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

Laskar, P., Somani, S., Altwaijry, N., Mullin, M., Bowering, D., Warzecha, M., Keating, P., Tate, R. J., Leung, H. Y. and Dufès, C. (2018) Redox-sensitive, cholesterol-bearing PEGylated poly(propylene imine)-based dendrimersomes for drug and gene delivery to cancer cells. Nanoscale, 2018(10), pp. 22830-22847. (doi:10.1039/c8nr08141g) (PMID:30488937)

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Abstract

Stimuli-responsive nanocarriers have attracted increased attention as materials that can facilitate drug and gene delivery in cancer therapy. The present study reports the development of redox-sensitive dendrimersomes comprising disulfide-linked cholesterol-bearing PEGylated dendrimers, which can be used as drug and gene delivery systems. Two disulfide-linked cholesterol-bearing PEGylated generation 3 diaminobutyric polypropylenimine dendrimers have been successfully synthesized via an 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 they also showed a redox-responsive sustained release of the entrapped guests in the presence of a glutathione concentration similar to that of a cytosolic reducing environment. The high-cholesterol-bearing dendrimersomes were found to have a higher melting enthalpy, increased adsorption tendency on mica surface, entrapping ability for a larger amount of hydrophobic drugs, and increased resistance to redox-responsive environments in comparison with their low-cholesterol counterpart. In addition, both dendrimersomes were able to condense more than 85% of the DNA at all the 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 when compared with naked DNA with low-cholesterol vesicles. As a result, they increased the gene transfection on the PC-3 prostate cancer cell line, with the highest transfection being obtained with low-cholesterol vesicle complexes at a dendrimer : DNA weight ratio of 5 : 1 and high-cholesterol vesicle complexes at a dendrimer : DNA weight ratio of 10 : 1. These transfection levels were about 5-fold higher than those observed when treated with naked DNA. These cholesterol-bearing PEGylated dendrimer-based vesicles are, therefore, promising as redox-sensitive drugs and gene delivery systems for potential applications in combination cancer therapies.

Item Type:Articles
Additional Information:This work was financially supported by a grant from Worldwide Cancer Research [grant number 16-1303] to C. D. and H. Y. L. P. L. and S. S. are respectively funded by research grants from Worldwide Cancer Research [grant number 16-1303] and The Dunhill Medical Trust [grant number R463/0216]. N. A. is in receipt of a PhD studentship from the Saudi Cultural Bureau and Princess Nourah bint Abdulrahman University (Kingdom of Saudi Arabia) [grant number 15678].
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Leung, Professor Hing
Authors: Laskar, P., Somani, S., Altwaijry, N., Mullin, M., Bowering, D., Warzecha, M., Keating, P., Tate, R. J., Leung, H. Y., and Dufès, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Nanoscale
Publisher:Royal Society of Chemistry
ISSN:2040-3364
ISSN (Online):2040-3372
Published Online:06 November 2018

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