Inhibition of the transport of HIV in vitro using a pH-responsive synthetic mucin-like polymer system

Alamelu Mahalingam, Julie I. Jay, Kristofer Langheinrich, Shetha Shukair, Mike D. McRaven, Lisa C. Rohan, Betsy C. Herold, Thomas J. Hope, Patrick F. Kiser*

*Corresponding author for this work

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

In conjunction with the routine role of delivering the active ingredient, carefully designed drug delivery vehicles can also provide ancillary functions that augment the overall efficacy of the system. Inspired by the ability of the cervicovaginal mucus to impede the movement of HIV virions at acidic pH, we have engineered a pH-responsive synthetic polymer that shows improved barrier properties over the naturally occurring cervicovaginal mucus by inhibiting viral transport at both acidic and neutral pH. The pH-responsive synthetic mucin-like polymer is constructed with phenylboronic acid (PBA) and salicylhydroxamic acid (SHA), each individually copolymerized with a 2-hydroxypropyl methacrylamide (pHPMA) polymer backbone. At pH 4.8, the crosslinked polymers form a transient network with a characteristic relaxation time of 0.9 s and elastic modulus of 11 Pa. On addition of semen, the polymers form a densely crosslinked elastic network with a characteristic relaxation time greater than 60 s and elastic modulus of 1800 Pa. Interactions between the PBA-SHA crosslinked polymers and mucin at acidic pH showed a significant increase in elastic modulus and crosslink lifetime (p < 0.05). A transport assay revealed that migration of HIV and cells was significantly impeded by the polymer network at pH ≥ 4.8 with a diffusion coefficient of 1.60 x 10 -4 μm 2/s for HIV. Additionally, these crosslinked polymers did not induce symptoms of toxicity or irritation in either human vaginal explants or a mouse model. In summary, the pH-responsive crosslinked polymer system reported here holds promise as a class of microbicide delivery vehicle that could inhibit the transport of virions from semen to the target tissue and, thereby, contribute to the overall activity of the microbicide formulation.

Original languageEnglish (US)
Pages (from-to)8343-8355
Number of pages13
JournalBiomaterials
Volume32
Issue number33
DOIs
StatePublished - Nov 2011

Keywords

  • Biomimetic
  • Crosslinked polymer
  • HIV
  • PH-responsive

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

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    Mahalingam, A., Jay, J. I., Langheinrich, K., Shukair, S., McRaven, M. D., Rohan, L. C., Herold, B. C., Hope, T. J., & Kiser, P. F. (2011). Inhibition of the transport of HIV in vitro using a pH-responsive synthetic mucin-like polymer system. Biomaterials, 32(33), 8343-8355. https://doi.org/10.1016/j.biomaterials.2011.05.001