Intravesical instillation of small interference RNAs (siRNAs) is an exciting new treatment option for urological diseases. siRNA oligonucleotides are an attractive therapeutic option because of their high selectivity and specificity, due to gene selective silencing of target protein expression. siRNAs, however, have a relatively short half-life and thus we will address the technical challenges of stabilization and intravesical delivery of siRNAs. To achieve this goal, we plan to create and test clinically viable, non-viral nanosphere- siRNA complexes that are intravesically instilled for treatment of bladder cancer and other diseases of the urinary tract. As we have: 1) developed transgenic mice that over- express bladder specific human survivin and that is associated with transcriptional activation of a specific gene signature; 2) established a nitrosamine induced murine bladder cancer model in which both survivin and VEGF are upregulated; and 3) developed, in collaboration with Dr.W. Mark Saltzman Professor and Chair, Department of Bio-engineering, poly (lactide-co-glycolide (PLGA) nanospheres for drug delivery, we are in an unique position to determine the effect of intravesical instillation of siRNA- PLGA in mouse disease models which will initially be tested in our transgenic and bladder cancer models. Specifically we plan to: 1) develop and test a siRNA controlled release system to stabilize and deliver siRNA; 2) test in a whole animal system, the ability of intravesically instilled microencapsulated human survivin siRNA to selectively reverse upregulation of transgenically induced bladder specific survivin and the matrix and inflammatory changes associated with survivin upregulation; and 3) test whether the combination of encapsulated survivin siRNA and VEGF siRNA more effectively reduces tumor burden, the time to onset, rate of occurrence and mortality than individual encapsulated siRNAs in a nitrosamine induced bladder cancer model. Thus, the challenges of more effective intravesical instillation protocols for treatment of common urological diseases including bladder cancer, overactive bladder and IC can be addressed using siRNAs encapsulated in microspheres to increase their stability and prolong their efficacy. Standard pharmacologic and chemotherapeutic treatment options for urological diseases including bladder cancer, overactive bladder and interstitial cystitis may cause undesirable side effects or may be ineffective. Small interference RNA (siRNA) can specifically and sensitively degrade RNA messages and thus reduce their target protein levels. In order to exploit the therapeutic potential of these siRNAs, which are short lived and easily degraded, we have designed strategies for stabilization and testing of these siRNAs. Then, these siRNA polymers will be intravesically instilled as a treatment for bladder cancer, using mouse models of bladder cancer. Furthermore, more than one siRNA can be intravesically instilled in order to target different cancer pathways. Thus, we can determine the therapeutic potential of siRNA for treatment of urologic diseases. ? ? ?
| Verma, Avanti; Degrado, Justin; Hittelman, Adam B et al. (2011) Effect of mitomycin C on concentrations of vascular endothelial growth factor and its receptors in bladder cancer cells and in bladders of rats intravesically instilled with mitomycin C. BJU Int 107:1154-61 |
