title: Evaluation of cationic polyamidoamine dendrimers' dermal toxicity in the rat skin model.
abstract: Polyamidoamine (PAMAM) dendrimers are multi-branched, three-dimensional polymers with unique architecture, which makes these molecules attractive for medical and pharmaceutical applications. Using PAMAM as drug carriers for topical delivery might be beneficial as they only produce a transient effect without skin irritation. To evaluate the dermal toxicity of cationic PAMAM dendrimers generation 2 and generation 3, skin irritation studies were performed in vivo in the rat skin model. After 10 days topical application of various concentrations of PAMAM-NH2 (0.3 mg/mL, 3 mg/mL, 6 mg/mL, 30 mg/mL, 300 mg/mL), skin irritation was evaluated by visual, histopathological, and immunohistochemical examination. Microscopic assessment after hematoxylin-eosin staining revealed significant morphological changes of epidermal cells after application of PAMAM-NH2 at a concentration of ≥6 mg/mL. Morphological alterations of epidermal cells included cytoplasmic vacuolization of keratinocytes in the basal and spinous layers. Cytomorphological changes in keratinocytes, overall picture of the epidermis, and histopathological changes in the dermis were dose dependent. Detected alterations concerned hyperplasia of connective tissue fibers and leukocyte infiltration. Visible granulocyte infiltration in the upper dermis and sockets formed by necrotic, cornified cells in the hyperplastic foci of epithelium were also noted. Immunohistochemical analyses revealed that increased nuclear immunoreactivity to PCNA correlated with the concentration of PAMAM-NH2, but no significant differences in the cell proliferation activity in skin treated with PAMAM-NH2 generation 2 or generation 3 were observed. Significantly higher expression of PCNA extended throughout the skin layers might suggest abnormal cell proliferation, which, as a consequence, might even lead to neoplastic changes.
authors.affiliation: Department of Pharmaceutical Technology, Faculty of Pharmacy, Medical University of Białystok, Białystok, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Winnicka
authors.affiliation: Department of Pharmaceutical Technology, Faculty of Pharmacy, Medical University of Białystok, Białystok, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Wroblewska
authors.affiliation: Department of Pharmaceutical Technology, Faculty of Pharmacy, Medical University of Białystok, Białystok, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Sosnowska
authors.affiliation: Department of Experimental Pharmacology, Faculty of Health Sciences, Medical University of Białystok, Białystok, Poland.
authors.forename: Halina
authors.initials: H
authors.lastname: Car
authors.affiliation: Department of Histology and Cytophysiology, Faculty of Pharmacy, Medical University of Białystok, Białystok, Poland.
authors.forename: Irena
authors.initials: I
authors.lastname: Kasacka
mesh_terms: D000818:Animals; D002412:Cations; D050091:Dendrimers / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity; D007150:Immunohistochemistry; D008297:Male; D015394:Molecular Structure; D011073:Polyamines / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D012871:Skin Diseases / Q000139:chemically induced* / Q000473:pathology*; D013194:Staining and Labeling
chemical_list: D002412:Cations; D050091:Dendrimers; D004337:Drug Carriers; C531249:Poly(amidoamine); D011073:Polyamines; D018809:Proliferating Cell Nuclear Antigen
keywords: cationic PAMAM dendrimers polymers; in vivo toxicity; nanomaterials; skin irritation test; topical delivery
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