Preparation And Property Of Tetraphenylsilane-Cored Star-Shaped Polymers As Anti-cancer Nanomedicine Carriers

Compared with traditional chemotherapeutics,polymer nanomedicine has the advantages of high efficiency,targeting,and no side effects.However,there are still some urgent problems in current research in this field,including:(1)During the circulation in the body,the polymer nanomedicine has the risk of being cleared by tissue cells and the drug was released in advance;(2)It is difficult to achieve high-efficiency accumulation of nanomedicine on tumor tissues and effective endocytosis of nanomedicine by cancer cells through enhanced permeability and retention effect(EPR effect)alone.(3)The current drug loading of polymer nanomedicine is not high enough;(4)A single chemotherapeutic nanomedicine may not be able to meet the clinical needs,how to achieve multiple drugs or multiple ways to treat cancer.In response to the above problems,this thesis designed and synthesized a series of stimulus-responsive polymer nano-drugs,aiming to introduce the star-shaped multi-arm polymer topology,active targeting function,multiple stimulus-response function,and combined chemotherapy of multiple drugs.To improve the efficiency of its circulation in the body,tumor tissue accumulation,endocytosis and intracellular drug release.The main research contents are as follows:Using tetrakis(4-(1-bromoethyl)phenyl)silane(BTES)as the initiator,pH-responsive four-arm star amphiphilic block copolymers with adjustable arm length(PDEAEMA-bPHEMA)were synthesized via atom transfer radical polymerization(ATRP)from diethylaminoethyl methacrylate(DEAEMA)and hydroxyethyl methacrylate(HEMA).Meanwhile,linear block copolymers with similar structures and similar molecular weights were also prepared for comparison.The hydrophilic-hydrophobic segments of the block copolymer are PHEMA and PDEAEMA,which can self-assemble with the anticancer drug doxorubicin(DOX)in water to form drug-loaded micelles.The drug loading of star micelles can reach 33.97%,far exceeding linear micelles(8.92%)and previously reported star copolymers with pentaerythritol as the core.The particle size of drug-loaded micelles is 123 nm-158 nm,which can be accumulated through the EPR effect.In vitro release realization experiments show that the structure of drug-loaded micelles changes in the tumor tissue environment to quickly release drugs.Cytotoxicity experiments confirmed that blank micelles have almost no cytotoxicity,and the cytotoxicity of drug-loaded micelles to human cervical cancer cells(Hela cells)has similar anti-cancer activity to free DOX.A series of pH/reduction dual response four-arm star amphiphilic polymers(BPSPF)with active targeting function were synthesized.With BTES as the core,the hydrophobichydrophilic segments are composed of pH-responsive PDEAEMA and polyethylene glycol(PEG)connected by disulfide bonds.The end of each arm is modified with the active targeting monomer folic acid(FA).The critical micelle concentration(CMC)of 1.03-2.51 mg/L was tested by pyrene fluorescent probe,indicating that it has good stability in the circulation in the body.BPSPF and DOX self-assembled to form a drug-loaded micelle DOX@BPSPF,and its drug-loading amount was up to 32.3%.The observation of confocal laser microscope confirmed that the modification of FA at the end of the polymer can effectively enhance its internalization ability in HeLa cells.Dynamic light scattering(DLS)and transmission electron microscopy(TEM)confirmed that BPSPF has a sensitive pH and redox dual responsiveness.In an in vitro drug release experiment that simulates the tumor environment,DOX@BPSPF can achieve a DOX release rate of 68%in 24 h.Cytotoxicity experiments show that the cytotoxicity of DOX@BPSPF to Hela cells is almost the same as that of the original drug DOX.A polymer prodrug(BT(DOX)SPF)with a star-shaped structure that releases a high drugloading capacity step by step with multiple responses was prepared.DOX is connected to the main chain of the polymer through acid-labile bonds and imine bonds to form a hydrophobic segment.PEG is connected to the hydrophobic segment through a disulfide bond with redox response.Finally,FA is modified to the end of the segment to increase the glue.The ability of the beam to actively target.The drug loading can be adjusted by the dosage ratio of DOX and polymer,and the maximum can reach 47.3%.and the encapsulation efficiency exceeds 90%.Zeta potential test BT(DOX)SPF is negatively charged at pH 7.4,which is conducive to long-term circulation in the body,while at pH 6.5,it is positively charged to improve the efficiency of drug endocytosis,In vitro drug release experiments showed that the drug release rate was still less than 10%after a week of continuous culture in a pH 7.4 environment,indicating that the chemical bonding method of drug delivery can effectively avoid early drug release.The DLS experriment proved that the structure of BT(DOX)SPF disintegrated under the dual response condition,and the DOX was more than 70%10 hours before the rapid release.For the in vivo experiments using mice,BT(DOX)SPF has a significant anti-tumor effect.and at the same time it has no additional toxic side effects on normal tissues and organs in the body.Designed and synthesized a four-arm star-shaped combination chemotherapy nanomedicine for simultaneous delivery of DOX and camptothecin(CPT)for the coordinated treatment of cancer.DOX and CPT are connected to the polymer through imine bonds and disulfide bonds,respectively.Biocompatible Dex was the hydrophilic segment,DOX and CPT were used as hydrophobic segments to self-assemble into polymer prodrug micelles in water.with a particle size of about 100 nm DLS.TEM and in vitro drug release experiments confirmed that the prodrug Dex(CPT)-BT(DOX)has good pH/reduction dual sensitivity and can quickly release DOX and CPT drugs in the tumor environment without early drug release The phenomenon occurs.The cytotoxicity experiment proved that the material itself has good biocompatibility and compared with polymer prodrugs loaded with a single drug,Dex(cPT)BT(DOX)shows higher cytostatic efficiency for HeLa cells.Obvious synergistic treatment effect.Cell resistance experiments also confirmed that Dex(CPT)-BT(DOX)can effectively overcome the multi-drug resistance of cancer cells to anticancer drugs.