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. 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.

雷公藤甲素（TPL）在肿瘤治疗中的临床应用受到其毒性和低效递送的极大限制。在本文中，开发了局部和持续释放的热敏水凝胶用于肿瘤内施用TPL。基于聚的两亲性结构（Ñ -isopropylacrylamide -CO-丙烯酸） -克-F68共聚物，它能够形成纳米胶束有效地包封TPL，然后变成水凝胶在37℃下。TPL @ nano-gel在体外表现出持续的药物释放特性以及由“两次打击”引起的更强的抗癌作用。“第一击”是其与游离TPL相比增强的细胞毒性，这归因于内源性线粒体途径的调节在MDA-MB-231和MCF-7细胞中均观察到了促凋亡作用。此外，TPL纳米凝胶通过其通过VEGFR-2信号转导抑制介导的抗血管生成能力表现出“第二次发作”。如预期的那样，在4T1荷瘤小鼠中，在14天内以0.45 mg / kg TPL等效剂量进行了3次肿瘤内注射后，与多次注射TPL相比，TPL @ nano-gel导致更低的全身毒性和更高的抗肿瘤功效。在这方面，这些发现表明，这种可注射的热响应水凝胶具有作为TPL作为安全有效的癌症治疗方法的巨大潜力。