Preparation And Application Of Stimulus-responsive Core/shell Cross-linked Polymer Nanoparticles

Smart polymeric materials based on stimuli-responsive which can undergo reversible or irreversible changes in physical properties and/or chemical structures in response to exogenous(light,temperature,ultrasound and voltage)or endogenous(pH,sugar,redox and enzyme)stimuli,had garnered gigantic attention and considerable development,owing to their wide applied field,such as catalysis,sensors,reactors,enzyme immobilization,and drug delivery.Up to now,the nanosystems based on stimuli-responsive polymer including micelles,polymersomes,nanogels,nanocages,and other nanoassemblies have been intensively designed and studied.In these nanosystems,nanomicelles based on block copolymers with excellent properties,such as easy preparation and storage,improving the solubility and circulation time in vivo of anticancer drugs,and increasing drug accumulation in target tumor tissue because of the enhanced permeability and retention(EPR)effect,were preferentially designed and studied.However,polymeric micelles have a "burst release"(20?30%of the loaded drug)within several hours post micelle formation and very slow release rate in the following process due to the diffusion of drug.In addition,the secondstage slow drug release results in the dosage of intracellular drug lower than the level of killing cancer cells after the nanocarriers are endocytosed into cancer cells.As far as we know cancer cells maintain an acidic microenvironment,for instance inside endosomes(pH<6.8)and lysosomes(pH 4.5?6.5),and they may overproduce the glutathione(GSH)or cysteine,resulting in several times higher than normalcells.More importantly,these DDS faces another important issue as the structure of micelles can be severely damaged below the critical micelle concentration(CMC)or under high salt concentrations and shearing forces.Up to now,the most promising strategy is that shell or core of SRPM is crosslinked by the disulfide bond with reversible reduction-responsive.To date,a majority of DDS are fabricated to respond single or double stimuli.Therefore,in the light of the advantages/disadvantages of the micelles and complex microenvironment of cancer cells,multi-stimuli-response core(or shell)crosslinked polymeric micelles will be one of the optimal candidates for cancer therapy.(1)Synthesis of temperature,pH,light and dual-redox quintuple-stimuli-responsive shell-crosslinked polymeric nanoparticles for controlled releaseA novel quintuple-stimuli-responsive shell-crosslinked(SCL)nanoparticle in respond to temperature,pH,light,and oxidation or reduction species was prepared.The well-defined amphiphilic diblock copolymer poly(2-methacryloyloxyethyl ferrocenecarboxylate)-(o-nitrobenzyl)-poly(dimethylaminoethyl methacrylate)(PMAEFc-ONB-PDMAEMA)was synthesized via atom transfer radical polymerization(ATRP)and click chemistry(CuAAC).The diblock copolymer self-assembled into spherical micelles with a uniform size in aqueous media as non-crosslinked(NCL)micelles,and then the micelles were crosslinked by N,N'-bis(bromoacetyl)cystamine(BBAC)through quaternization reaction between the nitrogen of DMAEMA and the bromine of BBAC to receive the SCL micelles which shrunk at higher temperature,swelled at acidic pH or a low concentration of hydrogen peroxide(H2O2),decrosslinked by a small amount of DL-dithiothreitol(DTT),and were disrupted with DTT and UV light.The multi-stimuli-sensitive properties of the SCL micelles were characterized in detail by dynamic light scattering(DLS),transmission electron microscopy(TEM),fluorescence spectra,and UV-Vis spectra.Owing to the protective effect of the crosslinked network,light response behaviors of the NCL and SCL micelles were different.In contrast to the single stimulus,the combined stimuli could trigger and regulate the release of hydrophobic drug model Nile Red(NR)more effectively and precisely from the SCL micelles.The obtained multi-stimuli-responsive nanocontainers may lead to a new generation of controlled release in the fields of nanotechnology and biotechnology.(2)Temperature,pH,and reduction triple-stimuli-responsive interlayer crosslinked polymeric micelles based on tetrablock copolymer for drug releaseTemperature,pH,and reduction triple-stimuli-responsive innerlayer crosslinked micelles as nanocarriers for drug delivery and release were designed.Well-defined tetrablock copolymer,poly(polyethylene glycol methacrylate)-poly(2-(dimethylamino)ethyl methacrylate)-poly(N-isopropylacrylamide)-poly(methylacrylic acid)(PPEGMA-PDMAEMA-PNIPAM-PMAA)was synthesized via ATRP,CuAAC and esterolysis reaction.The tetrablock copolymer self-assembled into non-crosslinked(NCL)micelles at acidic aqueous solution.The core-crosslinked(CCL)micelles,SCL micelles and shell-core dilayer-crosslinked(SCCL)micelles were prepared via quaternization reaction or the carbodiimide chemistry reaction.The crosslinked micelles were used as drug carriers to load doxorubicin(DOX),and drug encapsulation efficiency under 20%feed ratio reached to 59.2%,73.1%,and 86.1%,respectively.The cumulative release rate of DOX was accelerated by single or combined stimulations.MTT assay verified that the innerlayer crosslinked micelles showed excellent cytocompatibility,and DOX-loaded micelles exhibited significantly higher inhibition for HepG2 cells proliferation.The obtained innerlayer crosslinked polymeric micelles with triple-stimuli-responsive,higher drug loading content,and excellent stability and cytocompatibility hold great potential as smart nanocarriers in the field of drug delivery systems for cancer therapy.