Preparation And Anti-tumor Effect Of Nano Prodrug Carrier Based On Dithiocarbamate

The development of nano drug carriers provides a new strategy for cancer treatment.Conjugating drug to carrier molecules such as a polymer can create prodrug carriers that can significantly improve the solubility and stability of drugs,avoid unwanted premature drug release,increase the concentration of drugs in tumor sites by passive targeting,and reduce systemic toxicity.Besides,the drug release can be tailored using various linkers between the drug and the carrier molecule.For example,tumor-microenvironment-responsive linkers are able to respond to specific components of tumor microenvironment(e.g.high concentration of glutathione)and realize effective drugs release,which ultimately improves the efficacy of drugs.Copper plays an important role in tumor development and angiogenesis.Studies have shown that depletion of biologically available copper in tumor site can effectively inhibit tumor angiogenesis and tumor cell proliferation,and finally,tumor inhibition can be achieved.Disulfiram is a drug for abstinence from alcohol.Studies have found that its metabolite diethyldithiocarbamate(DTC)can chelate copper ions and produce anti-tumor activity.However,due to its hydrophobicity and rapid degradation into less effective molecules in vivo,the therapeutic effect of disulfiram is limited.Therefore,it is of great significance to develop a safe and effective DSF delivery system for in vivo application.Conjugating DTC to amphiphilic polymer through disulfide bond can create amphiphilic polymeric prodrug that self-assembles into nanoparticles.By this means it is feasible to not only avoid ineffective DSF metabolization and premature DSF release in the blood stream,but also enhance DTC accumulation in tumor sites by passive targeting.At the same time,using disulfiram to deplete bioavailable copper in tumor site is expected to inhibit angiogenesis and therefore cut off oxygen and nutrients to the tumor,which is worthy of further study.Based on the above content,this paper designed a kind of self-assembling nano prodrug carrier based on the conjugation of DTC and amphiphilic block copolymer,and studied the therapeutic effect of such a prodrug carrier on tumor proliferation and angiogenesis.This paper is divided into two parts:(1)Preparation and characterization of amphiphilic polymeric DTC prodrug that selfassembles into polymersomes.The amphiphilic polymeric DTC prodrugs PPEGA-b-PDTCM and PEG-b-PDTCM were designed,and the aqueous self-assembly behaviors of them were studied.It was found that they can co-self-assembled to form nano-sized DTC prodrug-based polymersomes.The particle size stability and hemocompatibility of the polymersome were also investigated,followed by the verification of DTC release from the polymersome in the presence of glutathione.(2)Study of anti-tumor effect and anti-angiogenesis activity of dual drug-loaded polymersomes.The utility of DTC prodrug-based polymersome as a drug delivery vehicle was tested using a well-known anticancer drug doxorubicin(DOX).The in vitro therapeutic efficacy of the DOX-loaded polymersomes(PS-DOX)was investigated,followed by the exploration of the angiogenesis inhibition effect of PS-DOX.Moreover,the in vivo therapeutic efficacy of PSDOX was also studied.