Synthesis of PEGylated hyaluronic acid for loading dichloro(1,2-diaminocyclohexane)platinum(Ⅱ)(DACHPt) in nanoparticles for cancer treatment

作     者：Xiu-Quan Quan Lin Kang Xue-Zhe Yin Zhe-Hu Jin Zhong-Gao Gao 

作者机构：State Key Laboratory of Bioactive Substance and Function of Natural MedicinesInstitute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical College Yanbian University Hospital 

出 版 物：《Chinese Chemical Letters》 (中国化学快报（英文版）)

年 卷 期：2015年第26卷第6期

页      面：695-699页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 07[理学] 070303[理学-有机化学] 0703[理学-化学] 10[医学] 

基　　金：supported by research grants from the National Natural Science Foundation of China (No.81373342) Beijing Natural Science Foundation (Nos.2141004,7142114) 

主　　题：DACHPt PEGylated hyaluronan A549 lung cancer cell 

摘      要：Dichloro（1,2-diaminocyclohexane）platinum（ll） （DACHPt）, a cisplatin （CDDP） analog, has shown lower toxicity than CDDP and no cross-resistance with CDDP in many CDDP-resistant cancers. PEGylated hyaluronan （mPEG-HA） is an mPEG conjugated with hyaluronan biodegradable polymer which is a naturally occurring biopolymer in the interstitium, is primarily cleared by the lymphatic system, mPEG- hyaluronan-DACHPt （PEG-HA-Pt） conjugate could circulate long-term in the bloodstream and increase DACHPt concentration in the tumor site and decrease systemic toxicity, mPEG-HA conjugates with the range of 1%-5% substitution were synthesized, and the structures were confirmed by 1H NMR and IR. The particle size of DACHPt incorporated with mPEG-HA was about 86 nm and the loading content and efficiency were about 19% （w/w） and 86%, respectively. The synthesized mPEG-HA with different PEG substitution degrees presented non toxicity, and the cell viability of DACHPt loaded in mPEG-HA nanoparticles increased with increasing doses of DACHPt. DACHPt release from nanoparticles slightly decreased with increasing PEG substitution degree from 1% to 5% at 37℃, pH 7.4 PBS solution. The DACHPt loaded in mPEG-HA nanoparticles significantly inhibited the growth ofA549 xenografts in nude mice when compared to the DACHPt loaded in HA nanoparticles and the control group after 4 weeks treatment （p 〈 0.01 compared with control）. The body weight change curve shows that the mice weight loss was less than 5% by treating with both DACHPt loaded in mPEG-HA and HA nanoparticles. In conclusion, a novel DACHPt loaded mPEG-HA delivery system was developed with sustained release and increased platinum concentration in the tumor.