Critical Design Features of Phenyl Carboxylate-Containing Polymer Microbicides
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Published:2006-09
Issue:9
Volume:50
Page:3081-3089
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ISSN:0066-4804
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Container-title:Antimicrobial Agents and Chemotherapy
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language:en
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Short-container-title:Antimicrob Agents Chemother
Author:
Rando Robert F.1, Obara Sakae2, Osterling Mark C.3, Mankowski Marie3, Miller Shendra R.4, Ferguson Mary L.4, Krebs Fred C.4, Wigdahl Brian4, Labib Mohamed1, Kokubo Hiroyasu2
Affiliation:
1. Novaflux Biosciences, Inc., Princeton, New Jersey 08540 2. Shin Etsu Chemical Company Limited, Cellulose & Pharmaceutical Excipients Department, Chiyoda-ku, Tokyo 100-0004, Japan 3. Southern Research Institute, Frederick, Maryland 21701 4. Department of Microbiology and Immunology and Center for Molecular Therapeutics and Resistance, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129
Abstract
ABSTRACT
Recent studies of cellulose-based polymers substituted with carboxylic acids like cellulose acetate phthalate (CAP) have demonstrated the utility of using carboxylic acid groups instead of the more common sulfate or sulfonate moieties. However, the pK
a
of the free carboxylic acid group is very important and needs careful selection. In a polymer like CAP the pK
a
is approximately 5.28. This means that under the low pH conditions found in the vaginal lumen, CAP would be only minimally soluble and the carboxylic acid would not be fully dissociated. These issues can be overcome by substitution of the cellulose backbone with a moiety whose free carboxylic acid group(s) has a lower pK
a
. Hydroxypropyl methylcellulose trimellitate (HPMCT) is structurally similar to CAP; however, its free carboxylic acids have pK
a
s of 3.84 and 5.2. HPMCT, therefore, remains soluble and molecularly dispersed at a much lower pH than CAP. In this study, we measured the difference in solubility and dissociation between CAP and HPMCT and the effect these parameters might have on antiviral efficacy. Further experiments revealed that the degree of acid substitution of the cellulose backbone can significantly impact the overall efficacy of the polymer, thereby demonstrating the need to optimize any prospective polymer microbicide with respect to pH considerations and the degree of acid substitution. In addition, we have found HPMCT to be a potent inhibitor of CXCR4, CCR5, and dual tropic strains of human immunodeficiency virus in peripheral blood mononuclear cells. Therefore, the data presented herein strongly support further evaluation of an optimized HPMCT variant as a candidate microbicide.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
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