Poly(ethylene glycol) (PEG) nanocarrier-based hydrogels for the prevention of vaginal HIV transmission

Women account for over half the global population with HIV. Given the high rate of new infections, the implementation of female-controlled preventive methods is critical to successfully curb HIV. Toward this end, vaginal microbicides- topically applied, self-administered products that protect against HIV are being investigated. A primary risk factor for cervicovaginal HIV acquisition is bacterial vaginosis (BV). BV is characterized by overgrowth of anerobic bacteria and decrease in healthy vaginal lactobacilli and acidity. The compromised vaginal environment in women with BV significantly increases their susceptibility to HIV. Thus a microbicide aimed at preventing and treating BV is likely to be effective at HIV prophylaxis. The overall goal of this thesis is to develop and evaluate poly(ethylene) glycol (PEG) nanocarrier-based hydrogels for application as vaginal microbicides. The hydrogels are formed in situ by covalently cross-linking 8-arm PEG-SH and 4-arm PEG-NHS polymers via degradable thioester bonds. First, the vaginal coverage, distribution and retention of the hydrogels in mice were evaluated using MRI. Hydrogel volumes and surface contact were measured at various times post-dose and compared with hydroxyethylcellulose (HEC) gel. The hydrogels showed significantly longer vaginal retention (12-24 h) than HEC gel (2 h). In the second part of this thesis, PEG nanocarrier-based hydrogels for the controlled release of lactic acid were developed for maintaining vaginal acidity in women with BV. Nanocarrier-based hydrogels with covalently attached lactic acid showed sustained release (10-14% lactic acid) over several days, while hydrogels with passively entrapped lactic acid showed burst release (90% release within 30 min). Hydrogels with passively entrapped lactic acid inhibited the predominant BV pathogen Gardnerella vaginalis. The cytotoxicity of the polymers was also evaluated using vaginal epithelial cells. Finally, hydrogels for the controlled release of subtilosin, an antimicrobial peptide with activity against G. vaginalis was developed. Subtilosin release from the hydrogels was two-phase with initial rapid release (4 µg/hr for 12 h) followed by slow release (0.26 µg/hr from 12-120 h). Subtilosin-containing hydrogels inhibited G. vaginalis but did not significantly inhibit healthy vaginal lactobacilli spp. The antiviral activity of subtilosin against HIV was investigated and subtilosin weakly inhibited HIV replication (IC50= 5.8 µM).Ph. D.Includes bibliographical referencesby Sujata Sundara Raja