Dimeric Camptothecin With High Drug Loading For Redox-responsive Drug Dilivery

In recent years,humans are suffering the threat of cancers,which incidence is increasing with years.One of the important methods for treatment of tumor is chemotherapy.However,most of current chemotherapy drugs have to be with some problems,such as low solubility,high side effects,and poor bioavailabiliy.The drug delivery system based on polymer materials is an important way to solve the above problems.Integrate the function of temperature,light,reduction,enzyme response of polymeric drug delivery system,effectively raise the efficiency of drug delivery and therapeutic effect,but also exist in different degrees in the process of drug delivery of drug-loading micelle stability low,cannot be controlled drug release,such problems as low drug loadings.Nonetheless,these drug delivery systems have several advantages,for instance,low stability of micelles,uncontrolled release and low drug loadings.Covalently linked drug dimers with freely rotatedσbonds,could decrease the fast self-aggregation of drug molecules non-encapsulated aggregation during preparing of drug loading micelles.This mothed can increase the drug loadings.In this thesis,we designed and synthesized two kinds of reductive camptothecin dimers drug delivery systems,as follows:In the first part,biocompatible methoxy poly（ethylene glycol）-b-poly（ε-caprolactone）（mPEG-b-PCL）loaded redox-responsive dimeric CPT（CPT-SS-CPT）nanoparticles were developed.CPT-SS-CPT with simply molecular structure was synthesized through the conjugation of cleaved disulfide to CPT monomer.The power X-ray diffractometer（XRD）results indicate low crystallinity and amorphous nature of CPT-SS-CPT.Then the dimeric CPT was encapsulated in mPEG-PCL via dialysis method.The obtained CPT-SS-CPT-loaded micelles showed a high drug loading content of 12.6%and a high drug loading efficiency of 75%.In addition,dimeric CPT micelles showed reduction-responsive release of free CPT under 10 mM DTT PBS buffer,while negligible CPT release was detected in the absence of DTT.MTT assay indicated cytotoxicity of dimeric CPT micelle was similar to free CPT.These results demonstrated that dimeric CPT-loaded mPEG-b-PCL-based micelle is a promising strategy for cancer therapy.In the second part,reductive responsive dimeric CPT（CPT-Mal-CPT）of maleimide sulfide conjugated was synthesized.The structure of CPT-Mal-CPT was characterized by ¹H NMR、¹³C NMR and ESI-MS.The XRD results indicate low crystallinity and amorphous nature of CPT-Mal-CPT.Then the CPT-Mal-CPT–loaded mPEG-b-PCL nanoparticles were prepared via dialysis method.The obtained CPT-Mal-CPT-loaded micelles showed a high drug loading content of 9.6%.In addition,dimeric CPT micelles could release free CPT under 10 mM DTT PBS buffer,and with CPT release was detected in the absence of DTT.MTT assay indicated cytotoxicity of CPT-Mal-CPT micelle was similar to free CPT.Thus,this dimeric CPT delivery system is a promising strategy demonstrated effective cytotoxicity.