Synthesis And Characterization Of Multi-Stimuli Sensitive Copolymer For Drug Delivery

In the pas’t decades,nanocarriers for targeted delivery of anticancer drugs have been regarded as a promising technology.However,the drug accumulation in tumor sites via the enhanced permeability and retention(EPR)effect cannot fully fulfill the requirements of cancer therapy.With the rise of "intelligent" materials,a variety of nanocarriers which can make changes in structures,morphology and physicochemical properties in response to the external stimuli and the differences between tumor cells and normal cells is designed.The stimuli include pH,redox,temperature,enzyme,light,ultrasound and so on.In addition,the response behaviors can be either reversible or irreversible,and the stimuli can be single or multiple.Herein,this dissertation is mainly focused on internal stimuli,and selects different biodegradable/biocompatible polymers including poly(ethylene glycol)(PEG),poly(ε-caprolactone)(PCL)and polyphosphoesters(PPEs)to fabricate a series of stimuli-responsive nanocarriers for the delivery of anticancer drugs.The main content of present work can be summarized as follows:1.Dual-Responsive Polyphosphoester-Based Core-Crosslinked Nanoparticles for pH/Redox-Triggered Anticancer Drug Delivery.We developed biodegradable pH/redox dual-responsive polyphosphoester-based core-crosslinked nanoparticles(DOX/CCL NPs)loaded with dual anticancer drugs PTX and DOX.First,the polyphosphoester prodrug PTX-PBYP-b-PEEP was prepared via one-pot sequential ring-opening polymerization of cyclic phosphate monomers by using the antieancer drug PTX as the initiator.Then,the functional carboxyl groups were ereated by the radical-mediated thiol-yne "click" reaction between the thiol group of 3-mercaptopropionic acid(MPA)and the alkynyl groups on the PBYP repeats of PTX-PBYP-b-PEEP.The introduced carboxyl groups were utilized for encapsulating the anticancer drug DOX·HCl via the electrostatic interaction and for partial crosslinking by amidation to endow the NPs with cleavable disulfide(S-S)linkages.The chemical structures of the obtained polymers were confirmed by 1H NMR,31P NMR,GPC and FT-IR,respectively.The self-assembly behavior of those polymers were investigated using TEM,DLS and zeta potential measurements.The functional prodrug could self-assemble into nanoparticles with average sizes of 147 nm in PB 7.4,and DOX·HCl could be encapsulated via the electrostatic interaction and crosslinking structure,which endow DOX/CCL NPs with high DOX-loading capacity of DLC(14.6%)and DLE(73.1%)and pH/redox dual stimuli responses.The in vitro drug release studies showed that DOX was released in a controlled and pH/redox manner,in which～10%,30%,45%and 65%of DOX was released after 72 h at pH 7.4,pH 5.0,10 mM GSH and pH 5.0 containing 10 mM GSH,respectively.Furthermore,DOX/CCL NPs could be efficiently internalized by HeLa cells and exhibited higher efficacy in inducing cell apoptosis as compared to free drugs in the studies of in vitro cytotoxicity and intracellular uptake.Herein,these biodegradable dual-responsive core-crosslinked NPs provided a promising platform for cancer therapy.2.Dual Redox Responsive Diselenium-Containing PCL-PEGSeSe-PCL Copolymers:Synthesis,Characterization,and Application in Drug DelivelryTo achieve rapid drug release behavior after arrival in the target sites,we deisgned a biocompatible and dual redox responsive diselenium-containing PCL-PEGSeSe-PCL triblock copolymer via the copper(Ⅰ)-catalyzed alkyne-azide cycloaddition(CuAAC)for active loading and triggered intracellular drug release.First,we prepared two kinds of bifunctional moleceules(N3-Sese-N3 and PA-PEG-PA)for the preparation of alternating copolymer PA-PEG-alt－SeSe-PA via CuAAC.After conjugation with poly(ε-caprolactone)(PCL),dual redox responsive triblock copolymer PCL-PEGSeSe-PCL(abbreviated as PCESeC)was obtained,which could self-assemble into nanoparticles with average size of 108 nm.The PCESeC nanoparticles exhibited rapid dual redox-responsive behaviors in the presence of 10 mM GSH and 0.5 wt%H2O2.The in vitro drug release studies can also prove it that the DOX release behavior was a controlled and dual redox manner,in which～72%and 23%of DOX was released after 60 h at 10 mM GSH and pH 7.4,respectively.In addition,The PCESeC nanoparticles showed almost non-toxic up to a tested concentration of 0.2 mg/mL both in L929 and HeLa cells.Furthermore,DOX-loaded diselenium-containing ABA triblock copolymer nanoparticles(DOX-dSeN)exhibited the efficacy in inducing cell apoptosis in the studies of the in vitro cytotoxicity.Furthermore,DOX-dSeN could be efficiently internalized by HeLa cells in the studies of intracellular uptake.Herein,these biocompatible dual-responsive diselenium-containing triblock copolymer provided a promising platform for cancer therapy.