Mucus Penetrating Particles for Rectal Microbicides

用于直肠杀菌剂的粘液穿透颗粒

• 批准号: 8110961
• 负责人: RICHARD CONE
• 金额: $ 19.98万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8110961
• 关键词: Achievement; Acquired Immunodeficiency Syndrome; Anhydrides; Antiviral Agents; Area; Back; Biocompatible; Cells; Chronic; Colon; Colorectal; Columnar Epithelium; Development; Diffusion; Disease; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Encapsulated; Entire transverse folds of palate; Epithelial; Epithelium; Esters; Gel; Goals; HIV; Health; Histology; Human; Infection; Inflammatory; Liquid substance; Lubricants; Measures; Membrane; Methods; Modeling; Molecular Weight; Mucous Membrane; Mucous body substance; Mus; Nanotechnology; Nature; Penetration; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Polyethylene Glycols; Predisposition; Property; Published Comment; Rectum; SCID Mice; Safety; Simplexvirus; Squamous Epithelium; Surface; Surface Properties; Testing; Thick; Time; Toxic effect; Trauma; Vagina; Water; base; cytokine; design; enema administration; microbicide; mouse model; nanoparticle; novel; pandemic disease; particle; pathogen; protective efficacy; rectal; rectal microbicide; transmission process; vaginal microbicide; valacyclovir

DESCRIPTION (provided by applicant): For reliable protection against STD transmission, rectal microbicides must be formulated in a way that will deliver the active agent to all the surfaces that are susceptible to infection. These include the entire rectum as well as a large fraction of the colon (due to peristaltic stirring of colonic contents). Colorectal surfaces are columnar epithelia that are mechanically and osmotically fragile, and are highly susceptible to STD transmission. Although continuous mucus secretion by these susceptible surfaces helps protect against trauma and pathogens, this continuously secreted mucus also poses a significant barrier against effective delivery of microbicides to the epithelial surface. Recently we developed novel mucus penetrating nanoparticles (MPP) that can overcome this barrier and provide sustained, well-distributed delivery of drugs to mucosal surfaces. Our hypothesis is that MPP will significantly increase the protective efficacy of rectal microbicides by achieving more uniform and complete colorectal distribution, sustained drug activity, and thus longer duration and more complete protection compared to drug delivered in gels ("free drug") or drug delivered in conventional nanoparticles, "CP", that adhere to mucus and fail to penetrate mucus barriers. In the R21 phase, we will determine optimal MPP properties for penetration of mouse colorectal mucus, and we will characterize the uniformity of MPP distribution and retention times in the mouse colorectum compared to CP and free drug. We will then prepare drug-loaded biodegradable and biocompatible MPP that provide sustained release of antiviral drugs (valacyclovir for HSV and UC-781 for HIV). We will deliver these MPP in both a rectal enema format and a rectal lubricant gel format since both formats are frequently used for enhancing rectal intercourse. Moreover, an enema may deliver MPP to large regions of the colon unlikely to be reached by a gel. The key milestone for the R21 phase will be development of valacyclovir-MPP and UC-781- MPP that provide more complete and persistent coverage of the rectal epithelial surface, with minimal toxicity, compared to CP formulations or free drug. In the R33 phase, we will extensively test these MPP formulations for safety and protective efficacy in our mouse/HSV rectal model and in the hu-BLT-SCID mouse/HIV model (via a subcontract with Dr. J. Victor Garcia-Martinez at UNC). PUBLIC HEALTH RELEVANCE: Rectal transmission of HIV significantly increases the AIDS pandemic. The aim of this project is to develop mucus penetrating particles for colorectal drug delivery that will maximize protective efficacy and minimize toxic effects of rectal microbicides for protection against HIV and other STDs. These novel particles can be delivered in enemas and lubricant gels designed to be highly acceptable to potential users since enemas and gels are frequently used for rectal intercourse even though they provide no disease protection.

描述（由申请人提供）：为了可靠地保护性病传输，必须以将活性剂传递到容易感染的所有表面的方式制定直肠微生物。这些包括整个直肠以及大部分结肠（由于结肠含量的蠕动搅拌）。结直面的表面是柱状上皮，在机械上易碎，并且非常容易受到性病的传播。尽管这些敏感表面的连续粘液分泌有助于预防创伤和病原体，但这种不断分泌的粘液也构成了明显的障碍，可防止有效递送微生物剂向上皮表面递送。最近，我们开发了新型的穿透性纳米颗粒（MPP），可以克服这一障碍，并提供持续的，持续的药物递送到粘膜表面。 Our hypothesis is that MPP will significantly increase the protective efficacy of rectal microbicides by achieving more uniform and complete colorectal distribution, sustained drug activity, and thus longer duration and more complete protection compared to drug delivered in gels ("free drug") or drug delivered in conventional nanoparticles, "CP", that adhere to mucus and fail to penetrate mucus barriers.在R21阶段，我们将确定小鼠结直肠粘液穿透的最佳MPP特性，并且与CP和Free Drug相比，我们将表征MPP分布和保留时间的均匀性和保留时间。然后，我们将准备载有药物的可生物降解和生物相容性的MPP，该MPP可提供抗病毒药物的持续释放（HSV的Valacyclovir和HIV的UC-781）。我们将以直肠灌肠格式和直肠润滑剂凝胶格式传递这些MPP，因为两种格式经常用于增强直肠性交。此外，灌肠可能会向结肠的大区域传递MPP，这不太可能被凝胶交付。 R21阶段的关键里程碑将是开发Valacyclovir-MPP和UC-781- MPP，与CP配方或自由药物相比，具有最小的直肠上皮表面的更完整和持续的覆盖范围，具有最小的毒性。在R33阶段，我们将在小鼠/HSV直肠模型和HU-BLT-SCID小鼠/HIV模型中广泛测试这些MPP公式的安全性和保护性功效（通过与UNC的J. Victor Garcia-Martinez博士进行分包）。 公共卫生相关性：直肠艾滋病毒的直肠传播显着增加了艾滋病大流行。该项目的目的是开发粘液穿透性颗粒进行结直肠药物的递送，这将最大程度地发挥保护作用，并最大程度地减少直肠微生物剂的毒性作用，以保护抗HIV和其他性病。这些新颖的颗粒可以在灌肠和润滑剂凝胶中递送，旨在对潜在使用者高度接受，因为灌肠和凝胶也经常用于直肠性交，即使它们没有提供疾病保护。