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

Laskar, Partha and Somani, Sukrut and Campbell, Sara Jane and Mullin, Margaret and Keating, Patricia and Tate, Rothwelle J. and Irving, Craig and Leung, Hing Y. and Dufès, Christine (2019) Camptothecin-based dendrimersomes for gene delivery and redox-responsive drug delivery to cancer cells. Nanoscale, 11 (42). pp. 20058-20071. ISSN 2040-3372 (https://doi.org/10.1039/c9nr07254c)

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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.

ORCID iDs

Laskar, Partha, Somani, Sukrut ORCID logoORCID: https://orcid.org/0000-0002-0697-1110, Campbell, Sara Jane, Mullin, Margaret, Keating, Patricia, Tate, Rothwelle J., Irving, Craig, Leung, Hing Y. and Dufès, Christine ORCID logoORCID: https://orcid.org/0000-0002-7963-6364;
CORE (COnnecting REpositories)