基于联合调控前转移微环境中血小板和中性粒细胞的载药微球抗肿瘤转移研究

Tumor metastasis is a major obstacle in current anti-cancer therapy and the prime cause of cancer fatalities. It has been noted that the metastasis of tumor is highly organ specific, and that the formation of “premetastatic niche” in the target organ prior to the implantation of tumor cell is crucial for the eventual formation of metastases. Among the characteristics of this premetastatic microenvironment, elevated platelet activation, and neutrophil recruitment through local inflammation provide attractive therapeutic targets. Given that the target organ of metastasis is often highly predictable, this project intends to propose a novel anti-metastasis strategy based on specific regulation of premetastatic organ microenvironment. A biocompatible and biodegradable microsphere-based drug delivery system will be used to deliver platelet and neutrophil inhibitors specifically to the premetastatic lung. By inhibiting the platelet activation and neutrophil recruitment in the tissue, this microsphere system would be able to “normalize” the pro-metastasis microenvironment within the lung before the formation of detectable metastases, therefore prevent the eventual development of metastatic tumor. Currently the clinical anti-metastasis therapies often suffer the late diagnosis of detectable metastatic tumor, and many anti-metastasis drugs under development that target tumor cells are subject to resistance due to tumor heterogeneity as well as side effects caused by systemic application. Our strategy would provide a solution to overcome both limitations. In this project we will construct and optimize the microsphere-based delivery system as described above to obtain maximum targeting and delivery efficiency, as well as employ appropriate animal models to validate the impact of the proposed therapy on the targeted lung microenvironment, and its in vivo therapeutic effect against lung-specific metastasis. The in vivo pharmacokinetics and adverse effects of the system will also be assessed. This project is expected to open new possibilities for timely and safe treatment against organ-specific tumor metastasis.

肿瘤的转移是癌症治疗的重要障碍和癌症病人死亡的主要原因，目前临床尚缺乏治疗和预防肿瘤转移的有效手段。研究表明，肿瘤的转移具有器官特异性，目标器官在肿瘤细胞植入之前，预先形成前转移微环境的过程对转移灶的形成起到重要作用。在前转移微环境的诸多成分中，血小板和局部炎症招募的中性粒细胞起到了重要的促转移作用。本研究拟利用肿瘤转移目标器官的高度可预测性，以及微球型药物载体高效肺部靶向的特点，构建生物可降解的新型联合载药微球，将血小板和中性粒细胞抑制剂特异性靶向至肺部，在器官出现可见转移灶之前，使微环境正常化，针对性抑制肿瘤的肺部转移，从而克服现有抗转移药物全身用药的局限，同时解决癌症转移的治疗时机和特异性问题。研究将优化载药体系的形貌和理化特性，阐明其影响载体靶向输运效率的机制，在动物模型中评价载药体系调控肺部微环境和抑制肿瘤肺转移的效果，并研究药物的体内代谢行为和安全性，为抗转移治疗提供新的思路。

肿瘤的转移是癌症治疗的重要障碍和癌症病人死亡的主要原因，目前临床尚缺乏治疗和预防肿瘤转移的有效手段。研究表明，肿瘤的转移具有器官特异性，目标器官在肿瘤细胞植入之前，预先形成前转移微环境的过程对转移灶的形成起到重要作用。在前转移微环境的诸多成分中，血小板和局部炎症招募的中性粒细胞起到了重要的促转移作用。本研究利用肿瘤转移目标器官的高度可预测性，以及微球型药物载体高效肺部靶向的特点，成功构建了生物可降解的新型联合载药微球，将血小板和中性粒细胞抑制剂特异性靶向至肺部，以期在器官出现可见转移灶之前，使微环境正常化，针对性抑制肿瘤的肺部转移。实验结果表明，双重载药微球在小鼠黑色素瘤肺转移模型中，能够显著抑制前转移微环境中性粒细胞的招募和血小板的激活，并表现出明显的抗转移效果。这一思路有可能克服现有抗转移药物全身用药的局限，同时解决癌症转移的治疗时机和特异性问题。本项目执行期间还得到了一系列以靶向或调控肿瘤微环境为作用机制的抗肿瘤纳米药物，在动物模型中取得了良好的治疗效果，对于未来新型抗肿瘤药物的开发具有重要参考价值。