光学控释靶向温敏纳米颗粒及其光化学协同抗肿瘤研究

The cancer is one of the diseases of serious threat to mankind's health and life. Clinical treatment of cancer exists many defects, such as unsynchronized diagnosis and therapy, high side effects, poor effects. We recently reported the targeting nanoparticles for cancer diagnosis (Biomaterials, 2012, 7810) and nanoparticles co-loaded chemotherapeutic agent and gene or chemotherapeutic and thermo-optical agents cooperatively suppress cancer (Biomaterials, 2013, 3431; ACS nano, 2013, 2056). The project seeks to develop novel thermosensitive lipid nanoparticles as cancer targeting, laser controlled-release and chemo-photothermal combination therapy for cancer highly effective therapeutic and diagnosis. Antitumor effect of the thermosensitive lipid nanoparticles in vitro will be investigated. The breast cancer MCF-7 or ovarian cancer Skov3 tumor-bearing model will be constructed, and fluorescence of drug and photothermal agent of nanoparticles can be monitored to demonstrate targeting accumulation in the tumour and metabolic distribution. By triggering thermosensitive nanoparticles gathering in the tumor with the near infrared laser, the temperature of nanoparticles will rise and local release of drugs can be promoted. The nanoparticles combine therapeutic modalities of burst release chemotherapy and hyperthermia to co-suppress tumor. The therapeutic strategy that packages imaging，targeting，controlled-release and photochemical synergistic therapey simultaneous in one of nanoscaled carrier system may provide a novel thoughtway to improve the bioavailability and reduce the side effects of drugs.

癌症是严重威胁健康和生命的疾病，临床存在诊疗不同步、治疗副作用大、疗效差等困难。纳米科技的发展给癌症的诊疗带来机遇，前期我们已制备纳米探针诊断癌症(Biomaterials,2012,7810)；并采用纳米颗粒介导化学-基因、化学-光热协同治疗癌症(Biomaterials,2013,3431; ACS nano,2013,2056)。本项目拟制备兼有特异靶向示踪、光学控释和化学-光热联合作用的靶向温敏磷脂纳米颗粒，与肿瘤细胞株共孵育，研究其体外抗肿瘤效应；并构建乳腺癌MCF-7 或卵巢癌Skov3 荷瘤小鼠模型，通过活体成像实时监控纳米载体在肿瘤的靶向富集及代谢，利用激光激发肿瘤内的纳米颗粒，促使温度上升，形成快速释药，借助突释的化疗药物的毒性及光热试剂的热毒性，共同抑制肿瘤。研究有助于实现多功能纳米颗粒的成像、靶向和治疗肿瘤一体化，为探讨纳米技术协同抗肿瘤机制提供新方法和新思路。

构建共包载阿霉素和吲哚菁绿的温敏纳米载体用于近红外光驱动的肿瘤可视化精准治疗。对内部/外部刺激响应的智能纳米颗粒能够用于实现药物在肿瘤部位的选择性释放。在高于43℃的条件下，温敏脂质能够发生从固态到液态的相转变，破坏载体结构，从而快速释放药物。本项目设计了一种近红外光驱动、共包载阿霉素（DOX）和吲哚菁绿（ICG）的温敏纳米药物DI-TSL。该体系采用温敏脂质控制药物释放，DOX和ICG荧光实时监控纳米颗粒分布，及DOX和ICG的化疗/光热治疗效果联合抑制肿瘤。结果表明，DI-TSL尺寸均一，荧光/粒径稳定性良好，近红外激光触发后药物释放效率提高3倍；被细胞内吞后，近红外激光触发，溶酶体内部的DI-TSL产生高热导致溶酶体破裂，DI-TSL“打开”释放出DOX，增强了化疗效果；在活体肿瘤中，DI-TSL具有增强的药物驻留（ICG和DOX驻留量提高4倍和7倍）和激光驱动的药物释放，能够高效的诱导肿瘤细胞凋亡，完全消除肿瘤且无毒副作用。DI-TSL体系将提供一种按需释放药物的新策略用于肿瘤联合治疗。