Selective biophysical interactions of surface modified nanoparticles with cancer cell lipids improve tumor targeting and gene therapy

• Biophysical properties of cancer cell membranes differ from normal cell membranes.
• These characteristics may be exploited for tumor-targeting of nanoparticles (NPs).
• Surface modification of NPs improved biophysical interactions with cancer cells versus normal cells.
• These interactions correlated with greater cell uptake and tumor accumulation of NPs.
• Surface modified NPs improved efficacy of p53 gene therapy to inhibit tumor growth.

Targeting gene- or drug-loaded nanoparticles (NPs) to tumors and ensuring their intratumoral retention after systemic administration remain key challenges to improving the efficacy of NP-based therapeutics. Here, we investigate a novel targeting approach that exploits changes in lipid metabolism and cell membrane biophysics that occur during malignancy. We hypothesized that modifications to the surface of NPs that preferentially increase their biophysical interaction with the membrane lipids of cancer cells will improve intratumoral retention and in vivo efficacy upon delivery of NPs loaded with a therapeutic gene. We have demonstrated that different surfactants, incorporated onto the NPs’ surface, affect the biophysical interactions of NPs with the lipids of cancer cells and normal endothelial cells. NPs surface modified with didodecyldimethylammoniumbromide (DMAB) demonstrated greater interaction with cancer cell lipids, which was 6.7-fold greater than with unmodified NPs and 5.5-fold greater than with endothelial cell lipids. This correlated with increased uptake of DMAB-modified NPs with incubation time by cancer cells compared to other formulations of NPs and to uptake by endothelial cells. Upon systemic injection, DMAB-NPs demonstrated a 4.6-fold increase in tumor accumulation compared to unmodified NPs which also correlated to improved efficacy of p53 gene therapy. Characterization of the biophysical interactions between NPs and lipid membranes of tumors or other diseased tissues/organs may hold promise for engineering targeted delivery of therapeutics.