Injectable thermo-responsive nano-hydrogel loading triptolide for the anti-breast cancer enhancement via localized treatment based on “two strikes” effects
Yao-Yao Luo, Jingjing Li, Yichen Hu, Fei Gao, Gph Leung, Funeng Geng, Chaomei Fu, Jinming Zhang
Abstract
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 37 °C. [email protected] 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, [email protected] 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, [email protected] 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.