Modular nanotransporters: a versatile approach for enhancing nuclear delivery and cytotoxicity of Auger electron-emitting 125I.

Abstract

UNLABELLED: BACKGROUND: This study evaluates the potential utility of a modular nanotransporter (MNT) for enhancing the nuclear delivery and cytotoxicity of the Auger electron emitter 125I in cancer cells that overexpress the epidermal growth factor receptor (EGFR). METHODS: MNTs 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 125I using N-succinimidyl-4-guanidinomethyl-3-[125I]iodobenzoate (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. RESULTS: [125I]SGMIB-MNT bound to A431 and D247 MG cells with an affinity comparable to that of native EGF. More than 60% of internalized [125I]SGMIB-MNT radioactivity accumulated in the cell nuclei after a 1-h incubation. The cytotoxic effectiveness of [125I]SGMIB-MNT compared with 125I-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. CONCLUSIONS: MNT can be utilized to deliver 125I into the nuclei of cancer cells overexpressing EGFR, significantly enhancing cytotoxicity. Further evaluation of [125I]SGMIB-MNT as a targeted radiotherapeutic for EGFR-expressing cancer cells appears warranted.

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Published Version (Please cite this version)

10.1186/2191-219X-2-59

Publication Info

Slastnikova, Tatiana A, Eftychia Koumarianou, Andrey A Rosenkranz, Ganesan Vaidyanathan, Tatiana N Lupanova, Alexander S Sobolev and Michael R Zalutsky (2012). Modular nanotransporters: a versatile approach for enhancing nuclear delivery and cytotoxicity of Auger electron-emitting 125I. EJNMMI Res, 2(1). p. 59. 10.1186/2191-219X-2-59 Retrieved from https://hdl.handle.net/10161/11046.

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Vaidyanathan

Ganesan Vaidyanathan

Professor Emeritus in Radiology

Dr. Vaidyanathan is a professor in the Department of Radiology.  He is a member of the Nuclear Medicine track of the Medical Physics Graduate Program.  His research involves development of radiopharmaceuticals especially for oncologic applications.  Some of the projects he is involved in are given below.

I.          New methods of radiohalogenating antibodies and its variants 

a) Development of newer residualizing agents for the radiohalogenation of internalizing monoclonal antibodies.

b)  Development of fluorine-18 labeled residualizing agents for labeling nanobodies.

c) Pre-targeting approach via bioorthogonal chemistry for in vivo labeling of antibodies and nanobodies with 18F and 211At.

d)  Methods to label antibodies pre-conjugated with a prosthetic group of the tin precursor of residualizing agents.

e) Multimodal prosthetic groups for labeling antibodies and peptides with multiple radioisotopes.

II.         MIBG Analogs for PET imaging

Radioiodinated MIBG is used in the diagnosis of the pathophysiology of the heart as well as neuroendocrine tumors such as neuroblastoma (NB).  Design and development of newer fluorine-18 labeled MIBG analogues useful in the PET imaging of NB as well as that of myocardial diseases.

III. Noninvasive Imaging of Alkylguanine-DNA alkyltransferase (AGT) 

AGT is a DNA repair protein and is primarily responsible for drug resistance in alkylator chemotherapy. An inverse correlation has been established between the tumor AGT content and the therapeutic outcome. The amount of AGT varies from tumor to tumor and within a group of patients of similar cancer. Thus, it is important to quantify tumor AGT of individual patients before administering alkylator chemotherapy. Our goal is to develop radiolabeled agents with which AGT can be quantified in a noninvasive manner by PET or SPECT imaging. 

IV. PSMA targeting for prostate cancer therapy 

Development of At-211 labeled urea-based inhibitor of Prostate-specific membrane antigen.

Zalutsky

Michael Rod Zalutsky

Jonathan Spicehandler, M.D. Distinguished Professor of Neuro Oncology, in the School of Medicine

The overall objective of our laboratory is the development of novel radioactive compounds for improving the diagnosis and treatment of cancer. This work primarily involves radiohalo-genation of biomolecules via site-specific approaches, generally via demetallation reactions. Radionuclides utilized for imaging include I-123, I-124 and F-18, the later two being of particular interest because they can be used for the quantification of biochemical and physiological processes in the living human through positron emission tomography. For therapy, astatine-211 decays by the emission of alpha-particles, a type of radiation considerably more cytotoxic that the beta-particles used in conventional endoradiotherapy. The range of At-211 alpha particles is only a few cell diameters, offering the possibility of extremely focal irradiation of malignant cells while leaving neighboring cells intact. Highlights of recent work include: a)
development of reagents for protein and peptide radioiodination that decrease deiodination in vivo by up to 100-fold, b) demonstration that At-211 labeled monoclonal antibodies are effective in the treatment of a rat model of neoplastic meningitis, c) synthesis of a thymidine analogue labeled with At-211 and the demonstration that this molecule is taken up in cellular DNA with highly cytotoxicity even at levels of only one atom bound per cell and d) development of
radiohalobenzylguanidines which are specifically cytotoxic for human neuroblastoma cells.


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