(190ai) Engineering Peptide Targeting Liposomal Drug Delivery to Improve Selectivity for HER2-Overexpressing Breast Cancer

Breast cancer is the second leading cancer in the U.S. women for whom approximately 15% of them have the likelihood of risk in development of breast cancer in their life-time. Human epidermal growth factor receptor 2 (HER2) is the most widely known biomarker for the development of breast cancer that has been utilized as a therapeutic target owing to its overexpression in approximately 30% of the breast cancer cases. The FDA-approved monoclonal antibody therapies such as Trastuzumab with chemotherapeutic drugs have been used as the first-line treatment of HER2-positive breast cancer. Despite the successful clinical outcomes, the current treatments necessarily induce systemic toxicity in the patient’s bodies due to their non-selective and off-target binding. Here, we report a HER2 targeting liposome that could enhance selectivity of a drug on HER2-overexpressing breast cancer cells by utilizing HER2 targeting peptide ligand. In order to improve selectivity of our targeted liposomal drug delivery, we rationally controlled several variables of liposomal formulation, such as peptide density, peptide-lipid linker length, and the size of liposome and then performed in vitro cellular uptake assays on HER2-overexpressing (SK-BR-3 and BT-474) and HER2-negative (MCF-7) human breast cancer cell lines. The results showed that the HER2 targeting liposomes were selectively uptaken by HER2-overexpressing human breast cancer cells, demonstrating approximately 40 to 160-fold uptake enhancement over HER2-negative cells depending upon the liposomal surface peptide density and the size of liposome. In addition to the in vitro studies, we performed liposome tissue biodistribution studies by utilizing allograft transplantation breast cancer mouse model to investigate whether our HER2 targeting liposomes selectively target HER2-overexpressing breast tumor cells. The results showed higher fluorescence signals in tumor, comparing with other organ tissues. More importantly, 0.3% peptide presenting liposomes were uptaken by the tumor cells with 2-fold enhancement as compared to non-targeted liposomes while the accumulation of both liposomes at tumor site is comparable. Overall, the results demonstrated enhancement in breast tumor cellular uptake of our targeted liposomes while they selectively bind to the HER2-overexpressing breast cancer cells, suggesting that the HER2 targeting liposomes could be a very promising therapeutic drug carrier that possibly improves drug efficacy as well as reduces systemic toxicity. In the future, we will perform drug efficacy and toxicity tests to investigate whether our targeted liposomes loaded with chemotherapeutic drugs selectively induce the cytotoxicity in HER2-overexpressing breast cancer cells using in vivo mouse model.