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).

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
5R33AI094519-05
Application #
8882229
Study Section
Special Emphasis Panel (NSS)
Program Officer
Turpin, Jim A
Project Start
2011-07-01
Project End
2016-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
5
Fiscal Year
2015
Total Cost
$464,117
Indirect Cost
$174,365
Name
Johns Hopkins University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
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Maisel, Katharina; Reddy, Mihika; Xu, Qingguo et al. (2016) Nanoparticles coated with high molecular weight PEG penetrate mucus and provide uniform vaginal and colorectal distribution in vivo. Nanomedicine (Lond) 11:1337-43
Date, Abhijit A; Hanes, Justin; Ensign, Laura M (2016) Nanoparticles for oral delivery: Design, evaluation and state-of-the-art. J Control Release 240:504-526
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Maisel, Katharina; Ensign, Laura; Reddy, Mihika et al. (2015) Effect of surface chemistry on nanoparticle interaction with gastrointestinal mucus and distribution in the gastrointestinal tract following oral and rectal administration in the mouse. J Control Release 197:48-57
Maisel, Katharina; Chattopadhyay, Sumon; Moench, Thomas et al. (2015) Enema ion compositions for enhancing colorectal drug delivery. J Control Release 209:280-7
Ensign, Laura M; Cone, Richard; Hanes, Justin (2014) Nanoparticle-based drug delivery to the vagina: a review. J Control Release 190:500-14
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Wang, Ying-Ying; Lai, Samuel K; Ensign, Laura M et al. (2013) The microstructure and bulk rheology of human cervicovaginal mucus are remarkably resistant to changes in pH. Biomacromolecules 14:4429-35
Ensign, Laura M; Henning, Andreas; Schneider, Craig S et al. (2013) Ex vivo characterization of particle transport in mucus secretions coating freshly excised mucosal tissues. Mol Pharm 10:2176-82

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