Intravesical liposome drug delivery to treat interstitial cystitis

描述（由申请人提供）：自2002年以来，我们已成功开发膀胱内脂质体用于治疗膀胱疼痛综合征/间质性膀胱炎（PBS/IC）。我们已经发现并翻译了膀胱内灌注脂质体制剂，可以覆盖和保护膀胱。生物分布研究的结果证实了我们的假设，即输送到膀胱腔的脂质体在膀胱中停留较长时间，并且具有较低的系统生物利用度。有一个巨大的未满足的医疗需求，一个更好的和更安全的方式将BoNT输送到膀胱。我们的基于脂质体的BoNT递送新技术是合乎逻辑的和有前途的。这项资助的成功资助和完成可以导致脂质体- bont临床IND试验的提交，并完成NIH转化研究优先的使命。博蒙特泌尿科的研究团队和设备得到了大幅加强。Pradeep Tyagi博士是匹兹堡大学（University of Pittsburgh）的前顾问，自2008年秋季被招募加入博蒙特大学（Beaumont）的Chancellor博士。Drs。Tyagi和Chancellor已经合作了8年，凭借Tyagi博士在脂质体药理学方面的强大专业知识，该设施和资源现已准备就绪，可以成功完成该资助项目。在本项目中，我们将评估液体脂质体- BoNT在膀胱内的输送，而不需要膀胱镜引导下的PBS/IC针注射，并研究膀胱内脂质体给药的作用机制。提案中描述的项目目标是：1)将BoNT制成脂质体；2)评估内吞作用作为膀胱在没有或存在膀胱膨胀的情况下从输注的脂质体BoNT中摄取BoNT的机制；3)确定BoNT与膀胱膨胀协同作用的最低有效剂量。目的1：制备BoNT-A脂质体并测定其体外稳定性和缓释度。目的2a：研究内吞作用作为脂质体- bont输注后膀胱摄取的机制。目的2b：评估脂质体- bont的局部毒性。目的3：研究脂质体bont在大鼠体内的生物学功效。项目目标的成功完成将提高BoNT的安全性，并促进泌尿外科社区对BoNT的广泛接受。

DESCRIPTION (provided by applicant): 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 2a: To study endocytosis as a mechanism of bladder uptake of liposomal-BoNT after instillation. Aim 2b: 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.