title: Synthesis, characterization and antitumor evaluation of CMCS-DTX conjugates as novel delivery platform for docetaxel.
abstract: The purpose of this study is to synthesis and evaluate the antitumor efficacy of a novel carboxymethyl chitosan-docetaxel (CMCS-DTX) conjugates and the availability of CMCS as the polymer material in polymer-drug conjugates development. Docetaxel (DTX) was attached to carboxymethyl chitosan (CMCS) via biodegradable linker for the first time and the weight percentage of DTX in the CMCS-DTX conjugates was up to 20%. The resulting CMCS-DTX conjugates could spontaneously self-assemble into nanoparticles in aqueous buffer, with uniform size of 127.2±3.58 nm and zeta potential of -25.65 mV. The stability test result showed that only 12.46% of DTX was released after incubation in plasma for 48 h, indicating good stability of CMCS-DTX conjugates in plasma. The results of in vitro cytotoxicity and Hoechst staining indicated that CMCS-DTX conjugates exhibited significant cytotoxicity against B16 and HepG2 cells. CMCS-DTX conjugates also displayed better antitumor effect than Duopafei® by inhibiting tumor growth and prolonging the survival time of B16 melanoma bearing mice more effectively (the median survival time was >30 days for CMCS-DTX conjugates versus 24 days for the Duopafei®). Besides, CMCS-DTX conjugates demonstrated an excellent safety profile with a maximum tolerated dose (MTD) of >250 mg/kg in mice, which was more than 4 fold higher than that of Duopafei® (50 mg/kg). CMCS-DTX conjugates could be exploited as a promising platform for the effective delivery of DTX and CMCS was a favorable choice as the polymer material in polymer-drug conjugates development.
authors.affiliation: The School of Pharmaceutical Science, Shandong University, 44 Wenhua Xi Road, Ji'nan, Shandong Province 250012, China.
authors.forename: Fengxi
authors.initials: F
authors.lastname: Liu
authors.forename: Lixia
authors.initials: L
authors.lastname: Feng
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.forename: Na
authors.initials: N
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology; D048271:Chitosan / Q000031:analogs & derivatives* / Q000737:chemistry; D000077143:Docetaxel; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D004355:Drug Stability; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology; D020714:Maximum Tolerated Dose; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D053758:Nanoparticles; D010316:Particle Size; D015996:Survival Rate; D043823:Taxoids / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D043823:Taxoids; C514968:carboxymethyl-chitosan; D000077143:Docetaxel; D048271:Chitosan