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Multi-component bioresponsive nanoparticles for synchronous delivery of docetaxel and TUBB3 siRNA to lung cancer cells

Conte, Claudia; Monteiro, Patricia; Gurnani, Pratik; Stolnik, Snow; Ungaro, Francesca; Quaglia, Fabiana; Clarke, Philip; Grabowska, Anna; Kavallaris, Maria; Alexander, Cameron

Multi-component bioresponsive nanoparticles for synchronous delivery of docetaxel and TUBB3 siRNA to lung cancer cells Thumbnail


Authors

Claudia Conte

Patricia Monteiro

Pratik Gurnani

Snow Stolnik

Francesca Ungaro

Fabiana Quaglia

Philip Clarke

ANNA GRABOWSKA ANNA.GRABOWSKA@NOTTINGHAM.AC.UK
Professor of Cancer Microenvironment

Maria Kavallaris



Abstract

Bioresponsive nanoparticles (NPs) are of interest for anticancer nanomedicines, owing to the possibility to ‘design in’ selective modulation of drug release at target sites. Here we describe the double emulsion formulation of redox-responsive NPs based on modified polyethylene glycol (PEG)-co-poly(lactic-co-glycolic acid) (PLGA) block copolymers and oligo (β-aminoesters) (OBAE), both of which contained disulfide linkages, for the co-delivery of a cytotoxic small molecule drug and a nucleic acid. In particular, we focused our attention on docetaxel (DTX) and a siRNA against TUBB3, a gene that encodes for βIII-tubulin, in order to have a synergistic effect in the treatment of lung cancer. Spherical NPs of around 150 nm with negative zeta potential and high loading efficiencies of both drugs were obtained. Stability and release studies showed “on demand” drug release under reducing conditions. Unloaded NPs containing PEG-disulfide-PLGA and OBAE were well-tolerated by lung cancer cells, thus masking the intrinsic cytotoxicity of OBAE, while for intracellular siRNA delivery, redox responsive NPs demonstrated a higher cell internalization with a preferential cytoplasmic accumulation of siRNA, with a subsequent fast gene-silencing efficiency. The viability of cells treated with combined DTX/TUBB3-siRNA NPs significantly decreased as compared to NPs loaded only with DTX, thus showing an efficient combined anticancer effect, due to a substantial reduction of β-tubulin expression. Finally, in an in vivo feasibility study employing an orthotopic lung cancer model, NPs formulated with an anti-luciferase siRNA distributed throughout the lungs following oro-tracheal administration, and demonstrated effective gene knockdown and no apparent cytotoxicity. Taken together, these results show that the double emulsion formulated redox responsive PEG-PLGA and OBAE systems represent a promising new therapeutic approach for the local combined chemo- and gene-therapy of lung cancer.

Citation

Conte, C., Monteiro, P., Gurnani, P., Stolnik, S., Ungaro, F., Quaglia, F., …Alexander, C. (2021). Multi-component bioresponsive nanoparticles for synchronous delivery of docetaxel and TUBB3 siRNA to lung cancer cells. Nanoscale, 13(26), 11414-11426. https://doi.org/10.1039/d1nr02179f

Journal Article Type Article
Acceptance Date May 19, 2021
Online Publication Date Jun 23, 2021
Publication Date Jul 14, 2021
Deposit Date May 21, 2021
Publicly Available Date Mar 28, 2024
Print ISSN 2040-3364
Electronic ISSN 2040-3372
Peer Reviewed Peer Reviewed
Volume 13
Issue 26
Pages 11414-11426
DOI https://doi.org/10.1039/d1nr02179f
Public URL https://nottingham-repository.worktribe.com/output/5564160
Publisher URL https://pubs.rsc.org/en/content/articlelanding/2021/NR/D1NR02179F#!divAbstract

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