Accumulation of ¹¹¹In-Labelled EGF-Au-PEG Nanoparticles in EGFR-Positive Tumours is Enhanced by Coadministration of Targeting Ligand

Abstract

The successful use of targeted radionuclide therapy in the treatment of solid tumours may be limited by radioresistance, which necessitates delivery of a high dose of radioactivity. Nanoparticle (NP)-based delivery systems possess a large surface area for attachment of radioisotopes and so offer a solution to this challenge. However, tumour uptake may be limited by rapid hepatic clearance of NP via the mononuclear phagocyte system. Liver uptake is further compounded when epidermal growth factor (EGF) is used as a targeting ligand, as EGF-tagged NP bind the EGF receptor (EGFR), which is expressed to a moderate extent by hepatocytes. This report describes an indium-111 (111In)-labelled PEGylated EGF-tagged gold (Au) NP (111In-EGF-Au-PEG) and an effective strategy of coadministration of targeting ligand to address these issues. Direct attachment of EGF to the surface of Au NP did not compromise surface coating with long-chain PEG. In vitro experiments showed that 111In-EGF-Au-PEG targets EGFR-positive cancer cells (MDA-MB-468): >11% of radioactivity was internalised after incubation for 4 h. In in vivo studies accumulation of NP was observed in MDA-MB-468 xenografts and tumour uptake was enhanced by the coadministration of 15 µg of the unlabelled targeting ligand, EGF, to block hepatic EGFR. Uptake was 3.9% versus 2.8% injected dose/g (%ID/g) of tumour tissue with and without unlabelled EGF, respectively. Coadministration of EGF reduced liver uptake by 25.95% to 7.56 %ID/g. This suggests that the coadministration of unlabelled targeting ligand with radiolabelled PEGylated NP offers a promising strategy for targeting EGFR-positive cancer and for minimising liver uptake.

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

“…Moreover, the inclusion of low dose methotrexate, a dihydrofolate reductase inhibitor and potent radiosensitiser, significantly enhanced cell killing. Similar to block copolymer micelles developed by Fonge et al 19 and our previous work employing 111 In-hEGF-labelled gold nanoparticles, 21 , 22 111 In-hEGF-PLGA nanoparticles described in the current study demonstrate substantial radiotoxicity towards p53-deficient EGFR-overexpressing cancer cells. Notably, radiotoxicity occurs with clear evidence of DNA damage induction, observable by strong activation of DDR signalling, despite the modest extent of nuclear localisation of 111 In.…”

“… 16 – 23 The single-photon emission computed tomography (SPECT) imaging capability of 111 In provides a means of direct visualisation of nanoparticle accumulation in vivo , thereby indicating the potential of 111 In-conjugates as theranostics. 22 , 23 …”

Auger electrons for cancer therapy – a review

“…Surface coating of nanoparticles with polyethylene glycol (PEG) can reduce MPS recognition. Song et al constructed 111 In-labelled PEGylated AuNPs modified with EGF to target EGFR for AE radiotherapy (Song et al 2017). In mice with EGFR-positive MDA-MB-468 xenografts, liver uptake of i.v.…”

Uptake and subcellular distribution of radiolabeled polymersomes for radiotherapy

“…In addition, recent work highlights the need for active targeting of PMs, especially in the presence of a tumour [60]. This could possibly change the uptake and processing dynamics of PMs, both in vitro and in vivo [61][62][63].…”