Review pubs.acs.org/CR

Mechanisms of Drug Release in Nanotherapeutic Delivery Systems Pamela T. Wong and Seok Ki Choi* Michigan Nanotechnology Institute for Medicine and Biological Sciences, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States 3.1. Pore Size 3.2. Effective Volume 3.3. Cross-Links 3.4. Conformation 3.5. Microbubbles 4. Conclusions 4.1. Summary 4.1.1. Ester Hydrolysis 4.1.2. Amide Hydrolysis 4.1.3. Hydrazone Hydrolysis 4.1.4. Disulfide Exchange 4.1.5. Hypoxia Activation 4.1.6. Mannich Base 4.1.7. Self-Immolation 4.1.8. Photochemistry 4.1.9. Thermolysis 4.1.10. Azo Reduction 4.1.11. Encapsulation 4.2. Status of Nanotherapeutic Development 4.3. Challenges in Nanotherapeutic Linker Design 4.3.1. Synthetic Chemistry 4.3.2. Binding Avidity 4.3.3. Physicochemical Properties 4.3.4. Pharmacokinetics (PK) 4.3.5. Tissue Penetration Author Information Corresponding Author Notes Biographies Acknowledgments Abbreviations References

CONTENTS 1. Introduction 1.1. Nanotherapeutics 1.2. Nanocarriers 1.3. Biomarkers 1.4. Aims and Scope 2. Mechanisms of Drug Release via Linker Cleavage 2.1. Ester Hydrolysis 2.1.1. Biological Mechanism 2.1.2. Chemical Mechanism 2.1.3. Representative Mechanisms of Drug Release 2.2. Amide Hydrolysis 2.2.1. Biological Mechanism 2.2.2. Chemical Mechanism 2.2.3. Representative Mechanisms of Drug Release 2.3. Hydrazone Hydrolysis 2.3.1. Mechanism 2.3.2. Synthetic Methods 2.3.3. Release Kinetics 2.4. Disulfide Exchange 2.4.1. Chemical Mechanism. Endogenous Thiols 2.4.2. Design of Disulfide-Tethered Drug Molecules 2.5. Hypoxia Activation 2.5.1. Biological Mechanism 2.5.2. Drug Release via Bioreductive Mechanisms 2.6. Mannich Base 2.7. Self-Immolation 2.8. Photochemistry 2.9. Thermolysis 2.10. Azo Reduction 3. Mechanisms of Drug Release via Control of Carriers

© 2015 American Chemical Society

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1. INTRODUCTION Targeted drug delivery refers to an established therapeutic strategy that develops platforms and nanoscale devices for selective delivery of small drug molecules and therapeutic genes to cells of interest.1−10 Molecular strategies to develop such delivery systems vary to a large extent, but all utilize nanometersized entities or other forms of nanocarriers to deliver therapeutic payloads to their targeted cells. The concept of nanotherapeutic delivery relies on the combination of three key mechanistic elements, each thought to play an essential role for efficient delivery (Figure 1): (i) specific cellular binding, (ii) intracellular uptake of drug-carrying nanomaterials by targeted cells, and (iii) controlled release of carried drug molecules in an

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anticancer therapeutics where almost all chemotherapeutic agents suffer from one or more of such issues. For example, doxorubicin (DOX), which is highly efficacious in treating various types of tumors, suffers from the drawback of serious cardiotoxicity11 due to the lack of tumor-specific cytotoxicity. Many other anticancer drugs such as paclitaxel (PTX), 10hydroxycamptothecin, 5-fluorouracil (5-FU), and tamoxifen present with the difficulties of making aqueous formulations due to the hydrophobic nature of these agents. Nanotechnology for drug delivery provides a diverse array of delivery platforms, and is uniquely suited for improving the safety and efficacy profiles of current chemotherapeutic agents. 1.2. Nanocarriers

Nanoscale entities can take various shapes such as globular particles, tubes, and rods, and can serve as versatile nanocarrier platforms that have the potential to also provide multifunctional properties. They have been actively investigated for the development of targeted nanotherapeutics and diagnostic devices for applications in cancer, as well as in inflammatory, infectious, and autoimmune diseases.3,4,12−15 Currently, there are many classes of such nanocarriers as summarized in Table 1.2 They include organic-based nanomaterials such as dendrimer nanoparticles (NPs),16−27 polymers and polymerbased micelles,28−38 carbon nanotubes,39−43 iron oxide NPs (IONPs),26,44,45 and gold NPs (AuNPs).46 Each of these nanomaterials is unique in its chemical and physical aspects such as synthetic methods, surface functionality and modification, core−shell architecture, size, and shape. Understanding the physicochemical properties of these materials and their interactions with biological systems is highly important in developing therapeutic applications, as some of these nanomaterials are known to cause undesired effects due to their intrinsic toxicity47,48 or immunogenicity49 often due to suboptimal surface modification.50 For example, cationic nanoparticles are cytotoxic due to their ability to disrupt cellular membranes as illustrated by unmodified PEI and PAMAM dendrimers.51−53 However, the cytotoxicity of these nanomaterials is reduced or fully eliminated by modification of the surface with neutral or anionic groups.54 This surface modification is also important for developing certain inorganic classes of nanoparticles which are known to be intrinsically toxic, such as cobalt−chromium nanoparticles and multiwalled nanotubes (MWNTs) that can damage DNA strands48 or suppress immune function,47 respectively. Various aspects of nanotoxicity related to therapeutic applications have been reviewed thoroughly in recent articles.55−63 Thus, the design and engineering of nanomaterials for drug delivery purposes necessitates a variety of approaches. In the main sections to follow, we will discuss selected methods for nanomaterial conjugation with drug molecules.

Figure 1. Schematic for cell targeted delivery of therapeutic agents carried by a nanoparticle (NP). The process is comprised of three sequential steps: (i) NP binding to target cells via multivalent receptor−ligand interactions, (ii) intracellular uptake of the NP via receptor-mediated endocytosis, and (iii) intracellular drug release or action.

active form. Thus, it is important that the third step involving the release of drug should occur in a precisely controlled manner in order for the drug to display its biological activity in the targeted cell only. Despite being a critical aspect in the design of nanotherapeutic delivery systems, the various mechanisms that have been developed for drug release have not yet been systematically reviewed from a molecular point of view. This review thoroughly surveys release mechanisms as classified on the basis of linker type for various drugs conjugated to nanocarriers, and discusses how such mechanisms are designed and incorporated specifically into the delivery platform to achieve specific targeted release in diseased cells. 1.1. Nanotherapeutics

Small molecule therapeutic agents often cause unwanted adverse events and systemic toxicity. There are many factors that play into these clinical issues; however, in most cases, the suboptimal activities and unwanted side effects observed for these drugs can be attributed to their pharmacokinetics and pharmacodynamics (PK/PD). PK/PD parameters that have hampered drug effectiveness include off-target activity that leads to a narrow therapeutic index (TI) (TI = lethal dose (LD50) ÷ effective dose (ED50)), low aqueous solubility due to drug hydrophobicity, rapid clearance and extensive metabolism of the drugs in vivo, and nonspecific tissue accumulation. Nanotherapeutic delivery strategies aim to overcome such problems and show great potential, in particular, in the area of

1.3. Biomarkers

Delivery of drug molecules by a nanocarrier is generally achieved through two approaches as summarized in Figure 2: (i) nontargeted delivery (passive targeting) and (ii) targeted delivery (active targeting). Passive targeting takes advantage of the increased permeability of the endothelial blood microvasculature in tumors where interstitial gaps between neighboring endothelial cells are larger (∼200−1200 nm)68 than in normal tissue. Thus, the enhanced permeability of these blood microvessels allows for easier extravasation of drugloaded nanocarriers into tumors, leading to greater accumulation and a longer duration of drug exposure in the tumor due 3389

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Table 1. Selected Nanometer-Sized Carriers Used for Drug Conjugation in Targeted Drug Deliverya class PAMAM16,17

PEI, PPI (linear, branched)19,23,24,26 poly(triazine)22,64 poly(lysine)25 poly(glycerol)18 poly(ester)65 PLGA, PEG−PLGA28−31 HPMA32 HA33,34 dextran35−38 SWNT39−42 MWNT43 IONP26,44,45 QD66,67 AuNP46

size (d, nm)

shape

Dendrimer Nanoparticle (NP) 3.6 (G3) S 4.5 (G4) 5.4 (G5) 6.7 (G6) ≤10 S ≤10−50 S − S − S − S Polymer and Polymeric Micelle ≤200 S − S, L − S, L − S, L Carbon Nanotube (NT) 1−2b T 2−25 T Inorganic Nanoparticle (NP) 5−50 S 1−10 S 8−70 S

surface functionality

conjugation chemistry

NH2, CO2H, CO2Me

Am, Es, thiol−alkene

NH2 NH2, CO2H NH2 OH CO2R

Am Am, Es Am Es, Et Am, Es

CO2H, OH OH CO2H, OH CO2H, OH

Am, Es Es Am, Es

CO2H, OH CO2H, OH

Am Am

NH2 CO2H Au

Am Am Au−S

a Gn = nth generation; S = spherical; L = linear; T = tubular; d = diameter; Am = amide; Es = ester; Et = ether; PEI = poly(ethylene imine); PPI = poly(propylene imine); PLGA = poly[(D/L)-lactic acid-co-glycolic acid]; PEG = poly(ethylene glycol); HPMA = 2-hydroxypropyl methacrylate; HA = hyaluronic acid; SWNT = single-walled carbon nanotube; MWNT = multiwalled carbon nanotube; IONP = iron oxide (Fe3O4) nanoparticle; QD = quantum dots; AuNP = gold nanoparticle. bLength = 200−500 nm.

to limited elimination.69−71 Even without targeting ligands on the nanocarrier surface, such nanotherapeutic agents are passively recruited to the tumors by this enhanced permeation and retention (EPR) effect.69−71 On the other hand, active targeting aims to both take advantage of the EPR effect and achieve specific cancer cell targeting. The concept for this targeted approach relies on modification of the nanocarrier surface through covalent attachment of targeting ligands specific for a cell surface biomarker or receptor molecule that is overexpressed in the cancerous cells (Figure 1). As summarized in Table 2, cancer-associated biomarker molecules include the following: families of vitamin receptors such as the folic acid (FA, vitamin B9) receptors (FAR-α, FARβ),72−74 riboflavin (vitamin B2) receptor75,76 and biotin receptor; the αvβ3 integrin receptor;77−79 prostate-specific membrane antigen (PSMA) receptor;80 a group of growth factor receptors including Her2,81 epidermal growth factor receptor (EGFR)81−83 and fibroblast growth factor receptor (FGFR);84 insulin and insulin-like receptors;85 a family of selectin protein molecules;86−88 and transferrin receptor (TfR89). In conjugating the ligand to the nanocarrier, the targeting ligand is attached typically in multiple copies to the nanocarrier surface, as the mechanism for endocytic uptake of such targeted nanocarriers requires multiple simultaneous interactions to occur collectively at the interface of multiple surface receptor−ligand pairs.77,90 This multivalent binding mechanism91 confers tight adhesion of the nanocarrier to the targeted cell surface, and is considered to be highly important during receptor-mediated uptake (endocytosis) of nanocarriers by the cell. Without it, the nanocarriers are bound weakly and have too short of a residence time to get taken up through the formation of coated pits.91−94 Therefore, each nanocarrier is covalently conjugated with multiple copies of a targeting ligand

on its periphery in order to maximize these multivalent effects.12,95−97 1.4. Aims and Scope

The scope of this article is primarily focused on nanodelivery systems that carry therapeutic molecules attached through covalent linkers (“conjugated”). Other delivery systems that carry unmodified drug molecules through complexation or encapsulation (such as within polymeric liposomes) are already extensively reviewed9,137−142 and are discussed only to a limited extent at the end of this review. Here, we focus on the rational design of the linker as it plays a primary role in not only covalent attachment for carrying the drug molecule but also in providing a mechanism for controlled drug release. The therapeutic agents to be discussed are summarized and categorized according to their therapeutic areas, ranging from anticancer to antimicrobial (viral, bacterial and fungal) to immunomodulatory agents (Table 3). However, greater focus will be placed on anticancer therapeutics because more applications have been investigated in this particular area. The conditions that control drug release by triggering linker cleavage involve pathophysiological features and subcellular properties specific to diseased cells. Select triggering mechanisms to be discussed include tumor hypoxia (low oxygen levels due to increased metabolic rates in tumor cells), low intracellular pH (endosomes and lysosomes where targeted nanomaterials are taken up),143 lowered extracellular pH for tumor cells,144 tumor-specific enzymes (matrix metalloproteinase, prostate-specific membrane antigen) overexpressed on the cell membrane,144 and upregulation of glutathione.145 Such mechanisms of drug release will be discussed according to the structure and function of the linker type. Linker type chemistries to be discussed include ester, amide/peptide, disulfide, hydrazone, hypoxia-activated, and self-immolative 3390

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linkages (Table 4). Finally, an emerging strategy that uses photochemistry or thermolysis for triggering drug release in an actively controlled manner will be discussed for its mechanism and applications. In summary, we aim to provide comprehensive coverage of the various aspects important to linker design and of the specific molecular mechanisms that are employed to achieve controlled release of therapeutic agents only under specific conditions. We believe this review article will serve as an invaluable source of information for understanding and developing innovative controlled drug release systems.

2. MECHANISMS OF DRUG RELEASE VIA LINKER CLEAVAGE 2.1. Ester Hydrolysis

2.1.1. Biological Mechanism. The use of carboxylic ester based linkers in targeted release applications is primarily influenced by their convenience and by the wide applicability of ester linker chemistry to many therapeutic molecules. As summarized in Table 3, having a functional group such as a carboxylic acid or alcohol allows the use of a conjugation strategy using ester-based drug attachment to the nanocarrier. The resulting ester bond subsequently opens a route for drug release due to its general susceptibility to hydrolysis when exposed to physiological conditions in vivo. The ester linker is readily cleaved by the hydrolytic reactions catalyzed by acids,182,183 bases,183,184 metal ions,183,185 and hydrolytic proteins such as human serum albumin186 and esterases.187,188 Despite its contribution to drug release, such physiological instability by itself is not effective and specific enough to trigger drug release in a controlled manner. In particular, metal ion catalyzed hydrolysis of ester bonds has been reported with certain metal ions such as Cu2+,183,185 but significant rate acceleration has only been observed in model substrates that are designed such that metal ions are chelated proximal to the carboxylate functional group.185,189,190 Additional mechanisms

Figure 2. Schematic illustration for tumor-directed delivery of drugcarrying nanoparticles (NP) via two mechanisms: (i) an enhanced permeation and retention (EPR) effect in tumors (passive targeting); (ii) the receptor-specific binding and uptake by a tumor cell (active targeting).

Table 2. List of Surface Biomarkers (Cell Surface Receptors, Antigens) Overexpressed in Cancers and Inflammatory Diseasesa biomarker receptor

cellular function

MTX (KD = ∼20−100 nM),33,99−101 quinazoline102 MTX quinacrine (KD = 264 nM)76

B, O Mc B, P

− peptide (GE11111) peptide113

O B, HN B

FGF (KD = 0.3 nM)115 Arg-Gly-Asp120 (KD = 0.2 μM)121

− cilengitide,116 c(RGDyK),119 RGD4C, ATN-161117

B, L, M B, M

peptide metabolism

N-Ac-Asp-Glu

P

glucose metabolism iron uptake

insulin (KD = 1.2 nM)131 transferrin (KD = 35 nM)134

urea-based (Lys-CO-Glu),80 aptamers,31 phosphoramidate124 benzoquinones (EC50 = 300 nM)126,127 −

B, P, O B, Br

cell adhesion cell adhesion blood coagulation

sLex, sLea epitope lectins factor VIIA

carbohydrate, glycopeptide mimics − −

P I, L HN

FA uptake FA uptake riboflavin uptake105

biotin receptor106−108 EGFR (Her1)82,109 Her281,112

biotin uptake cell growth cell growth, differentiation tissue homeostasis cell adhesion

insulin receptor126−130 transferrin receptor89,123,132,133 selectins (E, L, P)69−71,120 Ley135 tissue factor136

related tissues

synthetic ligand

FA (vitamin B9; KD ≈ 0.4 nM)99 FA riboflavin (vitamin B2; KD = 5 nM)76 biotin (Km = 4−22 μM)106 EGF (KD = 1−10 nM),110 TGF-α unknown

FAR-α12,72,90,97,98 FAR-β103,104 riboflavin receptor58,59,88−90

FGFR84,114 integrin receptor (αvβ3)78,116−119 PSMA (GCPII)31,80,122−125

endogenous ligand

a

FA = folic acid; FAR = folic acid receptor; MTX = methotrexate; EGF(R): epidermal growth factor (receptor); EGF = epidermal growth factor; FGF(R) = fibroblast growth factor (receptor); PSMA = prostate specific membrane antigen; B = breast; Br = brain; HN = head and neck; I = intestine; L = lung; M = melanoma; Mc = macrophage activated; O = ovary; P = prostate. 3391

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Table 3. List of Therapeutic Agents and Conjugation Chemistry Developed for Drug Release Mechanismsa drug name auristatin E (MMAE) bleomycin camptothecin calicheamicin cisplatin colchicine doxorubicin methotrexate mitomycin C maytansine paclitaxel α-TOS thapsigargin tamoxifen vancomycin erythromycin amphotericin B saquinavir ribavirin adenosine arabinoside amprenavir SDC-1721 cyclosporine FK506

mode of action

linkage functionality

Anticancer Therapeutics inhibition of tubulin polymerization NH-Me (Val), OH DNA fragmentation NH2 DNA topoisomerase I C20-OH DNA strand cleavage trisulfide DNA base cross-linking CO2H, NH2 inhibition of tubulin polymerization HNC(O)R DNA intercalation CO (C13), NH2 (daunosamine) DHFR, thymidylate synthase CO2H (Glu) DNA cross-linking carbamate, NH (aziridine) inhibition of tubulin polymerization N-Me (Ala) microtubule stabilization C2′-OH, C7-OH, C10 apoptosis succinate inhibition of Ca2+-ATPase C8-OH estrogen receptor NMe2 Antimicrobial Therapeutics inhibition of bacterial cell wall biosynthesis CO2H, NH2 inhibition of bacterial rRNA complex OH pore formation (fungal) CO2H, NH2 protease inhibitor (HIV) C26-OH inhibition of RNA metabolism (HCV) C5′-OH inhibition of viral DNA synthesis C5′-OH protease inhibitor (HIV) NH2 (Ph) fusion inhibitor (HIV) SH Immunomodulatory Therapeutics inhibitory regulation of calcineurin OH inhibitory regulation of calcineurin OH (C32)

conjugation chemistry Am,87 Hz146 Am,147 R174 Am,148 E149 Am,135 Hz150 Es,40,151 Hz152 Am153 Am,154,155 Hz,156 Mb,116 Cb157 Am,43,158,159 Es11,79,157−161 SS162 SS163,164 Am,165 Es,166 SS167 Es, Am168,169 Es32 Au−S170 Am171−174 Es175 Am42 Es176 P177 P178 Am179 S-Au180 Es181 Es38

α-TOS = α-tocopheryl succinate; Am = amide; Cb = carbamate; SS = disulfide; Es = ester; Hz = hydrazone; Mb = Mannich base; P = phosphoramidate; R = reductive amination. a

Table 4. Summary of Release Mechanisms by Linker Conjugation Chemistry linker ester amide hydrazone indolequinone Mannich base self-immolative (aminobenzyl) o-nitrobenzyl, coumarinyl diazo

release mechanism

therapeutic agents

enzymatic (hydrolases, alkaline phosphatase, carboxylesterase); chemical hydrolysis (low or high pH, metal cations) enzymatic (peptidases, matrix metalloproteinase, collagenase, prostate specific membrane antigen, plasmin) hydrolysis (pH 5.5−6.5) hypoxia (low O2) hydrolysis (acid) enzymatic, bioreduction, hydrolysis, thiol exchange

taxol, methotrexate, cisplatin, SN38, FK506, cyclosporine A, erythromycin methotrexate, doxorubicin, SN38, auristatin, α-TOS

light (UV, vis)

doxorubicin, methotrexate, 5-FU, taxol, tamoxifen, chlorambucil doxorubicin, aminosalicylic acid, 9aminocamptothecin

thermolysis, enzymatic reduction

doxorubicin, taxol naloxone, cisplatin, mustard agent doxorubicin doxorubicin, taxol, calicheamicin, naloxone

environment created by endosomes (pH 5.0−6.0)194 and lysosomes (pH 4.8)192,193 such that drug release occurs more rapidly and selectively after uptake than in other neutral environments such as the plasma and cytoplasm (pH 7.4) (Table 5). Thus, the primary mechanism of drug release from ester-based drug linkers on nanomaterials is attributable to specific uptake by a target cell and intracellular linker hydrolysis by the action of acid hydrolases occupying the acidic compartments. In addition to the intracellular activity of hydrolytic enzymes involved in controlled drug release, there are other diseaseassociated hydrolytic enzymes which are overexpressed in the extracellular membrane or plasma (soluble). Because of the upregulation in their expression due to certain abnormalities in diseased cells under pathological conditions, the activity of

that make a greater contribution to the controlled release relate to cellular events that occur during the uptake and processing of the drug-carrying nanomaterials by a target cell. As illustrated in Figure 1, the path proposed for nanomaterial uptake occurs primarily via receptor-mediated endocytosis in which nanomaterials are taken up into the cytosol through coated pits and end up in the compartment of an early endosome that is then sorted to late endosomes before being fused with lysosomes.191 The interiors of such cellular vesicular compartments contain numerous acid hydrolases192,193 including cholesteryl ester acid hydrolase, aryl sulfatase, acid phosphatase, N-acetylglucosaminidase, and cathepsin D.188 These hydrolases are typically involved in the ester or amide hydrolysis of a diverse set of substrates including ester-linked drug conjugates.183 Such enzymes display more optimal catalytic activity in the acidic 3392

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>8.0

peroxisome (8.2)198 plasma/extracellular membrane (7.4);197 cytoplasm (7.3);192 endoplasmic reticulum (7.1);192 mitochondrial matrix (7.9−8.0);195 nucleus (7.7)192

7.0−8.0

these enzymes can be exploited for the release of drugs from ester-linked NP−drug conjugates.187,188,199,200 Alkaline phosphatasea Zn2+/Mg2+-dependent membrane-bound metalloenzymehas been shown to be able to release a quinolinone drug molecule by catalyzing the hydrolysis of a drug−Ophosphate bond.201 Carboxylesterase 2 (CE-2) is a serinedependent esterase localized on the membrane, and it constitutes one of the biomarker proteins expressed abundantly in liver and colon tumors. This esterase catalyzes the hydrolysis of endogenous lipid esters and is involved in drug release such as in the cleavage of carbamate-based prodrug substrates including the anticancer agent irinotecan (CPT-11202). This enzyme cleaves the carbamate-based linker moiety of irinotecan, releasing SN38 as an active metabolite which serves as a potent inhibitor of topoisomerase I.202,203 Carboxylesterase 1 (CE-1), an isozyme of CE-2, also cleaves the carbamate linker and is involved in the first step of the metabolic pathway of capecitabine that leads to the release of 5-fluorouracil (5-FU). Such esterase-triggered drug release could also be achieved through the activity of other esterases including acetylcholine esterase (AChE), butyrylcholine esterase (BuChE), and paraoxonase 1 (PON1). However, each of these enzymes has not been clearly validated as a tumor-specific or other diseasespecific biomarker. Nevertheless, their utility as enzymatic tools for the control of drug release is illustrated in the hydrolytic activation of butyryl acyclovir (AChE),204 irinotecan (BuChE), and prulifloxacin (PON1205). 2.1.2. Chemical Mechanism. The ester bond used for drug conjugation is cleavable via chemical mechanisms such as hydrolytic reactions catalyzed by acids,182,183 bases,183,184 and metal ions. 183,185 Despite the general perception that compounds would be more stable under neutral conditions (pH 7.4), most esters, in fact, show greater stability in slightly acidic media (pH 5−6) because ester hydrolysis via acid or base catalysis has minimal impact at this pH range.183 Therefore, chemical hydrolysis of ester-linked drug molecules carried by nanoconjugates may play only a limited role in facilitating drug release even after uptake into acidic endosomes and lysosomes, or upon exposure to the extracellular matrix (ECM) of a tumor which is more acidic (pH 6.2−6.9) than the plasma (Table 5). However, the ester linker is more susceptible to base-catalyzed hydrolysis, which opens up the possibility for controlled release under conditions that target basic subcellular compartments such as mitochondrial matrixes (7.9−8.0)195 and peroxisomes (8.2).198 For example, the ester linkers in the ester conjugates of paclitaxel are hydrolyzed at a rate 10-fold faster with each increase in pH unit, such as observed for a change from pH 7 to 8.182 In summary, ester linkages show stability in mildly acidic conditions such that acid-catalyzed hydrolysis alone plays only a minor role in controlled drug release of these nanoconjugates. 2.1.3. Representative Mechanisms of Drug Release. 2.1.3.1. Release Mechanism of Taxol. The taxane class of anticancer agents includes paclitaxel and docetaxel (taxotere), and are classified as microtubule-stabilizing agents due to their ability to bind and stabilize cytosolic microtubules.206 Microtubule stabilization results in cell growth inhibition by interfering with the dynamic processes of cellular division and mobility which depend largely on the ability of microtubules to assemble and disassemble. Each microtubule is a hollow cylindrical polymer made up of repeating units of a heterodimer of α-tubulin and β-tubulin. The taxol molecule binds selectively to the β-tubulin unit on the luminal side207 of the tubular structure (outer diameter ≈ 25 nm; inner diameter ≈ 12

Golgi apparatus (6.6);195 extracellular matrix (tumor: 6.2−6.9)196

6.0−7.0 100-fold higher activity as compared to the free platinum(IV) prodrug agent in testicular cancer cells. Such enhanced activity is attributable to more efficient endocytic uptake and facilitated activation of the platinum(IV) prodrug carried by the SWNT carrier. 2.1.3.4. Release Mechanism of SN38. SN38 is an active metabolite of irinotecan. Despite its potent antitumor activity, it is poorly soluble in water and would thus benefit greatly from better targeted methods of delivery. Ghandehari et al.149 used carboxylic acid terminated PAMAM (G3.5) as a carrier for SN38 which was attached at the C20-OH position via an ester linker with a glycine or a β-alanine spacer (Figure 7). While

Figure 8. Structures of immunosuppressive agent (FK506, cyclosporine) conjugated macromolecules in which each drug is carried by a carboxylic acid terminated dextran or poly(lactide) and conjugated through an ester bond.

is 2 orders of magnitude more potent than cyclosporine in vitro, though FK506 is rapidly cleared in plasma following intravenous administration and is extensively metabolized by the liver cytochrome enzyme P450 3A. Hashida et al.38 developed a dextran-based delivery system for FK506 in order to control its pharmacokinetics and enhance its therapeutic efficacy. The drug molecule was conjugated through an ester linkage (Figure 8). Release studies of FK506 from its dextran conjugate indicated that the ester linker was fairly stable, and accordingly, the rate of drug release was slow in a phosphate buffer (pH 7.4) with a half-life of ∼150 h. Due to such a slow rate of release, the FK506−dextran conjugate showed an extended circulation time in blood with a clearance rate ∼1800fold lower than that of free FK506. Cyclosporine A (CsA) suffers from a lack of selectivity and a narrow therapeutic index, both of which cause major adverse events such as nephrotoxicity upon administering chronic doses. Abdi et al.181 employed a targeted drug delivery system to carry and release cyclosporine to the diseased organ in a sustained manner. They prepared a cyclosporine-tethered poly(lactide) (Figure 8), and coprecipitated it with PEG-linked poly(lactide) to prepare polymeric nanoparticles (∼100 nm).

Figure 7. Structure of an SN38 anticancer molecule carried by a carboxylic acid terminated PAMAM dendrimer (G3.5) where the drug is conjugated through a glycine or β-alanine ester at the C20 position.

these two spacers differ only by a methylene group, such differences in linkers could impact the rate of drug release and the activity of the conjugates. Both conjugates were stable in PBS with less than 5% of the drug being released after 24 h. When incubated in a rat plasma (50%) medium, release of SN38 was higher from the glycine (∼12%) than the β-alanine (∼8%) spacer. This difference suggests involvement of enzymes in the drug release since esterases are present in the plasma. Both conjugates were active in inhibiting proliferation of human colorectal cancer cells. However, the conjugate made with the glycine spacer (IC50 = 129 nM) was ∼3-fold more 3397

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ester linkage used for drug conjugation was quite susceptible to hydrolysis even in PBS buffer (pH 7.4), with about 90% of the drug being released within 10 h. The authors noted that the ester bond in the 2′ position was optimal for effective drug release as compared to the other ester bond located proximal to the dendrimer periphery. Such ester instability to hydrolysis is remarkable compared to other examples reviewed earlier, but is likely attributable to the involvement of a neighboring tertiary amine group that acts as an autocatalyst for the hydrolysis of the ester link.

They showed that this delivery system released CsA via cleavage of its ester linker in a sustained manner, and resulted in suppression of T-cell proliferation as potently as free CsA. It is notable that the CsA-linked poly(lactide) nanoparticles were internalized in dendritic cells and that these nanoparticleloaded cells migrated to lymph nodes where CsA was released in a sustained manner. 2.1.3.6. Release Mechanism of Erythromycin. As a member of the macrolide class of antibacterial molecules, erythromycin potently inhibits bacterial growth by blocking a rRNA complex involved in protein biosynthesis. It also has additional activities related to host cells including an anti-inflammatory effect and gastrointestinal pro-motility effect. Kannan et al.175 explored a dendrimer-based conjugate system for achieving sustained release of erythromycin. In the design, erythromycin was attached to a hydroxyl-terminated G4 PAMAM dendrimer through an ester bond by performing a regioselective reaction at its 2′-OH position with the glutarate spacer (Figure 9). The

2.2. Amide Hydrolysis

2.2.1. Biological Mechanism. Drug conjugation to the nanocarrier through an amide link is widely applicable for many therapeutic molecules because each drug molecule is commonly functionalized with a carboxylic acid or amine group. The resulting amide bond is much more stable and less susceptible to chemical hydrolysis than the corresponding ester bond. Unless designed with a special functional group, the amide linker is rarely cleaved by chemical hydrolysis under physiological conditions, and its chemical cleavage requires harsh conditions such as much higher temperatures in combination with the presence of strong acid or base catalysts.183 Such general stability can provide certain benefits for achieving improved pharmacokinetic profiles by extending the duration of circulation in the blood. However, its use for drug release requires more consideration including other nonchemical methods of amide cleavage. Generally, these methods are based on enzymatic mechanisms and are carried out by hydrolytic proteases 183 such as serine proteases,32,155,229−232 cysteine proteases,148 and zinc-dependent endopeptidases (Table 7).144,158,233 Each of these enzymes is localized in one or more sites in the cell ranging from the extracellular environment, to the cellular membrane, to intracellular lysosomes, and thus their site-specific action is directly related to the site of drug release. As an illustration, matrix metalloproteinases (MMPs) such as collagenases are zinc-dependent endopeptidases secreted primarily into the ECM environment.235 MMPs are normally involved in the remodeling of the extracellular matrixes through their degradation of ECM proteins. Several MMPs are overexpressed in a variety of tumor cells and are implicated in the dysregulation of angiogenesis leading to tumor growth and metastasis.236 Thus, use of an MMP-specific peptide as a cleavable linker serves as a strategy for controlling drug release at the tumor ECM. This is illustrated by MMP-mediated release of methotrexate linked to a poly(lysine) dendrimer through a peptide linker containing the MMP specific cleavage sequence, PVG↓LIG (Table 7).158 MTX release upon incubation with MMP 2 or MMP 9 was demonstrated in a time-dependent manner with ≤20% efficiency at 24 h.

Figure 9. Structure of a fourth generation (G4) PAMAM dendrimer conjugated with erythromycin, each drug attached through an ester at a D-desosamine sugar residue (C2′-OH) to a carboxylic acid terminated spacer to hydroxylated G4 dendrimer. Below is shown a proposed mechanism of drug release at neutral pH (7.4) that occurs via C2′ ester hydrolysis catalyzed by a neighboring tertiary amine at the C3′ position.

Table 7. List of Proteases Catalyzing Amide Hydrolysis for Anticancer Drug Releasea peptidase 144

MMP collagenase (MMP 1, 8, 13)158,233 PSA32,229,230 PSMA (GCPII)122,234 plasmin155,231,232 a

enzyme classification EC EC EC EC EC

3.4.24.x 3.4.24.7 (34) 3.4.21.77 3.4.17.21 3.4.21.7

enzyme function

localization

substrate sequence

zinc endopeptidase zinc endopeptidase serine protease zinc peptidase serine protease

extracellular; matrix, cell surface; lysosome extracellular; matrix, cell surface, lysosome extracellular matrix, serum, lysosome cell surface blood, lysosome

PQG↓LAG; PVG↓LIG LS↓N; HSSKLQ↓L; SSKYQ↓L Ac-D↓E; folate↓E (Y/F)(R/K)↓SR AFK↓

MMP = matrix metalloproteinase; ↓ = cleavage site; PSA = prostate-specific antigen; PSMA = prostate-specific membrane antigen. 3398

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DE). Incorporation of such substrates into a linker framework opens a potential approach for targeted drug release in prostate tumors. Plasmin is another example of a protease that is utilizable for the release of a drug molecule linked through a plasmin-susceptible peptide bond.155,231,232 It is also a serine protease that is localized in the plasma and in lysosomes. Therefore, this enzyme provides a method for controlled drug release both during circulation in blood and after intracellular uptake of drug conjugates in the lysosomes. 2.2.2. Chemical Mechanism. Cleavage of amide linkers by chemical hydrolysis does not constitute a general mechanism for drug release; however, certain classes of specialized linkers attached to drug molecules through an amide linker have been shown to be responsive to low pH environments. These linkers are composed of a group of maleic acid based frameworks such as citraconyl, cis-aconityl, and maleyl groups (Figure 11). Their

The MMP-cleavable peptide linker has been used for fluorescence imaging of primary tumors and metastases in vivo that overexpress MMPs through the use of ratiometric activatable cell-penetrating peptides (RACPPs).237−240 This imaging technology employs a protease-specific substrate peptide as a spacer that tethers two cell penetrating peptides, each terminated with a Cy5 and Cy7 reporter dye molecule, respectively (Figure 10).238,241,242 In noncancerous cells where

Figure 10. Concept of ratiometric activatable cell-penetrating peptide (RACPP). The protease-cleavable linker located in the middle of this RACPP is cleaved by specific proteases overexpressed in a pathologic cell, which leads to abolishment of intramolecular FRET emission (Cy5 to Cy7) and instead to emission of Cy5 alone.

MMP expression is relatively low, the cleavage of this RACPP is slow and the two tethered dye molecules undergo fluorescence resonance energy transfer (FRET) (λex,Cy5 = 620 nm; λem,Cy7 = 780 nm) due to their spatial proximity. However, in tumor cells that overexpress MMP 2 and MMP 9, the two dye molecules are separated upon cleavage of the MMP-specific peptide spacer, and FRET no longer occurs, resulting in emission at only the Cy5 wavelength (λex,Cy5 = 620 nm; λem,Cy5 = 670 nm). Application of this imaging technology has been broadly demonstrated for in vivo detection methods and for monitoring certain proteases (MMPs,237−239,243 thrombin242,244) in cancer and other therapeutic areas including asthma.243 Prostate-specific antigen (PSA) is another enzyme target that is applicable for controlled drug release. It belongs to the family of serine proteases and is expressed at high levels in prostate tumor tissue. The sequences of the peptide substrates most susceptible to PSA are comprised of serine (S)-glutamine (Q) and glutamine (Q)-leucine (L).32,229,230 Doxorubicin conjugated to a peptide spacer containing the SQ dipeptide sequence at its aminoglycoside was readily released via peptide cleavage by PSA.229,230 Prostate-specific membrane antigen (PSMA) constitutes the other enzyme biomarker highly expressed in prostate cancer cells.107,210 It is a zinc endopeptidase that acts as a glutamate carboxypeptidase (GCPII) on small molecule substrates including folate-γpolyglutamate (FA-En), methotrexate-γ-polyglutamate (MTXEn), and the neuropeptide N-acetyl-L-aspartyl-L-glutamate (Ac-

Figure 11. Structure of pH-susceptible amide linkers (top) and illustration of a proposed acid-catalyzed cleavage mechanism for a cisaconityl amide linker, leading to doxorubicin release (bottom).

utility is illustrated by amide conjugation of the cis-aconityl group to doxorubicin at its daunosamine sugar.245 When incubated in citrate−phosphate buffers at various pHs and 37 °C, this amide linker was hydrolyzed to release free doxorubicin with half-lives at pH 4, 5, and 6 of aconityl > maleyl amide).248 2.2.3. Representative Mechanisms of Drug Release. 2.2.3.1. Methotrexate. Several strategies have been reported for cancer targeted delivery of methotrexate conjugated through a peptide-based amide linker.33,35,158,159,249,262 In each of these approaches, drug conjugation is achieved through a peptidasesusceptible amide spacer, and drug release relies on a mechanism controlled by peptidases overexpressed on the cancer cell surface. Langer et al. designed a dextran-based delivery system for MTX which is conjugated through a peptide linker based on PVG↓LIG, the sequence susceptible to cleavage by matrix metalloproteinases (MMPs) (Figure 12, entry 1).35,249,250 Incubation of this conjugate with MMP 2 led to drug release with efficiencies of 67% (1 h) and 89% (24 h).250 The cleavage site of the peptide spacer (Figure 12) was determined by mass spectrometric detection of MTX-PVG after MMP treatment. Drug release efficiency was sensitive to the MMP subtype and the type of peptide spacer. Treatment with MMP 9 resulted in a lower level of release of 61% (24 h), and MTX molecules conjugated to the dextran polymer directly or through a random peptide sequence were not released. These results provide evidence supportive of MMP-controlled MTX release, and suggest that drug conjugation through a MMP-susceptible peptide spacer will be applicable for other types of anticancer agents as well. Porter et al. employed this MMP-specific peptide spacer for FAR-targeted MTX delivery using PEG−poly(lysine)-grafted 3400

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more favored for MTX molecules linked through a longer spacer.268 2.2.3.2. Doxorubicin. Delivery systems for doxorubicin attached through an amide or peptide-based linker are illustrated in Figure 14. Each of these conjugates is made

the MTX conjugate made through a peptide with the sequence NFF was active in inhibiting growth of synovial fibroblast cells. Collectively, these studies demonstrate a correlation between MTX release and the sensitivity of the peptide linker to different MMP subtypes. This linker design based on such peptide linkage can play a critical role in disease-targeted drug delivery. For example, certain subtypes of MMP 2 and MMP 9 are implicated in promoting cancer metastasis in ovarian and breast cancers, while other subtypes like MMP 1 and MMP 3 are more involved in the progression of rheumatoid arthritis.265−267 In the delivery approach discussed above, conjugated MTX serves as a cytotoxic agent upon release. However, MTX can also play a role as a cancer targeting ligand because it belongs to the antifolate class of drugs, and its high structural homology to FA confers a reasonable affinity to FAR (KD = ∼20−100 nM).99−101 Recent studies reported by Baker et al.268 and Thomas et al.98,252 explored this delivery concept based on a dual-acting MTX in which conjugation of MTX alone to a nanocarrier without FA led to both FAR targeting activity and cytotoxicity. This dual-action approach is illustrated by G5MTXn conjugates (Figure 12; entries 5, 6) in which MTX is not releasable due to its conjugation through a peptidase-insensitive linker. One of the stable linkers used for testing this strategy was cyclooctyne-based amide, which was prepared by conjugation chemistry based on the copper-free click reaction between MTX−linker−azide and cyclooctyne-presenting dendrimer (Figure 13).251 As designed, this G5-MTXn conjugate

Figure 13. Synthesis of PAMAM dendrimer conjugated with methotrexate (MTX) attached through an amide linkage at its γcarboxylic acid position. The conjugation is based on copper-free click reaction of the dendrimer presenting cycloalkyne groups with γ-azidoMTX.

Figure 14. Nanocarriers conjugated with doxorubicin (DOX), each attached through an amide linkage at its daunosamine sugar residue.

was stable in serum, was selectively taken up by FAR-positive cells, and proved to be cytotoxic.98 The other spacer, which was based on repeating units of oligo(ethylene glycol), was explored for its applicability in large scale synthesis and as a tool for determining the relationship between the linker length and subsequent cytotoxicity (Figure 12, entry 6).252 This study suggests that the cytotoxicity of the G5-MTXn conjugate is significantly affected by the linker length and that MTX attached through an elongated spacer is more potent. This structure−activity correlation is consistent with the theoretical model in which inhibition of the DHFR enzyme is sterically

through attachment of the daunosamine sugar residue to the linker to be cleaved by peptidase action or low pH. Jones et al.229 demonstrated release of doxorubicin attached to a peptide containing the LSQ sequence (Figure 14, entry 1) which is designed to be hydrolyzed at the S↓Q site by prostate-specific antigen (PSA) (↓ denotes a bond to be cleaved). Drug release yielded both free doxorubicin and doxorubicin−leucine when exposed to prostate tumor cells that secrete prostate-specific antigen. As a result, this peptide-conjugated doxorubicin was more cytotoxic to PSA-secreting cancer cells than those normal 3401

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for cancer cell specific drug release if conjugated through an active targeting system. As introduced earlier in section 2.2.2, the controlled release of an amide linked molecule can occur through a nonenzymatic reaction mechanism as illustrated by the maleimide-linked doxorubicin conjugates (Figure 14, entries 3, 4).245,258,259 Each of these amide linkers is unstable at pH 5 or 6; Table 5) but can occur faster after entering a tumor cell via endocytosis and exposure to the acidic environments of endosomes and lysosomes (pH 6.5−5.5). 2.3.2. Synthetic Methods. Hydrazone-based linkers refer to a class of linkers terminated with acyl hydrazone,131,135,238−240,242,243,278−281 alkoxy carbonyl hydrazone,152,260,270,271,282 and benzenesulfonyl hydrazone.25 Two synthetic approaches have been developed for hydrazone conjugation of a carbonyl group (ketone, aldehyde)-containing drug molecule to nanocarriers as summarized in Figure 17. First, a hydrazine-terminated linker is integrated onto the nanocarrier prior to the conjugation reaction with the drug molecule (method 1).152,156,270,274,277,279,280 This approach is illustrated by doxorubicin conjugation through its ketone.156,270,272,274,279,280 This method is preferred for certain types of drug molecules that have structures which contain nucleophilic functional groups such as amines as found in the daunosamine aminoglycoside of doxorubicin. If the nanocarrier is terminated with a nonhydrazine functional group such as a carboxylic acid instead, the amine from the drug will act competitively in the conjugation reaction with the nanocarrier, resulting in an amide linkage. However, the amide linker is chemically too stable and the high fraction of drug molecules linked through an amide linkage is subsequently not releasable even upon exposure to acidic subcellular compartments. Second, a hydrazone linker is installed first on the drug molecule by reaction with a hydrazine linker and the resulting drug linker is coupled to the carrier by a reaction chemoselective to the linker (method 2).25,282,283 This method is illustrated by paclitaxel conjugation in which a bifunctional linker comprised of an acyl hydrazine and maleimido group is used.276 The latter reacts selectively with the thiol presented on

Figure 15. Plasmin-catalyzed peptide cleavage that triggers doxorubicin release in a self-immolation process.

2.2.3.3. α-TOS. α-Tocopheryl succinate (α-TOS) is a vitamin E analogue that displays a potent apoptotic activity and has potential as an adjuvant for cancer immunotherapy.269 The structure of α-TOS consists of a chromanol substituted with a long hydrophobic tail which makes it poorly soluble in water. This physicochemical property reduces its biocompatibility and limits its application in cancer chemotherapy. In order to address this problem, Shi et al. employed FA-conjugated G5 PAMAM dendrimers as a nanoplatform for FAR-targeted delivery of α-TOS.168,169 In their approach, α-TOS was conjugated to the dendrimer through a succinyl amide bond at a density of 5−10 α-TOS molecules per dendrimer NP. The drug-conjugated dendrimers were water-soluble and further engineered to carry AuNPs partly encapsulated as a probe for imaging studies. In vitro and in vivo studies suggest that these drug-conjugated dendrimers are taken up by FAR(+) cancer cells and cause apoptosis as the result of α-TOS release. The release mechanisms are believed to occur by cleavage at one or two linkage points that include the ester bond to α-tocopherol and the amide bond to the dendrimer. Other amide linkers used for controlled drug release include peptides such as oligo(glycine)148 for camptothecin (SN38) and the valine−citruline peptide87,146 for auristatin. Each linker is cleavable by less selective proteases such as cathepsin B which is abundant in lysosomes (Table 8). However, drug conjugation through these peptide linkers can also open a route 3402

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Table 8. Amide Cleavage for Drug Releasea targeting ligand; nanocarrier

target receptor

drug delivered

linker chemistry

release mechanism

MTX; carboxymethyl dextran35,249,250 PEG−poly(Lys) G4 dendrimer158,159 MWNT43 HA33 PAMAM dendrimer (G5)98,251 PAMAM dendrimer (G5)252 PAMAM dendrimer (G5)109 albumin253 poly(L-lysine)254 antibody255,256 HPMA copolymer154 peptide scaffold229 RGD-4C155 PLGA257 pullulan258 chitosan245,259 PEG liposome260 dextran148

FAR

MTX

γ-amide; PVG↓LIG

MMP

FAR

MTX

MMP

FAR FAR FAR FAR cetuximab-EGFR lactose receptor FAR mammary tumor antigen human IgG PSA αvβ3 integrin receptor − FAR − − −

MTX MTX MTX MTX MTX MTX MTX MTX DOX DOX DOX DOX DOX DOX DOX SN38

α/γ-amide; PVG↓ LIG α/γ-amide; GFLG α-amide; N↓FF γ-amide α/γ-amide α/γ-amide α/γ-amide α/γ-amide α/γ-amide; LGLG peptide; GFLG Peptide; SGcHQSL peptide-carbamate carbamate maleamide cis-aconitamide cis-aconitamide (Gly)n

PAMAM dendrimer G5/ AuNP168,169 immunoconjugate87 immunoconjugate146

FAR

α-TOS

succinyl amide

protease MMP 1, 13 nd nd nd nd nd lysosomal proteases (cathepsins) protease PSA plasmin, protease nd pH 5 pH 100 h. There was no strong correlation between the linker types and the halflives, though half of the acyl and alkoxycarbonyl hydrazone linkers gave half-lives of less than 10 h. Furthermore, no correlation was observed between half-life and nanocarrier type, suggesting minimal effect of the carrier structure, shape, and size on drug release. Thus, drug conjugation via hydrazone linkage allows for controlled release in response to pH stimuli inside the cell. However, it is noteworthy that hydrazone hydrolysis occurs rather slowly even at pH 5, a condition more

Figure 18. Comparison of half-life values (t1/2, h) in doxorubicin release among three types of hydrazone linkers with variation in nanocarriers, each measured at pH 5. The half-life t1/2 is defined as the time required for half of the initial amount of a doxorubicin− hydrazone linker to be hydrolyzed for drug release. Each data point comes from the reference cited in the text.

3404

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Figure 19. Representative endogenous thiols that are involved in disulfide exchange reactions for drug release in the cytoplasm via disulfide cleavage.

distribution is localized primarily in the cytoplasm (2−10 mM; ≤85%), mitochondria (≤30%), and nucleus (≤10%).289 Such high cytoplasmic concentrations of GSH are due to its involvement in cellular detoxification mechanisms by forming GSH conjugates with cytotoxic xenobiotics including chemotherapeutic agents and by redox reactions with genotoxic reactive oxygen species. In addition, its cellular expression level is inducible and can be increased to levels as high as 10−14 mM. In malignant cells, GSH is often exploited as a means to reduce the cytotoxicity of anticancer therapeutics and has been implicated in the resistance of these cells toward certain drugs. However, such higher expression and reactivity of GSH in cancer cells can also serve as a mechanism for the controlled release of drugs targeted toward these cancer cells. 2.4.2. Design of Disulfide-Tethered Drug Molecules. Drug delivery via disulfide linkage has been extensively investigated for a group of cytotoxic compounds including those used currently in the clinic as summarized in Table 9. Unlike direct conjugation via amide or hydrazone linkage, the disulfide attachment of most anticancer drug molecules to a nanocarrier or cancer specific antibody is performed by indirect methods since each drug molecule lacks a free thiol or disulfide functional group in its chemical structure. Design and incorporation of such a linker in the spacer requires a rational approach in order to achieve the mechanism of controlled drug release. This is illustrated by paclitaxel-disulfide linked molecules (PTX-SS-1,292 PTX-SS-2,292 PTX-SS-3212) and taxoid-linker molecules (PTX-SS-4,210 PTX-SS-5210) in Figure 20. Here the disulfide spacer is attached to paclitaxel at its C-7, C-10, or C-13 side chain attached via a carbonate or ester

acidic than any found in subcellular compartments. In summary, the rate of drug release appears to be determined primarily by the intrinsic rates of hydrazone hydrolysis and is less influenced by the type of linker construct used and the size or shape of the nanocarriers. 2.4. Disulfide Exchange

2.4.1. Chemical Mechanism. Endogenous Thiols. Disulfide linkers constitute one of the primary linkers that have been employed for drug conjugation in targeted drug delivery. Unlike those linkers based on amide, ester, and hydrazone chemistry, the disulfide bond is not subject to hydrolytic cleavage but is cleaved through an electrochemical reduction reaction to yield the respective thiol or through disulfide exchange reactions.285−287 This cleavage reaction occurs via a chemical mechanism triggered by an endogenous thiol molecule such as cysteine, homocysteine, N-acetylcysteine, glutathione (L-γ-glutamyl-L-cysteinyl-L-glycine; GSH), other cysteine-containing peptides, and thiolglycolic acid (Figure 19).288 This disulfide linker is stable enough for targeted intracellular uptake of the drug-linked nanoparticles because the disulfide cleavage occurs primarily in the cytoplasm after their endocytosis. In addition, unless otherwise modified, drug release via cleavage of the disulfide linker is not contributed by redox machinery located on the cell surface but by the thioltriggered intracellular mechanisms.285 2.4.1.1. Cellular Distribution of GSH. Of those endogenous thiols, glutathione (GSH) plays the most significant role in cancer cell specific drug release. GSH exists predominantly in the reduced form inside the cell, and its total cellular 3405

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(PTX-SS4, PTX-SS5), each a close analogue to ortataxel (BAY59-8862). These taxoid-conjugated mAb molecules were 2−3 orders of magnitude more potent than paclitaxel and docetaxel. In vivo studies with these taxoid immunoconjugates demonstrated strong antitumor efficacy in a paclitaxel-resistant tumor model. Conjugate design via disulfide linkage has been applied to other important classes of anticancer chemotherapeutic agents including cisplatin,295 doxorubicin,295 mitomycin C,162 gemcitabine, maytansine,163,164,296 and calicheamicin294 as summarized in Figure 21. Drug release from each of these drug-linker conjugates is positively demonstrated based on its cytotoxicity in treated cancer cells in vitro or in vivo. However, beyond the cell-based evidence, its release kinetics in solution remains to be determined in a quantitative manner for rigorous evaluation of those disulfide linkers.

Table 9. Disulfide Linkers Designed for Drug Release of Anticancer Therapeutic Agents

a

nanocarrier; targeting ligand

drug linkera

targeting mechanism

FA mAb mAb triazine dendrimer FA FA mAb mAb

MMC-SS-1 DOX-SS-1, 2 PTX-SS-4, 5 PTX-SS-3 PTX-SS-1, 2 GEM-SS-1 MYT-SS-1 CM-SS-1

FAR Ley EGFR − FAR FAR cancer antigen polyepithelial mucin

drug delivered mitomycin C290 doxorubicin291 taxoid210 paclitaxel212 paclitaxel292 gemcitabine293 maytansine163,164 calicheamicin294

For structures of drug-linker code names, see Figures 19−21.

functionality. This combination of functional groups in the spacer is designed for enabling the mechanism of free drug release since a disulfide exchange reaction with GSH triggers the release of only a drug molecule terminated with a thiol moiety. However, since the ester or carbonate is reactive to the nucleophilic thiol, the transient drug intermediate subsequently undergoes a thiol-mediated intramolecular cyclization reaction, and free paclitaxel is released as a result of the formation of 2oxathiolone (PTX-SS-1) or a five-membered thiolactone (PTXSS-2). Ojima et al.210 employed this release mechanism for the design of an anti-EGFR mAb conjugated with a taxoid molecule

2.5. Hypoxia Activation

2.5.1. Biological Mechanism. Hypoxia is defined as the state of abnormally low oxygen supply in tissues and cells.297,298 Like acidosis (pH 6.5−6.9), it constitutes one of the hallmarks of solid tumors, as poor perfusion due to the growth of new immature vessels results in oxygen deprivation (Figure 22). Since tumor microenvironments are associated with low oxygen levels, the equilibrium of the enzymatic activities of oxidoreductases are shifted toward favoring the reduction of substrates. Thus, tumor cells can be selectively targeted by

Figure 20. Design of disulfide-tethered taxol constructs, and mechanisms for GSH-triggered, self-immolative release of paclitaxel or taxoid molecules. 3406

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Figure 21. Design of disulfide-tethered drug molecules for doxorubicin, mitomycin C, gemcitabine, maytansine, and calicheamicin.

several classes depending on the core functionality of the substrate including quinone-trimethyl lock systems,299,306 indolequinone,307 nitroaromatic heterocyclics (nitroimidazole,308 nitrofuran,309 nitrothiofuran310), and N-oxides (tirapazamine311,312) as summarized in Table 10. Representative examples of such hypoxia linkers include the quinone-trimethyl linker system.313 Drug release of this linker has been demonstrated by incubation with chemical agents such as NaBH4 and Na2S2O4, each able to trigger the release by a two electron reduction mechanism.314,315 However, use of potential reducing agents in vivo such as endogenous glutathione (GSH) fails to reduce the quinone to the hydroquinone precursor required to trigger the release, perhaps due to the weaker reduction potential of GSH.316

using substrates and prodrugs that are only activated by such enzymes which are activated in hypoxic conditions as the oxidoreductase (referred to as hypoxia-specific enzymes).200,299,300 Such enzymatic activation has been well documented in the discovery and development of numerous anticancer therapeutic agents such as mitomycin C,301 apaziquone (EO9),302 TH-302,303 banoxantrone (AQ4N), PR104A,304 and RH1.305 2.5.2. Drug Release via Bioreductive Mechanisms. Reductive activation of prodrugs catalyzed by oxidoreductases introduced above has also been employed in the design of certain linker-drug constructs in which the linker is cleaved in response to hypoxia, resulting in drug release in the tumor. Such linker types, dubbed as hypoxia linkers, are grouped into 3407

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heteroaromatic linkers based on imidazole, (thio)furan, or pyrrole core can also serve as hypoxia-susceptible linkers. Drug release is triggered via an electron push−pull mechanism in which the electron-withdrawing nitro group is reduced by nitroquinone oxidoreductase (NQO) to an electron-donating hydroxyl or amine. This nitro reduction mechanism is also applicable for a conjugated nitrobenzene system as demonstrated by release of paclitaxel upon reduction of the nitro group in a model reaction by chemical treatment.319 Finally, unlike the examples above, certain Pt-based anticancer drug conjugates are designed for release without the involvement of any hypoxic linkers but rather on the basis of the Pt oxidation state. This mechanism is illustrated by Pt(IV)Cl2(NH3)2, an oxidized form of cisplatin attached to a carbon nanotube carrier through its carboxylate axial ligand.28,40,226 This oxidized cisplatin is released in its active form, Pt(II), after exposure to the reductive environment of the cytoplasm. The efficiency of hypoxia-triggered drug release is dictated not only by the design and chemistry of the linker framework but also by physiological factors. For example, the hypoxic conditions found in tumors are the result of poor blood perfusion within the tumor, which also subsequently reduces the amount of exposure of the drug conjugates to the tumor cells. Second, hypoxia can also occur in normal tissue under certain conditions in which oxygen levels are low, which may lead to the reduction in drug specificity to tumor cells.298 However, such physiological factors which lower the selectivity of hypoxia-triggered drug release could be addressed by combining the use of a hypoxia-triggered linker with tumor cell specific targeted nanoparticles that enable cell-specific uptake of the nanoconjugate.

Figure 22. Hypoxia-triggered reductive activation of drug linker in tumor cells. L = linker.

Table 10. Bioreductive Mechanisms for Drug Release in Hypoxiaa redox linker indolequinone307 benzoquinone267,273,274 nitroaromatics

272,276−278,283

release mechanism POR; DT diaphorase (2e) NQO1 (2e); NQO2 (2e) POR

N-oxide311,312

POR

Pt(IV)-carboxylate40,226

reductase; thiol

drug release or activity DNA alkylation; naloxone amines

2.6. Mannich Base

The Mannich reaction refers to the aldehyde-mediated condensation between an amine molecule (primary or secondary) and a nucleophilic molecule including amines, carboxamides, phenols, and ketones (Figure 24). The product of this reaction, commonly called a Mannich base, serves as a prodrug for the parent drug molecule and is effective for improving its solubility and pharmacokinetics. This method is illustrated in the design of a tumor targeted doxorubicin conjugate in which the doxorubicin is conjugated through a formaldehyde-derived linkage to a small Arg-Gly-Asp (RGD) peptide ligand targeting an αvβ3 integrin receptor.116 Another example is doxorubicin linked to imidazolinedione, a nonsteroidal ligand which has micromolar affinity to the androgen receptor (Table 11).320 Koch et al. investigated the release mechanism for doxorubicin delivery in prostate cancer cells.320 Their study showed that this Mannich linker undergoes hydrolytic cleavage to its Schiff base (“imine”) form in the cytosol which undergoes subsequent hydrolysis to free doxorubicin. Interestingly, this androgen-receptor-targeted doxorubicin showed greater cytotoxicity than unmodified doxorubicin in both drug sensitive and drug resistant tumor cells. This remarkable activity was attributed to its additional mode of actioncovalent modification of DNA base pairs by the released doxorubicin Schiff base. As illustrated above, the Mannich base mediated release system serves as an important strategy for targeted drug delivery but has been employed less frequently than other methods (Table 11).116,320 However, this method provides a number of advantages from a synthetic point of view, such as

mustard alkylating agent oxidative DNA damage cisplatin

a

NQO = nitroquinone oxidoreductase; POR = cytochrome P450 oxidoreductase.

Instead, cleavage of this linker in vivo is mediated by cytochrome P450 oxidoreductase (POR) via a two electron (2e−) reduction mechanism, and the resulting hydroquinone intermediate undergoes an intramolecular six-membered-ring cyclization, leading to release of the drug molecule as a leaving group (Figure 23). The role played by three methyl groups involved as part of the extended spacer was originally conceived by Cohen et al. in their linker design for stereopopulation control,317 and aims to lock the conformation of the drug linker in a more favorable position for intramolecular attack by the phenol group and, thus, facilitate the rate of drug release. Another example of the hypoxia linkers is based on the reductive property of indolequinone. As a subgroup of the quinone system, the indolequinone linker is proposed to be activated in part by NAD(P)H:quinone oxidoreductase (DT diaphorase)318 via a two electron mechanism. This system lacks a trimethyl lock, but facilitates drug release via an electron push mechanism. Huang et al. studied this linker for controlled release of naloxone, an opioid receptor antagonist, and demonstrated that the drug molecule is released more selectively and rapidly under hypoxia (t50% = 2.5 h) than normoxia (t5% ≥ 24 h). In addition, nitro-substituted 3408

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Figure 23. Mechanisms of drug release triggered by reductases. POR = cytochrome P450 oxidoreductase; NQO1 = nitroquinone oxidoreductase 1.

2.7. Self-Immolation

A self-immolative reaction process refers to a cascade of spontaneous, intramolecular reactions that occur in response to an applied external stimulus trigger. The self-immolative linker has been considered for applications in controlled drug release.321 As illustrated in Figure 25, this self-immolative

Figure 24. Structure of a doxorubicin molecule tethered to an ArgGly-Asp (RGD) targeting ligand through a Mannich linker based on salicylamide.

chemo-selective conjugation to amines, and tolerance of the conjugation reaction to the presence of diverse functional groups which negates the need for orthogonal protection of these groups. Lastly, the reaction is performed in aqueous− alcoholic conditions which is important for the solubilization of many drug molecules which are often polar and charged.

Figure 25. Schematic illustration of self-immolative release mechanisms: (A) direct release; (B) self-immolative release of a single drug unit; (C) self-immolative release of multiple drug units via application of a single trigger.

Table 11. Doxorubicin-Targeting Ligand Conjugates for Drug Release via Hydrolysis of Mannich Basesa

a

targeting ligand

targeting receptor

drug

linker chemistry

release mechanism

RGD peptide116 imidazolinedione320

αvβ3 integrin androgen receptor

doxorubicin doxorubicin

formaldehyde−salicylamide formaldehyde−salicylamide

acid hydrolysis acid hydrolysis

RGD peptide = CDCRGDCFC; cyclic(N-Me-VRGDf-NH), where “f” refers to D-Phe. 3409

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Table 12. Self-Immolative Linkers for Controlled Drug Release trigger−spacer (Figure 26)

triggering mechanism

immolative reaction type

glycoside−carbamate (A)

β-glucuronidase,322 β-galactosidase323

cephalosporin−carbamate (B) peptide−carbamate; peptide−carbonate (C) disulfide−ester (D) disulfide−hydrazide (E) indolequinone−carbamate (F)

β-lactamase325,326 plasmin,155,165,232 cathepsin B,165 peptidase324 GSH, thiol low pH reductase (DT diaphorase)307

1,6-elimination, cyclization to carbamate 1,4-elimination cyclization to urea, 1,6-elimination mercapto-cyclization327 cyclization to thiadiazinanone135 1,4-elimination; cyclization to urea

linker incorporates dual functional features in its structural design with a triggering moiety linked to a self-immolative spacer rather than directly to the drug molecule. Thus, the drug release mechanism differs from that of direct release linkers due to the involvement of the intervening spacer. Numerous triggering mechanisms have been successfully integrated with an array of self-immolative spacers (Table 12). Each of these trigger moieties is rationally designed for specific cleavage in response to the application of certain external stimuli that include enzymes (glycosidases, 322,323 plasmin,155,165,232 cathepsin B,165 other peptidase,324 β-lactamase325,326), thiol−disulfide exchange,292,327 low pH,135 bioreduction,307 and light.328 Once the triggering moiety is removed from the terminus of the linker, the free spacer group is activated and undergoes spontaneous cyclization or electronic cascade reactions, leading to drug release. Each of such cascade reactions is based on elimination (1,4-; 1,6-) reactions, cyclization of an amine-terminated spacer to a fivemembered urea and carbamate fragment, and cyclization of a mercapto ester or “trimethyl lock”324 spacer to a lactone moiety (Figure 26). One of the primary advantages offered uniquely by selfimmolative release mechanisms relates to the amplification of release frequency through repeated release of multiple drug units per reaction cascade (Figure 25). Proof of concept studies for such amplification have been conducted as demonstrated by full breakdown of multiple branches of a dendritic molecule in response to the single cleavage event of a trigger moiety.328,329 Other beneficial features of these linkers come from the extension of the spacer length. Introduction of such additional spacer length provides relief from steric congestion164,330 between the trigger moiety and a bulkier drug molecule, and is essential for efficient cleavage of the trigger group by macromolecular enzymes such as glycosidases, peptidases, and bioreductive DT diaphorases (Table 12). Furthermore, direct attachment of a certain trigger group such as O-glycoside to a potentially unstable drug molecule can be highly challenging from a synthetic aspect. This synthetic problem can be addressed by synthesizing the trigger-terminated self-immolative linker prior to conjugation to the drug molecule in two separate steps. Given these beneficial features, self-immolation chemistry constitutes an important strategy for drug-linker conjugation in targeted drug delivery.

drug released doxorubicin,322 duocarmycin323 paclitaxel,326 doxorubicin325 paclitaxel,165,232 doxorubicin155,165 taxotere,327 paclitaxel292 calicheamicin135 naloxone307

2.8. Photochemistry

Figure 26. Types of self-immolative linkers and spontaneous release reactions triggered by glycosidase (A), cephalosporinase or βlactamase (B), peptidase (C), glutathione (D), low pH (E), and bioreduction (F).

An important aspect in drug release chemistry is the ability to control the timing of release after uptake of the drug conjugate by the targeted cell. Most of the release mechanisms discussed so far rely on either chemical or enzymatic cleavage of the linker that tethers the drug molecule. Such release reactions occur passively under the influence of specific factors or stimuli. Photochemistry, however, enables an orthogonal release

approach in which light is applied to actively trigger drug release (Figures 27 and 28). This approach is largely based on the concept of photocaging,331,332 in which a drug molecule is temporarily inactivated by derivatization with a photoncleavable trigger group (photocage). This photocaged molecule releases its parent drug molecule in an actively controlled 3410

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Table 13. Light-Controlled Drug Releasea photon-cleavable linker

drug released

light wavelength (nm)

o-nitrobenzyl (ONB)

methotrexate doxorubicin 5-FU tegafur tamoxifen camptothecin doxycycline paclitaxel chlorambucil

365,160,161 254161 365,157 980 (UCN)355 365341 365345 365338,339,343,349,356,357̀

coumarin a

UV348 365342 355,346 365,346 430347 800344 (two-photon)

UCN = upconversion nanocrystal; 5-FU = 5-fluorouracil.

Figure 27. Schematic illustrating the concept of photon-triggered drug release.

Figure 28. Reaction mechanisms for photon-triggered release of a drug molecule linked to o-nitrobenzyl (A) and coumarin (B) linkers.

manner only when the photocage is cleaved by light irradiation (Figure 28). Applications of such photochemical means to control drug release have been demonstrated in numerous types of biological systems331−337 and for drug molecules157,160,161,338−345 including doxorubicin,157 methotrexate,160,161 5-fluorouracil,341 paclitaxel,346,347 camptothecin,348 doxycycline,342 and tamoxifen (Table 13).338,339,343,349 Photon-cleavable linkers that are amenable to release applications are based on those UV-light-responsive aromatic rings comprised of o-nitrobenzyl (ONB),332,335,337,340,350 coumarin,333,335,350 quinoline,351 xanthene,334 and benzophenone.352 Figure 29 illustrates the structures of these photoncleavable linkers. Of these, the ONB group has been frequently applied for drug conjugation to nanocarrriers including PAMAM dendrimers157,160,161 and AuNP.341 This ONB linker allows for high flexibility in its aromatic ring substitution and further derivatization, and allows for synthetic modifications for use in linker installation and drug attachment. ONB is rapidly cleaved by one-photon (254−365 nm157,160,161,341,343) and twophoton (710 nm,337 750 nm340) excitation mechanisms. Coumarin-based linkers represent another major class of

Figure 29. Examples of photocontrolled release of drug molecules.

photon-cleavable linkers in which each drug molecule is covalently attached to a methyl group located at the C-4 position of 7-dialkylaminocoumarin or 6-bromo-7-hydroxycoumarin. These linkers are cleavable by one-photon (365 nm,333,353 475 nm354) as well as by two-photon (740 nm,333,353 800 nm354) mechanisms in which they are reported to provide a greater cross section of two-photon absorption for uncaging for more efficient drug release than the ONB class.333 In addition to light wavelengths, absorption mechanisms (one photon, two photon), and exposure time, the pH condition of the media where the drug release occurs is 3411

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types of nanocarriers. Liu et al.348 reported shell cross-linked (SCL) micelles with hydrophobic cores conjugated with photocaged camptothecin (ONB-CPT) and coronas functionalized with the FA ligand for tumor cell targeting. These micelles were taken up more efficiently in FAR expressing cancer cells than FAR deficient cells, and showed ∼10-fold enhanced cytotoxicity after UV exposure in the cancer cells. Rotello et al. employed gold nanoparticles (AuNP; hydrodynamic diameter = 10 nm) as the nanocarrier for phtocaged 5fluorouracil (5-FU).341 The AuNP modified with photocaged 5FU on the surface displayed light (365 nm) dependent cytotoxicity in MCF-7 cells which increased as a function of exposure time. In summary, light serves as an effective trigger mechanism for drug release. This photochemical mechanism is applicable in an active manner in contrast to other passive release mechanisms we discussed in earlier sections. It is potentially applicable for those therapeutic and diagnostic applications in vivo that require noninvasive or spatiotemporal drug/probe activation. The technical challenges facing such applications in vivo relate to the limited tissue penetration of UV or visible light, which makes it less efficient than in vitro. However, recent advancements in upconversion nanocrystals (UCNs) open up promising opportunities for the photochemical control of drug release. Certain classes of UCNs show unique optical properties which allow them to emit light in the UV range upon excitation by near-infrared (NIR) light at 980 nm.360−362 In contrast to UV light, NIR has a much deeper range of tissue penetration depth.363 Exposure of photocaged drug molecules carried by the UCNs to NIR light provided a mechanism for efficient doxorubicin release in deep tissues which are otherwise unreachable by UV−vis light.355

considered to be important for determining the rate of photochemical drug release. The release rates are slightly greater in acidic (pH 5.0) or basic (pH 9.0) conditions than in neutral conditions (pH 7.4).161,331,358,359 Such dependency is attributable to pH-dependent changes in the molar absorptivity (ε) of the ONB or coumarin group, the leaving group effect of the drug itself,331,358,359 or the combination of these two. The photocontrolled targeted delivery of anticancer therapeutics was demonstrated by a fifth-generation (G5) PAMAM dendrimer conjugated with a folate (FA) ligand as the targeted carrier for a photocaged doxorubicin (G5(FA)(ONB-Dox; Figure 30).157 This dendrimer conjugate was taken up by folic

2.9. Thermolysis

Chemical bonds for certain types of drug linkers are unstable to thermal stimulus and undergo thermal cleavage, providing a mechanism for drug release. These linkers include an Au−S bond364 and a diazo (NN)365 bond-containing spacer group. Application of heat to a targeted tissue, however, is difficult to control and can cause serious damage at temperatures above a physiological range. One approach to circumvent this problem is to apply the irradiation-induced thermal effect by specialized nanoparticles which release heat in response to irradiation stimuli. This approach enables controlled release and localization of heat around the drug-conjugated nanoparticles after they are taken up or bound by the diseased cells. Iron oxide nanoparticles (IONPs) facilitate such mechanisms due to their ability to generate heat when exposed to an alternating magnetic field (AMF). Riedinger et al.365 demonstrated this release approach by conjugating doxorubicin to the IONP through an azo linker (Figure 31). AMF triggered release of the drug in a cytotoxicity assay on KB cancer cells.

Figure 30. Examples of photocontrolled drug delivery using nanocarriers. G5 PAMAM dendrimer conjugated with the folate ligand and photocaged doxorubicin (A) or photocaged methotrexate (B). Gold nanoparticle (AuNP) conjugated with photocaged 5fluorouracil (5-FU) (C).

acid receptor (FAR)-overexpressing KB cancer cells via FARmediated endocytosis, but was not cytotoxic prior to UV light exposure. Exposure to UV light led to inhibition of cell proliferation as a function of exposure time and a maximum level of the cytotoxicity (70% inhibition) was comparable to that by free doxorubicin (85% inhibition). This result demonstrates that FAR-targeted dendrimer carrying photocaged doxorubicin is only cytotoxic to the target cells once it is exposed to UV light. In a similar approach, targeted photocontrolled delivery of methotrexate (MTX) was demonstrated in KB cells by G5 PAMAM dendrimer conjugated with a photocaged MTX (G5(FA)(ONB-MTX; Figure 30).160 Lighttriggered drug release was also demonstrated by using other

2.10. Azo Reduction

In addition to cleavage via a thermolytic mechanism, the azo linker is also cleavable via a biological mechanism (Figure 32).366,367 This cleavage mechanism has been employed for the activation of an anti-inflammatory class of azo-linked prodrugs of 5-aminosalicylic acid (ASA; mesalazine)368,369 that includes sulfasalazine, balsalazide, ipsalazide, and olsalazine. Sulfasalazine, for example, undergoes reductive cleavage of its azo linker by bacterial enzymes in the colon to an active metabolite, ASA.370 This mechanism has been further applied for the design of colon-targeted polymer therapeutics based on 3412

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Figure 31. Thermal cleavage of an azo linker for doxorubicin release.

physical encapsulation in a container375,376 and play significant roles in drug delivery. The kinetics of drug release is controllable by altering various design features of the nanocarrier such as particle size,377 shape,378 and surface modification chemistry.379,380 Particle size,377,381,382 geometry,383,384 and shape378 are physical properties; however, they are known to play a significant role in dictating the biological activity of the nanoparticles. Processes such as cell surface adhesion, phagocytosis, and degradation have all been shown to be influenced by the size, geometry, and shape of the nanoparticles, as reviewed thoroughly in numerous articles.56,377,378 Surface modification of nanoparticles is one of the fundamental approaches used for altering their biocompatibility56,385,386 as well as for creating sites for host−guest interactions and drug complexation.379,387−397 Thus, the release rates of drug complexes vary in response to the physicochemical properties (charge, hydrophobicity, hydrophilicity) and the density of the drug binding sites.379,398−401 This latter topic has been extensively reviewed for the principles of drug complexation and release kinetics in various nanocarriers such as dendrimers,9,137−139,402 polymers,140 and liposomes.141,142 Here we will briefly discuss selected examples of release mechanisms involved in drug encapsulation that occur through the control of drug diffusion rates by varying pore sizes of encapsulating containers375 and the controlled gating (open/closed) mechanism of the container via alterations in its effective volume, cross-links, and conformation, and the generation of microbubbles. Each of these release mechanisms occurs in response to physicochemical stimuli376 including changes in pH/ion gradient,403−406 reaction with thiols,407−413 exposure to ultrasound,414,415 elevated temperature,376,412,416−420 and light421,422 (Figures 33 and 34, Table 14).

Figure 32. Biological cleavage of an azo linker for drug release.

poly(vinyl amine)371 and 2-hydroxypropyl methacrylate (HPMA) polymer.372,373 Poly(vinyl amine) conjugates with azo-linked ASA and HPMA conjugates with 9-aminocamptothecin have been well-studied.374

3.1. Pore Size

Controlling the size of pores in the delivery vehicle serves as a mechanism of controlled release of guest molecules. This type of release control is illustrated by hollow mesoporous silica nanoparticles (HMSNPs) designed with various pore sizes (diameter = 3.2, 6.4, 12.6 nm) (Figure 33a).375 Li et al. demonstrated that this drug carrier shows differential release rates of its doxorubicin payloads in which the rate of drug diffusion is proportional to the pore size. Accordingly, the duration of drug release can be adjusted by selecting a certain pore size of the vehicle.

3. MECHANISMS OF DRUG RELEASE VIA CONTROL OF CARRIERS The focus of this review is on compiling various release mechanisms of covalently conjugated drug molecules through controlled cleavage of drug linkers. Drug loading and release can also occur through noncovalent mechanisms such as through complexation interactions with the carrier139,140 or 3413

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Figure 33. Mechanisms for alteration of carrier properties for controlled drug release: (a) pore-size-dependent diffusion control; (b) pH-dependent alteration in effective volume, porosity, and permeability; (c) alternative magnetic field (AMF) stimulated uncapping of magnetic nanoparticles (MNPs). Figure 34. Mechanisms of controlled drug release: (a) enhanced permeability via disulfide exchange; (b) configuration-dependent alteration in permeability; (c) ultrasound-mediated perfluorocarbon (PFC) evaporation or vesicle shrinkage; (d) thermally induced generation of bubbles in liposomes.

Compared to mesoporous silica nanoparticles (MSNs) which have been extensively studied,423−428 other types of porous materials have been identified but studied only limitedly for controlled drug release.382,429 Selected examples of these include poly(lactide-co-glycolide) polymer microspheres430 and mesoporous particles made of aluminosilicates (MCM41 431 ). Each of these studies tested piroxicam 430 or ibuprofen431 as the drug payload and suggests that the rate of drug release is inversely proportional to the pore size.

in response to the pH condition of the solution. Voit et al. demonstrated that the release of encapsulated doxorubicin from cross-linked polymersomes of a block copolymer (PEG-bP(DEAEMA-BMA)) is tunable by pH-dependent permeability of the polymer brushes.403 At pH 5 the release is on state due to polymer expansion, while at pH 7.4 it is off state due to polymer collapse. Magnetic nanoparticles have the ability to produce heat when subjected to a localized alternating magnetic field (AMF). Such magnetic hyperthermia constitutes a mechanism used for controlled release. Ruiz-Hernández et al.433 reported on the design of mesoporous silica nanoparticles (MSN; diameter = 100 nm) loaded with a fluorescein payload (Figure 33c). In this system, the surface of each MSN is premodified by conjugation with multiple residues of a single-stranded cDNA. This cDNA oligo serves as a linker for noncovalent attachment of an iron oxide magnetic nanoparticle conjugated with the complementary oligo. Each magnetic NP is thus, in essence, capped in the area proximal to the pore entrance, blocking payload release. When an AMF is applied, the magnetic NPs are heated to temperatures of ≥42 °C, which is high enough to melt the cDNA linker. As a result of DNA dehybridization, the magnetic

3.2. Effective Volume

Another method to control release is to alter the effective volume of the vehicle available for drug encapsulation by applying external stimuli. For example, after cellular uptake by cancer cells, the loading capacity of the drug encapsulating nanosystem can be lowered by a decrease in pH (endosomes, lysosomes),403−406 ultrasound stimulation,414 and temperature alteration.376,416,417,419,420 This release mechanism frequently is used for polymers152 and polymer grafted core−shell systems based on liposomes404 and inorganic nanoparticles414,417,432 because the local density of certain polymer residues on the liposome surface increases with the protonation of the polymer pendant groups, triggering the collapse of the liposomal membrane and release of its payloads. This is illustrated by poly(acrylic acid)-grafted liposomes loaded with arsenic trioxide (As2O6) as an anticancer agent (Figure 33b).404 However, with the use of a different type of polymer sensor, a mechanism for drug release can be designed in a different way 3414

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Table 14. Mechanisms of Drug Release via Control of Carrier Properties for Payload Encapsulation trigger

carrier

mechanism

mesoporous silica NP375,453,454 PAA-grafted liposome,404 PEG cross-linked nanogel,455 polymersome,403,456 mesoporous silica NP,457 lipid/polymer conjugate,458 AuNP-covered mesoporous silica NP459 disulfide cross-linked PEG hydrogel,408,455,460 cationic polymer,439 polymer micelle,440,441,461,462 AuNP-coated polymer micelle,463 mesoporous silica NP412

diffusion rate altered porosity

light

azobenzene-coated silica NP,422 liposome,464 azobenzene block polymer,465 graphene oxide466

temperature

cellulose-grafted magnetic particle,418 liposome,467 PMAA polymer468

cis−trans isomerization, altered porosity altered porosity

pore size pH gradient thiol (GSH)

ultrasound nanoemulsion,415 polymer micelle,414 mesoporous silica particle469 magnetic field iron oxide NP (IONP),433,434 zinc-doped IONP436

NPs are uncapped, and the fluorescein molecules are released through the open pore. This magnetic control of hyperthermia mediated release has been similarly applied in other systems as well,434−436 including a nanovalve437 which has been shown to be effective for controlled gating.

disulfide exchange

altered porosity localized hyperthermia

payload released doxorubicin,375,454 trypsin inhibitor453 arsenic trioxide (As2O6),404 doxorubicin,403,455,458,459 rutheniumpyridyl,457 prednisolone456 DNA plasmid,408,439 doxorubicin,412,440,460−462 methotrexate,441 paclitaxel463 irinotecan,422 doxorubicin464,466 gemcitabine,418 doxorubicin,419,420,467 daunorubicin468 paclitaxel,415 doxorubicin414,469 fluorescein,433,434 doxorubicin,436 methylene blue435

conformational switch as well.2 Typically these polymers or their micelles are composed of pH-responsive block copolymers such as poly(histidine-b-PEG-folate) and poly(lactic acidb-PEG-folate).446 Other mechanisms frequently used for conformational control are based on ultrasound irradiation414,449 and temperature alteration.376,416,417,419,420,450,451

3.3. Cross-Links

3.5. Microbubbles

Alteration of the effective volume and internal permeability of a delivery vehicle is also controllable by reduction of disulfide cross-links used for stabilizing the interior of nanoparticles and for payload encapsulation.407−411,413,438,439 This release mechanism is applied for DNA delivery using a PEG-based hydrogel in which exposure to GSH led to cleavage of the disulfide crosslinks, and facilitated DNA release after its intracellular uptake (Figure 34a). It serves as a route for tumor targeted gene modulation because of the higher expression levels of GSH in tumor cells.408 This mechanism has been applied for the controlled release of doxorubicin and methotrexate encapsulated in disulfide cross-linked polymer micelles.440,441

Ultrasound plays an active role in the controlled release of drug payloads.414,415 A number of nanocarriers including nanoemulsions415,452 and polymer vesicles414 have been investigated for this release mechanism.376 While exact release mechanisms vary with the specific design features of each nanocarrier, the release is attributable to the ability of ultrasound to physically stimulate individual structural components that comprise the nanocarrier. This is illustrated by a nanoemulsion droplet system in which paclitaxel is entrapped in combination with perfluorocarbon (PFC) as an ultrasound-responsive gas molecule (Figure 34c).415 Exposure of the nanodroplet to ultrasound irradiation triggered the generation and escape of microbubbles filled with paclitaxel, resulting in an increase in the effective volume of the nanodroplet. Application of ultrasound for controlled drug release is also demonstrated by using polymer vesicles prepared by the self-assembly of the amphiphilic block copolymer (PEO-b-P(DEA-stat-TMA) carrying doxorubicin as the payload.414 Ultrasound irradiation was selected for this application due to its ability to alter the structural morphology of the vesicles. In particular, ultrasound was able to alter the size of the nanoparticles, decreasing the size (mean hydrodynamic diameter = 377 nm) 3 times (124 nm) following irradiation. The authors suggest that this shrinkage accounts for the release of drug molecules because it directly affects the effective volume of the hydrophobic core housing the payload. Thermal-stimulus-triggered release mechanisms have been investigated using temperature-responsive liposomes as the drug carrier. Advantages of using liposomes for temperature control include the ability to simultaneously encapsulate several types of molecules including a thermally responsive component. Chen et al.419 encapsulated doxorubicin and ammonium bicarbonate together in liposomes (Figure 34d). Ammonium bicarbonate is thermally unstable and begins to decompose at an elevated temperature (42 °C), resulting in the generation of bubbles made up of CO2 and ammonia gas. These bubbles create defects in the lipid bilayer structure resulting in the release of entrapped doxorubicin molecules. Another liposome system is reported by Al-Ahmady et al.420 employing an

3.4. Conformation

Light serves an effective tool to alter the internal configuration and permeability of a delivery system.421,442 Unlike use of a photocleavable linker to a drug molecule, the linker is incorporated as the building block of the delivery system such as in lipid membranes.421 Best et al. designed ONBincorporated lipid and demonstrated light triggered release of dye molecules loaded in the liposomes made of the photocleavable lipid.421 In addition to irreversible cleavage of the photosensitive linker, light triggers a reversible change in the linker configuration such as from trans-to-cis isomerization of azobenzene, and this change leads to a decrease in the volume available for drug encapsulation as demonstrated by the faster rate of release of irinotecan encapsulated in azobenzenecoated silica nanoparticles (Figure 34b).422 In addition to light, there are other types of stimuli that have been investigated for controlled drug release through conformational changes of nanocarriers.2,376 Some of these mechanisms were already discussed in section 3.2.152,405,414,416 One of the mechanisms is control by pH, as illustrated by Abraxane, the albumin-bound paclitaxel delivery system.443,444 Its mode of action is believed to involve albumin receptor-mediated intracellular uptake and subsequent drug release triggered by low pH-induced protein denaturation in the acidic endosomal compartment (Table 5). Nonprotein carriers that include sterically stabilized liposomes,445 polymer nanoparticles, or polymeric micelles446−448 are believed to utilize a pH-triggered 3415

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localized primarily in the cytoplasm (2−10 mM; ≤85%) and mitochondria (≤30%). 4.1.5. Hypoxia Activation. Certain linkers based on indolequinone and nitroaromatics are reductively cleaved by hypoxia-activated enzymes. Thus, use of such linkers allows tumor-targeted drug release. However, their tumor selectivity can be compromised because hypoxia can also occur in normal tissues under certain conditions in which oxygen levels are low. 4.1.6. Mannich Base. Drug conjugation via a Mannich base link is applicable for certain classes of drug molecules functionalized with amines, carboxamides, phenols, or ketones. The release mechanism for this Mannich conjugated drug molecule involves hydrolytic cleavage to its Schiff base form in acidic cellular compartments followed by hydrolysis to release the parent drug. In contrast to amide and ester linkers, drug conjugation through a Mannich base can be performed in aqueous solutions without the need to protect the other functional groups. 4.1.7. Self-Immolation. Release of a drug molecule conjugated via a self-immolative linker begins by activation of a triggering moiety linked to the self-immolative spacer. Numerous triggering mechanisms have been designed to occur in response to external stimuli that include enzymes, low pH, bioreduction, and light. The hallmark of this release mechanism relates to the amplification of release frequency through repeated release of multiple drug units per reaction cascade. However, conjugation through a self-immolative linker for targeted delivery requires convergent synthetic approaches and thus can be challenging to integrate with existing carrier platforms. 4.1.8. Photochemistry. Release of a drug molecule attached through a photocleavable linkage is triggered by light exposure and serves as an effective mechanism for spatiotemporal control of drug release. Photochemical control is challenging for applications in subepidermal cells and tissues due to the limited light penetration of radiation sources such as UV light. However, these limitations are currently being addressed by the use of two-photon excitation which has a deeper penetration range, as it utilizes visible light (740−800 nm). In addition, recent developments in biophotonic nanomaterials have opened up several promising applications for photon-controlled drug release. In particular, the use and development of upconversion nanocrystals (UCNs)360−362 which are excited by IR radiation (980 nm)363 and emit UV light has great potential for photochemical release applications in deep tissue. 4.1.9. Thermolysis. Thermolysis relies on a thermal stimulus to trigger cleavage of the chemical bond that constitutes the linker such as an Au−S bond or a diazo (N N) bond. Despite its simple mechanism of drug release, application of this mechanism is challenging due to the lack of effective methods for localized heat exposure to only the targeted tissue. However, this issue is addressed in part by integration of the linker with specialized magnetic nanoparticles which generate a localized thermal effect upon exposure to an alternating magnetic field (AMF). 4.1.10. Azo Reduction. Biological cleavage of an azo linker by enzymes in the colon allows for colon-targeted drug delivery, giving this linker great potential for use in extended release of drug molecules associated with gastrointestinal cancers and irritable bowel diseases. 4.1.11. Encapsulation. Parent drug molecules can also be loaded through noncovalent complexation with and/or physical

amphiphilic leucine zipper peptide. Incorporation of this peptide in the lipid bilayer occurs through a self-assembly process that results in a stable bundle of peptides inserted in the membrane. When the liposomes are exposed to an elevated temperature, the peptides in the bundle become highly disordered in conformation and open pores are formed in the lipid bilayer large enough for drug release.

4. CONCLUSIONS 4.1. Summary

Targeted drug delivery using nanometer-sized carriers aims to deliver therapeutic payloads precisely to targeted cells. Key design elements that play an essential role for enabling this strategy are comprised of selective cell targeting by multivalent ligand design and subsequent cell inhibition by timely release of carried drug molecules. The release of drug needs to occur in a precisely controlled manner in order to deliver the cytotoxic payload to the targeted cell only. Here we systematically reviewed various mechanisms of drug release developed for targeted delivery from a chemical and biochemical point of view. These release mechanisms are classified on the basis of drug linker functionalities, and are summarized below with regard to rationale, linker properties, and their inherent limitations. We believe this review article will help give a better understanding of the molecular basis of each of these release mechanisms and provide important insights for the rational design of drug release systems. 4.1.1. Ester Hydrolysis. Drug attachment through a carboxylic ester linker is widely used due to its synthetic convenience and general applicability to numerous therapeutic molecules, as most of these molecules have a carboxylic acid or alcohol functional group. Controlled drug release through cleavage of the ester bond is facilitated by (i) esterases and hydrolases in acidic endosomes and lysosomes, (ii) certain hydrolytic enzymes overexpressed in the extracellular membrane or plasma, and, (iii) to a lesser extent, acid- or basecatalyzed hydrolysis. 4.1.2. Amide Hydrolysis. Like the ester linker, drug attachment via an amide linker is widely applicable due to synthetic convenience and functional compatibility. In comparison to the ester bond, the amide bond is much more stable and less susceptible to chemical hydrolysis unless certain classes of specialized linkers are employed such as citraconyl, cis-aconityl, and maleyl groups. Thus, release of amide-linked drug molecules occurs via enzymatic mechanisms through the activity of hydrolytic proteases localized in the plasma, ECM, plasma membrane, and intracellular lysosomes. 4.1.3. Hydrazone Hydrolysis. Drug conjugation via a hydrazone linkage is applicable for drug molecules containing a ketone or aldehyde functional moiety. This linker is fairly stable under physiological conditions but undergoes rapid cleavage in acidic conditions (pH ≤5), allowing for pH-regulated drug release. Thus, acid-responsive release occurs after internalization into the acidic environments of endosomes and lysosomes (pH 5−6) rather than in the extracellular environment (pH >6). 4.1.4. Disulfide Exchange. Unlike the ester, amide, and hydrazine linkers, the disulfide bond is not cleavable by hydrolysis but is cleaved through reduction or disulfide exchange reactions. Thus, drug release is triggered by endogenous thiol molecules including glutathione (GSH) 3416

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Table 15. Polymer-Based Nanotherapeutics Approved or Advanced to Clinical Studiesa conjugate name

polymers

drug (therapeutic area)

linker chemistry (release mechanism)

Xyotax (CT-2103)211,470−472 PNU16645473,474 CT-2106472 XMT-1001475,476 MAG-CPT (PNU166148)477 CRLX101 (IT-101)478 Delimotecan (T-2513)479 PK1, PK2480,481 NK911447,482−484 ProLindac (AP5280)475,485,486 HAS-MTX487,488 XMT-1107475,489 MOVANTIK (naloxegol; NKTR-118)490

poly(L-Glu) HPMA poly(L-Glu) PHF (Fleximer) HPMA CD−PEG carboxymethyl dextran HPMA PEG−poly(L-Asp) HPMA HSA PHF (Fleximer) PEG

paclitaxel (cancer) paclitaxel (cancer) camptothecin (cancer) camptothecin (cancer) camptothecin (cancer) camptothecin (cancer) camptothecin (cancer) doxorubicin (cancer) doxorubicin (cancer) cisplatin (cancer) methotrexate (cancer) fumagillol (cancer) naloxone (OIC)

Glu ester (cathepsin B211) GFLG ester (lysosomal peptidases) Gly ester (cathepsin B211) GGFG amide (intramolecular transacylation) Gly ester Gly ester amide GFLG amide (lysosomal peptidases481) Asp amide malonate-Pt (hydrolysis) lysine amide (lysosomal peptidases487) carbamate (plasma489) ether (C6)

HPMA = N-(2-hydroxypropyl)methacrylate; CD−PEG = β-cyclodextrin−poly(ethylene glycol) copolymer; HSA = human serum albumin; PHF = poly(1-hydroxymethylethylene hydroxymethylformal); OIC = opioid-induced constipation. a

4.3. Challenges in Nanotherapeutic Linker Design

encapsulation in the nanocarrier. Release then occurs in a diffusion controlled manner. Systems designed for such diffusion control include variation in pore sizes of the encapsulating containers and controlled gating of the container that is triggered in response to such stimuli as pH/ion gradient, thiol, ultrasound, temperature, and light.

A number of challenges exist in the optimal design of nanotherapeutics. We address certain aspects that need to be considered in the drug linker design. 4.3.1. Synthetic Chemistry. Drug conjugation through certain linker types such as photocleavable, hypoxia, and disulfide linkers require prederivatization of each drug molecule with a custom-tailored linker. Synthesis of such linkers and subsequent drug modification require multiple steps of synthetic operation and can be more challenging to nonchemists in particular during the scale-up process. This opens up an area of multidisciplinary collaboration among synthetic chemists, biologists, and biomedical engineers. 4.3.2. Binding Avidity. Co-attachment of drug molecules with targeting ligands on the surface of a nanocarrier increases steric congestion491,492 around the ligands, and thus can interfere with binding avidity of the nanoconjugate to the targeted cell, resulting in lower cell selectivity. Use of a dualacting drug molecule that can serve as a targeting ligand as well can overcome such a potential issue in nanotherapeutic design. Methotrexate is a good example of such dual-acting molecules because of its affinity to FAR.98,252,268,493 This unavoidable design issue is also addressable by optimizing the length and conformational flexibility of a spacer to the drug or ligand molecule. Use of a shorter spacer for the drug molecule reduces steric hindrance around the ligand. 4.3.3. Physicochemical Properties. Heavy payloads of hydrophobic drug molecules carried by a single nanoparticle result in low aqueous solubility. Hydrophilic groups in the spacer that have high polarity and charge such as amide, ethylene oxide (EO), carboxylic acid, and amine are more effective in improving the solubility of the conjugate than hydrophobic alkane spacers. 4.3.4. Pharmacokinetics (PK). In vivo efficacy of a nanotherapeutic is also determined by its PK properties during systemic circulation such as metabolic stability, low clearance rate, and minimal level of premature drug release. Prediction of these PK properties is difficult but can be evaluated in part by performing in vitro PK studies through measurement of conjugate stability and nonspecific drug release kinetics in PBS and serum solutions. Optimization of PK properties is achievable by varying the structural features and chemical compositions (size, shape, polarity, charge) of a nanocarrier, the linker, and the spacer. Excessive charge is often linked to

4.2. Status of Nanotherapeutic Development

Drug delivery in nanotechnology has served as a promising strategy for improving safety and efficacy profiles of existing therapeutic agents which are otherwise associated with poor aqueous solubility, plasma instability, generally high toxicity, and serious side effects.382,390,393,394,474,475,490 Development of such nanotherapeutic agents have been focused primarily on cancer treatment, but recently has been expanding to other therapeutic applications including opioid-induced constipation.490 Currently there are dozens of polymer-based nanotherapeutics which have been approved or evaluated in clinical trials (Table 15). Most clinical candidates have been focused on improving the therapeutic performance of anticancer compounds with poor aqueous solubilities such as paclitaxel and camptothecin, as well as those causing serious systemic toxicity such as doxorubicin and cisplatin. However, the progress of these clinical candidates toward regulatory approval has been slow, resulting in only one approved drug (Xyotax),190,381−383 with many others still in clinical trial stages (eg., ProLindac, XMT-1001). Several candidates resulted in clinical failures,473,474,477 though such poor outcomes are, in principle, attributable to their suboptimal design features due to lack of targeting ligands, nonspecific release mechanisms, or a combination of these factors. Many of the current candidates that have been developed rely on a passive mechanism of tumor targeting, the EPR effect,69−71 which is known to occur in leaky tumor vasculatures (section 1.3). Recent candidates, in contrast, incorporate an active targeting mechanism as illustrated by a hepatic tumor targeting conjugate in which multivalent presentation of a galactosamine ligand enables binding to liver cells with high avidity.480,481 Looking forward, the combination of active tumor targeting with precise control of drug release through the mechanisms discussed in this review is expected to play a more crucial role in disease-specific drug delivery and personalized medicine. 3417

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adsorption of serum proteins to the nanocarrier, and large sizes result in prolonged tissue retention, slow renal clearance (hydrodynamic diameter >8 nm),494 and systemic toxicity.494,495 4.3.5. Tissue Penetration. Targeting cells through an ECM or dense layer of tissues adds another challenge compared to endothelial cells. Such conjugate diffusion is a slower process in which premature drug release can occur via the metabolic breakdown of the drug linker by enzymes secreted in the ECM including MMPs. Use of a nonpeptidic drug linker inert to MMP activity is needed for achieving intracellular drug release. However, such an MMP-selective release mechanism is also considered as a route for tumor targeting since it enables localized drug exposure to tumor cells overexpressing MMPs (section 2.2.1).141,213 In summary, nanocarriers are a very powerful tool for drug delivery when combined with precise mechanisms for spatially and temporally controlling drug release. Conjugation of currently used drugs to nanocarriers will likely lead to better strategies for improving the therapeutic index of these drugs and significantly enhance our ability to treat several human diseases.

Seok Ki Choi earned his B.S. and M.S. degrees at Seoul National University, Korea, and Ph.D. degree at Columbia University, New York, NY (advisor Prof. Koji Nakanishi), and then completed his postdoctoral training at the laboratory of Prof. George M. Whitesides, Harvard University, Cambridge, MA. In mid-1997, he joined Theravance, Inc. (then, Advanced Medicine), South San Francisco, CA, where he developed expertise in translation of the polyvalent concept for small molecule drug discovery. In late 2008, he moved to the University of Michigan Medical School, Ann Arbor, MI, and currently serves as a faculty member in the Department of Internal Medicine with a joint appointment at the Michigan Nanotechnology Institute for Medicine and Biological Sciences. His research interests are focused on biologic nanotechnology, multivalency, photogenetic probes, and biophotonic nanomaterials.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Tel.: (734) 647-0052. Fax: (734) 936-2990.

ACKNOWLEDGMENTS The authors thank the Michigan Nanotechnology Institute for Medicine and Biological Sciences for support, and the University of Michigan Office of the Vice President for Research and Shanghai Jiao Tong University (SKC) for funding.

Notes

The authors declare no competing financial interest. Biographies

ABBREVIATIONS AMF alternating magnetic field AuNP gold nanoparticle CD β-cyclodextrin DHFR dihydrofolate reductase DOX doxorubicin ECM extracellular matrix EGF epidermal growth factor EGFR epidermal growth factor receptor EPR enhanced permeation and retention FA folic acid FAR folate receptor FGF fibroblast growth factor FGFR fibroblast growth factor receptor 5-FU 5-fluorouracil GSH glutathione HA hyaluronic acid HSA human serum albumin HMSNP hollow mesoporous silica nanoparticle HPMA N-(2-hydroxypropyl)methacrylamide IONP iron oxide nanoparticle MMP matrix metalloproteinase MTX methotrexate MWNP multiwalled carbon nanotube NIR near infrared NP nanoparticle

Pamela T. Wong received her Ph.D. in biological chemistry from the University of Michigan, Ann Arbor, MI, in 2009 under the guidance of Prof. Ari Gafni, where her research focused on the biochemical and biophysical characterization of amyloid-beta oligomerization and interaction with liposomal membrane surfaces. Currently, she is a postdoctoral fellow with Prof. James R. Baker, Jr., at the University of Michigan Medical School Nanotechnology Institute for Medicine and Biological Sciences. Her research interests focus on the design and biological characterization of nanoemulsion based adjuvants for subunit vaccines and on nanoparticle based targeted delivery and release systems including dendrimer, AuNP, and upconversion nanocrystal platforms. 3418

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Chemical Reviews NQO ONB PAMAM PEG PEI PHF PPI PLGA POR PSA PSMA PTX RF RFR SWNT α-TOS UCN UV TI

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(16) Tomalia, D. A.; Naylor, A. M.; William, A.; Goddard, I. Starburst Dendrimers: Molecular-Level Control of Size, Shape, Surface Chemistry, Topology, and Flexibility from Atoms to Macroscopic Matter. Angew. Chem., Int. Ed. 1990, 29, 138−175. (17) Tomalia, D. A.; Baker, H.; Dewald, J.; Hall, M.; Kallos, G.; Martin, S.; Roeck, J.; Ryder, J.; Smith, P. A New Class of Polymers: Starburst-Dendritic Macromolecules. Polym. J. (Tokyo, Jpn.) 1985, 17, 117−132. (18) Zimmerman, S. C.; Quinn, J. R.; Burakowska, E.; Haag, R. Cross-Linked Glycerol Dendrimers and Hyperbranched Polymers as Ionophoric, Organic Nanoparticles Soluble in Water and Organic Solvents. Angew. Chem., Int. Ed. 2007, 46, 8164−8167. (19) Zhou, Z.; Shen, Y.; Tang, J.; Jin, E.; Ma, X.; Sun, Q.; Zhang, B.; Van Kirk, E. A.; Murdoch, W. J. Linear polyethyleneimine-based charge-reversal nanoparticles for nuclear-targeted drug delivery. J. Mater. Chem. 2011, 21, 19114−19123. (20) Fischer, M.; Vö gtle, F. Dendrimers: From Design to ApplicationA Progress Report. Angew. Chem., Int. Ed. 1999, 38, 884−905. (21) Bosman, A. W.; Janssen, H. M.; Meijer, E. W. About Dendrimers: Structure, Physical Properties, and Applications. Chem. Rev. (Washington, DC, U. S.) 1999, 99, 1665−1688. (22) Zhang, W.; Nowlan, D. T.; Thomson, L. M.; Lackowski, W. M.; Simanek, E. E. Orthogonal, Convergent Syntheses of Dendrimers Based on Melamine with One or Two Unique Surface Sites for Manipulation. J. Am. Chem. Soc. 2001, 123, 8914−8922. (23) Sideratou, Z.; Kontoyianni, C.; Drossopoulou, G. I.; Paleos, C. M. Synthesis of a folate functionalized PEGylated poly(propylene imine) dendrimer as prospective targeted drug delivery system. Bioorg. Med. Chem. Lett. 2010, 20, 6513−6517. (24) Paleos, C. M.; Tsiourvas, D.; Sideratou, Z.; Tziveleka, L. Acidand Salt-Triggered Multifunctional Poly(propylene imine) Dendrimer as a Prospective Drug Delivery System. Biomacromolecules 2004, 5, 524−529. (25) Kaminskas, L. M.; Kelly, B. D.; McLeod, V. M.; Sberna, G.; Owen, D. J.; Boyd, B. J.; Porter, C. J. H. Characterisation and tumour targeting of PEGylated polylysine dendrimers bearing doxorubicin via a pH labile linker. J. Controlled Release 2011, 152, 241−248. (26) Chertok, B.; David, A. E.; Yang, V. C. Polyethyleneiminemodified iron oxide nanoparticles for brain tumor drug delivery using magnetic targeting and intra-carotid administration. Biomaterials 2010, 31, 6317−6324. (27) Chen, H.-T.; Neerman, M. F.; Parrish, A. R.; Simanek, E. E. Cytotoxicity, Hemolysis, and Acute in Vivo Toxicity of Dendrimers Based on Melamine, Candidate Vehicles for Drug Delivery. J. Am. Chem. Soc. 2004, 126, 10044−10048. (28) Dhar, S.; Gu, F. X.; Langer, R.; Farokhzad, O. C.; Lippard, S. J. Targeted delivery of cisplatin to prostate cancer cells by aptamer functionalized Pt(IV) prodrug-PLGA-PEG nanoparticles. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 17356−17361. (29) Eniola, A. O.; Hammer, D. A. Artificial polymeric cells for targeted drug delivery. J. Controlled Release 2003, 87, 15−22. (30) Farokhzad, O. C.; Cheng, J.; Teply, B. A.; Sherifi, I.; Jon, S.; Kantoff, P. W.; Richie, J. P.; Langer, R. Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 6315−6320. (31) Gu, F.; Zhang, L.; Teply, B. A.; Mann, N.; Wang, A.; RadovicMoreno, A. F.; Langer, R.; Farokhzad, O. C. Precise Engineering of Targeted Nanoparticles by Using Self-Assembled Biointegrated Block Copolymers. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 2586−2591. (32) Chandran, S. S.; Nan, A.; Rosen, D. M.; Ghandehari, H.; Denmeade, S. R. A prostate-specific antigen-activated N-(2-hydroxypropyl) methacrylamide copolymer prodrug as dual-targeted therapy for prostate cancer. Mol. Cancer Ther. 2007, 6, 2928−2937. (33) Homma, A.; Sato, H.; Okamachi, A.; Emura, T.; Ishizawa, T.; Kato, T.; Matsuura, T.; Sato, S.; Tamura, T.; Higuchi, Y.; Watanabe, T.; Kitamura, H.; Asanuma, K.; Yamazaki, T.; Ikemi, M.; Kitagawa, H.; Morikawa, T.; Ikeya, H.; Maeda, K.; Takahashi, K.; Nohmi, K.; Izutani, N.; Kanda, M.; Suzuki, R. Novel hyaluronic acid-methotrexate

nitroquinone oxidoreductase o-nitrobenzyl poly(amidoamine) poly(ethylene glycol) poly(ethylene imine) poly(1-hydroxymethylethylene hydroxymethylformal) poly(propylene imine) poly(D/L-lactic acid-co-glycolic acid) P450 oxidoreducatse prostate-specific antigen prostate-specific membrane antigen paclitaxel riboflavin riboflavin receptor single-walled carbon nanotube α-tocopheryl succinate upconversion nanocrystal ultraviolet therapeutic index

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