Synergistic Therapy of Metastatic Breast Cancers by Biomimetic Chemotherapeutic Drug-Gene Nanoparticles

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_VEGF@MM NPs) were constructed for the combination therapy of MBC. First, topotecan hydrochloride (TPT) and vascular endothelial growth factor antisense oligonucleotide (ASO_VEGF) were coself-assembled in water through electrostatic interaction to produce chemotherapeutic drug-gene nanoparticles (TPT-ASO_VEGF NPs). Then, the nanoparticles were encapsulated within macrophage membranes (MM) to form biomimetic TPT-ASO_VEGF@MM NPs with long circulation time in blood and active tumor-targeting ability. TPT-ASO_VEGF@MM NPs can be effectively internalized by breast cancer cells and then the nanoparticles collapse to simultaneously release TPT and ASO_VEGF. ASO_VEGF 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_VEGF. In MBC mouse models, the in vivo inhibition rate of TPT-ASO_VEGF@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_VEGF@MM NPs would be a promising biomimetic nanodrug for chemo-gene combination therapy of MBC with high efficacy and safety in clinics.