Improved Peptide-Targeted Liposome Design Through Optimized Peptide Hydrophilicity, Ethylene Glycol Linker Length, and Peptide Density

Ligand-targeted liposomes are increasingly used as drug delivery carriers for cancer therapy, yet have not consistently produced successful outcomes. Here, we demonstrated the significant enhancement in cellular uptake of peptide-targeted liposomes by simultaneously increasing the hydrophilicity of the targeting peptide, optimizing the EG peptide-linker length, and using appropriate peptide surface density. We analyzed these parameters in a HER2-overexpressing breast cancer model system where the liposomes were functionalized with one of four distinct HER2-antagonist peptides to evaluate cellular uptake. Our results demonstrated that including a short oligolysine chain adjacent to the targeting peptide sequence effectively improved cellular uptake similar to 6-10 fold when using an EG6-EG18 linker depending on the selected antagonist peptide. Uptake efficiency reached a maximum and a plateau with similar to 2% peptide density with higher observed sensitivity at lower peptide densities for the more hydrophilic peptides. Taken together, these findings demonstrated the importance of optimizing liposome design for improved cellular uptake.