Synergistic Therapy\nof Metastatic Breast Cancers by\nBiomimetic Chemotherapeutic Drug-Gene Nanoparticles

Cancer metastasis is responsible for more than 90% of\ntumor-related\ndeaths. Especially, metastatic breast cancer (MBC) is a common malignancy\nwith a high mortality among women worldwide. It is urgent to develop\neffective drugs for the treatment of MBC. Herein, biomimetic chemotherapeutic\ndrug-gene nanoparticles (named TPT-ASO<sub>VEGF</sub>@MM NPs) were\nconstructed for the combination therapy of MBC. First, topotecan hydrochloride\n(TPT) and vascular endothelial growth factor antisense oligonucleotide\n(ASO<sub>VEGF</sub>) were coself-assembled in water through electrostatic\ninteraction to produce chemotherapeutic drug-gene nanoparticles (TPT-ASO<sub>VEGF</sub> NPs). Then, the nanoparticles were encapsulated within\nmacrophage membranes (MM) to form biomimetic TPT-ASO<sub>VEGF</sub>@MM NPs with long circulation time in blood and active tumor-targeting\nability. TPT-ASO<sub>VEGF</sub>@MM NPs can be effectively internalized\nby breast cancer cells and then the nanoparticles collapse to simultaneously\nrelease TPT and ASO<sub>VEGF</sub>. ASO<sub>VEGF</sub> can inhibit\nthe expression of VEGF, impeding the process of neovascularization\nand blocking the metastatic pathway of cancer cells. Meanwhile, TPT\ncan bind to the topoisomerase I-DNA complex to prevent DNA repair\nand replication, and further induce apoptosis of cancer cells. In\naddition, TPT can also affect hypoxia-inducible factor 1α (HIF-1α)\nexpression and inhibit hypoxia-induced tumor metastasis to achieve\nsynergistic therapy with ASO<sub>VEGF</sub>. In MBC mouse models,\nthe in vivo inhibition rate of TPT-ASO<sub>VEGF</sub>@MM NPs for lung\nmetastasis was 89.5%, with minor toxic side effects and the least\nnumber of metastatic nodules in the lungs. In summary, TPT-ASO<sub>VEGF</sub>@MM NPs would be a promising biomimetic nanodrug for chemo-gene\ncombination therapy of MBC with high efficacy and safety in clinics.