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 αvβ3 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.
Sarah R MacEwan1,2, Daniel J Callahan1,2 & Ashutosh Chilkoti†1,2
1Department of Biomedical Engineering, PO Box 90281, Duke University, Durham, NC 27708, USA
2Center for Biologically Inspired Materials & Material Systems, Duke University, Durham, NC 27708, USA
†Author for correspondence
Tel.: +1 919 660 5373 Fax: +1 919 660 5409 chilkoti@duke.edu
Tumor accumulation of macromolecules & nanoparticles
Leaky vasculature and lack of lymphatics allow increased accumulation of systemically delivered macromolecules and nanoparticles in tumor tissue.
Macromolecular carriers and nanoparticle vehicles enhance the circulation, accumulation and efficacy of chemotherapeutics.
Thermally responsive peptide polymers improve tumor accumulation by creating local depots of aggregated carriers in heated tumor vasculature.
Improved tumor distribution of macromolecule & nanoparticle payloads
High interstitial fluid pressure and low diffusivity inhibit the intratumoral penetration of anticancer therapeutics encapsulated in drug vehicles.
Release of drug from responsive carriers triggered by localized intrinsic or extrinsic cues can improve the penetration of drug into tumor tissue.
Further investigation is needed to verify the effect of tumor-localized release of drug from conjugates or carriers on intratumoral drug distribution and to demonstrate its therapeutic benefit.
Enhanced cellular uptake of drug carriers & control of the intracellular fate of drug cargo
Cellular uptake and intracellular drug release is critical for the therapeutic action of many targeted anticancer drugs.
Tumor-specific presentation of bioactive molecules in response to enzymatic, pH or temperature stimuli affords improved specificity and efficacy of targeted drug delivery to tumors.
Reducing conditions and low pH can trigger drug release in intracellular compartments.
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