Tumor Microenvironment Activated Membrane Fusogenic Liposome with Speedy Antibody and Doxorubicin Delivery for Synergistic Treatment of Metastatic Tumors.

Metastasis is the principal event leading to breast cancer death. Discovery of novel therapeutic approaches that are specific in targeting tumor metastasis factors while at the same time are an effective treatment of the tumor is urgently required. S100A4 protein is a key player in promoting metastasis and sequestrating the effect of tumor-suppressor protein p53. Here, a tumor microenvironment activated membrane fusogenic liposome was prepared to deliver rapidly anti-S100A4 antibody and doxorubicin into the cytoplasm directly in a fusion-dependent manner in order to bypass the cellular endocytosis to avoid the inefficient escape and degradation in the acidic endosome. After intracellular S100A4 blockage with anti-S100A4 antibody, the cytoskeleton of breast cancer 4T1 cells was rearranged and cell motility was suppressed. In the meantime, the antitumor effect of doxorubicin was enormously enhanced by reversing the effect of S100A4 on the sequestration of tumor-suppressor protein p53. Importantly, both local growth and metastasis of 4T1 cells were inhibited in a xenograft mouse model. Together, the speedy delivery of antibody and doxorubicin into cytoplasm based on a new membrane fusogenic liposome was an innovative approach for metastatic breast cancer treatment.