(198o) Optimizing Design Parameters of a VLA-4-Targeted Liposomal Nanoparticle in a Multiple Myeloma Disease Model

Ligand-targeted liposomes have gathered attention as potential chemotherapeutic delivery vehicles, but inconsistencies in liposomal design have led to varying levels of success. We have systematically evaluated and discovered the significant roles that peptide-linker length, peptide hydrophilicity, peptide density, and liposome size play both in vitro and in vivo. By using a multifaceted synthetic strategy to prepare highly controlled and consistent peptide-targeted liposomes, these parameters were evaluated in a VLA-4-expressing multiple myeloma model. Studies demonstrated that increasing peptide hydrophilicity through the addition of a short oligolysine sequence while simultaneously optimizing the EG peptide-linker length led to greatly increased liposome uptake in vitro. A peptide-linker of length EG6 specifically lead to the greatest increase in uptake over the industry standard of an EG45 linker. In vivo, although peptide-targeted liposomal formulations did not lead to increased tumor accumulation compared to non-targeted liposomes, targeted liposomes demonstrated significantly increased tumor cell uptake relative to non-targeted liposome. These results show the importance of a comprehensive understanding of all facets of liposomal design on multiple biological endpoints in order to determine and properly optimize the design of a peptide-targeted liposome system.