Description
TitleThe development of a nano-based colorectal pre-exposure prophylaxis for HIV
Date Created2018
Other Date2018-05 (degree)
Extent1 online resource (xv, 188 p. : ill.)
DescriptionThe colorectal mucosa is a highly vulnerable site for Human Immunodeficiency Virus (HIV) transmission. The epithelium of this region is comprised of a thin single-cell layer that serves as a protective barrier, to prevent foreign pathogens from entering the body. Beneath the epithelial layer, the lamina propria provides direct access to an extensive population of immune cells that are highly susceptible to HIV infection. There is also access to the lymphatic system, which serves as an outlet for HIV to enter the systemic circulation, initiating permanent infection. To prevent HIV infection, it is important to achieve, and maintain, therapeutically effective concentrations of anti-HIV drugs within mucosal tissues. The objective of the current thesis is to fabricate and assess a nanoparticle (NP) platform, for use in a colorectal PrEP, with the goal to (1) deliver antiretroviral agents directly to the colorectal mucosa to minimize dosage requirements; (2) achieve high drug loading and sustained drug release; and (3) establish prolonged, therapeutically effective, drug concentrations within mucosal tissue to minimize dosing frequency to once-a-week. Based on average epithelial cell turnover rates in the colon of rodents and humans, 2-3 days in a murine model is considered equivalent to 5-8 days in humans. The overall objective of this thesis is to design, fabricate, and evaluate a nanoparticle (NP) drug delivery system (DDS), for colorectal mucosal pre-exposure prophylaxis (mPrEP) of HIV. Within the first part of this thesis, the feasibility of a modified cell penetrating peptide (CPP) bactenicin 7 (Bac7), to transport poly(ε-caprolactone)-poly(ethylene glycol) (PCL-PEG) NPs into, and across, a colorectal epithelial barrier, was evaluated. The hypothesis is that by functionalizing NPs with Bac7, NP transport across Caco-2 colonic cells will increase in vitro. Additionally, NPs of optimal architecture (dense PEG corona and effective Bac7 ligand density) will successfully traverse the colorectal mucus mesh lining in vivo. Bac7-labeled NPs with varied ligand densities resulted in a 163.2% to 384.6% increase in NP transport across a Caco-2 epithelial cell monolayer compared with plain NPs. NPs of 1% to 5% Bac7 surface coverage showed successful translocation across colorectal mucus to associate with the epithelial layer in vivo in a rat model. In the second portion of this thesis, rilpivirine-loaded NPs were assessed for sustained drug release. The hypothesis that flash nanoprecipitation can be used to fabricate NPs with high RPV drug loading via in situ salt formation, and that NP formulations can be tuned to achieve sustained release for a minimum of 24 hours, was tested. RPV was successfully encapsulated within PCL-PEG NPs resulting in high encapsulation efficiencies (85% to 98%), and moderate to high drug loadings (10.9 % to 17.7%). Cumulative release over 24 hours was modulated to achieve between 20% and 40% extent of release. Poly(lactide)-poly(ethylene glycol) (PLA-PEG) NPs resulted in a greater extent of release (58% compared with 40% for PCL-PEG). However, PLA-PEG NPs achieved an approximately 10% lower encapsulation efficiency and 1% decrease in drug loading compared with PCL-PEG NPs, resulting in low cost-efficiency. Furthermore, rilpivirine-loaded Bac7 NPs were evaluated as a long-acting PrEP platform in vivo. The postulation is that Bac7 labeling will increase NP residence within the mucosa to deliver RPV to epithelial tissue and NPs will persist within mucosal tissue for 2 to 3 days in vivo. Greater than 13% and 26% RPV tissue association is reported for Bac7 NPs and plain NPs, respectively, after 2 hours. At this time, placebo Bac7 NPs showed 3-fold increase in mucosal tissue association compared with plain NPs (~1.7% and ~0.45%, respectively). However, Bac7 NPs were significantly cleared from tissue at 24 hours, although both plain NPs and Bac7 NPs were present at low levels past 48 hours. This project demonstrates the potential of a Bac7 NP platform for use as a colorectal mPrEP DDS. Further optimization is needed to achieve feasibility as a long-acting PrEP approach.
NotePh.D.
NoteIncludes bibliographical references
Noteby Antoinette Gail Nelson
Genretheses, ETD doctoral
Languageeng
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
Statistical Profile