Evaluation of Cytotoxic Effect of Cholesterol End-Capped Poly(N-Isopropylacrylamide)s on Selected Normal and Neoplastic Cells

• Main Authors: Misiak P, Niemirowicz-Laskowska K, Markiewicz KH, Misztalewska-Turkowicz I, Wielgat P, Kurowska I, Siemiaszko G, Destarac M, Car H, Wilczewska AZ
• Format: Article
• Language: English
• Published: Dove Medical Press 2020-09-01
• Series: International Journal of Nanomedicine
• Subjects: cholesterol-end capped poly(n-isopropylacrylamide); cell-penetrating molecules; thermoresponsive polymer micelles; drug carriers
• Online Access: https://www.dovepress.com/evaluation-of-cytotoxic-effect-of-cholesterol-end-capped-polyn-isoprop-peer-reviewed-article-IJN

Pawel Misiak,1 Katarzyna Niemirowicz-Laskowska,2 Karolina H Markiewicz,1 Iwona Misztalewska-Turkowicz,1 Przemysław Wielgat,3 Izabela Kurowska,1,4 Gabriela Siemiaszko,1 Mathias Destarac,5 Halina Car,2 Agnieszka Z Wilczewska1 1Faculty of Chemistry, University of Bialystok, Bialystok, Poland; 2Department of Experimental Pharmacology, Medical University of Bialystok, Bialystok, Poland; 3Department of Clinical Pharmacology, Medical University of Bialystok, Bialystok, Poland; 4Doctoral School of Exact and Natural Sciences, University of Bialystok, Bialystok, Poland; 5IMRCP, CNRS UMR 5623, Université de Toulouse, Toulouse, FranceCorrespondence: Agnieszka Z Wilczewska; Karolina H Markiewicz Tel [phone]Email [e-mail]; [e-mail]: Efficient intracellular delivery of a therapeutic compound is an important feature of smart drug delivery systems (SDDS). Modification of a carrier structure with a cell-penetrating ligand, ie, cholesterol moiety, is a strategy to improve cellular uptake. Cholesterol end-capped poly(N-isopropylacrylamide)s offer a promising foundation for the design of efficient thermoresponsive drug delivery systems.Methods: A series of cholesterol end-capped poly(N-isopropylacrylamide)s (PNIPAAm) with number-average molar masses ranging from 3200 to 11000 g·mol– 1 were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization from original xanthate-functionalized cholesterol and self-assembled into micelles. The physicochemical characteristics and cytotoxicity of cholesterol end-capped poly(N-isopropylacrylamide)s have been thoroughly investigated.Results: Phase transition temperature dependence on the molecular weight and hydrophilic/hydrophobic ratio in the polymers were observed in water. Biological test results showed that the obtained materials, both in disordered and micellar form, are non-hemolytic, highly compatible with fibroblasts, and toxic to glioblastoma cells. It was found that the polymer termini dictates the mode of action of the system.Conclusion: The cholesteryl moiety acts as a cell-penetrating agent, which enables disruption of the plasma membrane and in effect leads to the restriction of the tumor growth. Cholesterol end-capped PNIPAAm showing in vitro anticancer efficacy can be developed not only as drug carriers but also as components of combined/synergistic therapy.Keywords: cholesterol-end capped poly(N-isopropylacrylamide), cell-penetrating molecules, thermoresponsive polymer micelles, drug carriers