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

Laskar, Partha and Somani, Sukrut and Altwaijry, Najla Abdullah S and Mullin, Margaret and Bowering, Deborah and Warzecha, Monika and Keating, Patricia and Tate, Rothwelle J. and Leung, Hing Y. and Dufès, Christine (2018) Redox-sensitive, cholesterol-bearing PEGylated poly(propyleneimine)-based dendrimersomes for drug and gene delivery to cancer cells. Nanoscale. pp. 1-79. ISSN 2040-3372 (In Press)

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    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.

    Author(s):Laskar, Partha, Somani, Sukrut ORCID: https://orcid.org/0000-0002-0697-1110, Altwaijry, Najla Abdullah S ORCID: https://orcid.org/0000-0002-1203-9522, Mullin, Margaret, Bowering, Deborah, Warzecha, Monika ORCID: https://orcid.org/0000-0001-6166-1089, Keating, Patricia, Tate, Rothwelle J., Leung, Hing Y. and Dufès, Christine ORCID: https://orcid.org/0000-0002-7963-6364
    Item type:Article
    ID code:65993
    Keywords:dendrimer, polyethylene glycol, cholesterol, redox sensitivity, gene delivery, drug delivery, atomic force microscopy, Therapeutics. Pharmacology, Pharmacology (medical)
    Subjects:Medicine > Therapeutics. Pharmacology
    Department:Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
    Faculty of Science > Pure and Applied Chemistry
    Technology and Innovation Centre > Bionanotechnology
    Depositing user: Pure Administrator
    Date deposited:06 Nov 2018 10:12
    Last modified:05 Jul 2019 04:26
    Related URLs:
    URI:https://strathprints.strath.ac.uk/id/eprint/65993
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