摘要
The clinical application of triptolide(TPL)in tumor therapy has been greatly limited by its toxicity and inefficient delivery.Herein,a localized and sustained-release thermo-sensitive hydrogel was developed for the intra-tumor administration of TPL.Based on the amphiphilic structure of poly(N-isopropylacrylamide-co-acrylic acid)-g-F68 copolymer,it was able to form nano-micelles to efficiently encapsulate TPL,and then turn into a hydrogel at 37C.TPL@nano-gel exhibited a sustained drug release profile in vitro and a stronger anticancer effect caused by"two strikes".The"first strike"was its enhanced cytotoxicity compared to free TPL,due to the enhanced pro-apoptosis effect observed in both MDA-MB-231 and MCF-7 cells caused by the regulation of endogenous mitochondrial pathways.Furthermore,TPL@nano-gel exhibited a"second-strike"through its anti-angiogenesis capabilities mediated through VEGFR-2 signaling inhibition.As expected,after intra-tumoral injection at a 0.45 mg/kg TPL-equivalent dose three times over 14 days in 4 T1 tumor-bearing mice,TPL@nano-gel led to lower systemic toxicity and higher antitumor efficacy compared to multiple injections of TPL.In this regard,these findings indicate that this injectable thermo-responsive hydrogel carries great potential for TPL as a safe and effective cancer therapy.
基金
the financial support from the National Natural Science Foundation of China(Grant Nos.81973662and 8170371)
Scientific Development Program of Sichuan Province(2019JDJQ0049,China)
China Postdoctoral Science Foundation(Grant Nos.2017M612930 and 2019T120817)
Young Elite Scientists Sponsorship Program by CAST(2018QNRC1-01,China)
