Document text
Principal Investigator: Laura A Hansen
Organization: CREIGHTON UNIVERSITY
Fiscal Year: 2019
Award: $176,997
Funding agency: National Institute of Environmental Health Sciences
ABSTRACT
Nonmelanoma skin cancer is the most common cancer in the USA, occurring in 1 of 5 Americans during their
lifetime. The incidence of skin cancer is rising as well, due to increased exposure to sunlight and other sources
of ultraviolet (UV) irradiation, the primary cause of approximately 90% of skin cancers. Excessive UV radiation
exposure to the skin results in oxidative stress that can overwhelm the natural antioxidant defenses of the skin.
This leads to significant and rapid generation of reactive oxygen species (ROS). ROS can cause DNA
damage and lead to mutations and cancer. Currently used sunscreens and antioxidants are not adequate to
prevent or protect against UV exposure. Sunscreens are particularly poor at blocking the long wavelength UVA
that produces much of the ROS and must be frequently reapplied, while antioxidants typically used to protect
skin have poor stability and do not penetrate the skin to reach the basal epidermal keratinocytes at risk for
oncogenic transformation. Therefore, we reasoned that effective and sustained delivery of antioxidants,
particularly superoxide dismutase (SOD) and catalase (CAT), to the skin could prevent oxidative stress-
induced oncogenic responses and hence skin cancer. To investigate this hypothesis, we will utilize a novel
agent, Pro-NP™, which consists of a biodegradable nanoparticle shell containing the antioxidant enzymes
SOD and CAT. Pro-NP™ is formulated using an FDA approved biodegradable and biocompatible polymer that
protects the encapsulated enzymes from degradation and allows their release in active form over a sustained
period of time. Our preliminary data in human epidermal tissue equivalents show that Pro-NP™ penetrates to
the deepest layers of the epidermis and prevents UV-induced increases in ROS and DNA damage. We
hypothesize that topical application of Pro-NP™ will safely deliver SOD and CAT to the basal keratinocytes of
the skin to prevent ROS generation in response to UV irradiation, and thus reduce DNA damage and skin
cancer development. This hypothesis will be tested using UV exposure of Hairless SKH1 mice to 1) evaluate
the effectiveness of Pro-NP™ for delivering antioxidant enzymes into the skin for prevention of UV-
induced ROS, reactive nitrogen species, and DNA damage and 2) assess the safety and efficacy of Pro-
NP™ for prevention of UV-induced skin cancer. We anticipate successful proof-of-principle evidence of the
ability of topical Pro-NP™ treatment to safely prevent skin cancer in chronically UV irradiated skin.
Terms: <Actinic Rays><Active Oxygen><American><Antioxidants><Body Tissues><Cancer Causing Agents><Cancers><Carcinogens><Cellular injury><Chronic><Clinical><Clinical Trials><Cutaneous><DNA Damage><DNA Injury><Data><Development><Effectiveness><Encapsulated><Enzyme Gene><Enzymes><Epidermis><Erythrocuprein><Exhibits><Exposure to><Exposure to ultraviolet radiation><FDA approved><Future><Gene Alteration><Gene Mutation><Generations><Genetic Alteration><Genetic Change><Genetic defect><Goals><HGF gene><HGF/SF><Hemocuprein><Hepatocyte Growth Factor><Hepatopoietin A><Human><Incidence><Inflammation><Lead><Lipid Peroxidation><Lung Fibroblast-Derived Mitogen><Malignant Neoplasms><Malignant Skin Neoplasm><Malignant Tumor><Melanins><Mice><Mice Mammals><Modern Man><Murine><Mus><Mutation><Non-Melanoma Skin Cancer><Oncogenic><Oncogens><Organ><Oxidative Stress><Oxygen Radicals><P53><Pb element><Plasticizers><Prevalence><Prevent skin cancer><Prevention><Pro-Oxidants><Production><Reactive Nitrogen Species><Reactive Oxygen Species><Research><Resistance><Risk><Role><Safety><Scatter Factor><Signal Pathway><Site><Skin><Skin Cancer><Skin Carcinoma><Skin Neoplasms><Skin Tumor><Source><Sun Exposure><Sunblock><Sunlight><Sunscreening Agents><Sunscreens><Superoxide Dismutase><TP53><TP53 gene><TRP53><Testing><Therapeutic><TiO2><Time><Tissues><Topical Drug Administration><Topical application><Transgenic Mice><Transgenic Organisms><Tumor Burden><Tumor Load><Tumor Protein p53 Gene><U.V. protection><UV Radiation Exposure><UV exposure><UV induced><UV irradiated><UV irradiation><UV irridated><UV light><UV protection><UV radiation><UV radiation-induced><Ultraviolet Radiation Related Exposure><Ultraviolet Rays><Ultraviolet radiation exposure><anti-oxidant><anti-oxidant enzyme><antioxidant enzyme><base><biocompatible polymer><biodegradable polymer><bioresorbable polymer><cancer type><carcinogenicity><catalase><cell damage><cell injury><cytocuprein><degradable polymer><design><designing><developmental><experiment><experimental research><experimental study><genome mutation><heavy metal Pb><heavy metal lead><in vivo><keratinocyte><malignancy><malignant skin tumor><melanocyte><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><neoplasm/cancer><nonmelanoma skin cancer><novel><oncogenic agent><oxidative damage><p53 Genes><prevent><preventing><resistant><response><skin cancer prevention><social role><solar exposure><sunlight exposure><systemic toxicity><titanium dioxide><titanium oxide><topical administration><topical delivery><topical drug application><topical treatment><topically applied><transgenic><tumor><ultra violet irradiation><ultraviolet><ultraviolet exposure><ultraviolet induced><ultraviolet irradiation><ultraviolet light><ultraviolet protection><ultraviolet radiation>