携氧载药微泡协同声动力治疗卵巢癌的实验研究

Lines of pre-clinical and clinical evidences suggest that tumor hypoxia is a key contributing factor for tumor resistance to various treatment modalities. Ultrasound-mediated destruction of paclitaxel and oxygen loaded lipid microbubbles for combination therapy in ovarian cancer xenografts with improved efficiency. However, destruction and monitoring MBs destruction is not efficient and safe because ovarian cancer cells primarily disseminate within the peritoneal cavity and only superficially invasive, the energy of the ultrasound interference with gas in the bowl will influence the imaging and treatment . Therefore, it is clinically important to develop new techniques for monitoring and targeted delivery of oxygen and anti-cancer drugs to the tumor site with safe ultrasound intensity . We synthesized oxygen and ICG-PTX loaded multifunctional microbubbles for ultrasound mediated delivery of oxygen and drugs with ultrasound and fluorescence imaging guidance. We hypothesize that sonodynamic treatment(SDT) will facilitate controlled delivery of oxygen and paclitaxel with improved efficiency. This hypothesis will tested experimentally in hypoxia ovarian cancer cells in vitro and ovarian cancer model in vivo . This study may provide a new way to therapy hyperoxic ovarian cancer, and also provide a new mode of SDT mediated with chemitherapy that is efficiency for both tumor and tumor microenvironment.

乏氧是导致肿瘤对化疗及声动力治疗产生抵抗的关键因素，项目组前期研究已经证实携氧载药超声微泡造影剂可改善肿瘤组织局部乏氧微环境，提高化疗药物的敏感性。但对以腹腔播散及浅表浸润为主要复发及转移模式的卵巢癌而言，由于腹腔内肠道气体对声场的干扰，势必要求微泡不但具有低强度超声激发特性，同时具有多模态成像功能，以便在避免超声对肠道损伤同时可对治疗过程进行监控。因此，合成具有光声动力效应的载药微泡，赋予微泡多功能显影特性同时改变其激发的声学环境，降低微泡激发所需的超声能量十分必要。本项目基于吲哚菁绿（ICG）的声敏特性及荧光成像能力，通过同轴电流动聚焦技术合成具有光声动力效应的携氧载ICG及紫杉醇微泡造影剂（IOPMBs），以声动力治疗为手段，体内外系统研究超声激发该多功能微泡造影剂对卵巢癌的杀伤作用，为携氧载药微泡协同声动力治疗肿瘤奠定基础，有望建立一种化疗与声动力协同治疗肿瘤的新模式。

卵巢癌为女性生殖系统最常见的恶性肿瘤之一，也是妇科肿瘤中预后最差的癌症，除了其起病隐匿及特异性的筛查手段缺乏，早期诊断困难外，乏氧导致肿瘤对化疗及光动力治疗产生抵抗也是治疗失败的主要原因之一。项目组前期研究已经证实携氧载药超声微泡造影剂可改善肿瘤组织局部乏氧微环境，提高化疗药物的敏感性。但对以腹腔播散及浅表浸润为主要复发及转移模式的卵巢癌而言，由于腹腔内肠道气体对声场的干扰，势必要求微泡不但具有低强度超声激发特性，同时具有多模态成像功能，以便在避免超声对肠道损伤同时可对治疗过程进行监控。本项目基于吲哚菁绿（ICG）的光/声敏特性及荧光成像能力，分别采用同轴电流动聚焦技术及改良双乳化技术制备多种具有光声动力效应的多功能携氧载药纳米粒，通过体内外系统研究超声激发该多功能纳米造影剂对卵巢癌的杀伤作用。结果发现该类纳米粒不但具有超声/光声双模态成像能力，同时在低剂量激光及低剂量超声作用下，可提高纳米粒对卵巢癌的杀伤能力，延长荷瘤鼠生存期，其主要机制主要与促进肿瘤细胞凋亡，减少肿瘤组织CD34及VEGF表达，降低肿瘤微血管密度，同时降低HIF-1α及MDR-1的表达，提高化疗药物对卵巢癌细胞的敏感性、诱导肿瘤抗原暴露，激发特异性抗肿瘤免疫。综上，本项目合成的具有光声动力效应携氧载药纳米粒在卵巢癌诊疗中具有重要的应用前景。