Mucus Penetrating Particles for Rectal Microbicides

描述（由申请人提供）：为了可靠地防止STD传播，直肠杀微生物剂的配制方式必须能够将活性剂递送到所有易受感染的表面。这些包括整个直肠以及大部分结肠（由于结肠内容物的蠕动搅拌）。结直肠表面是柱状上皮，其在机械和免疫上是脆弱的，并且对STD传播高度敏感。尽管这些易感表面的连续粘液分泌有助于防止创伤和病原体，但这种连续分泌的粘液也对杀微生物剂有效递送至上皮表面构成显著屏障。最近，我们开发了新的粘液穿透纳米颗粒（MPP），可以克服这一障碍，并提供持续的，良好分布的药物输送到粘膜表面。我们的假设是，MPP将通过实现更均匀和完全的结肠直肠分布、持续的药物活性，以及因此与凝胶中递送的药物（“游离药物”）或粘附于粘液且不能穿透粘液屏障的常规纳米颗粒“CP”中递送的药物相比更长的持续时间和更完全的保护，显著增加直肠杀微生物剂的保护功效。在R21阶段，我们将确定MPP渗透小鼠结直肠粘液的最佳特性，并将表征MPP在小鼠结直肠中的分布均匀性和保留时间，与CP和游离药物相比。然后，我们将制备载药的生物可降解和生物相容性MPP，提供抗病毒药物（用于HSV的伐昔洛韦和用于HIV的UC-781）的持续释放。我们将以直肠灌肠剂和直肠润滑剂凝胶形式提供这些MPP，因为这两种形式经常用于增强直肠性交。此外，灌肠剂可以将MPP递送到凝胶不太可能到达的结肠的大区域。R21阶段的关键里程碑将是开发伐昔洛韦-MPP和UC-781- MPP，与CP制剂或游离药物相比，它们能更完整和持久地覆盖直肠上皮表面，毒性最小。在R33阶段，我们将在我们的小鼠/HSV直肠模型和hu-BLT-SCID小鼠/HIV模型中广泛测试这些MPP制剂的安全性和保护效力（通过与J.维克托Garcia-Martinez博士在北京的合作）。 公共卫生相关性：艾滋病毒的直肠传播显著增加了艾滋病的流行。该项目的目的是开发用于结肠直肠药物递送的粘液穿透颗粒，以最大限度地提高保护功效并最大限度地减少直肠杀微生物剂的毒性作用，以保护免受艾滋病毒和其他性病的侵害。这些新的颗粒可以在灌肠剂和润滑剂凝胶中递送，其被设计为对潜在用户高度可接受，因为灌肠剂和凝胶经常用于直肠性交，即使它们不提供疾病保护。

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.