Rapid in situ forming PEG hydrogels for mucosal drug delivery.

In situ gelling polymeric biomaterials have proven useful as drug delivery vehicles to enable sustained release at sites of disease or injury. However, if delivered to mucosal tissues, such as the eyes, nose, gastrointestinal, and cervicovaginal tract, these gels must also possess the ability to adhere to an epithelium coated in mucus. Towards this end, we report a new rapid in situ gelling polyethylene glycol-based hydrogel. Unlike other chemistries that enable rapid gel formation which form via irreversible covalent bonds, we use a bio-reducible linker allowing the gels to be naturally degraded over several days once administered. We identified a set of 6 lead formulations, which rapidly form into disulfide-linked PEG hydrogels in 30 seconds or less. These rapidly forming PEG hydrogels were also able to conform and adhere to mucosal tissues via PEG-mucin entanglements and hydrogen bonding. Controlled release of protein-based cargoes from the PEG gels was achieved over several hours whereas 40 nm nanoparticle-based cargos were retained over 24 hours. We also found these rapid in situ forming PEG gels were well-tolerated by mammalian cells. These studies support further testing and development of rapid in situ forming PEG gels for drug delivery to improve therapeutic retention and efficacy at mucosal sites.

Hydrogels for Mucosal Drug Delivery.

Mucosal tissues are often a desirable site of drug action to treat disease and engage the immune system. However, systemically administered drugs suffer from limited bioavailability in mucosal tissues where technologies to enable direct, local delivery to these sites would prove useful. In this Spotlight on Applications article, we discuss hydrogels as an attractive means for local delivery of therapeutics to address a range of conditions affecting the eye, nose, oral cavity, gastrointestinal, urinary bladder, and vaginal tracts. Considering the barriers to effective mucosal delivery, we provide an overview of the key parameters in the use of hydrogels for these applications. Finally, we highlight recent work demonstrating their use for inflammatory and infectious diseases affecting these tissues.

Enzyme Responsive Delivery of Anti-Retroviral Peptide via Smart Hydrogel.

In response to an urgent need for advanced formulations for the delivery of anti-retrovirals, a stimuli-sensitive hydrogel formulation that intravaginally delivers HIV-1 entry inhibitor upon being exposed to a specific protease was developed. The hydrogel formulation consists of PEG-azide and PEG-DBCO covalently linked to the entry inhibitor peptide, enfuvirtide, via substrate linker that is designed to undergo proteolysis by prostate specific antigen (PSA) present in seminal fluid and release innate enfuvirtide. Of the tested PSA substrate linkers (HSSKLQYY, GISSFYSSK, AYLMYY, and AYLMGRR), HSSKLQ was found to be an optimal candidate for PEG-based hydrogel with kcat/KM of 2.2 M-1 s-1. The PEG-based hydrogel displayed a pseudoplastic, thixotropic behavior with overall viscosity varying between 1516 and 2.2 Pa.s, within the biologically relevant shear rates of 0.01-100 s-1. It also exhibited viscoelastic properties appropriate for uniform spreading and being retained in vagina. PEG-based hydrogels were loaded with N3-HSSKLQ-enfuvirtide (HF42) that is customarily synthesized enfuvirtide prodrug with its N-terminus connected to HSSKLQ linker. The stimuli-sensitive PEG-based hydrogel formulations upon being exposed to PSA released 36.5 ± 4.8% of enfuvirtide over 24 h in human ejaculate mimic of vaginal simulant fluid and seminal simulant fluid mixed in 1:3 ratio, which is significantly greater than its IC50. The PEG-based hydrogel was non-cytotoxic to both vaginal epithelial cells (VK2/E6E7) and murine macrophages (RAW 264.7) and did not significantly induce the production of nitric oxide, an inflammatory mediator. The PEG-based hydrogel is found to have suitable physicochemical properties for an intravaginal formulation of the PSA substrate-linked anti-retrovirals and is safe towards vaginal epithelium. It is capable of delivering enfuvirtide with effective concentrations to prevent women from HIV-1 infection.

Regulation of Vaginal Microbiome by Nitric Oxide.

In this review, the composition and regulation of vaginal microbiome that displays an apparent microbial diversity and interacts with other microbiota in the body are presented. The role of nitric oxide (NO) in the regulation of vaginal microflora in which lactobacillus species typically dominate has been delineated from the perspective of maintaining gynecologic ecosystem and prevention of onset of bacteriostatic vaginosis (BV) and/or sexually transmitted diseases (STD) including HIV-1 transmission. The interactions between NO and vaginal microbiome and its influence on the levels of Lactobacillus, hormones and other components are described. The recent progress, such as NO drugs, probiotic Lactobacilli and Lactobacillus microbots, that can be explored to alleviate abnormality of vagina microbiome, is also discussed. An identification of Oral-GI-Vagina axis, as well as the relationship between NO and Lactobacillus regulation in the healthy or pathological status of vagina microbiome, surely offers the advanced drug delivery option against BV or STD including AIDS.