Citation: Xiu-Quan Quan, Lin Kang, Xue-Zhe Yin, Zhe-Hu Jin, Zhong-Gao Gao. Synthesis of PEGylated hyaluronic acid for loading dichloro(1,2-diaminocyclohexane)platinum(II) (DACHPt) in nanoparticles for cancer treatment[J]. Chinese Chemical Letters, ;2015, 26(6): 695-699. doi: 10.1016/j.cclet.2015.04.024 shu

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

Xiu-Quan Quan ^a,b ,
Lin Kang ^a ,
Xue-Zhe Yin ^b ,
Zhe-Hu Jin ^b ,
Zhong-Gao Gao ^a,b,,

1.
a 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, Beijing 100050, China;
2.
b Yanbian University Hospital, Yanji 133000, China

Corresponding author: Zhong-Gao Gao,
Received Date: 26 November 2014
Available Online: 13 March 2015
Fund Project: This study was supported by research grants from the National Natural Science Foundation of China (No. 81373342) (No. 81373342) Beijing Natural Science Foundation (Nos. 2141004, 7142114). (Nos. 2141004, 7142114)

Dichloro(1,2-diaminocyclohexane)platinum(II) (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. mPEGhyaluronan-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 inmPEG-HA nanoparticles significantly inhibited the growth of A549 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.
- DACHPt,
- PEGylated hyaluronan,
- A549 lung cancer cell
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