Modification of the phenylboronate-diol crosslink: applications in pH-responsive vehicles and synthetic lectin for women controlled HIV prevention

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.