Synthesis, Self-assembly And Drug Release Studies Of Redox-responsive Amphiphilic Block Copolymers

Stimuli-responsive block copolymers are the most studied and most widely used type of polymers at present.Especially,redox-sensitive amphiphilic block copolymers have developed rapidly in recent years.Compared with normal tissues,tumors cells contain high level of active oxygen free radicals(ROS).Therefore,the site-specific,controllable and targeted drug release at various cancerousposotions could ultimately be achieved by tuning redox-sensitivity of drug delivery carriers in view of this distinction in physiological environments.At present,the redox sensitive block copolymers have been extensively used as the delivery vectors of small molecule drugs,siRNA,DNA,as well as pharmaceutical proteins.Based on the aforementioned research foundation,a series of redox-sensitive amphiphilic block copolymers were synthesized in this work via atom transfer radical polymerization(ATRP)method,and the self-assembly behavior in an aqueous solution,redox sensitivity and controlled drug release behaviors was studied.The main contents of this project were as follows:1.A series of poly(N-acryloylmorpholine-block-2-acryloyloxyethyl ferrocene carboxylate)(PACMO-b-PAEFC)amphiphilic block copolymers with various hydrophilic/hydrophobic molar ratios were synthesized via ATRP using N-acryloylmorpholine(ACMO)with biocompatibility,non-toxicity and low immunity as a raw material and 2-acryloyloxyethyl ferrocene-carboxylate(AEFC)as a comonomer.The chemical structures of copolymers were characterized by FT-IR,1H NMR and GPC measurements,and the crystalline behavior was determined by X-ray diffraction(XRD)and small-angle X-ray scattering(SAXS).The results showed that the copolymers assumed layered crystal packing structure.The size of the lamellar crystals and crystallinity vary with the systematic compositions,while the periodic structure of the lamellar stacks has no obvious change.2.TEM and DLS were employed to observe the self-assembly behavior of the block copolymers,and the results showed that the PACMO-b-PAEFC copolymers could self-assemble and form globular nanoscaled core-shell micellar aggregates in aqueous solution.Furthermore,we researched the morphological change of polymer micelles induced by different oxidants such as H2O2,NaCIO,FeCl3 or KMnO4 and reductant vitamin C(Vc).UV-vis,TEM and dynamic light scattering(DLS)measurements suggested that the ferrocene groups in reduced form could be oxidized into hydrophilic ferrocenium by water-soluble oxidants.As a consequence,the hydrophobic cores of the micelle in a curled state changed into a stretched state,leading to swelling of the micelles and increase in size of the micelles.When the ferrocenium in an oxidation state was reduced by vitamin C,the ferrocene with electroneutrality was generated,and the micelles were reversibly recover from their original states,showing the reversible redox self-assembly and disassembly feature.The cyclic voltammetry(CV)measurements demonostrated that the copolymers had(quasi)reversible redox electrochemical activitivites,which could be adjusted by the copolymer compositions.3.Paclitaxel(PTX)were chosen as model anticancer drugs to investigate the drug loading capacity of the copolymer micelles with various hydrophilic/hydrophobic ratios,and the oxidant stress drug release behavior from the drug-loaded copolymer micelles.The experimental results illustrated that the drug loading contents could be modulated by adjusting the composition of the copolymers,and increased with increasing the hydrophobic proportion.The in vitro drug release indicated that the release rate from the drug-loaded micelles was faster upon induced by oxidants in PBS solution of pH 5.8 than at PBS solution of pH 7.4,and the release amount increased,reaching at 61.4%.The release rate could be mediated by the kinds and concentrations of oxidants,achieving oxidation-controlled drug release.MTT assay was performed to evaluate the biomedical properties of the blank and the drug-loaded copolymer micelles.The results showed that the blank micelles were non-toxic,disclosing excellent biocompatibility.The PTX-loaded nanomicelles could enhance the anticancer activity,and further improve anticancer efficiency.This makes the developed copolymer nanomicelles become potential drug delivery carriers for cancer therapy.