Since 2002, we have been successful in developing intravesical liposomes for painful bladder syndrome/interstitial cystitis (PBS/IC). We have discovered and translated intravesical instillation of liposome formulation that can coat and protect the bladder. The results from biodistribution studies confirmed our hypothesis that liposomes delivered to the urinary bladder lumen reside in the bladder for an extended period and have low systemic bioavailability. There is a tremendous unmet medical need for a better and safer way to deliver BoNT to the urinary bladder. Our novel technology of liposome based delivery of BoNT is logical and promising. The successful funding and completion of this grant can lead to submission of a clinical IND trial for liposome-BoNT and fulfill the mission of NIH translational research priority. The research team and facility at the Urology department at Beaumont has been significantly strengthened. Dr. Pradeep Tyagi, a previous consultant at the University of Pittsburgh, has since been recruited to join Dr. Chancellor at Beaumont in the fall of 2008. Drs. Tyagi and Chancellor has worked together for eight years and with Dr. Tyagi's strong expertise in liposome pharmacology, the facility and resources are now full ready to successfully complete the projects of this grant. In this grant we will evaluate liquid liposome delivery of liposome- BoNT into the bladder without the need for cystoscopic-guided needle injection for PBS/IC, and study the mechanism of action of intravesical liposomal drug delivery. The goals of the project described in the proposal are to: 1) formulate BoNT into liposomes;2) assess endocytosis as a mechanism for the bladder uptake of BoNT from instilled liposomal BoNT in the absence or presence of bladder distension;and 3) determine the lowest effective dose of BoNT in synergy with bladder distension. We have three aims:
Aim 1 : Formulate BoNT-A into liposomes and determine in vitro stability and sustained release.
Aim 2 a: To study endocytosis as a mechanism of bladder uptake of liposomal-BoNT after instillation.
Aim 2 b: Assess liposomal-BoNT local toxicity.
Aim 3 : To study the biological efficacy of liposomal-BoNT in rat. Successful completion of the project goals will improve the safety of BoNT and promote wide acceptance in the urology community.

Public Health Relevance

The development of a safe and effective new treatment for painful bladder syndrome/interstitial cystitis (PBS/IC) is an unmet need for many Americans and a research priority at the NIH. The knowledge gained as a result of conducting the experiments under this grant will confirm our hypotheses regarding the potential for liquid instillation of botulinum toxin and move toward bring a new treatment for PBS/IC.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
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Mullins, Christopher V
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William Beaumont Hospital
Royal Oak
United States
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Hanna-Mitchell, Ann T; Wolf-Johnston, Amanda S; Barrick, Stacey R et al. (2015) Effect of botulinum toxin A on urothelial-release of ATP and expression of SNARE targets within the urothelium. Neurourol Urodyn 34:79-84
Rajaganapathy, Bharathi Raja; Chancellor, Michael B; Nirmal, Jayabalan et al. (2015) Bladder uptake of liposomes after intravesical administration occurs by endocytosis. PLoS One 10:e0122766
Nirmal, J; Wolf-Johnston, A S; Chancellor, M B et al. (2014) Liposomal inhibition of acrolein-induced injury in rat cultured urothelial cells. Int Urol Nephrol 46:1947-52