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 

机构地区：[1]State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College [2]Yanbian University Hospital

出　　处：《Chinese Chemical Letters》2015年第6期695-699,共5页中国化学快报（英文版）

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

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.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.

关 键 词：DACHPt PEGylated hyaluronan A549 lung cancer cell 

分 类 号：O627.8[理学—有机化学] TQ460.1[理学—化学]