Abstract 3712: Optimizing design parameters of a VLA-4-targeted liposomal nanoparticle in a multiple myeloma disease model

Ligand-targeted liposomes have garnered interest as drug delivery vehicles for cancer therapy, however they have not consistently produced successful outcomes. These inconsistencies likely arise from differences in disease models and target receptors, as well as from nanoparticle design parameters which can significantly influence therapeutic efficacy. We systematically evaluated the role that peptide-linker length, peptide hydrophilicity, peptide density, and nanoparticle size play on tumor targeting using a multifaceted synthetic strategy to prepare highly controlled and consistent peptide-targeted liposomes. We analyzed these parameters in a VLA-4-expressing multiple myeloma model system where liposomes were functionalized with a VLA-4-antagonist peptide to evaluate in vitro targeting efficiency and in vivo biodistribution and tumor cell uptake. Our studies demonstrated that by increasing the hydrophilicity of the targeting peptide sequence via addition of an oligolysine chain and simultaneously optimizing the EG peptide-linker length, cellular uptake of targeted liposomes was significantly enhanced in vitro. Specifically, the cellular uptake was greatly enhanced for 50-100 nm size liposomes with shorter peptide-linker lengths of EG6 when compared to the industry standard EG45 linker. For in vivo applications, although targeted formulations did not enhance tumor accumulation directly relative to non-targeted formulations, liposomes designed with EG6 linker and an oligolysine chain provided a significant advantage by demonstrating significantly enhanced tumor cell uptake relative to non-targeted liposomes. These results highlighted the importance of creating a comprehensive understanding of the effect of each liposome design parameter on multifactorial biological endpoints in determining the therapeutic potential of peptide-targeted liposomes. Citation Format: Basar Bilgicer, Tanyel Kiziltepe, David Omstead, Peter Deak. Optimizing design parameters of a VLA-4-targeted liposomal nanoparticle in a multiple myeloma disease model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3712.