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Int J Nanomedicine. 2017 Jan 10;12:395-410. doi: 10.2147/IJN.S125359. eCollection 2017.

Preparation, cytotoxicity, and in vivo antitumor efficacy of 111In-labeled modular nanotransporters.

Author information

1
Laboratory of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences.
2
Laboratory of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences; Department of Biophysics, Biological Faculty, Lomonosov Moscow State University.
3
Department of Anticancer Therapy Modifiers and Protectors, Moscow Hertsen Research Institute of Oncology, Russian Ministry of Health Care, Moscow.
4
National Medical Research Radiological Center, Russian Ministry of Health Care, Obninsk, Moscow Region; Department of Nuclear Medicine, National Research Nuclear University MEPhI (Moscow Engineering Physics Institute), Moscow, Russia.
5
Department of Radiology, Duke University Medical Center, Durham, NC, USA.

Abstract

PURPOSE:

Modular nanotransporters (MNTs) are a polyfunctional platform designed to achieve receptor-specific delivery of short-range therapeutics into the cell nucleus by receptor-mediated endocytosis, endosome escape, and targeted nuclear transport. This study evaluated the potential utility of the MNT platform in tandem with Auger electron emitting 111In for cancer therapy.

METHODS:

Three MNTs developed to target either melanocortin receptor-1 (MC1R), folate receptor (FR), or epidermal growth factor receptor (EGFR) that are overexpressed on cancer cells were modified with p-SCN-Bn-NOTA and then labeled with 111In in high specific activity. Cytotoxicity of the 111In-labeled MNTs was evaluated on cancer cell lines bearing the appropriate receptor target (FR: HeLa, SK-OV-3; EGFR: A431, U87MG.wtEGFR; and MC1R: B16-F1). In vivo micro-single-photon emission computed tomography/computed tomography imaging and antitumor efficacy studies were performed with intratumoral injection of MC1R-targeted 111In-labeled MNT in B16-F1 melanoma tumor-bearing mice.

RESULTS:

The three NOTA-MNT conjugates were labeled with a specific activity of 2.7 GBq/mg with nearly 100% yield, allowing use without subsequent purification. The cytotoxicity of 111In delivered by these MNTs was greatly enhanced on receptor-expressing cancer cells compared with 111In nontargeted control. In mice with B16-F1 tumors, prolonged retention of 111In by serial imaging and significant tumor growth delay (82% growth inhibition) were found.

CONCLUSION:

The specific in vitro cytotoxicity, prolonged tumor retention, and therapeutic efficacy of MC1R-targeted 111In-NOTA-MNT suggest that this Auger electron emitting conjugate warrants further evaluation as a locally delivered radiotherapeutic, such as for ocular melanoma brachytherapy. Moreover, the high cytotoxicity observed with FR- and EGFR-targeted 111In-NOTA-MNT suggests further applications of the MNT delivery strategy should be explored.

KEYWORDS:

Auger electrons; cancer; melanoma; nuclear delivery; radionuclide therapy

PMID:
28138237
PMCID:
PMC5238804
DOI:
10.2147/IJN.S125359
[Indexed for MEDLINE]
Free PMC Article

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