Ren Junjie, Han Ying, Xu Jie, Chen Tianbao, Huang Wei, Yan Deyue
School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, Shanghai 200240, China.
Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang 154007, China.
ACS Appl Mater Interfaces. 2024 Dec 25;16(51):70242-70255. doi: 10.1021/acsami.4c13535. Epub 2024 Dec 10.
Cancer metastasis is responsible for more than 90% of tumor-related deaths. Especially, metastatic breast cancer (MBC) is a common malignancy with a high mortality among women worldwide. It is urgent to develop effective drugs for the treatment of MBC. Herein, biomimetic chemotherapeutic drug-gene nanoparticles (named TPT-ASO@MM NPs) were constructed for the combination therapy of MBC. First, topotecan hydrochloride (TPT) and vascular endothelial growth factor antisense oligonucleotide (ASO) were coself-assembled in water through electrostatic interaction to produce chemotherapeutic drug-gene nanoparticles (TPT-ASO NPs). Then, the nanoparticles were encapsulated within macrophage membranes (MM) to form biomimetic TPT-ASO@MM NPs with long circulation time in blood and active tumor-targeting ability. TPT-ASO@MM NPs can be effectively internalized by breast cancer cells and then the nanoparticles collapse to simultaneously release TPT and ASO. ASO can inhibit the expression of VEGF, impeding the process of neovascularization and blocking the metastatic pathway of cancer cells. Meanwhile, TPT can bind to the topoisomerase I-DNA complex to prevent DNA repair and replication, and further induce apoptosis of cancer cells. In addition, TPT can also affect hypoxia-inducible factor 1α (HIF-1α) expression and inhibit hypoxia-induced tumor metastasis to achieve synergistic therapy with ASO. In MBC mouse models, the in vivo inhibition rate of TPT-ASO@MM NPs for lung metastasis was 89.5%, with minor toxic side effects and the least number of metastatic nodules in the lungs. In summary, TPT-ASO@MM NPs would be a promising biomimetic nanodrug for chemo-gene combination therapy of MBC with high efficacy and safety in clinics.
癌症转移导致超过90%的肿瘤相关死亡。特别是转移性乳腺癌（MBC）是一种常见的恶性肿瘤，在全球女性中死亡率很高。开发治疗MBC的有效药物迫在眉睫。在此，构建了仿生化疗药物-基因纳米颗粒（命名为TPT-ASO@MM NPs）用于MBC的联合治疗。首先，盐酸拓扑替康（TPT）和血管内皮生长因子反义寡核苷酸（ASO）通过静电相互作用在水中共自组装，产生化疗药物-基因纳米颗粒（TPT-ASO NPs）。然后，将纳米颗粒包裹在巨噬细胞膜（MM）内，形成在血液中具有长循环时间和主动肿瘤靶向能力的仿生TPT-ASO@MM NPs。TPT-ASO@MM NPs可被乳腺癌细胞有效内化，然后纳米颗粒解体，同时释放TPT和ASO。ASO可抑制VEGF的表达，阻碍新血管形成过程，阻断癌细胞的转移途径。同时，TPT可与拓扑异构酶I-DNA复合物结合，阻止DNA修复和复制，并进一步诱导癌细胞凋亡。此外，TPT还可影响缺氧诱导因子1α（HIF-1α）的表达，抑制缺氧诱导的肿瘤转移，以实现与ASO的协同治疗。在MBC小鼠模型中，TPT-ASO@MM NPs对肺转移的体内抑制率为89.5%，毒副作用小，肺内转移结节数量最少。综上所述，TPT-ASO@MM NPs将是一种有前景的仿生纳米药物，用于MBC的化疗-基因联合治疗，在临床上具有高效和安全性。
