Gene/Protein Disease Symptom Drug Enzyme Compound
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Achieving sustained drug delivery to mucosal surfaces is a major challenge due to the presence of the protective mucus layer that serves to trap and rapidly remove foreign particulates. Nanoparticles engineered to rapidly penetrate mucosal barriers (mucus-penetrating particles, "MPP") have shown promise for improving drug distribution, retention and efficacy at mucosal surfaces. MPP are densely coated with polyethylene glycol (PEG), which shields the nanoparticle core from adhesive interactions with mucus. However, the PEG density required to impart the "stealth" properties to nanoparticles in mucus, and thus, uniform distribution in vivo, is still unknown. We prepared biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles with a range of PEG surface densities by blending various ratios of a diblock copolymer of PLGA and 5 kDa poly(ethylene glycol) (PLGA-PEG5k) with PLGA. We then evaluated the impact of PEG surface density, measured using an (1)H NMR method, on mucin binding in vitro, nanoparticle transport in freshly obtained human cervicovaginal mucus (CVM) ex vivo, and nanoparticle distribution in the mouse cervicovaginal tract in vivo. We found that at least 5% PEG was required to effectively shield the nanoparticle core from interacting with mucus components in vitro and ex vivo, thus leading to enhanced nanoparticle distribution throughout the mouse vagina in vivo. We then demonstrated that biodegradable MPP could be formulated from blends of PLGA and PLGA-PEG polymers of various molecular weights, and that these MPP provide tunable drug loading and drug release rates and durations. Overall, we describe a methodology for rationally designing biodegradable, drug-loaded MPP for more uniform delivery to the vagina.
ACS Nano 2015 Sep 22
PMID:Impact of Surface Polyethylene Glycol (PEG) Density on Biodegradable Nanoparticle Transport in Mucus ex Vivo and Distribution in Vivo. 2630 76

Mucoadhesive delivery systems have attracted remarkable interest recently, especially for their potential to prolong dosage form resident times at sites of application such as the vagina or nasal cavity, thereby improving convenience and compliance as a result of less frequent dosage. Mucoadhesive capabilities need to be routinely quantified during the development of these systems. This is however logistically challenging due to difficulties in obtaining and preparing viable mucosa tissues for experiments. Utilizing artificial membranes as a suitable alternative for quicker and easier analyses of mucoadhesion of these systems is currently being explored. In this study, the mucoadhesive interactions between progesterone-loaded fibers (with varying carboxymethyl cellulose (CMC) content) and either artificial (cellulose acetate) or mucosa membranes are investigated by texture analysis and results across models are compared. Mucoadhesion to artificial membrane was about 10 times that of mucosa, though statistically significant ( p = 0.027) association between the 2 data sets was observed. Furthermore, a hypothesis relating fiber-mucosa interfacial roughness (and unfilled void spaces on mucosa) to mucoadhesion, deduced from some classical mucoadhesion theories, was tested to determine its validity. Points of interaction between the fiber and mucosa membrane were examined using atomic force microscopy (AFM) to determine the depths of interpenetration and unfilled voids/roughness, features crucial to mucoadhesion according to the diffusion and mechanical theories of mucoadhesion. A Kendall's tau and Goodman-Kruskal's gamma tests established a monotonic relationship between detaching forces and roughness, significant with p-values of 0.014 and 0.027, respectively. A similar relationship between CMC concentration and interfacial roughness was also confirmed. We conclude that AFM analysis of surface geometry following mucoadhesion can be explored for quantifying mucoadhesion as data from interfacial images correlates significantly with corresponding detaching forces, a well-established function of mucoadhesion.
ACS Appl Mater Interfaces 2018 Apr 25
PMID:Mucoadhesion of Progesterone-Loaded Drug Delivery Nanofiber Constructs. 2959 52

Glycosylated proteins (i.e., mucins, IgG) are important mediators of innate antiviral immunity in the vagina; however, our current knowledge of the role that glycan themselves play in genital immunity is relatively low. Herein, we evaluate the relationship between innate antiviral immunity and glycomic composition in cervicovaginal lavage fluid (CVL) collected as part of a Phase I clinical trial testing the impact of two distinct formulations of the antiretroviral drug dapivirine. Using lectin microarray technology, we discovered that formulation (hydrogel- versus film-based delivery) impacted the CVL glycome, with hydrogel formulations inducing more changes, including a loss of high-mannose. The loss of this epitope correlated to a loss of anti-HIV-1 activity. Glycoproteomic identification of high-mannose proteins revealed a cohort of antiproteases shown to be important in HIV-1 resistance, whose expression covaried with the high-mannose signature. Our data strongly suggests high-mannose as a marker for secreted proteins mediating innate antiviral immunity in vaginal fluids and that drug formulation may impact this activity as reflected in the glycome.
ACS Infect Dis 2018 11 09
PMID:Vaginal Product Formulation Alters the Innate Antiviral Activity and Glycome of Cervicovaginal Fluids with Implications for Viral Susceptibility. 3018 60