In Vitro And In Vivo Pharmacodynamic Evaluation And Manufacture Of Hydroxycamptothecin-conjugated And Reduction-sensitive Poly(Ethylene Glycol) Monomethyl Ether Poly(Β-Benzyl-L-Aspartic) Prodrug Micelle

Chemotherapeutics is playing an important role in the treatment of malignant tumor,and it can inhibit the growth of tumor cells in some extent.But chemotherapeutics also brings a lot of side effects to patients in the course of treatment.In addition,chemotherapy drugs generally have some disadvantages,such as poor water solubility,low bioavailability,and so on.In order to overcome these drawbacks,the researchers conducted a series of exploration,and developed many biodegradable polymer nanocarriers as drug delivery systems.These novel drug delivery systems can significantly increase the concentration and the bioavailability of drug in the tumor site by targeting action,and decrease the adverse effects of drug in the body.It will be an effective way to solve the multi-drug resistance of tumor cells produced in the course of drug treatment.In the present study,the work focusing on the structure-activity relationship of biodegradable amphiphilic block polymer micelles was carried out on the basis of the reduction-sensitive property of disulfide bonds.Poly(ethylene glycol)monomethyl ether poly(β-benzyl-L-aspartic)(mPEG-PBLA)diblock copolymers was synthesized by a ring opening polymerization with amine-terminated poly(ethylene glycol)monomethyl ether as a initiator to initiate BLA-NCA.Hydroxycamptothecin was grafted onto mPEG-PBLA by a disulfide bond into the reduction-sensitive prodrug(mPEG-PBLA-SS-HCPT,MPSH).The structural and molecular weights propertis of copolymers were characterized by 1H NMR,IR and GPC.Finally,the MPSH polymer micelles were prepared by the high-speed stirring and dialysis method.The micellization behavior of polymer prodrugs was evaluated by dynamic light scattering.The results showed that the polymer micelles had very good particle size distribution with the size ranging from 100 nm to 200 nm.TEM images showed polymer micelles were spherical in shape.The particle size of the polymer micelles with disulfide bonds was significantly increased under the high concentration of reducing glutathione solution,and the drug release was accelerated obviously,which showed a good redox sensitivity.In this paper,the inhibitory effect of MPSH polymer micelles on HepG2 cells was investigated by MTT method.The results showed that the disulfide-containing polymer micelles exhibit good antitumor effects.In addition,the toxic effects of mPEG-PBLA blank micelles on human normal hepatocytes L-02 cells were also investigated by MTT method.The results showed mPEG-PBLA blank micelles had not significant toxicity on L-02,which indicated mPEG-PBLA had the good biocompatibility.To examine the antitumor effect of disulfide-containing reduction-sensitive micelles,mice with H22 tumor were used as animal models.The tumor growth was inhibited significantly and the tumor inhibition rate was 61.43%.Compared with the normal saline group,MPSH polymer micelles group had significantly different.And the tumor inhibition effect of MPSH polymer micelles group was better than that of the HCPT solution group.We treated the mice with H&E staining.The results manifested that the reduction-sensitive polymer micelles had no obviously side effects on the main organs of mice,which indicated that the hydroxycamptothecin disulfide-grafted polymer micelles could effectively inhibit tumor growth and reduce the side effects of drugs at the same time.So the reduction-sensitive polymer micelle was a promising potential as a carrier for HCPT delivery and potentially for the delivery of other anti-cancer drugs with a poor solubility as well.