Mucus Penetrating Particles for Rectal Microbicides

说明（由申请人提供）：为了可靠地防止性病传播，直肠杀菌剂的配方必须能够将活性剂输送到所有易受感染的表面。这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，在机械上和渗透上都很脆弱，很容易传播性病。尽管这些敏感表面持续分泌粘液有助于防止创伤和病原体，但这种持续分泌的粘液也对杀微生物剂有效递送到上皮表面构成了重大障碍。最近，我们开发了一种新型的粘液穿透纳米颗粒（MPP），它可以克服这一屏障，并提供持续的、均匀分布的药物递送到粘膜表面。我们的假设是，MPP将显著提高直肠杀微生物剂的保护功效，通过实现更均匀和完整的结肠分布，持续的药物活性，从而比凝胶递送的药物（“游离药物”）或传统纳米颗粒递送的药物（“CP”）更长的持续时间和更完整的保护，这些药物粘附在粘液上，不能穿透粘液屏障。在R21期，我们将确定MPP穿透小鼠结肠粘液的最佳性能，并将MPP分布的均匀性和保留时间与CP和游离药物进行比较。然后，我们将制备载药的可生物降解和生物相容性MPP，提供抗病毒药物的持续释放（用于HSV的valacyclovir和用于HIV的UC-781）。我们将以直肠灌肠形式和直肠润滑凝胶形式提供这些MPP，因为这两种形式都经常用于增强直肠性交。此外，灌肠可以将MPP输送到凝胶不可能到达的结肠大区域。R21期的关键里程碑将是valacyclovir-MPP和UC-781- MPP的开发，与CP制剂或游离药物相比，它们提供更完整和持久的直肠上皮表面覆盖，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配方的安全性和保护功效（通过与UNC的J. Victor Garcia-Martinez博士的分包合同）。

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).