高效抑制VCAM-1的仿生杂合NO前药自组装纳米粒用于乳腺癌及肺转移的治疗研究

肺转移是导致乳腺癌患者死亡的重要原因，如何有效抑制肺转移是改善乳腺癌治疗效果的关键难题。研究发现VCAM-1为影响乳腺癌细胞向肺部转移定植的关键分子，因此，其为潜在的预防乳腺癌肺转移的关键靶点。然而，目前缺少靶向肿瘤细胞的特异性VCAM-1抑制剂。前期研究发现NO可以显著降低乳腺癌4T1细胞VCAM-1表达，据此推测靶向递送NO可有效抑制乳腺癌肺转移；将NO与乳腺癌一线化疗药物紫杉醇联用，可协同增效，高效抑制乳腺癌原位瘤及肺转移。针对现有NO供体以及NO递送系统存在的载药量低，敏感释药能力不足以及靶向效率低等缺陷，本课题将构建仿生NO供体/紫杉醇二聚体前药自组装纳米粒，利用自组装纳米粒的高载药量，敏感释药特性和巨噬细胞膜的主动靶向功能，高效递送NO和紫杉醇，协同抑制乳腺癌及其肺转移；深入研究其载药释药特性，评价其乳腺癌及转移治疗效果。相关成果将有助于开辟乳腺癌及其肺转移化学治疗新途径。

Lung metastasis of breast cancer is an important cause of death in breast cancer patients. How to effectively inhibit lung metastasis of breast cancer is an urgent issue to be overcome to improve the effectiveness of breast cancer treatment. Studies have found that vascular cell adhesion molecule (VCAM-1) is a key molecule that affects the metastasis and colonization of breast cancer cells to the lung. Therefore, VCAM-1 is a promising therapeutic target for preventing lung metastasis of breast cancer. At present, there is still a lack of specific VCAM-1 inhibitors that targeting tumor cells. Our previous studies have found that NO can significantly reduce the expression of VCAM-1 in 4T1 cells. Therefore, it is speculated that targeted delivery of NO will specifically reduce the VCAM-1 expression of breast cancer and block its metastasis to the lung. The combination of NO and paclitaxel, will synergistically inhibit in situ and lung metastasis of breast cancer. Based on the deficiencies of the existing NO donor and NO delivery vehicles, such as low drug loading efficiency, insufficient sensitivity to tumor microenvironment and poor active targeting ability, this project will construct prodrug dimer self-assembly nanoparticles of NO donor and paclitaxel, which is cloaked by macrophage membrane, to co-deliver NO and paclitaxel, thus synergistically inhibiting breast cancer and its lung metastasis. In this project, the drug loading and drug release characteristics will be further studied to evaluate the therapeutic effect on breast cancer and lung metastasis. This will help to open up new ways of chemotherapy for breast cancer and lung metastasis.