetic nanoparticles have attracted significant interest as they possess unique magnetic properties with the ability for surface functionalization, which makes them promising as contrast agents for magnetic resonance imaging (MRI) and as carriers for drug delivery [111]. A list of metal-based NPs approved/clinical trials have been shown in Table 4.

Challenges of NPs for cancer therapy Although development of NPs have been considered as a promising strategy for cancer therapy, however, various drawbacks limit their successful application [112]. First of all, nanocarrier-mediated drug delivery to cancer cells could develop drug resistance due to the insufficient and delayed drug release from the nanocarriers. Strategies, including development of multifunctional targeted nanocarriers for tumor selectivity, endosomal disruption for quick drug release in the cytoplasm as well as delivering combination therapy using multiple drugs or drug/nucleic acids have been adopted to overcome multiple drug resistance [113,114]. Apart from inclination for the development of multiple drug resistance, changes in the physico-chemical properties of the nanocarriers in the systemic circulation such as change in particle size, aggregation behavior and premature drug release could limit their successful therapeutic application.

Disease

Phase

Solid tumors

II

Solid tumor Tumor imaging MRI contrast agent MRI contrast agent

I Approved Approved Approved

Nanocarriers made out of novel materials, including organic polymers, and inorganic materials such as gold, silver oxide, silica nanoparticles, carbon nanotubes pose problem for clinical application due to the toxicity of the nanocarrier forming materials. In addition to developing new materials or selecting appropriate materials for each specific treatment, other parameters need to be registered in order to design efficient nanocarriers for cancer targeted drug delivery. These factors include the particles size, shape, sedimentation, drug encapsulation efficacy, desired drug release profiles, distribution in the body, circulation and cost. For instance, clearance rate of small nanoparticles of particle size less than 10 nm is high. In addition, majority of nanoparticles in the systemic circulation are recognized by reticulo-endothelial system and gets accumulated in the liver and spleen leading to toxicity to other organs. On the other hand, nanocarriers with larger diameters would not get accumulated in the tumor by EPR effect depending on the leakiness of the tumor vasculature [11,45]. Thus, selecting the right materials and particle size is another important aspect in targeted NPs for cancer therapy. Despite extensive research efforts to develop novel targeted nanocarriers, only a few of them, including DaunoXomeÕ , DoxilÕ , MyocetÔ and Onco-TCSÕ are approved so far by FDA for clinical use [46]. The major drawback for the slow development of effective targeted nanocarriers could be the lack of knowledge about the distribution and location of targeted nanoparticles after oral or intravenous administrations. Most studies have not examined the targeting efficiency of nanoparticles real time in vivo, thus precise bio-distribution and subsequently therapeutic effects are not well-known. Therefore, detecting cancer (malignant) cells in the body and monitoring treatment efficacy in real time is a challenge that needs to be overcome to develop efficient targeted nanocarrier system for cancer therapy.

Conclusion Various types of nanocarriers have been investigated which has allowed researchers to overcome limitations of conventional chemotherapy by increasing the solubility of the free drug and decreasing the toxicity to the healthy tissues. Due to the progress in the development of multifunctional nanocarriers, drugs loaded in nanocarriers can specifically be targeted to the disease site via passive and active targeting. Suitably engineered nanocarriers could evade renal clearance, which allows them to circulate in the system for a longer period. The limitation of anticancer drugs has been improved by the use of nanocarriers; however, new challenges have arisen. The challenges in nanocarrier design include nanoparticle-drug

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loading efficiency, the stability of nanoparticles with attached ligands, optimal receptor–ligand interactions and the duration of expression of the targeted receptor. In addition, attention is given to the factors related to toxicity of nanoparticles and ligand immunogenicity in the engineering of clinically effective nanocarriers for the targeting of anticancer drugs.

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Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. This work was supported by research initiation grant from Birla Institute of Technology & Science, Pilani, Hyderabad. Preeti Kumari gratefully acknowledges INSPIRE, Department of Science and Technology (DST), Ministry of Science and Technology, Government of India for receiving the Junior Research Fellowship award.

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Nanocarriers for cancer-targeted drug delivery

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Nanocarriers for cancer-targeted drug delivery.

Nanoparticles as drug delivery system have received much attention in recent years, especially for cancer treatment. In addition to improving the phar...
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