Sticky liposomes: a new binding geometry with implications in the targeted therapy of HER2-negative breast cancer

HER2-targeted nanoparticles encapsulating chemotherapeutics have shown promise for reducing the severity of side effects associated with traditional chemotherapeutics. However, the ability for conventionally functionalized HER2-targeted nanoparticles to effectively target stops to hold on cancer cells expressing less than 200,000 HER2 receptors per cell (<1+ HER2 by immunohistochemistry). For cases of cancer with HER2 expression below this threshold, there is a lack of targeted treatment options because tumors are still considered untargetable. In this dissertation, we describe pH-responsive lipid nanocarriers (liposomes) that present HER2-targeting lipopeptides on lipid domains with high local multivalency (‘sticky patches’). Sticky patches are formed by inducing preferential partitioning of lipopeptides into lipid raft-like domains that are triggered to form on the liposome membrane at acidic pH values (6.5 < pH < 7.0) matching the tumor interstitial pH. We investigate the preclinical feasibility of HER2-targeting sticky liposomal doxorubicin by first characterizing and understanding their binding geometries with cell receptor(s), then testing the reactivity and efficacy against a variety of breast cancer cells with variable expression of targeting receptors, and multicellular spheroids expressing a wide range of HER2. Overall, our results demonstrate the potential of sticky liposomes as an effective targeted therapy for breast cancers expressing low HER2 copies and, in particular, for Triple Negative Breast Cancers.Ph.D.Includes bibliographical referencesby Michelle Sempkowsk