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Redox-sensitive, cholesterol-bearing PEGylated poly(propyleneimine)-based dendrimersomes for drug and gene delivery to cancer cells

Abstract

Stimuli-responsive nanocarriers have attracted increasing attention for drug and gene delivery in cancer therapy. The present study reports the development of redox-sensitive dendrimersomes made of disulphide-linked cholesterol-bearing PEGylated dendrimers, that can be used as drug and gene delivery systems. Two disulphide-linked cholesterol-bearing PEGylated generation 3-diaminobutyric polypropylenimine dendrimers have been successfully synthesized through in situ two-step reaction. They were able to spontaneously self-assemble into stable, cationic, nanosized vesicles (or dendrimersomes), with lower critical aggregation concentration values for high cholesterol-bearing vesicles. These dendrimersomes were able to entrap both hydrophilic and hydrophobic dyes, and also showed a redox-responsive sustained release of the entrapped guests in presence of a glutathione concentration similar to that of the cytosolic reducing environment. The high cholesterol-bearing dendrimersome was found to have a higher melting enthalpy, an increased adsorption tendency on mica surface, was able to entrap a larger amount of hydrophobic drug and was more resistant to redox-responsive environment in comparison with its low cholesterol counterpart. In addition, both dendrimersomes were able to condense more than 85% of the DNA at all tested ratios for the low-cholesterol vesicles, and at dendrimer: DNA weight ratios of 1:1 and higher for the high-cholesterol vesicles. These vesicles resulted in an enhanced cellular uptake of DNA, by up to 15-fold compared with naked DNA with the low-cholesterol vesicles. As a result, they increased gene transfection on PC-3 prostate cancer cell line, with the highest transfection being obtained with low-cholesterol vesicle complex at a dendrimer: DNA weight ratio of 5:1 and high-cholesterol vesicle complex at a dendrimer: DNA weight ratio of 10:1. These transfection levels were about 5-fold higher than that observed when treated with DNA. These cholesterol-bearing PEGylated dendrimer-based vesicles are therefore promising as redox-sensitive drug and gene delivery systems for potential applications in combination cancer therapy.

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Publication details

The article was received on 08 Oct 2018, accepted on 26 Oct 2018 and first published on 06 Nov 2018


Article type: Paper
DOI: 10.1039/C8NR08141G
Citation: Nanoscale, 2018, Accepted Manuscript
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    Redox-sensitive, cholesterol-bearing PEGylated poly(propyleneimine)-based dendrimersomes for drug and gene delivery to cancer cells

    P. Laskar, S. Somani, N. Altwaijry, M. Mullin, D. Bowering, M. Warzecha, P. Keating, R. J. Tate, H. Leung and C. Dufes, Nanoscale, 2018, Accepted Manuscript , DOI: 10.1039/C8NR08141G

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