BERKELEY, CA (UroToday.com) - The androgen receptor (AR) plays a critical role in the progression of prostate cancer, and it has been demonstrated previously that silencing the AR results in tumor growth inhibition and decreases in prostate specific antigen (PSA).[1,2] There are two main challenges in delivering the AR siRNA to the target tumor tissue. First is that the siRNA needs to stay intact and not experience any degradation by non-specific serum nucleases, and second is that the AR siRNAs need to accumulate at the target tumour site. By encapsulating the AR siRNAs into lipid nanoparticles (LNPs), we are able to circumvent these issues as LNPs provide a proper shielding effect from serum nucleases, and LNPs tend to accumulate at tumor sites due to their leaky vasculature.
Our future studies are geared towards lowering the overall dose of LNP AR siRNA needed to obtain a significant AR silencing effect. The current study described here uses an LNP formulation method termed the “pre-formed vesicle” (PFV) approach, which has been the standard method for producing LNPs for well over 20 years. However, we are in the process of tailoring our LNP formulation method by using a microfluidic approach, which is described in one of our most recent publications.[3] Through this new microfluidic approach we are able to tailor the size and polydispersity of our LNPs, and consequently, improve the circulation lifetimes of our LNP system to prevent LNP clearance from the bloodstream. We are also using this approach to assist in integrating small molecular ligands that are able to target prostate cancer cell surface receptors such as prostate specific membrane antigen (PSMA). Our new formulation technique also allows us to modify our lipid compositions in our formulation, and we are therefore able to integrate a higher ratio of cationic lipids into our LNPs for better optimization. Overall, these improvements to our current LNP system as well as modifications to the formulation techniques have shown through preliminary data that there are significant improvements in AR silencing. We look forward to presenting this data soon in a future publication.
References
- Cheng H, Snoek R, Ghaidi F, Cox ME, Rennie PS. Short hairpin RNA knockdown of the androgen receptor attenuates ligand-independent activation and delays tumor progression. Cancer Res 2006;66:10613-20.
- Snoek R, Cheng H, Margiotti K, Wafa LA, Wong CA, Wong EC, Fazli L, Nelson CC, Gleave ME, Rennie PS. In vivo knockdown of the androgen receptor results in growth inhibition and regression of well-established, castration-resistant prostate tumors. Clin Cancer Res 2009;15:39-47.
- Zhigaltsev IV, Belliveau NM, Hafez I, Leung AK, Huft J, Hansen C, Cullis PR. Bottom-Up Design and Synthesis of Limit Size Lipid Nanoparticle Systems with Aqueous and Triglyceride Cores Using Millisecond Microfluidic Mixing. Langmuir 2012. Epub ahead of print.
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Justin B. Lee, PhD candidate as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.