Design,preparation And Anti-tumor Research Of Nanodrug Delivery System For Combination Chemotherapy

Cancer is a serious threat to people’s health,and chemotherapy is still one of the most effective clinical treatments.As we all know,Small molecule chemotherapeutics generally have weak water solubility,low targeting,poor bioavailability,tall toxicity and side effects,and drug restraint,which severely limit their clinical applications.At present,platinum metal anticancer drugs have become indispensable drugs in the treatment of cancer.According to statistics,chemotherapy regimens involving cisplatin or cisplatin drugs account for approximately 70% to 80% of all treatment regimens.However,severe neurotoxicity,nephrotoxicity,and congenital or acquired drug resistance make the therapeutic effect impossible to achieve.In recent years,combination chemotherapy is gradually replacing cisplatin single-drug regimen for cancer treatment.Compared with single-drug regimens,combined chemotherapy uses chemotherapeutic drugs with different mechanisms of action,which can act on different molecular targets of tumor cells to maximize the therapeutic effect of the drug;reduce the dose of a single drug and the long-term effect of a single drug The possibility of toxic and side effects is enhanced;even the drug resistance is reversed to a certain extent.Therefore,combined chemotherapy is a very attractive chemotherapy method.However,combined chemotherapy also has problems such as weak targeting,wide distribution in the body,fast metabolism in the body,and low bioavailability.As we all know,polymer nano-drug delivery systems have many advantages over small-molecule chemotherapeutic drugs.For example,They can accelerate the dissolution of lowly soluble drugs in the blood,protect the drugs from premature degradation,increase the circulation time of the drugs entering the blood,improve the pharmacokinetics and tissue distribution of the drugs,and use the "EPR effect" to increase resistance.Accumulation of cancer drugs in tumor tissues,etc.Therefore,the controlled release system of polymer nano-drugs combined with combination chemotherapy has more research significance and clinical application prospects.Based on this,this paper mainly includes the following two parts:(1)By rational design,an acid and reduction dual-sensitive dextran-di-drugs conjugate(oDex-g-Pt+DOX)was synthesized by the covalent conjugation of Pt(Ⅳ)prodrug and doxorubicin(DOX)to an oxidized dextran(oDex).(Ⅳ)prodrug and DOX were linked by the versatile efficient esterification reactions and schiff base reaction,respectively.oDex-g-Pt+DOX could self-assemble into nanoparticle with an average diameter at around 180 nm.Acidic and reductive(GSH)environment induced degradation and drugs release behaviors of the resulted nanoparticle(oDex-g-Pt+DOX NPs)were carefully investigated by optical experiment,DLS analysis,TEM measurement and in vitro drugs release experiment.Effective cellular uptake of the oDex-g-Pt+DOX NPs was identified by the human cervical carcinoma He La cells via endocytosis pathway.Furthermore,oDex-g-Pt+DOX NPs displayed a closer antiproliferative activity to the simple combination of free cisplatin and DOX(Cis+DOX)as the extension of time.More importantly,oDex-g-Pt+DOX NPs exhibited remarkable reversal ability of tumor resistance to the cisplatin in cisplatin-resistant lung carcinoma A549 cells.Take advantage of the acidic and reductive microenvironment of tumor,this smart polymer-dual-drugs conjugate can serve as promising and effective nanomedicine for combination chemotherapy.(2)Through reasonable design,the (Ⅳ)prodrug and the tetraphenylethylene unit with aggregation-induced luminescence effect are first copolymerized to form a hydrophobic segment and then grafted to hydrophilic polyethylene glycol to construct a good biocompatibility,multifunctional triblock copolymer.The synthesized nano-carrier polymer prodrug(PtAIECP)has both the functions of fluorescence imaging and anti-cancer activity.We further physically load doxorubicin(DOX)into the above polymer prodrug(PtAIECP).The prepared nanomaterial(PtAIECP+DOX)is still a micellar structure,and the energy of the TPE molecule passes through fluorescence.Fluorescence resonance energy transfer(FRET)is transferred to DOX,causing TPE fluorescence to be turned off.However,based on the reductive microenvironment inside the tumor cell,the tetravalent platinum on the polymer backbone will be reduced to active divalent platinum,the polymer backbone will be destroyed,the encapsulated DOX will be further released,and the fluorescence of the TPE will be restored.The multifunctional nanomedicine system PtAIECP+DOX can be used for bioimaging to track the release behavior of drugs in real time.At the same time,platinum drugs and DOX can work together to exert anti-tumor effects and reduce system toxicity.