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Evaluation of cationic polyamidoamine dendrimers’ dermal toxicity in the rat skin model

Authors Winnicka K, Wroblewska M, Sosnowska K, Car H, Kasacka I

Received 30 November 2014

Accepted for publication 30 December 2014

Published 5 March 2015 Volume 2015:9 Pages 1367—1377

DOI https://doi.org/10.2147/DDDT.S78336

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Professor Shu-Feng Zhou


Katarzyna Winnicka,1 Magdalena Wroblewska,1 Katarzyna Sosnowska,1 Halina Car,2 Irena Kasacka3

1Department of Pharmaceutical Technology, Faculty of Pharmacy, Medical University of Bialystok, Bialystok, Poland; 2Department of Experimental Pharmacology, Faculty of Health Sciences, Medical University of Bialystok, Bialystok, Poland; 3Department of Histology and Cytophysiology, Faculty of Pharmacy, Medical University of Bialystok, Bialystok, Poland

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.

Keywords: cationic PAMAM dendrimers polymers, topical delivery, nanomaterials, in vivo toxicity, skin irritation test
 

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