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Development of HIV-1 rectal-specific microbicides and colonic tissue evaluation

Dezzutti, CS and Russo, J and Wang, L and Abebe, KZ and Li, J and Friend, DR and McGowan, IM and Rohan, LC (2014) Development of HIV-1 rectal-specific microbicides and colonic tissue evaluation. PLoS ONE, 9 (7).

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Abstract

The gastrointestinal tract is structurally and functionally different from the vagina. Thus, the paradigm of topical microbicide development and evaluation has evolved to include rectal microbicides (RMs). Our interest was to create unique RM formulations to safely and effectively deliver antiretroviral drugs to mucosal tissue. RMs were designed to include those that spread and coat all surfaces of the rectum and distal colon rapidly (liquid) and those that create a deformable, erodible barrier and remain localized at the administration site (gel). Tenofovir (TFV) (1%) was formulated as an aqueous thermoreversible fluid and a carbopol-based aqueous hydrogel. Lipid-based liquid and gel formulations were prepared for UC781 (0.1%) using isopropyl myristate and GTCC (Caprylic/Capric Triglycerides), respectively. Formulations were characterized for pH, viscosity, osmolality, and drug content. Pre-clinical testing incorporated ex vivo colonic tissue obtained through surgical resections and flexible sigmoidoscopy (flex sig). As this was the first time using tissue from both sources side-by-side, the ability to replicate HIV-1 was compared. Efficacy of the RM formulations was tested by applying the products with HIV-1 directly to polarized colonic tissue and following viral replication. Safety of the formulations was determined by MTT assay and histology. All products had a neutral pH and were isoosmolar. While HIV-1BaL and HIV-1 JR-CSF alone and in the presence of semen had similar replication trends between surgically resected and flex sig tissues, the magnitude of viral replication was significantly better in flex sig tissues. Both TFV and UC781 formulations protected the colonic tissue, regardless of tissue source, from HIV-1 and retained tissue viability and architecture. Our in vitro and ex vivo results show successful formulation of unique RMs. Moreover, the results of flex sig and surgically resected tissues were comparable suggesting the incorporation of both in pre-clinical testing algorithms. © 2014 Dezzutti et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Dezzutti, CScsd13@pitt.eduCSD13
Russo, J
Wang, L
Abebe, KZkza3@pitt.eduKZA3
Li, J
Friend, DR
McGowan, IMimcgowan@pitt.eduIMCGOWAN
Rohan, LCrohanl@pitt.eduROHANL
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorSandstrom, PaulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Centers: Other Centers, Institutes, Offices, or Units > Magee-Women's Research Institute
Date: 15 July 2014
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 9
Number: 7
DOI or Unique Handle: 10.1371/journal.pone.0102585
Schools and Programs: School of Medicine > Medicine
School of Medicine > Obstetrics, Gynecology, and Reproductive Sciences
School of Pharmacy > Pharmaceutical Sciences
Refereed: Yes
Date Deposited: 23 Sep 2014 15:05
Last Modified: 02 Feb 2019 16:58
URI: http://d-scholarship.pitt.edu/id/eprint/22991

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