Issue 2, 2015

The endocytic pathway and therapeutic efficiency of doxorubicin conjugated cholesterol-derived polymers

Abstract

Previously synthesized poly(methacrylic acid-co-cholesteryl methacrylate) P(MAA-co-CMA) copolymers were examined as potential drug delivery vehicles. P(MAA-co-CMA) copolymers were fluorescently labelled and imaged in SHEP and HepG2 cells. To understand their cell internalization pathway endocytic inhibition studies were conducted. It was concluded that P(MAA-co-CMA) are taken up by the cells via clathrin-independent endocytosis (CIE) (both caveolae mediated and cholesterol dependent endocytosis) mechanisms. The formation and characterization of P(MAA-co-CMA)–doxorubicin (DOX) nanocomplexes was investigated by fluorescence lifetime imaging microscopy (FLIM), UV-Visible spectroscopy (UV-Vis) and dynamic light scattering (DLS) studies. The toxicity screening between P(MAA-co-CMA)–DOX nanocomplexes (at varying w/w ratios) and free DOX, revealed nanocomplexes to exhibit higher cytotoxicity towards cancer cells in comparison to normal cells. FLIM and confocal microscopy were employed for investigating the time-dependent release of DOX in SHEP cells and the cellular uptake profile of P(MAA-co-CMA)–DOX nanocomplexes in cancer and normal cell lines, respectively. The endocytic pathway of P(MAA-co-CMA)–DOX nanocomplexes were examined in SHEP and HepG2 cells via flow cytometry revealing the complexes to be internalized through both clathrin-dependent (CDE) and CIE mechanisms. The drug delivery profile, reported herein, illuminates the specific endocytic route and therapeutic efficiency of P(MAA-co-CMA)–DOX nanocomplexes strongly suggesting these particles to be promising candidates for in vivo applications.

Graphical abstract: The endocytic pathway and therapeutic efficiency of doxorubicin conjugated cholesterol-derived polymers

Supplementary files

Article information

Article type
Paper
Submitted
18 Jun 2014
Accepted
15 Sep 2014
First published
25 Sep 2014

Biomater. Sci., 2015,3, 323-335

The endocytic pathway and therapeutic efficiency of doxorubicin conjugated cholesterol-derived polymers

S. Sevimli, S. Sagnella, A. Macmillan, R. Whan, M. Kavallaris, V. Bulmus and T. P. Davis, Biomater. Sci., 2015, 3, 323 DOI: 10.1039/C4BM00224E

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