细胞膜靶向药物自运载系统用于抗炎增强肿瘤光热治疗

Light overexposure in tumor photothermal therapy (PTT) would induce tissue damages, and liable to cause induce pro-inflammatory responses in tumor tissue even may stimulate tumor regeneration and therapy resistance. Based on our previous research, in this project, we would develop a cell membrane targeting and drug self-delivery systems for PTT by self-assembly from photothermal therapeutic agent conjugated amphiphilic chimeric peptides. The positive charges in peptides were shielded by acid liable protective group to improve the stability of the nanoparticles under circulation. Under the acidic tumor microenvironment, the drug nanoparticles could recover positive charges, and disintegrate into peptide monomers, further inserting into tumor cell membrane and killing tumor cells under low-dose light irradiation. Cell membrane targeting photothermal therapy has potential to improve therapeutic efficacy and reduce light dosage. To inhibit the photothermal therapy induced tumor inflammation, anti-inflammatory drug was further introduced into the photothermal therapeutic chimeric peptide to fabricate BoLa-style cell membrane targeting drug self-delivery system. In this project, we would research the photothermal therapeutic and the tumor inflammation inhibition efficacies of the drug system in vitro and in vivo and select the most promising drug system for clinical usage in tumor therapy. The cell membrane targeting and anti-inflammatory improvement strategies for photothermal therapy provide new prospects for effective tumor photothermal therapy.

肿瘤光热治疗采用的强烈光照往往会损伤正常组织，同时容易引起肿瘤炎性反应，诱导肿瘤的复发和治疗耐受性。本项目在前期研究基础上，拟采用细胞膜靶向的两亲性嵌合肽共价连接光热制剂，通过自组装作用构建新型肿瘤细胞膜靶向的自运载光热治疗纳米药物。采用微酸性敏感基团屏蔽多肽序列中正电荷残基，改善自运载纳米药物稳定性。在肿瘤区域纳米药物响应于微酸环境恢复正电荷，促使纳米粒子解离，通过靶向肽作用于肿瘤细胞膜，在低剂量光照下实现光热治疗。光热治疗的细胞膜靶向性有望提高治疗效率并降低光照剂量。同时，为抑制光热治疗引发的肿瘤炎性反应，拟进一步引入抗炎药物，构建BoLa型细胞膜靶向、抗炎增强的肿瘤光热治疗药物自运载体系。本项目将在细胞水平和动物实验完成纳米药物的光热治疗效率和肿瘤炎症抑制水平的评价，筛选出具有临床应用潜力的药物体系用于癌症治疗。细胞膜靶向并增强抗炎的光疗策略有望为高效肿瘤光热治疗提供新思路。

为达到有效治疗温度，肿瘤光热治疗所需强烈光照会损伤正常组织。过高热易引起肿瘤炎性反应，诱导肿瘤的复发和治疗耐受性。本项目通过自运载肿瘤细胞膜靶向光热制剂并引入抗炎药物，以实现高效、安全的肿瘤低温光热治疗及抗炎协同治疗。本研究已按计划顺利完成：（1）合成了细胞膜靶向的两亲性光热制剂嵌合肽，其通过自组装过程构建新型肿瘤细胞膜靶向的自运载光热治疗纳米药物（CCP NPs），通过原位产热破坏肿瘤细胞膜，在低剂量近红外光照下实现高效低温光热治疗同时引发机体强烈抗肿瘤免疫效应进一步清除残留肿瘤细胞；（2）为抑制光热治疗引发的肿瘤炎性反应，本项目在细胞膜靶向的两亲性光热嵌合肽自组装过程中载入抗炎药物双氯芬酸，构建细胞膜靶向、抗炎增强的肿瘤光热治疗药物自运载体系（CCPD）。该体系能够在高效低温光热治疗的同时有效抑制肿瘤炎性反应，避免了肿瘤转移。这些新型肿瘤细胞膜靶向自运载纳米药物有望为高效肿瘤光热治疗提供新思路。在项目执行期间，负责人在国际重要刊物上发表标注本项目资助共1篇EI论文，7篇SCI论文（1篇第一作者综述，6篇（共同）通讯作者论文），其中中科院二区及以上期刊5篇。另有2篇相关研究论文在投稿送审后正在返修，1篇相关研究论文正在整理数据撰写论文。负责人已指导2名硕士研究生顺利毕业，参加国内重要学术会议2次。