With the incidence of HIV infection on the rise, the development of vaccines and topical microbicides has been a major worldwide priority. However, the results of recent trials have been disappointing. As such, the induction of sterilizing immunity and protection against HIV infection continues to be a major public health goal. 'Microbicides', topically applied agents that prevent HIV transmission from person to person, are still believed to hold considerable promise. In fact, it has been suggested that a microbicide with only 60% efficacy could prevent about 1 million HIV infections per year. Given recent clinical failures, there is an urgent need to rethink the concept of microbicides. Therefore, the long-term objective of the proposed research is to design, construct and evaluate a multiplex nanocarrier-based polyethylene glycol (PEG) vaginal hydrogel for preventing HIV transmission. PEG is nontoxic and biocompatible. Hydrogels resemble living tissue due to their high-water content and soft/rubbery characteristics. The hydrogel is a liquid upon instillation allowing for high vaginal dispersion/mucosal coverage where it then undergoes a rapid phase transition to form a visco-elastic gel. The proposed gel must be multifunctional since it has been shown that (1) sexually transmitted and genital infections such as bacterial vaginosis (BV) increase the risk of HIV transmission by weakening mucosal barriers and by stimulating an inflammatory response that may activate or recruit HIV target cells to the portals of viral entry, (2) low vaginal pH (<4.5) is essential for the prevention of vaginal infections but is not sufficient to inhibit vaginal pathogens and to prevent infection, and (3) cell-associated HIV breaches the normal vagina stratified squamous epithelial barrier but with low frequency. The gel matrix will be formed by crosslinking various PEG nanocarriers each of which plays a unique role in the functional properties of the hydrogel (e.g., promoting mucosal adhesion, maintaining mildly acidic pH, releasing microbicide and spermicides, and preventing HIV virion binding). We will design, synthesize, characterize, and evaluate a series of crosslinking nanocarriers that impart a variety of functional properties to the microbicide hydrogel.
Aim 1 : To construct an effective physical viral barrier using a fast forming, degradable hydrogel with high vaginal dispersion, high mechanical strength, and viscoelastic properties.
Aim 2 : To create nanocarriers possessing acidifying agents using natural acids and/or the microbicide/spermicide subtilosin.
Aim 3 : To fabricate polyanionic or RGD nanocarriers to prevent free or cell-associated HIV binding.
Aim 4 : To evaluate the various crosslinking nanocarriers and hydrogels in cell, tissue and animal models. If successful, the proposed research will result in a novel multifunctional hydrogel technology that possesses the ideal properties of an anti-HIV microbicide: it will be colorless, odorless, inexpensive to manufacture, safe to use more than once a day and for long periods of time, fast-acting, undetectable to either partner, and available in contraceptive and noncontraceptive forms. With the incidence of HIV infection on the rise, the development of vaccines and topical microbicides has been a major worldwide priority but the results of recent trials have been disappointing. 'Microbicides', topically applied agents that prevent HIV transmission from person to person, are still believed to hold considerable promise. The proposed research seeks to design, construct and evaluate an instantly-forming multifunctional vaginal hydrogel to prevent the initial infection and dissemination of HIV through the vaginal mucosa to distant tissues in the body.
With the incidence of HIV infection on the rise, the development of vaccines and topical microbicides has been a major worldwide priority but the results of recent trials have been disappointing. 'Microbicides', topically applied agents that prevent HIV transmission from person to person, are still believed to hold considerable promise. The proposed research seeks to design, construct and evaluate an instantly-forming multifunctional vaginal hydrogel to prevent the initial infection and dissemination of HIV through the vaginal mucosa to distant tissues in the body.
|Pinkerton, Nathalie M; Gindy, Marian E; Calero-DdelC, Victoria L et al. (2015) Single-Step Assembly of Multimodal Imaging Nanocarriers: MRI and Long-Wavelength Fluorescence Imaging. Adv Healthc Mater 4:1376-85|
|Tang, Christina; Xiao, Edward; Sinko, Patrick J et al. (2015) Responsive foams for nanoparticle delivery. Colloids Surf B Biointerfaces 133:81-7|
|Sundara Rajan, Sujata; Turovskiy, Yevgeniy; Singh, Yashveer et al. (2014) Poly(ethylene glycol) (PEG)-lactic acid nanocarrier-based degradable hydrogels for restoring the vaginal microenvironment. J Control Release 194:301-9|
|Sundara Rajan, Sujata; Cavera, Veronica L; Zhang, Xiaoping et al. (2014) Polyethylene glycol-based hydrogels for controlled release of the antimicrobial subtilosin for prophylaxis of bacterial vaginosis. Antimicrob Agents Chemother 58:2747-53|
|Palombo, Matthew; Deshmukh, Manjeet; Myers, Daniel et al. (2014) Pharmaceutical and toxicological properties of engineered nanomaterials for drug delivery. Annu Rev Pharmacol Toxicol 54:581-98|
|Quintana, V M; Torres, N I; Wachsman, M B et al. (2014) Antiherpes simplex virus type 2 activity of the antimicrobial peptide subtilosin. J Appl Microbiol 117:1253-9|
|Gao, Jieming; Chen, Peiming; Singh, Yashveer et al. (2013) Novel monodisperse PEGtide dendrons: design, fabrication, and evaluation of mannose receptor-mediated macrophage targeting. Bioconjug Chem 24:1332-44|
|Torres, Nicolás I; Noll, Katia Sutyak; Xu, Shiqi et al. (2013) Safety, formulation, and in vitro antiviral activity of the antimicrobial peptide subtilosin against herpes simplex virus type 1. Probiotics Antimicrob Proteins 5:26-35|
|Singh, Yashveer; Gao, Dayuan; Gu, Zichao et al. (2012) Noninvasive detection of passively targeted poly(ethylene glycol) nanocarriers in tumors. Mol Pharm 9:144-55|
|Noll, Katia Sutyak; Prichard, Mark N; Khaykin, Arkady et al. (2012) The natural antimicrobial peptide subtilosin acts synergistically with glycerol monolaurate, lauric arginate, and ?-poly-L-lysine against bacterial vaginosis-associated pathogens but not human lactobacilli. Antimicrob Agents Chemother 56:1756-61|
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