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LEVERAGING MUCOADHESIVE THIOMERS AND PLA-BASED POLYMERS TO DESIGN BIODEGRADABLE EXTENDED RELEASE VAGINAL FILMS FOR HIV PREVENTION

Li, Jing (2018) LEVERAGING MUCOADHESIVE THIOMERS AND PLA-BASED POLYMERS TO DESIGN BIODEGRADABLE EXTENDED RELEASE VAGINAL FILMS FOR HIV PREVENTION. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

HIV is one of the most serious health issues in the world. Women are disproportionally affected by sexually transmitted HIV-1 infection. Without effective vaccine in hand, topical microbicides are developed to prevent the HIV-1 incidence. Tenofovir gel and dapivirine vaginal ring were shown to have some effectiveness in the clinic. However, it is also noticed that low user adherence is one of the major reasons for inconsistent effectiveness across different clinical trials and age groups. The approaches that do not require daily or coitally-dependent use could potentially improve user adherence. This dissertation describes our efforts in the design and characterization of extended-release microbicides through modification of film matrix with functional polymers or nanotechnology to improve user adherence in HIV prevention.
To achieve the extended-release profile of the vaginal film, prolongation of the film mucosal residence is one of the promising strategies. Thiolated chitosan was synthesized and incorporated into poly(vinyl alcohol) based film. This bioadhesive film performed one-week tissue adhesion in pigtailed macaques and showed the feasibility of delivering non-nucleoside reverse transcriptase inhibitor dapivirine and progestin levonorgestrel simultaneously. To further sustained the release profile of bioadhesive film, poly(lactide-co-Ɛ-caprolactone) (PLACL) were synthesized and incorporated into the bioadhesive film matrix for delivering an integrase inhibitor MK-2048. We demonstrated the sustained release profile, excellent safety and in vitro effectiveness of this PLACL bioadhesive film.
Nanoparticles have been well developed for controlled or sustained release, which is very promising to be applied for coitally-independent vaginal microbicide to improve the user adherence. We developed a thiomer coated poly(lactic-co-glycolic acid) nanoparticle loaded film with prolonged mucoadhesion and enhanced tissue penetration of MK-2048. This delivery system demonstrated sustained release profile over 30 days in vaginal fluid simulant, improved tissue permeability and potent anti-HIV activity.
Collectively, these studies demonstrate the safety and efficacy of three novel sustained release polymeric film platforms, which can potentially improve the user adherence and provide more options for women to protect themselves from HIV infection.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Li, Jingjil132@pitt.edujil132
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRohan, Lisalrohan@mwri.magee.edu
Committee MemberGold, Barrygoldbi@pitt.edu
Committee MemberLi, Songsol4@pitt.edu
Committee MemberSant, Shilpashs149@pitt.edu
Committee MemberMeyer, Taratara.meyer@pitt.edu
Date: 4 December 2018
Date Type: Publication
Defense Date: 2 October 2018
Approval Date: 4 December 2018
Submission Date: 4 December 2018
Access Restriction: 3 year -- Restrict access to University of Pittsburgh for a period of 3 years.
Number of Pages: 173
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: No
Uncontrolled Keywords: HIV prevention, extended release film, mucoadhesion, PLA-based polymers
Date Deposited: 04 Dec 2018 18:33
Last Modified: 04 Dec 2018 18:33
URI: http://d-scholarship.pitt.edu/id/eprint/35699

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