Elsevier

Advanced Drug Delivery Reviews

Volume 66, February 2014, Pages 58-73
Advanced Drug Delivery Reviews

Stimuli-responsive cross-linked micelles for on-demand drug delivery against cancers

https://doi.org/10.1016/j.addr.2013.09.008Get rights and content

Abstract

Stimuli-responsive cross-linked micelles (SCMs) represent an ideal nanocarrier system for drug delivery against cancers. SCMs exhibit superior structural stability compared to their non-cross-linked counterpart. Therefore, these nanocarriers are able to minimize the premature drug release during blood circulation. The introduction of environmentally sensitive cross-linkers or assembly units makes SCMs responsive to single or multiple stimuli present in tumor local microenvironment or exogenously applied stimuli. In these instances, the payload drug is released almost exclusively in cancerous tissue or cancer cells upon accumulation via enhanced permeability and retention effect or receptor mediated endocytosis. In this review, we highlight recent advances in the development of SCMs for cancer therapy. We also introduce the latest biophysical techniques, such as electron paramagnetic resonance (EPR) spectroscopy and fluorescence resonance energy transfer (FRET), for the characterization of the interactions between SCMs and blood proteins.

Graphical abstract

Schematic illustration of stimuli-responsive cross-linked micelles (SCMs) for cancer therapy.

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Introduction

Nanotechnology offers new opportunities for diagnosis and treatment of a variety of cancers [1], [2], [3], [4], [5]. Multifunctional nanoparticles possessing functions including tumor targeting [6], [7], [8], [9], [10], imaging [11], [12], [13], [14] and therapy [10], [15], [16], [17] are under intensive investigation aiming to overcome limitations associated with conventional cancer diagnosis and therapy [18], [19], [20]. Over the past decade, polymeric micelles have been extensively investigated as nanocarriers to deliver conventional anticancer drugs. These nanoparticles provide several distinct advantages for the drugs, such as improved solubility, prolonged in vivo circulation time and preferential accumulation at tumor site via the enhanced permeability and retention effect [21], [22], [23], [24]. Despite the recent progress in the research of micellar nanoparticles, some shortcomings are gradually revealed which may limit their application in clinic. In blood circulation, blood proteins and lipoproteins such as high density lipoprotein (HDL), low density lipoprotein (LDL), very low density lipoprotein (VLDL) and chylomicron may interact with the polymeric micellar nanoparticles [25]. This process can result in the early disintegration or aggregation of micelles and premature drug release [26]. Besides, polymeric micelles are thermo-dynamic self-assemble system which has a well-known equilibrium existed between micelles and unimers (assembly unit) in aqueous condition. After being injected into the blood stream, conventional self-assembled polymeric micelles are susceptible to dilution below the critical micelle concentration (CMC). This may lead to the dissociation of micelles into unimers.

Cross-linking strategy has been utilized to solve the above mentioned stability problems following the pioneer work by Wooley's group [27]. Since then, this strategy has been exploitedby a number of other groups [28], [29], [30], [31], [32], [33]. Covalent cross-links between specific domains of the micelles are formed in order to improve the micelles' structural stability suitable to drug delivery rather than the weak non-covalent intermolecular hydrophobic interactions existing in the conventional polymeric micelles that facilitate polymer micelles assembly and integrity [27]. To be more effective, anticancer drugs should be released exclusively in tumor tissue or inside tumor cell. However, excessively stabilized micelles may prevent the drug from releasing to target sites, thus reducing the therapeutic efficacy [28], [29]. Stimuli-responsive cross-linked micelles (SCMs) are introduced to improve the drug delivery [30], [31], [32], [33]. SCMs exhibit unique stability in blood circulation and can better retain the drug contents. The utilization of environmentally sensitive cross-linkers or assembling units makes SCMs responsive to single or multiple stimuli in the microenviroment of tumor site or inside the tumor cells [34], [35] or the application of exogenous stimuli (Fig. 1). The cleavage of the intra-micellar cross-linkage or disassembly of the micelles responding to stimuli leads to exclusively drug release in the target site [36], [37]. The special micelles are often called ‘smart’ or ‘intelligent’ micellar nanoparticles. This review briefly summarizes the recent advances in stimuli-responsive cross-linked micellar nanocarriers with the main focus on the design, characterization, cross-link strategy, protein interaction, stimuli-sensitive release mechanism and preclinical evaluation.

Section snippets

Design of stable SCMs with single or multiple responsive properties

The basic elements need to be considered in the design of SCMs include how and where to introduce cross-linkages to the micelles and how to endow the micelles with responsiveness to the microenvironments of the target sites or exogenous stimuli. The cross-linkage can be introduced at the hydrophilic shell [38], [39], hydrophobic core [26], [40], [41] or core–shell interface [35], [42] of the micelle via chemical cross-link, photo cross-link or polymerization after the micelle formation via

List of all abbreviations

    EPR

    Electron paramagnetic resonance

    FRET

    Fluorescence resonance energy transfer

    MDR

    Multidrug resistance

    CMC

    Critical micelle concentration

    HDL

    High density lipoprotein

    LDL

    Low density lipoprotein

    VLDL

    Very low density lipoprotein

    DCMs

    Disulide cross-linked micelles

    NCMs

    Non-cross-linked micelles

    BCMs

    Boronate cross-linked micelles

    EPR

    Enhanced permeability and retention

    PTX

    Paclitaxel

    DOX

    Doxorubicin

    VCR

    Vincristine

    MTX

    Methotrexate

    GSH

    Glutathione

    RAFT

    Reversible addition-fragmentation chain transfer

    PEG-b-PHPMA-LA

Acknowledgments

The authors thank the financial support from NIH/NCI (R01CA115483 to K.S.L.), NIH/NIBIB (R01EB012569 to K.S.L.), Prostate Cancer Foundation Creative Award (to K.S.L.), US Department of Defense (DoD) PCRP Award (W81XWH-12-1-0087 to Y.L.) and DoD BCRP Award (W81XWH-10-1-0817 to K.X.).

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    This review is part of the Advanced Drug Delivery Reviews theme issue on "Cancer Nanotechnology".

    1

    Yuanpei and Kai contributed equally to this work.

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