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Critical Design Features of Phenyl Carboxylate-Containing Polymer Microbicides

Novaflux Biosciences, Inc., Princeton, New Jersey 08540,¹ Shin Etsu Chemical Company Limited, Cellulose & Pharmaceutical Excipients Department, Chiyoda-ku, Tokyo 100-0004, Japan,² Southern Research Institute, Frederick, Maryland 21701,³ 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 19129⁴

Received 19 December 2005/ Returned for modification 4 April 2006/ Accepted 10 July 2006

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_as 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.