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，我们已经成功地开发了用于疼痛膀胱综合征/间质性膀胱炎（PBS/IC）的内内脂质体。我们已经发现并翻译了可以覆盖和保护膀胱的脂质体配方的插入式滴注。生物分布研究的结果证实了我们的假设，即脂质体在膀胱中延伸至膀胱延长，并且具有较低的全身生物利用度。有一种巨大的未满足的医疗需求，需要一种更好，更安全的方法来向膀胱运送bot。我们的新型基于脂质体的骨出现技术是合乎逻辑和有前途的。这笔赠款的成功资金和完成可能会导致提交脂质体主体临床IND试验，并履行NIH转化研究优先级的使命。博蒙特泌尿外科部的研究团队和设施得到了显着加强。此后，匹兹堡大学的先前顾问Pradeep Tyagi博士于2008年秋天被招募，加入Beaumont博士。 Tyagi和Chancellor共同努力了八年，并且与Tyagi博士在脂质体药理学方面的强大专业知识相关，该设施和资源现在已经准备好成功完成这笔赠款的项目。在这笔赠款中，我们将评估脂质体润滑脂向膀胱的液体脂质体递送，而无需用于PBS/IC的膀胱镜面引导针头注射针头，并研究插入性脂质体药物递送的作用机理。提案中描述的项目的目标是：1）将BONT配合到脂质体中； 2）评估内吞作用是在不存在或存在膀胱延伸的情况下从灌输的脂质体散发膀胱吸收膀胱的机制； 3）确定与膀胱延伸协同作用中最低有效剂量。我们有三个目的：目标1：将Bont-A形成脂质体并确定体外稳定性和持续释放。 AIM 2A：将内吞作用研究作为滴注后脂质体泡的膀胱吸收的机制。 AIM 2B：评估脂质体局部局部毒性。目标3：研究脂质体孔在大鼠中的生物学功效。成功完成项目目标将提高BONT的安全性并促进泌尿外科社区的广泛接受。公共卫生相关性：开发安全有效的膀胱综合征/间质性膀胱炎（PBS/IC）的新方法是对许多美国人的未满足需求，也是NIH的研究优先级。根据该赠款进行实验，获得的知识将证实我们关于液体滴注肉毒杆菌毒素潜力的假设，并朝着为PBS/IC带来新的治疗方法。