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 > School 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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