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

Partha Laskar, Sukrut Somani, Najla Abdullah S Altwaijry, Margaret Mullin, Deborah Bowering, Monika Warzecha, Patricia Keating, Rothwelle J. Tate, Hing Y. Leung, Christine Dufès

Research output: Contribution to journalArticle

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.
LanguageEnglish
Pages22830-22847
Number of pages18
JournalNanoscale
Volume10
Issue number48
Early online date6 Nov 2018
DOIs
Publication statusPublished - 28 Dec 2018

Fingerprint

Bearings (structural)
Cholesterol
Genes
Cells
Dendrimers
DNA
Pharmaceutical Preparations
Disulfides
poly(propyleneimine)
Oxidation-Reduction
Mica
Glutathione

Keywords

  • dendrimer
  • polyethylene glycol
  • cholesterol
  • redox sensitivity
  • gene delivery
  • drug delivery
  • atomic force microscopy

Cite this

@article{39b5a8db20e84c49a44eaa5ae1e407e7,
title = "Redox-sensitive, cholesterol-bearing PEGylated poly(propyleneimine)-based dendrimersomes for drug and gene delivery to cancer cells",
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.",
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author = "Partha Laskar and Sukrut Somani and Altwaijry, {Najla Abdullah S} and Margaret Mullin and Deborah Bowering and Monika Warzecha and Patricia Keating and Tate, {Rothwelle J.} and Leung, {Hing Y.} and Christine Duf{\`e}s",
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Redox-sensitive, cholesterol-bearing PEGylated poly(propyleneimine)-based dendrimersomes for drug and gene delivery to cancer cells. / Laskar, Partha; Somani, Sukrut; Altwaijry, Najla Abdullah S; Mullin, Margaret; Bowering, Deborah; Warzecha, Monika; Keating, Patricia; Tate, Rothwelle J.; Leung, Hing Y.; Dufès, Christine.

In: Nanoscale, Vol. 10, No. 48, 28.12.2018, p. 22830-22847.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Redox-sensitive, cholesterol-bearing PEGylated poly(propyleneimine)-based dendrimersomes for drug and gene delivery to cancer cells

AU - Laskar, Partha

AU - Somani, Sukrut

AU - Altwaijry, Najla Abdullah S

AU - Mullin, Margaret

AU - Bowering, Deborah

AU - Warzecha, Monika

AU - Keating, Patricia

AU - Tate, Rothwelle J.

AU - Leung, Hing Y.

AU - Dufès, Christine

PY - 2018/12/28

Y1 - 2018/12/28

N2 - 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.

AB - 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.

KW - dendrimer

KW - polyethylene glycol

KW - cholesterol

KW - redox sensitivity

KW - gene delivery

KW - drug delivery

KW - atomic force microscopy

UR - https://pubs.rsc.org/en/Journals/JournalIssues/NR

U2 - 10.1039/C8NR08141G

DO - 10.1039/C8NR08141G

M3 - Article

VL - 10

SP - 22830

EP - 22847

JO - Nanoscale

T2 - Nanoscale

JF - Nanoscale

SN - 2040-3364

IS - 48

ER -