Camptothecin-based dendrimersomes for gene delivery and redox-responsive drug delivery to cancer cells

Research output: Contribution to journalArticle

Abstract

Combination therapy involving chemotherapeutic drugs and genes is emerging as a promising strategy to provide a synergistic therapeutic effect, to overcome drug resistance while reducing the severe side effects associated with conventional chemotherapeutic drugs. However, the lack of nanomedicines able to simultaneously carry anti-cancer drugs and nucleic acids limits the application of this therapeutic strategy. To overcome this issue, we proposed to synthesize a pro-drug dendrimer by conjugating the PEGylated, positively charged generation 3-diaminobutyric polypropylenimine dendrimer to the anti-cancer drug camptothecin with a redox-sensitive disulphide linkage, and evaluate its efficacy to co-deliver the complexed DNA and camptothecin to cancer cells. This PEGylated pro-drug dendrimer was found to spontaneously self-assemble into cationic (∼3-5 mV) vesicles at pH 7.4, at a critical aggregation concentration of about 200 μg mL-1. These vesicles (dendrimersomes) became smaller (150-200 nm) with increasing dendrimer concentration and remained stable over 7 days. They were able to release about 70% of the conjugated camptothecin in presence of 50 mM glutathione (equivalent to the intracellular environment of tumor tissue). They could also condense more than 85% of the DNA at dendrimer : DNA weight ratios of 5 : 1 and higher. DNA condensation occurred instantly and was found to be stable for at least 24 h. This led to an enhanced cellular uptake of DNA (by up to 1.6-fold) and increased gene transfection (by up to 2.4-fold) in prostate cancer cells in comparison with the unmodified dendrimer. These novel dendrimersomes are therefore promising for single carrier-based combination cancer therapy.

LanguageEnglish
Pages20058-20071
Number of pages14
JournalNanoscale
Volume11
Issue number42
Early online date15 Oct 2019
DOIs
Publication statusPublished - 14 Nov 2019

Fingerprint

Dendrimers
Camptothecin
Drug delivery
Oxidation-Reduction
Genes
Cells
DNA
Pharmaceutical Preparations
Neoplasms
Prodrugs
Nanomedicine
Medical nanotechnology
Nucleic acids
Therapeutic Uses
Drug Resistance
Disulfides
Nucleic Acids
Transfection
Glutathione
Tumors

Keywords

  • camptothecin
  • PEG
  • dendrimersomes
  • redox responsiveness
  • drug and gene delivery

Cite this

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title = "Camptothecin-based dendrimersomes for gene delivery and redox-responsive drug delivery to cancer cells",
abstract = "Combination therapy involving chemotherapeutic drugs and genes is emerging as a promising strategy to provide a synergistic therapeutic effect, to overcome drug resistance while reducing the severe side effects associated with conventional chemotherapeutic drugs. However, the lack of nanomedicines able to simultaneously carry anti-cancer drugs and nucleic acids limits the application of this therapeutic strategy. To overcome this issue, we proposed to synthesize a pro-drug dendrimer by conjugating the PEGylated, positively charged generation 3-diaminobutyric polypropylenimine dendrimer to the anti-cancer drug camptothecin with a redox-sensitive disulphide linkage, and evaluate its efficacy to co-deliver the complexed DNA and camptothecin to cancer cells. This PEGylated pro-drug dendrimer was found to spontaneously self-assemble into cationic (∼3-5 mV) vesicles at pH 7.4, at a critical aggregation concentration of about 200 μg mL-1. These vesicles (dendrimersomes) became smaller (150-200 nm) with increasing dendrimer concentration and remained stable over 7 days. They were able to release about 70{\%} of the conjugated camptothecin in presence of 50 mM glutathione (equivalent to the intracellular environment of tumor tissue). They could also condense more than 85{\%} of the DNA at dendrimer : DNA weight ratios of 5 : 1 and higher. DNA condensation occurred instantly and was found to be stable for at least 24 h. This led to an enhanced cellular uptake of DNA (by up to 1.6-fold) and increased gene transfection (by up to 2.4-fold) in prostate cancer cells in comparison with the unmodified dendrimer. These novel dendrimersomes are therefore promising for single carrier-based combination cancer therapy.",
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Camptothecin-based dendrimersomes for gene delivery and redox-responsive drug delivery to cancer cells. / Laskar, Partha; Somani, Sukrut; Campbell, Sara Jane; Mullin, Margaret; Keating, Patricia; Tate, Rothwelle J.; Irving, Craig; Leung, Hing Y.; Dufès, Christine.

In: Nanoscale, Vol. 11, No. 42, 14.11.2019, p. 20058-20071.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Camptothecin-based dendrimersomes for gene delivery and redox-responsive drug delivery to cancer cells

AU - Laskar, Partha

AU - Somani, Sukrut

AU - Campbell, Sara Jane

AU - Mullin, Margaret

AU - Keating, Patricia

AU - Tate, Rothwelle J.

AU - Irving, Craig

AU - Leung, Hing Y.

AU - Dufès, Christine

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KW - camptothecin

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KW - redox responsiveness

KW - drug and gene delivery

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