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.
Highlights
Oesophageal cancer is an aggressive and highly lethal form of cancer.[1]
Transmission electron microscopy (TEM) confirmed Ru1-loading within the PLGA core, as direct visualisation of the complex due to the electron-dense ruthenium is evident by this technique (Fig. 1a)
These results indicated Ru content in nanoparticle-treated cells was approximately 1.5-fold higher in OE21 cells compared to OE33; a result in agreement with radioactivity data above (Fig. 2b). These results indicated the amount of Ru detected was lower than cells treated with an equivalent concentration of free Ru1. This finding may be explained by relatively low loading of Ru1 within PLGA, a common outcome for hydrophilic compounds,[24] and different uptake pathways: PLGA nanoparticles are thought to be internalised primarily by endocytosis[48] while a non-endocytic mechanism of active transport has been indicated for Ru1.49 as Ru1 is an metal to ligand charge transfer (MLCT) “light switch” complex that demonstrates a large increase in emission intensity when bound to DNA, we examined nanoparticle-treated cells by confocal laser scanning microscopy
Summary
Oesophageal cancer is an aggressive and highly lethal form of cancer.[1]. Current non-surgical treatments are based on the use of radiotherapy in combination with cisplatin DNA-damaging chemotherapy, usually alongside the antimetabolite fluorouracil (5FU). There remains an urgent need to develop new therapeutics active towards EGFRoverexpressing oesophageal cancers
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