Stimulus-responsive Macromolecules and Nanoparticles for Cancer Drug Delivery

Sarah R MacEwan; Daniel J Callahan; Ashutosh Chilkoti

Nanomedicine. 2010;5(5):793-806.

Abstract and Introduction

Abstract

Nanoparticles and macromolecular carriers have been widely used to increase the efficacy of chemotherapeutics, largely through passive accumulation provided by the enhanced permeability and retention effect. Stimulus-responsive peptide and polymer vehicles can further enhance the efficacy of antitumor therapeutics compared with the administration of free drug by three mechanisms: increasing the overall accumulation within solid tumors; providing a homogeneous spatial distribution in tumor tissues; and increasing the intracellular localization of anticancer therapeutics. This article highlights recent developments in 'smart' – stimulus-responsive – peptide, polymer and lipid drug carriers designed to enhance the localization and efficacy of therapeutic payloads as compared with free drug.

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Table 1. Summary of drug-delivery vehicles and stimulus-responsive drug carriers that have been developed to increase targeted accumulation of a drug, enhance its distribution, and control its intracellular or subcellular localization, with the ultimate goal of increasing the efficacy of anticancer therapeutics.
Drug carrier	Stimulus response	Drug	Application	Ref.
Abraxane® (albumin–drug conjugate)	–	Paclitaxel	Clinically approved for the treatment of breast cancer	^[14]
NK105 (drug-loaded PEG–poly(aspartic acid) micelle)	–	Paclitaxel	In clinical trials for the treatment of colon and stomach cancers	^[19]
Doxil® (drug-loaded PEGylated liposome)	–	Doxorubicin	Clinically approved for the treatment of recurrent ovarian cancer	^[22]
ELP unimer	Temperature-triggered aggregation	–	Increased accumulation in hyperthermia treated tumors in mice	^[34]
Dextran–peptide–drug conjugate	MMP cleavage of peptide linker for release of free drug	Methotrexate	Improved inhibition of tumor growth in subcutaneous murine models of human fibrosarcoma and glioblastoma	^[40]
Poly(histidine)-β-PEG, poly(L-lactic acid)-β-PEG mixed micelle	pH-triggered disassembly for release of free drug	Doxorubicin	Increased accumulation and improved efficacy in subcutaneous breast cancer tumors in mice	^[47]
Pluronic® micelle	Ultrasound-induced disassembly for release of free drug	Doxorubicin	Improved regression with ultrasound treatment in subcutaneous colon cancer tumors in mice in comparison to treatment with drug-loaded micelles alone	^[50]
Oligoarginine–peptide–oligoglutamate conjugate	MMP-2 cleavage of peptide linker for CPP activation	–	Increased accumulation compared with uncleavable controls in a variety of subcutaneously implanted tumor types in mice	^[65]
PEG–poly(L-histidine), poly(L-lactic acid)–PEG–poly(L-histidine)–TAT mixed micelle	pH-triggered display of TAT for CPP activation	Doxorubicin	Selective cellular uptake in slightly acidic conditions of pH 7.0 improved cytotoxicity in drug-resistant breast cancer cells	^[71]
RGD-functionalized ELP diblock	Temperature-triggered micelle assembly for polyvalent ligand display	–	Increased accumulation with hyperthermia-triggered micelle assembly in leukemia cells overexpressing α_vβ₃ integrin	^[77]
Thiolated heparin nanogel	Destabilization of disulfide bonds in reducing intracellular environment for free drug release	Heparin	Increased cytotoxicity by induction of apoptosis in melanoma cells as compared with free drug	^[84]
ELP–drug conjugate micelle	pH-triggered drug release in acidic endosomal compartment	Doxorubicin	Enhanced accumulation, increased MTD and improved regression of colon carcinoma tumors in mice	^[20]
Poly(L-histidine)-based micelle	pH-triggered protonation of histidine for endosomal disruption	Doxorubicin	Improved cytotoxicity of intracellularly released drug in doxorubicin-resistant ovarian carcinoma cells	^[92]
Amidized poly(L-lysine)–drug conjugate	pH-triggered charge reversal for nuclear targeting	Camptothecin	Nuclear localization of drug-enhanced cytotoxicity, compared with free drug, in adenocarcinoma cells	^[93]
TPP-modified liposome	–	Ceramide	Improved inhibition of tumor growth with mitochondrial targeting in a subcutaneous mouse model of mammary carcinoma tumors	^[94]

CPP: Cell-penetrating peptide; ELP: Elastin-like polypeptide; MMP: Matrix metalloproteinase; MTD: Maximum tolerated dose; PEG: Polyethylene glycol; RGD: Arginine–glycine–aspartic acid; TAT: Transactivator of transcription; TPP: Triphenylphosphonium.

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Stimulus-responsive Macromolecules and Nanoparticles for Cancer Drug Delivery

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