title: Critical design features of phenyl carboxylate-containing polymer microbicides.
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.
authors.affiliation: Novaflux Biosciences, Inc., 1 Wall Street, Princeton, New Jersey 08540, USA. robertrando@patmedia.net
authors.forename: Robert F
authors.initials: RF
authors.lastname: Rando
authors.forename: Sakae
authors.initials: S
authors.lastname: Obara
authors.forename: Mark C
authors.initials: MC
authors.lastname: Osterling
authors.forename: Marie
authors.initials: M
authors.lastname: Mankowski
authors.forename: Shendra R
authors.initials: SR
authors.lastname: Miller
authors.forename: Mary L
authors.initials: ML
authors.lastname: Ferguson
authors.forename: Fred C
authors.initials: FC
authors.lastname: Krebs
authors.forename: Brian
authors.initials: B
authors.lastname: Wigdahl
authors.forename: Mohamed
authors.initials: M
authors.lastname: Labib
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Kokubo
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology; D019817:Benzoic Acid / Q000737:chemistry / Q000494:pharmacology; D002482:Cellulose / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy; D015497:HIV-1 / Q000254:growth & development / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D065347:Hypromellose Derivatives; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D008747:Methylcellulose / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011108:Polymers / Q000737:chemistry; D019713:Receptors, CCR5 / Q000378:metabolism; D013329:Structure-Activity Relationship; D014233:Tricarboxylic Acids / Q000737:chemistry / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D000890:Anti-Infective Agents; D011108:Polymers; D019713:Receptors, CCR5; D014233:Tricarboxylic Acids; D065347:Hypromellose Derivatives; C014871:trimellitic acid; D019817:Benzoic Acid; D002482:Cellulose; C011708:cellulose acetate phthalate; D008747:Methylcellulose