pH-responsive Intravaginal Electrospun Fibers Containing CatSper Inhibitor and Tenofovir: A Novel Multipurpose Non-Hormonal Contraception and HIV Prevention Technology
Poster #: 190
Session/Time: A
Author:
Deborah Aderoju Ogundemuren, B.Pharm, MS
Mentor:
Gustavo F. Doncel, MD, PhD
Research Type: Pharmaceutical Science
Abstract
INTRODUCTION:
Hormonal contraception is widely used in modern contraceptive practices to prevent unintended pregnancies; however, it is typically associated with menstrual bleeding irregularities that lead to discontinuation. Hence there is an urgent need for a non-hormonal contraceptive (NHC) option. Furthermore, no on-demand or topical HIV prevention method exists for women. For those at risk of HIV and pregnancy, multipurpose prevention technologies (MPTs) conferring contraception and HIV prevention are highly desirable. Electrospun fibers (EF) offer a promising platform for formulation of topical MPTs. For a proof-of-concept development, we chose two prototype active pharmaceutical ingredients (APIs), HC-056456, a sperm-specific Ca2+ channel (CatSper) inhibitor, as NHC, and tenofovir (TFV), a nucleotide reverse transcriptase inhibitor, FDA-approved in its prodrug forms, for HIV prevention. Here we present data on pH-responsive release of HC-056456 and TFV formulated in a multilayer EF construct.
METHODS:
EF were fabricated using cellulose acetate phthalate (CAP) for HC-056456 delivery and a CAP/polyvinyl alcohol blend for TFV delivery. Optimization and characterization of mechanical and stability properties were conducted by established methods. Safety and efficacy of EF-formulated HC-056456 and TFV were tested on human sperm (viability, motility, and hyperactivation) and in TZM-bl cells (single-round infection assay to assess anti-HIV-1 activity), respectively. Statistical analysis were performed using GraphPad Prism 9 (Graph-Pad Software). All data are shown as the mean ± standard deviation.
RESULTS:
Drug loading analysis confirmed successful incorporation of TFV and HC-056456 with encapsulation efficiency of 63.5% (p<0.0001) and 96% (p<0.0001), respectively. Well-formed fiber structures were observed with no impact on chemical integrity of active compounds. CAP fibers remained undissolved in simulated vaginal fluid (pH 4.2) but dissolved within 2 mins upon semen exposure (pH 7.4-8.4), releasing the encapsulated APIs. Preliminary in vitro experiments showed 77µg/mL of CAP-HC-056456 reduced sperm hyperactivation by 99.3% (p<0.05) within 30 sec of incubation without affecting sperm viability. CAP and TFV within the nanofibers effectively blocked HIV-1 infection in a dose-dependent manner, with a concentration of 1.16 μg/mL achieving 90% inhibition under pre-exposure conditions.
CONCLUSION:
Multilayered EFs delivering a specific sperm-based NHC (HC-056456) and the antiretroviral, TFV, in a simulated vaginal environment in the presence of semen represent a first-in-class "smart" pH-responsive topical MPT for simultaneously prevention of unplanned pregnancy and HIV in women.
Hormonal contraception is widely used in modern contraceptive practices to prevent unintended pregnancies; however, it is typically associated with menstrual bleeding irregularities that lead to discontinuation. Hence there is an urgent need for a non-hormonal contraceptive (NHC) option. Furthermore, no on-demand or topical HIV prevention method exists for women. For those at risk of HIV and pregnancy, multipurpose prevention technologies (MPTs) conferring contraception and HIV prevention are highly desirable. Electrospun fibers (EF) offer a promising platform for formulation of topical MPTs. For a proof-of-concept development, we chose two prototype active pharmaceutical ingredients (APIs), HC-056456, a sperm-specific Ca2+ channel (CatSper) inhibitor, as NHC, and tenofovir (TFV), a nucleotide reverse transcriptase inhibitor, FDA-approved in its prodrug forms, for HIV prevention. Here we present data on pH-responsive release of HC-056456 and TFV formulated in a multilayer EF construct.
METHODS:
EF were fabricated using cellulose acetate phthalate (CAP) for HC-056456 delivery and a CAP/polyvinyl alcohol blend for TFV delivery. Optimization and characterization of mechanical and stability properties were conducted by established methods. Safety and efficacy of EF-formulated HC-056456 and TFV were tested on human sperm (viability, motility, and hyperactivation) and in TZM-bl cells (single-round infection assay to assess anti-HIV-1 activity), respectively. Statistical analysis were performed using GraphPad Prism 9 (Graph-Pad Software). All data are shown as the mean ± standard deviation.
RESULTS:
Drug loading analysis confirmed successful incorporation of TFV and HC-056456 with encapsulation efficiency of 63.5% (p<0.0001) and 96% (p<0.0001), respectively. Well-formed fiber structures were observed with no impact on chemical integrity of active compounds. CAP fibers remained undissolved in simulated vaginal fluid (pH 4.2) but dissolved within 2 mins upon semen exposure (pH 7.4-8.4), releasing the encapsulated APIs. Preliminary in vitro experiments showed 77µg/mL of CAP-HC-056456 reduced sperm hyperactivation by 99.3% (p<0.05) within 30 sec of incubation without affecting sperm viability. CAP and TFV within the nanofibers effectively blocked HIV-1 infection in a dose-dependent manner, with a concentration of 1.16 μg/mL achieving 90% inhibition under pre-exposure conditions.
CONCLUSION:
Multilayered EFs delivering a specific sperm-based NHC (HC-056456) and the antiretroviral, TFV, in a simulated vaginal environment in the presence of semen represent a first-in-class "smart" pH-responsive topical MPT for simultaneously prevention of unplanned pregnancy and HIV in women.