Nonviral genetic manipulation system with microenvironmental cascade sensitivity for the treatment of TNBC-associated metastatic bone tumor

Abstract

Gene therapy is an efficacious therapeutic modality for triple negative breast cancer (TNBC). However, the practicable applicability is strictly confined in TNBC-associated metastatic bone tumor due to the low blood flow and poor accumulation in bone tissue, as well as the vicious cycle of mutual promotion between tumor growth and bone erosion. To address those problems, a versatile nonviral genetic manipulation system PSMCA/miR-34a, with caveolae-activated endocytosis and microenvironmental cascade-responsive release profile was exploited. In vitro and in vivo experiments confirmed that PSMCA/miR-34a not only possessed bone-targeting properties to accumulate at bone tumor tissue, also could respond to the bone tumor microacidic environment to release alendronate to inhibit the bone erosion. After internalized into cells mainly through caveolae-mediated endocytosis, it was spurred to disassemble for controlling release the miR-34a by high intracellular GSH environment, generating an effective anti-tumor effect. Moreover, due to the synergistic effect, PSMCA/miR-34a could breakdown the vicious cycle between bone destruction and tumor growth in the tumor microenvironment, showing high potential in the clinical gene therapy for TNBC-associated metastatic bone tumor.