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ASHLAND, MA, United States

Desai P.R.,Florida A&M University | Shah P.P.,Florida A&M University | Hayden P.,Mattek Corporation | Singh M.,Florida A&M University
Pharmaceutical Research | Year: 2013

Purpose: To investigate the percutaneous permeation pathways of cell penetrating peptide modified lipid nanoparticles and oleic acid modified polymeric nanoparticles. Methods: Confocal microscopy was performed on skin cultures (EpiDermFT™) for modified and un-modified nanoparticles. Differential stripping was performed following in vitro skin permeation of Ibuprofen (Ibu) encapsulated nanoparticles to estimate Ibu levels in different skin layers and receiver compartment. The hair follicles (HF) were blocked and in vitro skin permeation of nanoparticles was then compared with unblocked HF. The surface modified nanoparticles were investigated for response on allergic contact dermatitis (ACD). Results: Surface modified nanoparticles showed a significant higher (p < 0.05) in fluorescence in EpiDermFT™ cultures compared to controls. The HF play less than 5% role in total nanoparticle permeation into the skin. The Ibu levels were significantly high (p < 0.05) for surface modified nanoparticles compared to controls. The Ibu levels in skin and receiver compartment were not significantly different when HF were open or closed. Modified nanoparticles showed significant improvement in treatment of ACD compared to solution. Conclusions: Our studies demonstrate that increased skin permeation of surface modified nanoparticles is not only dependent on a follicular pathway but also occur through non-follicular pathway(s). © 2012 Springer Science+Business Media New York. Source


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.21M | Year: 2009

DESCRIPTION (provided by applicant): During Phase 1 research, the effects of 6 model test materials on a highly differentiated vaginal- ectocervical (VEC) tissue model were studied. Effects on tissue viability, structure, barrier function, and inflammatory cytokine release were monitored. Many of the assays gave results which supported one another and increased confidence in the in vitro results. For instance, histological damage and cytokine release paralleled losses in tissue viability. In addition, decreases in barrier function were measured when tissue viability decreased although the data indicated that barrier function was a more sensitive endpoint (i.e. decreases in barrier function occurred at lower concentrations that did not decrease tissue viability). Importantly, the one material which was mildly irritating in the rabbit vaginal irritation test induced significant decreases in tissue viability and barrier function and increased inflammatory mediator release. In addition, an economic analysis showed the in vitro method to be a cost-effective alternative to the currently used rabbit vaginal irritation test methodology. During Phase 2, the utility of the in vitro assay system will be further expanded to predict vaginal irritation following chronic, repeat exposure. Using the endpoints developed in Phase 1, a prediction model will be developed to accurately assess the in vivo vaginal irritation of test materials and formulations. The method will be transferred to outside contract testing labs and a multi-lab GLP validation study will be performed. In addition, the short and long term reproducibility of the assay will be assessed, and a high throughput version of the assay method will be developed. PUBLIC HEALTH RELEVANCE: A predictive test system for assessing the vaginal irritation potential of chemicals and formulations will have far reaching application in industries involved in women's care products, microbicide, contraceptives, excipient development, and topical pharmaceutical products. Evaluation of vaginal irritation is important to minimize chemical hazards to millions of women. The proposed human reconstructed tissue based system will provide a sensitive and validated assay method for screening of chemicals/formulations with vaginal irritation potential. Furthermore, the assay method will be cost effective and reduce the use of laboratory animals for experimentation.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 819.10K | Year: 2009

DESCRIPTION (provided by applicant): As part of a standard toxicological evaluation, all new products must be tested to insure they are not genotoxic. Animal tests are available but European legislation that takes effect in 2009 will ban animal testing. This legislation will affect almost all large US multinational personal care, cosmetic, and pharmaceutical companies. Non-animal, in vitro tests exist; however, they lack specificity and result in an unacceptably high rate of false positives. This leads to a large number of materials being excluded from further development even though are safe. The long term goal of the proposal is to validate an in vitro test method to accurately determine human skin genotoxicity. Phase 1 research made significant progress in developing a reconstructed skin micronucleus (RSMN) assay for genotoxicity testing. A standardized protocol, a pre- screen cytotoxicity assay, and a prediction model (based on statistically significant increases in micronuclei in dividing cells) were defined and tested. A previously published method was improved to increase the sensitivity of the assay for detecting genotoxins requiring metabolic activation. In addition, long term reproducibility studies utilizing tissue from multiple donors showed highly reproducible results. Phase 2 will further build on Phase 1 results to optimize the assay method, automate scoring, expand the database of materials tested, demonstrate interlaboratory reproducibility, and adapt the assay to a high throughput format. These studies will lay the groundwork for formal validation and regulatory acceptance of the assay. PUBLIC HEALTH RELEVANCE: Current genotoxicity test methods rely on animals or in vitro tests. However, the in vitro methods give an unacceptable percentage of false positive test results and animal testing will be banned for US based multinational companies due to pending legislation. This project will develop an in vitro assay which accurately predicts human genotoxicity.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 221.24K | Year: 2009

DESCRIPTION (provided by applicant): The goal of the current proposal is to apply state of the art gene modification technology including lentiviral delivery systems and RNA interference technology to commercially available tissue engineered human in vitro models. These models will consist of differentiated 3-D epidermal cultures and tracheal/bronchial epithelial cultures, as well as epidermal and airway epithelia co-cultured with mesenchymal cells. In Phase I research, the technology will be used to produce 3 types of genetically modified tissue engineered culture products: 1) stable addition of a functional gene, 2) stable silencing of a gene, and 3) stable introduction of a reporter for detection of gene activation. During Phase II, the techniques will be applied to additional tissue engineered human in vitro models, and the inventory of available gene modified products will be expanded. These proposed commercially available in vitro model systems will provide researchers in the pharmaceutical industry and academic research laboratories a readily available means for studying the functional genomics of nearly any gene in human epithelial cells, as well as crosstalk between epithelial and stromal cells in the differentiated organotypic state. Use of these models will aid in identification and validation of targets for development of novel therapeutics for treatment of human skin and airway epithelial diseases including cancers, chronic wounds, blistering diseases, scarring, and airway remodeling associated with asthma and COPD. Public Health Relevance: The gene modified tissue engineered models to be produced by the current project will provide researchers in the pharmaceutical industry and academic research laboratories a readily available means for studying the functional genomics of nearly any gene in human epithelial cells, as well as crosstalk between epithelial and stromal cells in the differentiated organotypic state. The models will be utilized to identify and validate targets for the development of novel therapeutics for treatment of human skin and airway epithelial diseases including cancers, chronic wounds, blistering diseases, scarring, and airway remodeling associated with asthma and COPD.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 835.98K | Year: 2011

DESCRIPTION (provided by applicant): Hazard assessment, including evaluation of acute inhalation toxicity potential, is a mandatory international regulatory requirement for chemicals utilized in international commerce. Acute inhalation toxicity or irritation potential is an important consideration in establishing procedures for the safe handling, packaging and labeling and transport of chemicals and chemical mixtures, and in formulating responses to emergency exposure situations. Recently enacted legislation including the European Union (EU) Registration, Labeling and Authorization of Chemicals (REACH) program, and the US EPA High production Volume (HPV) Chemical Challenge will dramatically increase the need for inhalation toxicity information. The goal of the present grant proposal is to validate the EpiAirway in vitro human airway model for prediction of in vivo human inhalation toxicity hazard potential following Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) and European Center for Validation of Alternative Methods (ECVAM) guidelines. Phase I experiments produced several prediction models that will be further tested in the current Phase II project. One hundred chemicals that have available in vivo human or animal inhalation toxicity data and established immediately Dangerous to Life or health (IDLH) concentrations established by NIOSH will be utilized in the Phase II validation project. Interlaboratory transferability of the method will also be evaluated in 4 laboratories using a subset of 30 chemicals chosen from the original 100 tested during the Phase II study. The study data will then be submitted for independent statistical analysis and the final results and report will be submitted to regulatory agencies (i.e. ICCVAM) in support of regulatory acceptance. The technology to be validated in the current Phase II proposal will address a critical barrier to implementation of worldwide requirements for inhalation toxicity testing of chemicals, and a technical capacity thatis urgently needed but that does not presently exist. The methodology developed will provide a transformative technology that will facilitate the paradigm shift from in vivo rodent to in vitro human inhalation toxicology testing envisioned in the resent National Research Council Report Toxicity Testing in the 21st Century: A Vision and a Strategy . PUBLIC HEALTH RELEVANCE: Hazard assessment, including evaluation of acute inhalation toxicity potential, is a mandatory international regulatory requirement for chemicals utilized in international commerce. Acute inhalation toxicity or irritation potential is an important consideration in establishing procedures for the safe handling, packaging and labeling and transport of chemicals and chemical mixtures, and in formulating responses to emergency exposure situations. The technology to be validated in the current Phase II proposal will address a critical barrier to implementation of worldwide requirements for inhalation toxicity testing of chemicals, and provide a technical capability that is urgently needed but that does not presently exist.

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