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, 10 (48). pp. 22830-22847. ISSN 2040-3372 (https://doi.org/10.1039/C8NR08141G)

[thumbnail of Laskar-etal-Nanoscale2018-Redox-sensitive-cholesterol-bearing-PEGylated-poly-propyleneimine]
Preview
 Text. Filename: Laskar_etal_Nanoscale2018_Redox_sensitive_cholesterol_bearing_PEGylated_poly_propyleneimine.pdf
Accepted Author Manuscript
Download (2MB)| Preview

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.

ORCID iDs

Laskar, Partha, Somani, Sukrut ORCID logoORCID: https://orcid.org/0000-0002-0697-1110, Altwaijry, Najla Abdullah S ORCID logoORCID: https://orcid.org/0000-0002-1203-9522, Mullin, Margaret, Bowering, Deborah ORCID logoORCID: https://orcid.org/0000-0002-8934-3469, Warzecha, Monika ORCID logoORCID: https://orcid.org/0000-0001-6166-1089, Keating, Patricia, Tate, Rothwelle J., Leung, Hing Y. and Dufès, Christine ORCID logoORCID: https://orcid.org/0000-0002-7963-6364;
CORE (COnnecting REpositories)