Multiple Stimuli-Responsive and Core-Crosslinked Micelles for Tumor-Targeted Delivery of Dual Drugs
Poly(ethylene glycol)monomethyl ether-b-poly(diisopropylaminoethyl methacrylate-b-poly(methacrylic acid)/lipoic acid(mPEG-b-PDPA-b-PMAA/LA),a novel amphiphilic triblock polymer,was designed and synthesized.A core-crosslinked micelle(CCM)for drug delivery was then formed by mPEG-b-PDPA-b-PMAA/LA through self-assembly and crosslinking reaction.The resulting CCM exhibited high stability in blood serum and against dilution compared to uncrosslinked micelles(UCM).CCM achieved high drug loading compared to UCM through investigating the encapsulation and release kinetics of DOX.With increasing polymerization of PDPA and PMAA,the drug-loading content(DLC)and drug-loading efficiency(DLE)of doxorubicin(DOX)in CCM increased,suggesting that the encapsulation capacity for DOX was enhanced with an increase in the hydrophobic core of the micelles.In addition,the CCM was shown to be capable of controlled release of drugs.An acidic pH and the presence of glutathione(GSH)led to the protonation of PDPA and collapse of PMAA gel,respectively,which caused the collapse of the micellar construct.This enabled a maximal DOX release rate of 90%.Then,the simultaneous loading and release of two therapeutics,DOX and HApt,using the micellar system was investigated.HApt and DOX were sought to be encapsulated in the PMAA gel and PDPA layer,respectively.The dual drug-release behaviors of the system were evaluated under different environmental stimulations.The CCM system for drug delivery designed in this paper is expected to achieve a synergistic effect of gene therapy and chemotherapy.
tumor targetingdual pH/GSH responseCCMdual drug loadingcontrolled drug releaseintracellular delivery of biomolecule
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