Modification of the Phenylboronate-diol Crosslink: Applications in pH-Responsive Vehicles and Synthetic Lectin for Women Controlled HIV Prevention

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Publication Type dissertation
School or College College of Pharmacy
Department Pharmacology & Toxicology
Author Jay, Julie I
Title Modification of the Phenylboronate-diol Crosslink: Applications in pH-Responsive Vehicles and Synthetic Lectin for Women Controlled HIV Prevention
Date 2010-02-19
Description The HIV-1 pandemic continues to devastate women in resource-poor regions. Without a vaccine, the development of microbicides, vaginal drug delivery systems containing anti-HIV-1 active agents for topical delivery to the cervico-vaginal tissue to locally prevent the male-to-female sexual transmission of HIV-1, has become paramount. Design of a microbicide with the capacity to halt the very initial stages of the heterosexual transmission of HIV-1 in the vaginal lumen has the potential to inactivate the viral titer prior to exposure to any susceptible cells. HIV-1 must first physically diffuse from seminal plasma through the mucosal layer in order to breach the cervio-vaginal epithelium. Cellular binding events initiated by the HIV-1 surface protein, gp120, then induce the primary routes to infection. The rational design of materials with the capacity to halt these two steps has the potential to improve microbicide development. To address these issues new materials were developed and characterized through the exploitation of the well-known complexation between phenylboronic acid (PBA) and diols. Use of the modified diol, salicylhydroxamic acid (SHA), provides a pHresponsive crosslink capable of forming at the slightly acidic procoital vaginal pH; exposure to semen then neutralizes the pH of the vaginal lumen, stabilizing the crosslink. Harnessing this pH change and the pH-sensitive equilibrium of the PBA-SHA complex provides a hydrogel capable of modulating its viscoelastic properties as a function of pH. The rheological properties of symmetrically and asymmetrically crosslinked PBA-SHA gels were characterized. The ability of the symmetrically crosslinked 5 mol% PBA-SHA gel to impede the transport of HIV-1 was assessed as well as how exposure to simulated physiological fluids impacted its performance. The cytotoxicity of the individual polymers in a vaginal cell line was also investigated. Modification of the arylboronic acid provided the means to create a polymer-based entry inhibitor. Multivalent oligomers were functionalized with the ortho substituted o-hydroxymethylphenylboronic acid (benzoboroxole). These oligomers demonstrated binding to gp120 by surface plasomon resonance (SPR). Larger molecular weight polymers functionalized with benzoboroxole exhibited consistent suppression of viral activity in two clades and both coreceptor tropisms. Higher degrees of functionality revealed higher activities. Minimal cytotoxicity was exhibited against a vaginal cell line.
Type Text
Publisher University of Utah
Subject Drug Delivery Systems; HIV Infections; AIDS (Disease)
Subject MESH Drug Delivery Systems; HIV Infections; Acquired Immunodeficiency Syndrome
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Modification of the phenylboroate-diol crosslink: applications in pH-responsive vehicles and synthetic lectin for women controlled HIV prevention." Spencer S. Eccles Health Sciences Library. Print version of "Modification of the phenylboronate-diol crosslink: applications in pH-responsive vehicles and synthetic lectin for women controlled HIV prevention." available at J. willard Marriott Library Special Collection. RS43.5 2009.J39.
Rights Management © Julie I. Jay
Format Medium application/pdf
Format Extent 2,794,859 bytes
Source Original: University of Utah Spencer S. Eccles Health Sciences Library
Conversion Specifications Original scanned on Fujitsu fi-5220G as 400 dpi to pdf using ABBYY FineReader 10
ARK ark:/87278/s6862wxp
Setname ir_etd
Date Created 2012-04-23
Date Modified 2012-04-23
ID 192524
Reference URL https://collections.lib.utah.edu/ark:/87278/s6862wxp