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Intravesical liposome drug delivery to treat interstitial cystitis

膀胱内脂质体给药治疗间质性膀胱炎

基本信息

批准号：
8293399
负责人：
MICHAEL B CHANCELLOR
金额：
$ 19.76万
依托单位：
WILLIAM BEAUMONT HOSPITAL RESEARCH INST
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-15 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8293399
关键词：
Accounting Acetic Acids Acetylcholine Affect American Basic Science Belief Binding Biodistribution Biological Biological Availability Bladder Bladder Dysfunction Bladder Urothelium Botox Botulinum Toxins Businesses Capsaicin Catheterization Cells Cholinesterase Inhibitors Clinical Communities Confocal Microscopy Core Facility Development Dose Drug Delivery Systems Drug Formulations Endocytosis Epithelial Cells Evaluation Fluorescence Funding Future Goals Grant Hospitals Image In Vitro Incidence Infusion procedures Injection of therapeutic agent Interstitial Cystitis Intravesical Instillation Knowledge Laboratories Lead Legal patent Licensing Liposomes Liquid substance Measures Medical Methods Micturition Reflex Mission Molecular Probes Needles Neostigmine Nerve Endings Patients Penetration Peptide Hydrolases Pharmaceutical Preparations Pharmacologic Substance Pharmacology Physicians Physiological Physostigmine Prevention Principal Investigator Rattus Recruitment Activity Refractory Reporting Research Research Institute Research Priority Research Proposals Residual state Resources Risk Safety Science Scientist Signal Transduction Small Business Innovation Research Grant Solutions Stretching Technology Testing Therapeutic Time Tissues Toxic effect Toxin Translating Translational Research United States National Institutes of Health Universities Urinary Retention Urine Urology Urothelium Work absorption afferent nerve base cytokine detrusor muscle falls improved inhibitor/antagonist intravesical irritation neurotransmitter release new technology painful bladder syndrome programs public health relevance quinoline receptor mediated endocytosis research and development research facility research study uptake

项目摘要

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.

描述（由申请人提供）：自2002年以来，我们已经成功开发了用于疼痛性膀胱综合征/间质性膀胱炎（PBS/IC）的膀胱内脂质体。我们已经发现并翻译了可以涂覆和保护膀胱的脂质体制剂的膀胱内滴注。生物分布研究的结果证实了我们的假设，即递送至膀胱腔的脂质体在膀胱中停留较长时间，并且具有较低的全身生物利用度。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提供BoNT到膀胱。我们基于脂质体的BoNT递送新技术是合乎逻辑的和有前途的。成功的资助和完成这一赠款可以导致提交临床IND试验的脂质体-BoNT和履行的使命的NIH转化研究的优先事项。博蒙泌尿科的研究团队和设施得到了显著加强。Pradeep Tyagi博士曾是匹兹堡大学的顾问，2008年秋天被招募加入博蒙的财政大臣博士。Tyagi博士和Chancellor博士一起工作了八年，凭借Tyagi博士在脂质体药理学方面的强大专业知识，该设施和资源现已完全准备好成功完成该赠款的项目。在这项研究中，我们将评估液体脂质体递送脂质体- BoNT进入膀胱而不需要膀胱镜引导的PBS/IC针注射，并研究膀胱内脂质体药物递送的作用机制。该提案中描述的项目的目标是：1）将BoNT配制成脂质体; 2）评估内吞作用作为在不存在或存在膀胱扩张的情况下从滴注的脂质体BoNT中膀胱摄取BoNT的机制;以及3）确定与膀胱扩张协同作用的BoNT的最低有效剂量。目的1：将BoNT-A制备成脂质体，并进行体外稳定性和缓释性研究。目的2a：研究内吞作用作为灌注后膀胱摄取脂质体-BoNT的机制。目的2b：评估脂质体-BoNT局部毒性。目的3：研究脂质体BoNT在大鼠体内的生物学效应。项目目标的成功完成将提高BoNT的安全性，并促进泌尿外科界的广泛接受。公共卫生相关性：开发一种安全有效的膀胱疼痛综合征/间质性膀胱炎（PBS/IC）新疗法是许多美国人尚未满足的需求，也是NIH的研究重点。在该资助下进行实验所获得的知识将证实我们关于肉毒杆菌毒素液体滴注潜力的假设，并为PBS/IC带来新的治疗方法。