Protein and oligonucleotide delivery systems for vaginal microbicides against viral STIs

Abstract

Intravaginal delivery offers an effective option for localized, targeted, and potent microbicide delivery. However, an understanding of the physiological factors that impact intravaginal delivery must be considered to develop the next generation of microbicides. In this review, a comprehensive discussion of the opportunities and challenges of intravaginal delivery are highlighted, in the context of the intravaginal environment and currently utilized dosage forms. After a subsequent discussion of the stages of microbicide development, the intravaginal delivery of proteins and oligonucleotides is addressed, with specific application to HSV and HIV. Future directions may include the integration of more targeted delivery modalities to virus and host cells, in addition to the use of biological agents to affect specific genes and proteins involved in infection. More versatile and multipurpose solutions are envisioned that integrate new biologicals and materials into potentially synergistic combinations to achieve these goals.

Fig. 1

Schematic of the variety of microbicide dosage forms currently available or in development: a vaginal gels (semi-solids); b vaginal films; c vaginal rings; and d nanoparticles

Fig. 2

Schematic of intravaginal cross-section, denoting microbicide mechanism of action. Adapted in part, and redrawn from [48]. Microbicides have traditionally acted as a physical barrier, in the form of a cream or gel. They can act at the first step of virus contact with the mucus barrier by non-specifically or specifically disrupting the virus membrane prior to attachment by blocking/binding via polyanionic interactions. However, this has often resulted in inflammation, and has failed to provide complete protection. Microbicides must also maintain the normal flora and pH of the vaginal tract, which acts as an innate defense against pathogen and sperm. More recently, second generation microbicides have been designed to more specifically impair virus binding and entry to cells through the incorporation of antivirals, with the most recent generation focusing on the incorporation of proteins and oligonucleotides to protect and treat against infection