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

V. Labhasetwar
Cleveland Clinic Lerner Research Institute, US

Keywords: cancer, drug delivery, cell membrane

Summary:

Cell membrane lipids are involved in a variety of cellular activities; however, their role in drug delivery has not been fully explored. Recent advances in membrane lipid research show the varied roles of lipids in regulating membrane P-glycoprotein function, membrane trafficking, apoptotic pathways, drug transport, and endocytic functions, particularly endocytosis, the primary mechanism of cellular uptake of nanoparticle (NP)-based drug delivery systems. The presentation highlights the role of biophysics of membrane lipids in cancer drug resistance and targeting of NPs for cancer therapy. Since acquired drug resistance alters lipid biosynthesis, understanding the role of lipids in cell membrane biophysics and its effect on drug transport is critical for developing effective therapeutic and drug delivery approaches to overcoming drug resistance. Two different novel strategies are being investigated to overcome drug resistance: (a) modulating the biophysical properties of membrane lipids of resistant cells to facilitate drug transport and regain endocytic function and (b) developing effective NPs based on their biophysical interactions with membrane lipids to enhance drug delivery and overcome drug resistance. In another study, we investigated 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 than normal cells will improve intratumoral retention and in vivo efficacy upon delivery of NPs loaded with a therapeutic gene. Our study demonstrated that NPs that preferentially increase their biophysical interaction with the membrane lipids of cancer cells show improve intratumoral retention and in vivo efficacy upon delivery of NPs loaded with p53 gene. Biophysical interaction studies can improve our understanding of the role of membrane lipids in the transport of drugs/nanocarriers across biological barriers, and can provide a simple yet effective mechanistic and rational approach for efficient drugs or engineering nanocarrier systems for targeted delivery of therapeutics.