My thesis project involves developing an RNA interference strategy to solve a compelling drug resistance problem in breast cancer. Although there are efficacious drugs available, some patients acquire resistance and relapse, often in a more aggressive form. Given the recent progress in molecular medicine, this challenge can be addressed with gene silencing methodologies. I plan to target this issue using siRNA therapeutics. siRNA is a promising therapeutic candidate at the forefront of biotechnology. However, there remains drug delivery issues and challenges associated with in vivo stability.
Current methods for delivery are less than ideal and have room for improvement. Owing to its hydrophilic nature and a large net negative charge, siRNA is difficult to deliver on its own. A relatively new delivery strategy that has gained traction are siRNA-GalNAc conjugates, which selectively target hepatocytes. Most pharmaceutical companies now employ GalNAc conjugates because of this specificity. Nevertheless, for targets outside the liver, options are very limited. Lipid nanoparticles (LNP) are quite promising for drug delivery that spans outside the liver, however those have some serious drawbacks. These LNPs are cationic, where charge complementarity is exploited to capture siRNA. Positive charge, however, causes cellular toxicity due to interaction with the negatively charged phosphates of the cell membrane and destabilizing the lipid bilayer.
To solve this issue, I am currently developing an innovative polymer nanoparticle that would eliminate cationic toxicity and be able to be delivered to drug resistant breast cancer cells to solve the resistance problem. Preliminary demonstrations in our laboratory with this strategy show excellent promise. My work will specifically focus on leveraging these findings and optimizing the nanoparticles for impacting drug resistant breast cancer. After optimizing the polymeric nanoparticle and siRNA in vitro, I will test the efficacy under in vivo conditions. I plan to use relevant mouse models to check if the delivery of the siRNA works in vivo and if it targets the breast cancer cells effectively without having a great amount of off-target effects.