Modular nanotransporters: a versatile approach for enhancing nuclear delivery and cytotoxicity of Auger electron-emitting 125IReport as inadecuate




Modular nanotransporters: a versatile approach for enhancing nuclear delivery and cytotoxicity of Auger electron-emitting 125I - Download this document for free, or read online. Document in PDF available to download.

EJNMMI Research

, 2:59

First Online: 29 October 2012Received: 14 July 2012Accepted: 02 October 2012

Abstract

BackgroundThis study evaluates the potential utility of a modular nanotransporter MNT for enhancing the nuclear delivery and cytotoxicity of the Auger electron emitter I in cancer cells that overexpress the epidermal growth factor receptor EGFR.

MethodsMNTs are recombinant multifunctional polypeptides that we have developed for achieving selective delivery of short-range therapeutics into cancer cells. MNTs contain functional modules for receptor binding, internalization, endosomal escape and nuclear translocation, thereby facilitating the transport of drugs from the cell surface to the nucleus. The MNT described herein utilized EGF as the targeting ligand and was labeled with I using N-succinimidyl-4-guanidinomethyl-3-Iiodobenzoate SGMIB. Membrane binding, intracellular and nuclear accumulation kinetics, and clonogenic survival assays were performed using the EGFR-expressing A431 epidermoid carcinoma and D247 MG glioma cell lines.

ResultsISGMIB-MNT bound to A431 and D247 MG cells with an affinity comparable to that of native EGF. More than 60% of internalized ISGMIB-MNT radioactivity accumulated in the cell nuclei after a 1-h incubation. The cytotoxic effectiveness of ISGMIB-MNT compared with I-labeled bovine serum albumin control was enhanced by a factor of 60 for D247 MG cells and more than 1,000-fold for A431 cells, which express higher levels of EGFR.

ConclusionsMNT can be utilized to deliver I into the nuclei of cancer cells overexpressing EGFR, significantly enhancing cytotoxicity. Further evaluation of ISGMIB-MNT as a targeted radiotherapeutic for EGFR-expressing cancer cells appears warranted.

KeywordsModular nanotransporters Auger radiotherapy Iodine-125 Targeted delivery EGFR AbbreviationsBSABovine serum albumin

CPMCounts per minute

DPBSDulbecco-s phosphate-buffered saline

DPMDecays per minute

DTPADiethylenetriaminepentaacetic acid

DToxTranslocation domain of diphtheria toxin

EGFEpidermal growth factor

EGFREpidermal growth factor receptor

HDAC-1Histone deacetylase 1

HMPE. coli hemoglobin-like protein

IUdR5-Iiodo-2-deoxyuridine

MNTModular nanotransporter

NLSNuclear localization sequence

SGMIBN-succinimidyl-4-guanidinomethyl-3-Iiodobenzoate.

Electronic supplementary materialThe online version of this article doi:10.1186-2191-219X-2-59 contains supplementary material, which is available to authorized users.

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Author: Tatiana A Slastnikova - Eftychia Koumarianou - Andrey A Rosenkranz - Ganesan Vaidyanathan - Tatiana N Lupanova - Alexander

Source: https://link.springer.com/







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