Mucus Penetrating Particles for Rectal Microbicides

RFA-AI-10-011杀菌剂创新计划(MIP VI)(R21/R33) 用于直肠杀微生物剂的粘液穿透颗粒 项目摘要 为了可靠地预防性病传播，直肠杀微生物剂的配方必须符合以下条件 将活性物质输送到所有易受感染的表面。这些包括整个直肠作为 以及很大一部分结肠(由于结肠内容物的蠕动搅拌)。结直肠表面 柱状上皮在机械上和渗透性上是脆弱的，并且对STD高度敏感 变速箱。尽管这些敏感表面持续的粘液分泌有助于防止 创伤和病原体，这种持续分泌的粘液也构成了一种显著的屏障，防止有效 将杀微生物剂输送到上皮表面。最近我们开发了一种新的粘液穿透 纳米粒(MPP)可以克服这一障碍，并提供持续、均匀的药物输送到 粘膜表面。我们的假设是，MPP将显著增加直肠的保护效果 通过实现更均匀和完整的结直肠分布、持续的药物活性，从而 与凝胶药物(“游离药物”)或药物相比，持续时间更长，保护更全面 以传统的纳米颗粒“CP”递送，这种纳米颗粒附着在粘液上，无法穿透粘液屏障。在……里面 在R21阶段，我们将确定MPP对小鼠结肠粘液的最佳穿透性能，我们将 将比较MPP在小鼠结肠和直肠中的分布和滞留时间的一致性 CP和免费药物。然后，我们将制备载药、可生物降解和生物兼容的MPP，以提供 抗病毒药物的缓释(针对HSV的万乃洛韦和针对HIV的UC-781)。我们将把这些MPP送到 直肠灌肠形式和直肠润滑剂凝胶形式，因为这两种形式经常用于 加强直肠交感。此外，灌肠可能会将MPP传递到结肠的大片区域，但不太可能 用凝胶到达的。R21阶段的关键里程碑将是万乃洛韦-MPP和UC-781的开发。 MPP提供更完整和持久的直肠上皮表面覆盖，毒性最小， 与CP制剂或免费药物相比。在R33阶段，我们将广泛测试这些MPP配方 在我们的小鼠/HSV直肠模型和Hu-BLT-SCID小鼠/HIV模型中的安全性和保护效果 (通过与北卡罗来纳大学的J.Victor Garcia-Martinez博士签订分包合同)。

RFA-AI-10-011 Microbicide Innovation Program (MIP VI) (R21/R33) Mucus penetrating particles for rectal microbicide delivery Project Summary 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).