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

Laskar, P., Somani, S., Campbell, S. J., Mullin, M., Keating, P., Tate, R. J., Irving, C., Leung, H. Y. and Dufès, C. (2019) Camptothecin-based dendrimersomes for gene delivery and redox-responsive drug delivery to cancer cells. Nanoscale, 11(42), pp. 20058-20071. (doi: 10.1039/C9NR07254C) (PMID:31612185)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Mullin, Mrs Margaret
• Authors: Laskar, P., Somani, S., Campbell, S. J., Mullin, M., Keating, P., Tate, R. J., Irving, C., Leung, H. Y., and Dufès, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Nanoscale
• Publisher: Royal Society of Chemistry
• ISSN: 2040-3364
• ISSN (Online): 2040-3372
• Published Online: 15 October 2019
• Copyright Holders: Copyright © 2019 The Royal Society of Chemistry
• First Published: First published in Nanoscale 11(42): 20058-20071
• Publisher Policy: Reproduced in accordance with the publisher copyright policy