(701c) Triggered Ligand Clustering on Lipid Nanoparticles Enables Selective Targeting and Killing of Untargetable Cancer Cells: The Case for 'sticky Patches'
Methods: Using HER2-targeting sticky liposomes loaded with doxorubicin, on a variety of cells expressing a wide range of HER2 (>1M copies per cell to 54,000 copies per cell), we evaluate the: 1) targeting selectivity, 2) killing efficacy, 3) endocytic pathway, 4) intracellular localization, 5) mechanism of action, and 6) potential toxicity to human cardiomyocytes and normal human mammary epithelial cells. In all studies, we compare to liposomes uniformly functionalized with HER2-targeting ligands via (or not) a PEG tether, and to non-targeted liposomes.
Results: Our studies show that sticky liposomes selectively and effectively kill otherwise untargetable breast cancer cells with as few as 54,000 HER2 receptors per cell utilizing both clathrin- and caveolar-mediated endocytosis, and are nontoxic to normal breast cells and cardiomyocytes which minimally express HER2. Sticky liposomes also demonstrate KD values which are independent of HER2 expression, and long enough residence times on the cell surface (t1/2 of dissociation ranged from 82 to 140 minutes) to allow for internalization of vesicles (t1/2 of internalization ranged from 27 to 29 minutes).
Conclusions: These studies demonstrate the potential of sticky liposomes to selectively target and effectively kill cancer cells considered otherwise untargetable.
Acknowledgements: NJCCR, American Cancer Society RSG-12-044-01, NSF DMR-1207022, NSF CBET-1510015, GAANN.