Robert M. Weiss MD, FACS, FAAP
Donald Guthrie Professor of Urology; Director, Pediatric Urology
Smooth muscle pharmacology; Signal transduction; Bladder cancer; Drug delivery
Using nanospheres that contain siRNAs to survivin in combination with chemotherapeutic agents to affect growth and spread of bladder cancer in in vitro and in vivo animal models
Use of nanoparticles for localization and treatment of prostatic carcinoma in a in vivo animal model.
We are involved in using nano-particle delivery systems to diagnose and treat diseases of the urinary system with special emphasis on benign and malignant diseases of the bladder. These studies, which are presently focused on diagnosing and treating bladder and prostate cancer utilizing nano-particles loaded with specifically targeted siRNAs are directed by Darryl T. Martin, PhD. In addition we are studying the pharmacology and physiology on ureteral-vesical smooth muscle.
Extensive Research Description
The Proof of Concept that we are testing is that intravesical instillation of small interference RNA (siRNA) packaged in biodegradable nanospheres provides wide opportunities for the treatment of urologic diseases including transitional cell carcinoma of the bladder (TCC), interstitial cystitis (IC), overactive bladder, and detrusor hyperreflexia.
Because of their robust, gene selective silencing of target protein expression, siRNA oligonucleotides are an attractive therapeutic option with high selectivity and specificity and minimal toxicity to neighboring cells. siRNAs, however, have a relatively short half-life and thus we are addressing the 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 diseases of the urinary tract.
We plan to develop and test a number of nanoparticle controlled release systems containing targeting proteins that will stabilize and deliver siRNAs and drugs and initially test these on bladder cancers
- Martin DT*, Steinbach J, Liu JC, Shimizu S, Kaimakliotis H, Wheeler MA, Hittelman AB, Saltzman WM, and Weiss RM. Surface-modified nanoparticles enhance transurothelial penetration and delivery of survivin siRNA in treating bladder cancer. Mol Cancer Ther. 2014 Jan;13(1):71-81.
- Martin, D.T., Hoimes, C.J., Kaimakliotis, H.Z., Cheng, C.J., Zhang, K., Liu, J., Wheeler, M.A., Kelly, W.K., Tew, G.N., Saltzman, W.M., Weiss, R.M. Nanoparticles for urothelium penetration and delivery of the histone deacetylase inhibitor belinostat for treatment of bladder cancer. Nanomedicine: Nanotechnology, Biology, and Medicine. Nanomedicine. 2013 Nov;9(8):1124-34
- Weiss, R,M., Guo, S., Shan, A., Shi, H., Rnomano, R-A., Sinha, S., Cantley, L.G., and Guo, J-K.: Brg1 determines urothelial cell fate during ureter development. J. Amer. Soc. Nephrology 24: 618-626, 2013.
- Verma A. Degrado J. Hittelman AB. Wheeler MA. Kaimakliotis HZ. Weiss RM. 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 International. 107(7):1154-61, 2011.
- Ikeda K, Wada Y, Sanematsu H, Foster HE Jr, Shin D, Weiss RM and Latifpour J. Regulatory
effect of experimental diabetes on the expression of endothelin receptor subtypes and their gene
transcripts in the rat adrenal gland. J Endocrin 168:163-175, 2001.
- Wada Y, Latifpour J, Sanematsu H, Wang-J, Saito M, Nishi K and Weiss RM. Age-related
changes in contractile responses of rabbit lower urinary tract to endothelin. J Urol 164:806-813,
- Takizawa BT, Uchio EM, Cohen JJ, Wheeler MA and Weiss RM. Down-regulation of survivin is associated with reductions in TNF receptors mRNA and protein and alterations in nuclear factor kappa B signaling in urothelial cancer cells. Cancer Invest. 25;678-684, 2007
- Smith SD, Wheeler MA, Plescia J, Colberg JW, Weiss RM and Altieri DC. Urine detection of survivin and diagnosis of bladder cancer. JAMA 285:324-328, 2001.
- Salz W. Eisenberg D. Plescia J. Garlick DS. Weiss RM. Wu XR. Sun TT. Altieri DC. A survivin gene signature predicts aggressive tumor behavior. Cancer Res. 65:3531-3534, 2005.