Mucus Penetrating Nanoparticles for Vaginal Drug Delivery

用于阴道药物输送的粘液穿透纳米颗粒

基本信息

批准号：
7695565
负责人：
Justin S. Hanes
金额：
$ 24.49万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7695565
关键词：
Acquired Immunodeficiency Syndrome Adhesives Adverse effects Animals Artificial nanoparticles Binding Biodistribution Biological Assay Caliber Cell Adhesion Molecules Cell Line Cells Characteristics Charge Chemistry Data Development Diffuse Disease Drug Carriers Drug Delivery Systems Drug Formulations Engineering Ensure Entire transverse folds of palate Epithelial Epithelial Cells Epithelium Frozen Sections Funding Gel Head Histologic Hour Human Image Individual Infection Investigation Label Latex Particles Lead Life Ligands Light Liquid substance Malignant neoplasm of cervix uteri Measures Metabolic Clearance Rate Methods Modeling Mono-S Movement Mucous Membrane Mucous body substance Mus Nanotechnology Nature Particle Size Penetration Pharmaceutical Preparations Pharmacotherapy Polyethylene Glycols Polymers Polystyrenes Principal Investigator Process Property Retinal Cone Rheology Sampling Sexually Transmitted Diseases Surface Surface Properties Techniques Technology Testing Therapeutic Thick Time Tissues Topical application Toxin Vagina Vaginal Douching Vaginal Spermicides Vaginal delivery procedure Virion Virus Water base biodegradable polymer carboxyl group cryostat density design fluorescence imaging fluorophore high risk improved in vivo insight microbicide nanoparticle particle pathogen prevent programs prophylactic protective efficacy public health relevance residence sebacic acid sound surface coating time use vaginal microbicide web site zeta potential

项目摘要

DESCRIPTION (provided by applicant): Sustained drug release from nanoparticles can improve mucosal therapies by reducing systemic side-effects, and sustained topical vaginal delivery is likely to greatly improve protective efficacy, and user-acceptability, of microbicides now being developed for protection against AIDS and other sexually transmitted diseases. Nanoparticles now used for mucosal drug delivery are mucophilic and bind tightly to mucus gels. Unfortunately, these conventional nanoparticles are rapidly cleared with luminal mucus and very few reach the epithelial surface; luminal mucus is cleared within minutes to hours. Our first hypothesis is that non-mucophilic particles that rapidly penetrate mucus will provide longer, and more efficient, sustained delivery, by diffusing through luminal mucus to reach the unstirred layer of mucus that adheres to the epithelium. Our second hypothesis is that mucus-penetrating particles decorated with cell-adhesion molecules will reach and bind to epithelial cells with high efficiency, and will persist in place until the epithelial cells are shed, a much slower process than clearance of mucus secretions. Viruses evolved mechanisms to penetrate mucus secretions and bind to target epithelial cells, and, using virus particles as guides, we have recently developed nanoparticles that can rapidly diffuse through human mucus secretions and bind tightly to epithelial cells. We will test in mice whether our mucus-penetrating, and cell-adherent, particles are retained more efficiently and for longer times in the vagina than conventional mucophilic nanoparticles. In Aim 1, we will fully characterize particle size and surface properties, and use particle tracking to observe diffusional transport rates of mucus-penetrating and conventional nanoparticles in undiluted human cervico-vaginal mucus. In Aim 2, we will determine in mice the retention times and vaginal distributions of the nanoparticles characterized in Aim 1. The particles will be fluorescently labeled, and details of epithelial distribution will be examined with histologic methods. Vaginal retention times will be quantified in living animals using whole-body fluorescence imaging. In Aim 3, we will synthesize mucus-penetrating, cell-adherent particles using a new biodegradable polymer platform. We expect conventional mucophilic particles will be cleared within hours, but mucus-penetrating, and especially cell-adherent mucus-penetrating particles, will achieve complete epithelial coverage and be retained for days. Public Health Relevance: Vaginal microbicides now being developed to prevent AIDS and other sexually transmitted diseases, and drug therapies for many types of vaginal infections are likely to be greatly enhanced if methods can be developed for sustained vaginal delivery. Topical applications of drugs typically reduces most types of side effects, but topical applications typically have relatively short durations of action or protection: Vaginal spermicidal are effective for only about 1 hour. Recently we discovered ways to produce mucus-penetrating nanoparticles that are likely to provide an efficient method for sustained topical delivery of drugs and microbicides to the vaginal epithelium. This application seeks funds to test in animals the hypothesis that mucus-penetrating nanoparticles will be retained within the vagina for significantly longer times than conventional drug-delivery nanoparticles since conventional nanoparticles adhere strongly to mucus and hence are cleared as rapidly as the mucus is shed (typically minutes to hours). In addition, it appears possible to develop mucus-penetrating particles than can diffuse to, and bind to, the epithelial cells that line the vagina. Such particles are likely to provide sustained topical drug delivery for several days. If successful, this project could lead to the development of sustained drug delivery systems that are more convenient, and more effective, for preventing and treating diseases than methods now available.

描述（由申请人提供）：从纳米颗粒中释放的持续药物可以通过减少系统性副作用来改善粘膜疗法，而持续的局部阴道递送可能会大大提高保护性的疗效，而用户认可的微生物现在正在开发出用于保护艾滋病和其他性传播疾病。现在用于粘膜药物递送的纳米颗粒是粘液性的，并与粘液凝胶紧密结合。不幸的是，这些常规的纳米颗粒用腔粘液迅速清除，很少有人到达上皮表面。腔内粘液在几分钟到几个小时内清除。我们的第一个假设是，迅速穿透粘液的非核粒颗粒通过通过腔内粘液扩散到达粘附于上皮的粘液层来提供更长，更有效，持续的递送。我们的第二个假设是，用细胞粘附分子装饰的粘液渗透颗粒将以高效率到达并与上皮细胞结合，并将持续到位，直到上皮细胞脱落为止，比粘液分泌的清除率要慢得多。病毒进化的机制穿透了粘液分泌并与靶向上皮细胞结合，并使用病毒颗粒作为指南，我们最近开发了可以通过人粘液分泌迅速扩散并与上皮细胞紧密结合的纳米颗粒。我们将在小鼠中测试与传统的粘液性纳米颗粒相比，在阴道中，粘液渗透和细胞粘附的颗粒是否更有效，更长的时间保留。在AIM 1中，我们将充分表征粒径和表面特性，并使用粒子跟踪观察未稀释的人宫颈膜阴道粘液中粘液 - 渗透和常规纳米颗粒的扩散传输速率。在AIM 2中，我们将在小鼠中确定AIM 1中特征的纳米颗粒的保留时间和阴道分布。颗粒将被荧光标记，并使用组织学方法来检查上皮分布的细节。使用全身荧光成像，将在活动物中量化阴道保留时间。在AIM 3中，我们将使用新的可生物降解聚合物平台合成粘液胶质粘附的细胞粘附颗粒。我们预计，常规的粘液颗粒将在几小时内清除，但是粘液穿透，尤其是细胞粘附的粘液 - 渗透颗粒将达到完整的上皮覆盖范围并保留数天。公共卫生相关性：现在开发阴道杀菌剂来防止艾滋病和其他性传播疾病，如果可以开发出持续的阴道分娩方法，则可能会大大增强许多类型的阴道感染的药物疗法。药物的局部应用通常会减少大多数类型的副作用，但是局部应用通常具有相对较短的作用或保护时间：阴道精子剂仅在1小时内有效。最近，我们发现了产生粘液渗透纳米颗粒的方法，这些纳米颗粒可能会提供有效的方法，可持续局部递送药物和杀生性杀菌剂到阴道上皮。该应用程序寻求资金在动物中测试一个假说，即粘液穿透纳米颗粒将在阴道内保留时间比传统的药物传递纳米颗粒更长的时间，因为传统的纳米颗粒强烈地粘附在粘液上，因此随着粘液的速度而迅速清除（典型的粘液至小时）。另外，似乎可以发展出粘液渗透颗粒，而不是扩散并结合到阴道上的上皮细胞。这样的颗粒可能会在几天内提供持续的局部药物输送。如果成功的话，该项目可能会导致与现在可用的方法相比，可以开发持续的药物输送系统，以防止和治疗疾病更方便，更有效。