The next-generation prevention tool-microbicides (vaginally or rectally delivered topical products) - hold great promise as new HIV and STD prevention methods to be controlled by women. The microbicide research community has identified knowledge gaps in microbicide development which include a lack of knowledge in delivery vehicle design and a lack of efficacy predictors for decisions on which products to advance to Phase II/III trials. Our long-term goal is to identify structure-property-function relationships of topical epithelial drug delivery systems and to apply that knowledge to designing therapeutic/prophylactic agents and their delivery vehicles. The objective of this project is to demonstrate a method to design new microbicide delivery vehicles, specific to selected female populations, with simultaneously-optimized physicochemical properties, biocompatibility, and innate microbicidal activity. The overall hypothesis of this project is that biophysical measurements of in vivo tissue mechanics, vehicle properties, and vehicle performance can be used with mathematical and experimental tools to rationally design and optimize the efficacy of vaginally-delivered microbicides. The rationale for the proposed research is that, once the vaginal tissue properties and vehicle structure-property-function relationships are characterized and modeled, the delivery vehicle structure can be adjusted rationally to optimize microbicide efficacy, saving time and money. The overall objectives of the R21 Phase are to establish feasibility of a new in vivo instrument and create models (experimental and computational) of structure-property-function relationships. The 3 specific aims during the R21 phase are: 1. Characterize a new instrument and measure squeezing forces and elastic modulus of human vaginal tissue in vivo. 2. Determine the property-function relationship for polymeric delivery vehicles and identify target values of critical vehicle physicochemical properties. 3. Quantify relationships between molecular structure and measured physicochemical and microbicidal properties of polymeric delivery vehicles. The overall objectives of the R33 Phase are to show utility of the in vivo instrument and computational structure- property-function models of the R21 phase and expand the features of the instrument and models. Ultimately, the goal is to determine the efficacy of novel polymeric delivery vehicles to prevent Chlamydia trachomatis and Neisseria gonorrhea infections, while simultaneously exhibiting target physicochemical properties. Our contribution here is to demonstrate a new method to optimize polymeric delivery vehicles for a set of target properties, against two bacterial pathogens, and for specific groups of women. This contribution is significant because it will show that the methodologies of computational molecular design and biomechanical analysis are able to effectively develop novel polymer formulations for a delivery vehicle in an efficient and expedient manner.
Relevance to Public Health The results of the proposed research will benefit public health because the outcomes are a necessary step to making tools to efficiently design and optimize vaginal delivery vehicles. New screening tools will reduce the time and cost of clinical trials, and help to bring urgently needed microbicides to women.
|Osaka, Ichie; Hefty, P Scott (2014) Lipopolysaccharide-binding alkylpolyamine DS-96 inhibits Chlamydia trachomatis infection by blocking attachment and entry. Antimicrob Agents Chemother 58:3245-54|
|Osaka, Ichie; Hefty, P Scott (2013) Simple resazurin-based microplate assay for measuring Chlamydia infections. Antimicrob Agents Chemother 57:2838-40|
|Kheyfets, Vitaly O; Kieweg, Sarah L (2013) Experimental and numerical models of three-dimensional gravity-driven flow of shear-thinning polymer solutions used in vaginal delivery of microbicides. J Biomech Eng 135:61009-14|