Stimuli-responsive cross-linked micelles for on-demand drug delivery against cancers☆
Graphical abstract
Schematic illustration of stimuli-responsive cross-linked micelles (SCMs) for cancer therapy.
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.).
References (82)
- et al.
Toward a siRNA-containing nanoparticle targeted to breast cancer cells and the tumor microenvironment
Int. J. Pharm.
(2012) - et al.
The effect of mechanical properties of iron oxide nanoparticle-loaded functional nano-carrier on tumor targeting and imaging
J. Control. Release
(2012) - et al.
Hydrolysable core-crosslinked thermosensitive polymeric micelles: synthesis, characterisation and in vivo studies
Biomaterials
(2007) - et al.
Lysine-block-tyrosine block copolypeptides: Self-assembly, cross-linking, and conjugation of targeted ligand for drug encapsulation
Polymer
(2012) - et al.
Intracellular drug release nanosystems
Mater. Today
(2012) - et al.
Supramolecular assemblies of block copolymers in aqueous media as nanocontainers relevant to biological applications
Prog. Polym. Sci.
(2006) - et al.
Well-defined, reversible disulfide cross-linked micelles for on-demand paclitaxel delivery
Biomaterials
(2011) - et al.
Biodegradable micelles with sheddable poly(ethylene glycol) shells for triggered intracellular release of doxorubicin
Biomaterials
(2009) - et al.
Core-crosslinked polymeric micelles with controlled release of covalently entrapped doxorubicin
Biomaterials
(2010) - et al.
Targeted core-crosslinked polymeric micelles with controlled release of covalently entrapped doxorubicin
J. Control. Release
(2010)
The role of glutathione-dependent enzymes in drug resistance
Pharmacol. Ther.
Mechanisms of resistance to cisplatin
Mutat. Res.
A detailed examination of boronic acid–diol complexation
Tetrahedron
Polymer micelles with cross-linked ionic cores for delivery of anticancer drugs
J. Control. Release
Core cross-linked block ionomer micelles as pH-responsive carriers for cis-diamminedichloroplatinum(II)
J. Control. Release
Nanotechnologies and cancer: diagnosis and therapeutic future
Bull. Cancer
Preliminary evaluation of a nanotechnology-based approach for the more effective diagnosis of colon cancers
Nanomedicine
In vivo tumor diagnosis and photodynamic therapy via tumoral pH-responsive polymeric micelles
Chem. Commun. (Camb.)
Nanoparticle ‘fingerprinting’ technique could improve cancer diagnosis
Bioanalysis
The potential of targeting nanoparticle for breast cancer diagnosis
Eur. J. Cancer
The ligand nanoparticle conjugation approach for targeted cancer therapy
Curr. Drug Metab.
Nanoparticle-mediated measurement of target-drug binding in cancer cells
ACS Nano
pH and redox dual responsive nanoparticle for nuclear targeted drug delivery
Mol. Pharm.
Simultaneous detection of intracellular tumor mrna with bi-color imaging based on a gold nanoparticle/molecular beacon
Chem. Eur. J.
A novel clinically translatable fluorescent nanoparticle for targeted molecular imaging of tumors in living subjects
Nano Lett.
Nanoparticle-enabled terahertz imaging for cancer diagnosis
Opt. Express
Current status of nanoparticle-based imaging agents for early diagnosis of cancer and atherosclerosis
J. Biomed. Nanotechnol.
Applications of polymeric micelles with tumor targeted in chemotherapy
J. Nanopart. Res.
Multi-dye theranostic nanoparticle platform for bioimaging and cancer therapy
Int. J. Nanomedicine
Preclinical evaluation of injectable sirolimus formulated with polymeric nanoparticle for cancer therapy
Int. J. Nanomedicine
Design of biocompatible dendrimers for cancer diagnosis and therapy: current status and future perspectives
Chem. Soc. Rev.
Application of near-infrared fluorescence imaging using a polymeric nanoparticle-based probe for the diagnosis and therapeutic monitoring of colon cancer
Dig. Dis. Sci.
Aoe, Multifunctional Nanoparticle with Diagnosis and Therapeutics for Tumour
Nanotechnology applications in cancer
Annu. Rev. Biomed. Eng.
Diacyllipid-polymer micelles as nanocarriers for poorly soluble anticancer drugs
Nano Lett.
Nanoparticle therapeutics: an emerging treatment modality for cancer
Nat. Rev. Drug. Discov.
Overcoming limitations in nanoparticle drug delivery: triggered, intravascular release to improve drug penetration into tumors
Cancer Res.
Probing of the assembly structure and dynamics within nanoparticles during interaction with blood proteins
ACS Nano
Making polymeric nanoparticles stimuli-responsive with dynamic covalent bonds
Polym. Chem.
Reversibly stabilized multifunctional dextran nanoparticles efficiently deliver doxorubicin into the nuclei of cancer cells
Angew. Chem. Int. Edit.
Biological stimuli responsive drug carriers based on keratin for triggerable drug delivery
J. Mater. Chem.
Cited by (267)
Emerging trends in nano-carrier based gene delivery systems for targeted cancer therapy
2024, Journal of Drug Delivery Science and TechnologyROS-responsive camptothecin-linked thioketal drug delivery system based on ring-closing polymerization
2024, European Polymer JournalMineralized vectors for gene therapy
2022, Acta BiomaterialiaCitation Excerpt :The mineralization of pre-assembled particles provides an extra acid-labile protection layer to crosslinking techniques of the shell, in which stimuli-labile crosslinks are introduced to polymer NPs, making it stable at extracellular conditions. Upon stimuli, the labile crosslinks can be cleaved, increasing the efficacy of drug delivery due to protection against drug leakage in the extracellular environment [288]. However, the breaking of the crosslinks may be accompanied by changes in the polymer structures leading to undefined species as well as the generation of toxic by-products [289].
Effect of diisocyanate structure on steric restructuring of hindered urea bonds for self-healable coating
2022, Progress in Organic Coatings
- ☆
This review is part of the Advanced Drug Delivery Reviews theme issue on "Cancer Nanotechnology".
- 1
Yuanpei and Kai contributed equally to this work.