Abstract:
Rapid proliferation and a faster rate of glycolysis in cancer cells often result in an elevated local temperature (40-43 °C) at the tumor site. Nanoparticles prepared from polymers with two lower critical solution temperatures (LCSTs) can be utilized to take advantage of this subtle temperature elevation to deliver anticancer drugs preferably to the cancer cells, thereby enhancing the overall therapeutic efficacy and reducing side effects. In this direction, we synthesized N-vinyl-2-pyrrolidone (NVP) and substituted NVP (sub-NVP: C2-NVP, C4-NVP)-based polymers with precisely controlled LCSTs by varying the ratio of NVP and sub-NVP. The first LCST (LCST1) was kept below 37 °C to promote self-assembly, drug loading, and structural stability in physiological conditions and the second LCST (LCST2) was in the range of 40-43 °C to ensure mild hyperthermia-induced drug release. Additionally, covalent attachment of tetraphenylethylene (TPE, AIEgen) resulted in aggregation-induced emission in thermoresponsive micellar nanoparticles in which TPE acted as a Förster Resonance Energy Transfer (FRET) pair with the loaded anticancer drug doxorubicin (DOX). Tracking of FRET-induced fluorescence recovery of TPE molecules was utilized to confirm the real-time thermoresponsive release of DOX from nanoparticles and eventual localization of TPE in the cytoplasm and DOX in the nucleus. In vitro cellular studies such as cytotoxicity, cellular uptake, and thermoresponsive drug release showed that the DOX-loaded polymeric nanoparticles were nontoxic to normal cells (HEK-293) but significantly more effective in cancer cells (MCF-7) at 40 °C. To our knowledge, this is the first report of preferential delivery of anticancer drugs only by exploiting the slightly elevated temperature of cancer cells.
摘要:
癌细胞中的快速增殖和更快的糖酵解速率通常导致肿瘤部位的局部温度升高(40-43°C)。由具有两个较低临界溶解温度(LCST)的聚合物制备的纳米颗粒可用于利用这种微妙的温度升高来将抗癌药物优选地递送到癌细胞。从而提高整体疗效和减少副作用。在这个方向上,我们合成了N-乙烯基-2-吡咯烷酮(NVP)和取代的NVP(sub-NVP:C2-NVP,通过改变NVP和sub-NVP的比例,具有精确控制的LCST的基于C4-NVP)的聚合物。第一个LCST(LCST1)保持在37°C以下以促进自组装,药物装载,和生理条件下的结构稳定性,第二个LCST(LCST2)在40-43°C的范围内,以确保轻度高热诱导的药物释放。此外,四苯基乙烯(TPE,AIEgen)导致热响应性胶束纳米颗粒中的聚集诱导发射,其中TPE与负载的抗癌药物多柔比星(DOX)充当Förster共振能量转移(FRET)对。利用TPE分子的FRET诱导的荧光恢复的跟踪来确认DOX从纳米颗粒的实时热响应性释放以及TPE在细胞质中和DOX在细胞核中的最终定位。体外细胞研究,如细胞毒性,细胞摄取,和热响应性药物释放表明,负载DOX的聚合物纳米颗粒对正常细胞(HEK-293)无毒,但在40°C时对癌细胞(MCF-7)明显更有效。据我们所知,这是首次报道仅通过利用癌细胞的温度略有升高来优先提供抗癌药物。