Women who acquired HIV-1 through vaginal intercourse represent ~60% of new infections in endemic regions. There is no known cure for the condition. Thus, there is a critical and urgent need for effective control methods and strategies to prevent the continuous spread of HIV/AIDS and to break the cycle of new infections. Although an effective HIV vaccine would be the most suitable prevention strategy, a candidate has yet to be identified. Thus, the development of a topical microbicide, which can be used (unlike condoms) by women without the knowledge of their partner, would provide a major benefit for slowing the global spread of HIV-1. Ideally, a successful microbicide delivery system will have to (i) protect mucosal surfaces at risk of HIV-1 transmission, (ii) prevent the dissemination of infected cells in the body, (iii) provide a controlled release of the microbicide to ensure a long-lasting protective effect, and (iv) be stimuli-sensitive to maximize the drug efficacy. The current drug delivery systems do not meet all these requirements. We have recently engineered tenofovir loaded, lipid based, bioadhesive, pH and hyaluronidase-sensitive nanoscale medicines (nanomedicines, NMs) with average size less than 500nm that represent promising drug delivery templates for HIV prevention. Our long-term goal is to identify novel, stimuli-sensitive NMs for controlled drug delivery in HIV/AIDS prevention. The objective of this proposal is to develop a novel NM for controlled delivery of topical microbicides. We hypothesize that a topical microbicide containing stimuli-sensitive NM can improve both safety and efficacy compared to those of the native drug. We will test this hypothesis with the following three specific aims.
Specific aim #1 : To formulate and characterize a topical microbicide containing phosphatase- sensitive NM in order to take advantage of the increase in the acid phosphatase activity (abundant enzyme in human semen) to trigger drug release during intercourse.
Specific aim #2 : To formulate and characterize a topical microbicide containing hyaluronidase-sensitive NM in order to take advantage of the selective increase in the hyaluronidase activity of human semen as an alternative triggering agent.
Specific aim #3 : To formulate and characterize a topical microbicide containing mannose-sensitive NM in order to trigger drug release by mannose, a major glycan component of the HIV envelope. In each aim we entrap T-20 and Tenofovir (as model microbicides) and optimize the NMs based on physicochemical, biological, and immunological analyses. The specifications and acceptance criteria, chemistry, manufacturing, controls, microbiology, and preclinical toxicology studies of the NM are performed following the current US FDA guidance. Moreover, the biological fate of the NM is elucidated using computer and mathematical modeling in collaboration with Dr. Sarah Kieweg (Dept. Mechanical Engineering, University of Kansas, KS). The safety and efficacy studies are to be conducted with Carol Lackman-Smith and Roger Ptak (Southern Research Institute, MD). The knowledge gained from this innovative and collaborative work for HIV/AIDS will also be applicable to the management of other diseases.
Our long-term goal is to thoroughly identify and characterize a novel nanomedicine microbicide to improve the safety and efficacy of microbicides used in the prevention of the HIV/AIDS transmission process. Specifically, the objective of this application is to develop a model microbicide containing inside stimuli- sensitive nanomedicines that may be made available via either enzyme sensitive components (hyaluronidase, acid phosphatase, and mannose) for a triggered release by semen, or through a viral envelope taking advantage of the unusually high density of mannose on the HIV envelope. Moreover, we will use mathematical modeling to rationalize/optimize drug formulation, release, and transport through biological systems. It is anticipated that knowledge gained from this work may be applicable to other microbicides and to other sexually transmitted or human diseases.
|Agrahari, Vivek; Meng, Jianing; Purohit, Sudhaunshu S et al. (2017) Real-Time Analysis of Tenofovir Release Kinetics Using Quantitative Phosphorus (31P) Nuclear Magnetic Resonance Spectroscopy. J Pharm Sci 106:3005-3015|
|Ngo, Albert N; Ezoulin, Miezan J M; Murowchick, James B et al. (2016) Sodium Acetate Coated Tenofovir-Loaded Chitosan Nanoparticles for Improved Physico-Chemical Properties. Pharm Res 33:367-83|
|Agrahari, Vivek; Putty, Sandeep; Mathes, Christiane et al. (2015) Evaluation of degradation kinetics and physicochemical stability of tenofovir. Drug Test Anal 7:207-13|
|Meng, Jianing; Zhang, Tao; Agrahari, Vivek et al. (2014) Comparative biophysical properties of tenofovir-loaded, thiolated and nonthiolated chitosan nanoparticles intended for HIV prevention. Nanomedicine (Lond) 9:1595-612|
|Coulibaly, Fohona S; Youan, Bi-Botti C (2014) Concanavalin A-polysaccharides binding affinity analysis using a quartz crystal microbalance. Biosens Bioelectron 59:404-11|
|Agrahari, Vivek; Meng, Jianing; Zhang, Tao et al. (2014) Application of Design of Experiment and Simulation Methods to Liquid Chromatography Analysis of Topical HIV Microbicides Stampidine and HI443. J Anal Bioanal Tech 5:|
|Zhang, Chi; Zhang, Tao; Oyler, Nathan A et al. (2014) Direct and real-time quantification of tenofovir release from ph-sensitive microparticles into simulated biological fluids using (1)h nuclear magnetic resonance. J Pharm Sci 103:1170-1177|
|Ngo, Albert N; Ezoulin, Miezan Jm; Youm, Ibrahima et al. (2014) Optimal Concentration of 2,2,2-Trichloroacetic Acid for Protein Precipitation Based on Response Surface Methodology. J Anal Bioanal Tech 5:|
|Agrahari, Vivek; Zhang, Chi; Zhang, Tao et al. (2014) Hyaluronidase-sensitive nanoparticle templates for triggered release of HIV/AIDS microbicide in vitro. AAPS J 16:181-93|
|Zhang, Tao; Zhang, Chi; Agrahari, Vivek et al. (2013) Spray drying tenofovir loaded mucoadhesive and pH-sensitive microspheres intended for HIV prevention. Antiviral Res 97:334-46|
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