Preparation Of Stimuli-responsive Copolymer/Zinc Imidazde Framework-8 Carrier For Drug Release

At present,nanotechnology as a new technology of material preparation in the 21st century,especially for the rise of nanocomposites,is widely applied in the field of medicine.For example,it has extremely important research value in drug modification,human heart stent,wound bone repairing,anticancer therapy and drug delivery.This work mainly studies and prepares intelligent nanocarrier systems for controlled anticancer drug release and photodynamic therapy.Due to the controlled molecular weight,flexible and adjustable self-assemble morphologies,modified degree and good biocompatibility of the block copolymer,and further combination with the imidazole zeolite framework(ZIF-8)that is designed as a "drug entry and exit gate",a series of multifunctional drug controlled release systems with pH,H2O2 and light sensitivity were designed and prepared.Due to stable physicochemical properties,large specific surface area,open microporous channels and facile degradation of ZIF-8,the drug delivery system can effectively transport drug molecules to targeted location and reduce toxic side effects to normal tissues and cells during the drug delivery process.Meanwhile,combination with photodynamic therapy,the synergistic effect of the two methods can kill tumor cells more effectively and reduce cancer cell resistance.The experimental results show that the prepared nanocomposite carrier has excellent sustained release and controlled release effects,good biocompatibility,and easy cell uptaken and low cytotoxicity.This study provides ideas for the application of composite nanomaterials in medical diagnosis and treatment.The main research contents are divided into three parts:1.In first part,pH-responsive core-shell nanocomposites have been prepared by the growth of zeolitic imidazolate framework-8(ZIF-8)on the surface of polymeric aggregates self-assembled from poly(ε-caprolactone)-block-poly(quaternized vinylbenzyl chloride/bipyridine)(PCL-b-q(PVBC/BPy)in water,in which the core of the micelles or the inner cavity of vesicles serves as the drug storage reservoir for the doxorubicin hydrochloride(DOX)and the ZIF-8 shells act as the gatekeeper to prevent drugs premature release at physiological environment.Upon pH stimulus,the core-shell nanocomposites show a retarded drug release behavior compared with DOX-loaded polymeric aggregates counterparts(without the shell of ZIF-8).Moreover,the as-prepared nanocomposites perform good biocompatibility towards MCF-7 cell.Meanwhile,the DOX-loaded nanocomposites present lower cytotoxicity and the loaded DOX could be successfully released under acidic intracellular environment.The above result shows that the core-shell nanocomposite could be a promising candidate for pH-responsive drug delivery system in the cancer therapy2.In this part,a novel reactive oxygen species(ROS)synergistic pH/H2O2-responsive nanocomposite has been prepared from the self-assembly of poly(L-lactic acid)-block-poly(sodium 4-styrenesulfonate)(PLLA-b-PSS)in aqueous solution,followed by adding ferric citrate(Cit-Fe(III))through electrostatic interaction and growing ZIF-8 among the surface of the particles.Upon H2O2 and visible light stimuli,efficient ROS such as hydroxyl radicals(·OH)and sulfate radicals(SO4·-)can be generated through the catalyst of Cit-Fe(III).Meanwhile,sulfonate-containing polymeric vesicles are disassembled through oxidization by ROS and the encapsulated doxorubicin(DOX)will gradually diffuse into the ZIF-8 channels.The gatekeepers,ZIF-8,will collapse only under low pH condition and a burst drug release is achieved.In the presence of H2O2 and pH stimuli upon visible light exposure,the prepared DOX-loaded nanocomposite exhibits good selectivity of both generating ROS and releasing drug in tumor cell instead of normal cell3.In the last part,the pendant phenylboronic acid-containing triblock copolymer poly(ethylene glycol)-block-poly(3-acrylamidophenylboronic acid)-block-poly(2-(dimethylamino)ethyl methacrylate)(PEG-b-PAPBA-b-PDMAEMA)was prepared by two-step RAFT polymerization.Using the triblock copolymer as the electron acceptor and doxorubicin as the electron donor,the high-efficiency drug loading system was achieved.Similarly,the dual responsiveness of H2O2/pH nanocomposite drug delivery system with core-shell structure was prepared by growing ZIF-8 framework on the surface of drug loaded micelle.The ZIF-8 shell would collapse under acidic condition,while the excessive production of H2O2 in cancer cells could destroy the electron donor-receptor structure,thus the encalpusalted DOX could be released from nanocarrers.Meanwhile,it was also observed that the nanocomposite carrier was almost non-toxic,while the drug-loaded nanocomposite carrier had a strong inhibitory effect on the growth and reproduction of cancer cells,which was attributed to the highly efficient and quantitative drug-loading function of the carrier.