Preparation, cytotoxicity, and in vivo antitumor efficacy of 111In-labeled modular nanotransporters
Tatiana A Slastnikova,1,* Andrey A Rosenkranz,1,2,* Natalia B Morozova,3 Maria S Vorontsova,3 Vasiliy M Petriev,4,5 Tatiana N Lupanova,1 Alexey V Ulasov,1 Michael R Zalutsky,6 Raisa I Yakubovskaya,3 Alexander S Sobolev1,2 1Laboratory of Molecular Genetics of Intracellular Transport, Institute of Ge...
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Dove Medical Press
2017
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oai:doaj.org-article:248aafe2b25849bcb187121a97781a272021-12-02T00:09:56ZPreparation, cytotoxicity, and in vivo antitumor efficacy of 111In-labeled modular nanotransporters1178-2013https://doaj.org/article/248aafe2b25849bcb187121a97781a272017-01-01T00:00:00Zhttps://www.dovepress.com/preparation-cytotoxicity-and-in-vivo-antitumor-efficacy-of-111in-label-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Tatiana A Slastnikova,1,* Andrey A Rosenkranz,1,2,* Natalia B Morozova,3 Maria S Vorontsova,3 Vasiliy M Petriev,4,5 Tatiana N Lupanova,1 Alexey V Ulasov,1 Michael R Zalutsky,6 Raisa I Yakubovskaya,3 Alexander S Sobolev1,2 1Laboratory of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences, 2Department of Biophysics, Biological Faculty, Lomonosov Moscow State University, 3Department of Anticancer Therapy Modifiers and Protectors, Moscow Hertsen Research Institute of Oncology, Russian Ministry of Health Care, Moscow, 4National Medical Research Radiological Center, Russian Ministry of Health Care, Obninsk, Moscow Region, 5Department of Nuclear Medicine, National Research Nuclear University MEPhI (Moscow Engineering Physics Institute), Moscow, Russia; 6Department of Radiology, Duke University Medical Center, Durham, NC, USA *These authors contributed equally to this work 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: nuclear delivery, cancer, melanoma, radionuclide therapy, Auger electronsSlastnikova TARosenkranz AAMorozova NBVorontsova MSPetriev VMLupanova TNUlasov AVZalutsky MRYakubovskaya RISobolev ASDove Medical Pressarticlenuclear deliverycancermelanomaradionuclide therapyAuger electronsMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 12, Pp 395-410 (2017) |
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DOAJ |
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EN |
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nuclear delivery cancer melanoma radionuclide therapy Auger electrons Medicine (General) R5-920 |
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nuclear delivery cancer melanoma radionuclide therapy Auger electrons Medicine (General) R5-920 Slastnikova TA Rosenkranz AA Morozova NB Vorontsova MS Petriev VM Lupanova TN Ulasov AV Zalutsky MR Yakubovskaya RI Sobolev AS Preparation, cytotoxicity, and in vivo antitumor efficacy of 111In-labeled modular nanotransporters |
| description |
Tatiana A Slastnikova,1,* Andrey A Rosenkranz,1,2,* Natalia B Morozova,3 Maria S Vorontsova,3 Vasiliy M Petriev,4,5 Tatiana N Lupanova,1 Alexey V Ulasov,1 Michael R Zalutsky,6 Raisa I Yakubovskaya,3 Alexander S Sobolev1,2 1Laboratory of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences, 2Department of Biophysics, Biological Faculty, Lomonosov Moscow State University, 3Department of Anticancer Therapy Modifiers and Protectors, Moscow Hertsen Research Institute of Oncology, Russian Ministry of Health Care, Moscow, 4National Medical Research Radiological Center, Russian Ministry of Health Care, Obninsk, Moscow Region, 5Department of Nuclear Medicine, National Research Nuclear University MEPhI (Moscow Engineering Physics Institute), Moscow, Russia; 6Department of Radiology, Duke University Medical Center, Durham, NC, USA *These authors contributed equally to this work 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: nuclear delivery, cancer, melanoma, radionuclide therapy, Auger electrons |
| format |
article |
| author |
Slastnikova TA Rosenkranz AA Morozova NB Vorontsova MS Petriev VM Lupanova TN Ulasov AV Zalutsky MR Yakubovskaya RI Sobolev AS |
| author_facet |
Slastnikova TA Rosenkranz AA Morozova NB Vorontsova MS Petriev VM Lupanova TN Ulasov AV Zalutsky MR Yakubovskaya RI Sobolev AS |
| author_sort |
Slastnikova TA |
| title |
Preparation, cytotoxicity, and in vivo antitumor efficacy of 111In-labeled modular nanotransporters |
| title_short |
Preparation, cytotoxicity, and in vivo antitumor efficacy of 111In-labeled modular nanotransporters |
| title_full |
Preparation, cytotoxicity, and in vivo antitumor efficacy of 111In-labeled modular nanotransporters |
| title_fullStr |
Preparation, cytotoxicity, and in vivo antitumor efficacy of 111In-labeled modular nanotransporters |
| title_full_unstemmed |
Preparation, cytotoxicity, and in vivo antitumor efficacy of 111In-labeled modular nanotransporters |
| title_sort |
preparation, cytotoxicity, and in vivo antitumor efficacy of 111in-labeled modular nanotransporters |
| publisher |
Dove Medical Press |
| publishDate |
2017 |
| url |
https://doaj.org/article/248aafe2b25849bcb187121a97781a27 |
| work_keys_str_mv |
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1718403914171154432 |