Journal
ACTA PHARMACEUTICA SINICA B
Volume 10, Issue 11, Pages 2227-2245Publisher
INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
DOI: 10.1016/j.apsb.2020.05.011
Keywords
Thermo-responsive hydrogel; Triptolide; Tumor local treatment; Breast cancer; Anti-angiogenesis; Pro-apoptosis; Micelle; Survival rate
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Funding
- National Natural Science Foundation of China [81973662, 8170371]
- Scientific Development Program of Sichuan Province (China) [2019JDJQ0049]
- China Postdoctoral Science Foundation [2017M612930, 2019T120817]
- Young Elite Scientists Sponsorship Program by CAST (China) [2018QNRC1-01]
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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-iso-propylacrylamide-co-acrylic acid)-g-F68 copolymer, it was able to form nano-micelles to efficiently encapsulate TPL, and then turn into a hydrogel at 37 degrees C. 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 4T1 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. (C) 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
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