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111In-labelled polymeric nanoparticles incorporating a ruthenium-based radiosensitizer for EGFR-targeted combination therapy in oesophageal cancer cells

Martin Gill Orcid Logo, Jyothi U. Menon, Paul J. Jarman, Joshua Owen, Irini Skaripa-Koukelli, Sarah Able, Jim A. Thomas, Robert Carlisle, Katherine A. Vallis

Nanoscale, Volume: 10, Issue: 22, Pages: 10596 - 10608

Swansea University Author: Martin Gill Orcid Logo

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DOI (Published version): 10.1039/c7nr09606b

Abstract

Radiolabelled, drug-loaded nanoparticles may combine the theranostic properties of radionuclides, the controlled release of chemotherapy and cancer cell targeting. Here, we report the preparation of poly(lactic-co-glycolic acid) (PLGA) nanoparticles surface conjugated to DTPA-hEGF (DTPA = diethylene...

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Published in: Nanoscale
ISSN: 2040-3364 2040-3372
Published: Royal Society of Chemistry (RSC) 2018
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa52924
Abstract: Radiolabelled, drug-loaded nanoparticles may combine the theranostic properties of radionuclides, the controlled release of chemotherapy and cancer cell targeting. Here, we report the preparation of poly(lactic-co-glycolic acid) (PLGA) nanoparticles surface conjugated to DTPA-hEGF (DTPA = diethylenetriaminepentaacetic acid, hEGF = human epidermal growth factor) and encapsulating the ruthenium-based DNA replication inhibitor and radiosensitizer Ru(phen)2(tpphz)2+ (phen = 1,10-phenanthroline, tpphz = tetrapyridophenazine) Ru1. The functionalized PLGA surface incorporates the metal ion chelator DTPA for radiolabelling and the targeting ligand for EGF receptor (EGFR). Nanoparticles radiolabelled with 111In are taken up preferentially by EGFR-overexpressing oesophageal cancer cells, where they exhibit radiotoxicity through the generation of cellular DNA damage. Moreover, nanoparticle co-delivery of Ru1 alongside 111In results in decreased cell survival compared to single-agent formulations; an effect that occurs through DNA damage enhancement and an additive relationship between 111In and Ru1. Substantially decreased uptake and radiotoxicity of nanoparticles towards normal human fibroblasts and oesophageal cancer cells with normal EGFR levels is observed. This work demonstrates nanoparticle co-delivery of a therapeutic radionuclide plus a ruthenium-based radiosensitizer can achieve combinational and targeted therapeutic effects in cancer cells that overexpress EGFR.
College: Faculty of Science and Engineering
Funders: M. R. G. and K. A. V. received financial support from Cancer Research UK (C5255/A15935), the Medical Research Council (MC_PC_12004) and a Medical Research Council Confidence in Concept award. K. A. V., J. O., I. S. K., R. C. and J. U. M. received support from the Engineering and Physical Sciences Research Council (EP/L024012/1). We thank P. Holdship and F. Larner for ICP-MS analysis, and G. Brown and V. Kersemans for assistance.
Issue: 22
Start Page: 10596
End Page: 10608

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