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

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.

• Authors: Partha Laskar, Sukrut Somani, Najla Altwaijry, Margaret Mullin, Deborah Bowering, Monika Warzecha, Patricia Keating, Rothwelle J Tate, Hing Y Leung, Christine Dufès
• Journal: Nanoscale (Nanoscale) Vol. 10 Issue 48 Pg. 22830-22847 (Dec 28 2018) ISSN: 2040-3372 [Electronic] England
• PMID: 30488937 (Publication Type: Journal Article)

Chemical References

• Dendrimers
• Polypropylenes
• poly(propyleneimine)
• Polyethylene Glycols
• Cholesterol

Topics

• Cell Line, Tumor
• Cholesterol (chemistry, pharmacokinetics, pharmacology)
• Dendrimers (chemistry, pharmacokinetics, pharmacology)
• Drug Delivery Systems (methods)
• Gene Transfer Techniques
• Humans
• Male
• Polyethylene Glycols (chemistry, pharmacokinetics, pharmacology)
• Polypropylenes (chemistry, pharmacokinetics, pharmacology)
• Prostatic Neoplasms (genetics, metabolism, pathology, therapy)