基于载姜黄素纳米粒的声动力化疗联合热消融治疗肾细胞癌及其疗效评价的基础研究

Thermal ablation is an important non-surgical treatment of solid tumors, but it also has some inadequacies such as local recurrence and distant metastasis due to incomplete ablation. Combined use of other treatment methods can effectively eliminate residual cancer and improve the curative effect. Our previous study found that only if low-dose curcumin can obviously kill renal cell carcinoma （RCC） cells, while it is had no toxicity to human normal cells. In addition, curcumin is an excellent sonosensitive agent, which can produce reactive oxygen species (ROS) in the condition of low-intensity ultrasound irradiation, and that will further leading the death of tumor cells. However, the clinical application of curcumin is limited by its unstable and the low bioavailability pharmacological properties. Given this limitation in consideration, we intends to prepare a hollow mesoporous organosilicon nanoparticle with stable properties and high drug-loading efficiency in the present research. And curcumin payload can be achieved under the mild reaction conditions by immersion centrifugation method. The interaction between nanoparticles and ultrasound is discussed in vitro. And the ability of drug-loaded nanoparticles to kill RCC under different conditions is observed, to screen appropriate treatment parameters for further research; Sonodynamic chemotherapy and thermal ablation are combine applied for the treatment of RCC in vivo. The multi-index evaluation methods are used to comprehensive evaluate the therapeutic efficacy, to clarify its mechanism of action, to reveal the general rule of sonodynamic chemotherapy combined with thermal ablation for the treatment of RCC, and to develop a convenient and reliable evaluation system. The aim is to provide a new experimental basis and evidence-based evidence for effective non-surgical treatment and therapeutic evaluation of RCC, and provide new ideas for its clinical intervention.

热消融是重要的实体瘤非手术治疗方法，但存在消融不完全导致局部复发及远处转移等不足，联合应用其它治疗方法可有效消灭残癌改善疗效。课题组前期研究发现，低剂量姜黄素即可明显杀伤肾癌细胞，但对正常细胞无毒性，此外，姜黄素是良好的声敏剂，在低强度超声辐照后可产生活性氧，进一步杀灭肿瘤细胞，然而，该药理化性质不稳定且生物利用率极低，因而临床应用受限。鉴于此，本研究拟制备一种性质稳定且载药效能高的中空介孔有机硅纳米粒，利用浸渍离心法在温和反应条件下实现药物有效负载；体外实验探讨纳米粒与超声相互作用，及不同条件下纳米粒对肾癌杀伤能力，筛选适宜治疗参数；体内实验联合应用声动力化疗及热消融治疗肾癌，以多指标疗效评价方法进行综合评估，并阐明其作用机制，揭示声动力化疗联合热消融治疗肾癌的一般规律，制定简便可靠的疗效评价体系。旨在为肾癌非手术治疗及疗效评价提供新的实验基础及循证学依据，为临床干预及诊治提供新思路。

肾细胞癌（renal cell carcinoma，RCC）是最常见的肾脏恶性肿瘤，其标准疗法为手术切除。对于小肾癌及进展期肾癌，热消融则是其重要微创治疗方法，但该疗法存在消融不完全导致肿瘤局部复发或远处转移影响患者预后。针对这一重要临床问题，本项目按照研究计划，围绕研究内容开展了一系列相关研究，制备了一种大小形态均一、理化性质稳定且载药效能高的中空介孔有机硅纳米粒（Cur@HMON），构建了一种自然来源单药介导的双功能声动力化疗体系。并在原计划的基础上，进一步拓展项目研究深度，开发了一种温度敏感的可注射相变水凝胶，并以该水凝胶包裹所制备纳米体系，得到温度敏感的可注射声动力化疗水凝胶纳米体系（Cur@HMON@gel）。课题组在体外实验探讨该纳米体系与超声相互作用，及不同条件下纳米粒对肾癌杀伤能力，筛选出适宜治疗参数，证实该体系可有效抑制药物的持续低剂量自主释放及由此引起的药物耐受，实现了负载药物的低强度超声高度可控释放及对肾癌细胞的有效杀伤；体内实验联合应用纳米体系介导的声动力化疗及热消融治疗肾细胞癌，有效杀灭热消融后残癌，改善治疗效果；与此同时，证实了水凝胶纳米体系在体内外均有良好的降解性能及生物安全性，且可将纳米粒固定于肿瘤部位，便于在单次注射后接受反复多次低强度超声激发，抗肿瘤作用可维持半个月以上，从而解决了以往治疗体系需反复多次进行药物注射的问题，有效减少正常组织损伤；此外，项目组以多指标疗效评价方法进行综合评估，制定了基于动态三维超声造影（3D-CEUS）的简便可靠疗效评价体系，为实体瘤非手术治疗早期疗效评价提供良好范例。.总之，该项目的实施为肾癌非手术治疗及疗效评价提供了新的实验基础及循证学依据，为临床干预及诊疗策略的选择提供了新思路。