Intravesical liposome drug delivery to treat interstitial cystitis

膀胱内脂质体给药治疗间质性膀胱炎

• 批准号: 8088108
• 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
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8088108
• 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

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(申请人提供)：自2002年以来，我们已经成功地开发出治疗痛性膀胱综合征/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能够包裹和保护膀胱的脂质体制剂的膀胱内注入。生物分布研究的结果证实了我们的假设，即脂质体在膀胱腔内停留时间较长，系统生物利用度较低。有一个巨大的医疗需求尚未得到满足，需要一种更好、更安全的方法将BONT输送到膀胱。我们基于脂质体的BONT递送新技术是合理的和有前途的。这笔资金的成功资助和完成可以导致提交脂质体-BONT的临床IND试验，并完成NIH翻译研究优先的使命。博蒙特泌尿科的研究团队和设施得到了显著加强。普拉迪普·泰亚吉博士曾是匹兹堡大学的咨询师，自那以后，他于2008年秋天被聘为博蒙特大学的校长。Tyagi博士和Chauer博士已经合作了八年，凭借Tyagi博士在脂质体药理学方面的强大专业知识，该设施和资源现在已经完全准备好成功完成这笔赠款的项目。在这项资助中，我们将评估无需膀胱镜引导下针头注射的PBS/IC的液体脂质体在膀胱内的传递，并研究脂质体在膀胱内给药的作用机制。提案中描述的项目的目标是：1)将BONT制成脂质体；2)评估内吞作用作为一种机制，在没有或存在膀胱膨胀的情况下，从注入的脂质体BONT中摄取BONT；以及3)确定与膀胱扩张协同作用的BONT的最低有效剂量。我们有三个目标：目标1：将BoNT-A制备成脂质体，并测定其体外稳定性和缓释性。目的2a：研究膀胱内吞作用作为脂质体-BONT摄取的一种机制。目的2b：评价脂质体-BONT的局部毒性。目的：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，并促进泌尿外科社区的广泛接受。 公共卫生相关性：开发一种安全有效的治疗痛性膀胱综合征/间质性膀胱炎(PBS/IC)的新疗法是许多美国人尚未满足的需求，也是NIH的研究重点。根据这项拨款进行的实验所获得的知识将证实我们关于液体滴注肉毒杆菌毒素的可能性的假设，并朝着为PBS/IC带来新的治疗方法迈进。