纳米阿霉素热敏脂质体联合相控聚焦超声提高肿瘤疗效和安全性的基础研究

In order to improve efficacy while reducing the side effects .of drugs, combining several therapeutic modalities is one of the hottest fields in .the tumor treatments. The drugs used in the conventional chemotherapy usually have .poor selectivity and considerable side effects. How to improve the conventional .chemotherapy drug cytotoxicity on tumor cells and reduce the systemic toxicity is .our starting point in this study. Ultrasound, which can enhance the permeability .of the target cell membrane, is able to make the nano-level low-temperature-sensitive .liposomes (LTSLs) encapsulated doxorubicin release at the targeting spot. This proposed research aims to improve the absorption of the chemotherapeutic drugs by .the tumor cells while reducing its toxicity to the normal tissues and organs. In .the research, the phased high-intensity focused ultrasound (pHIFU) system is employed to deliver the energy outside the body at the tumor targets and produce .a uniform temperature field (39-45 celsius degree) within the target area, which .could make the LTSLs encapsulated doxorubicin fully release while the drugs in the .normal tissue below the temperature have the minimum concentration. In addition, .the nano-level LTSLs encapsulated doxorubicin combined with pHIFU is used to treat .the VX2 tumors transplanted in the rabbit.Through this research, we could evaluate .the efficacy and safety of LTSLs combined with pHIFU to treat the tumors in the large .animals, which provides the basis for the related clinical trials.

肿瘤综合治疗模式以提高疗效，减少药物毒副作用为目的，是当前国内外研究热点之一。传统化疗药物选择性差，毒副作用大。如何提高传统药物对肿瘤细胞的杀伤而减少对全身的毒性是我们研究的出发点。超声具有增强靶细胞膜的通透性和使纳米化阿霉素热敏脂质体定点释放的特征。本课题将采用相控阵聚焦超声(pHIFU)设备将能量由体外辐射到体内肿瘤靶区，在靶区产生 39-45℃均匀温度场，使纳米化阿霉素热敏脂质体在肿瘤靶区达到充分释放与浓聚，而低于该温度的正常组织中药物浓度降到最低，达到提高化疗药物对肿瘤细胞作用的同时减少对正常组织器官毒性的目的。本项目通过纳米化阿霉素热敏脂质体联合 pHIFU 治疗 VX2 兔移植瘤的动物实验，评判纳米化阿霉素热敏脂质体联合 pHIFU 治疗大动物活体肿瘤的可行性及安全性，并在此基础上评价该方法对肿瘤的疗效，为临床试验提供科学依据。

化疗在癌症治疗中占有重要地位。目前化疗药物多使用全身给药法，组织选择性低，会导致明显副作用及肿瘤部位药物浓度不足。如何显著改善化疗疗效，降低副作用是我们本次研究的主要目的。我们使用新西兰大白兔VX2模型，研究盐酸阿霉素脂质体联合肿瘤局部温热疗的抗瘤疗效，采用高压液相色谱法（HPLC）分析与测量肿瘤与正常器官/组织的阿霉素的浓度和生物分布，对比不同治疗方法时正常组织中阿霉素的浓度，明确阿霉素脂质体联合嵌入式超声温热治疗仪治疗的安全性，并且二者联合可显著提高肿瘤组织内药物浓度；此外，为实现完整的肿瘤缓解，进行多次高剂量给药，证明同传统化疗相比，局部温热疗联合阿霉素脂质体可能可以明显抑制肿瘤增殖率，提高生存时间，降低全身副作用。