Dataset Information

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.

SUBMITTER: Song L

PROVIDER: S-EPMC5646733 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

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

Song Lei L Able Sarah S Johnson Errin E Vallis Katherine A KA

Nanotheranostics 20170608 3

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 ...[more]

PMID: 29071190

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Project description:Overexpression of G protein-coupled receptors (GPCRs) in tumours is widely used to develop GPCR-targeting radioligands for solid tumour imaging in the context of diagnosis and even treatment. The human vasoactive neuropeptide urotensin II (hUII), which shares structural analogies with somatostatin, interacts with a single high affinity GPCR named UT. High expression of UT has been reported in several types of human solid tumours from lung, gut, prostate, or breast, suggesting that UT is a valuable novel target to design radiolabelled hUII analogues for cancer diagnosis. In this study, two original urotensinergic analogues were first conjugated to a DOTA chelator via an aminohexanoic acid (Ahx) hydrocarbon linker and then -hUII and DOTA-urantide, complexed to the radioactive metal indium isotope to successfully lead to radiolabelled DOTA-Ahx-hUII and DOTA-Ahx-urantide. The 111In-DOTA-hUII in human plasma revealed that only 30% of the radioligand was degraded after a 3-h period. DOTA-hUII and DOTA-urantide exhibited similar binding affinities as native peptides and relayed calcium mobilization in HEK293 cells expressing recombinant human UT. DOTA-hUII, not DOTA-urantide, was able to promote UT internalization in UT-expressing HEK293 cells, thus indicating that radiolabelled 111In-DOTA-hUII would allow sufficient retention of radioactivity within tumour cells or radiolabelled DOTA-urantide may lead to a persistent binding on UT at the plasma membrane. The potential of these radioligands as candidates to target UT was investigated in adenocarcinoma. We showed that hUII stimulated the migration and proliferation of both human lung A549 and colorectal DLD-1 adenocarcinoma cell lines endogenously expressing UT. In vivo intravenous injection of 111In-DOTA-hUII in C57BL/6 mice revealed modest organ signals, with important retention in kidney. 111In-DOTA-hUII or 111In-DOTA-urantide were also injected in nude mice bearing heterotopic xenografts of lung A549 cells or colorectal DLD-1 cells both expressing UT. The observed significant renal uptake and low tumour/muscle ratio (around 2.5) suggest fast tracer clearance from the organism. Together, DOTA-hUII and DOTA-urantide were successfully radiolabelled with 111Indium, the first one functioning as a UT agonist and the second one as a UT-biased ligand/antagonist. To allow tumour-specific targeting and prolong body distribution in preclinical models bearing some solid tumours, these radiolabelled urotensinergic analogues should be optimized for being used as potential molecular tools for diagnosis imaging or even treatment tools.

Dataset Information

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

Publications

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

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Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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