Journal
NANOSCALE
Volume 10, Issue 22, Pages 10596-10608Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c7nr09606b
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Funding
- Cancer Research UK [C5255/A15935]
- Medical Research Council [MC_PC_12004]
- Medical Research Council
- Engineering and Physical Sciences Research Council [EP/L024012/1]
- Engineering and Physical Sciences Research Council [EP/M015572/1] Funding Source: researchfish
- EPSRC [EP/M015572/1, EP/L024012/1] Funding Source: UKRI
- MRC [MC_PC_15029, MC_PC_12020] Funding Source: UKRI
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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 = diethyl-enetriaminepentaacetic 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 In-111 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 In-111 results in decreased cell survival compared to single-agent formulations; an effect that occurs through DNA damage enhancement and an additive relationship between In-111 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.
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