title: Preparation, cytotoxicity, and in vivo antitumor efficacy of111In-labeled modular nanotransporters.
abstract: OBJECTIVE
  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 emitting111In 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 with111In in high specific activity. Cytotoxicity of the111In-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-targeted111In-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 of111In delivered by these MNTs was greatly enhanced on receptor-expressing cancer cells compared with111In nontargeted control. In mice with B16-F1 tumors, prolonged retention of111In by serial imaging and significant tumor growth delay (82% growth inhibition) were found.
  
  
  CONCLUSIONS
  The specific in vitro cytotoxicity, prolonged tumor retention, and therapeutic efficacy of MC1R-targeted111In-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-targeted111In-NOTA-MNT suggests further applications of the MNT delivery strategy should be explored.
authors.affiliation: Laboratory of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences.
authors.forename: Tatiana A
authors.initials: TA
authors.lastname: Slastnikova
authors.affiliation: Laboratory of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences; Department of Biophysics, Biological Faculty, Lomonosov Moscow State University.
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Rosenkranz
authors.affiliation: Department of Anticancer Therapy Modifiers and Protectors, Moscow Hertsen Research Institute of Oncology, Russian Ministry of Health Care, Moscow.
authors.forename: Natalia B
authors.initials: NB
authors.lastname: Morozova
authors.affiliation: Department of Anticancer Therapy Modifiers and Protectors, Moscow Hertsen Research Institute of Oncology, Russian Ministry of Health Care, Moscow.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Vorontsova
authors.affiliation: 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.
authors.forename: Vasiliy M
authors.initials: VM
authors.lastname: Petriev
authors.affiliation: Laboratory of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences.
authors.forename: Tatiana N
authors.initials: TN
authors.lastname: Lupanova
authors.affiliation: Laboratory of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences.
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Ulasov
authors.affiliation: Department of Radiology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zalutsky
authors.affiliation: Department of Anticancer Therapy Modifiers and Protectors, Moscow Hertsen Research Institute of Oncology, Russian Ministry of Health Care, Moscow.
authors.forename: Raisa I
authors.initials: RI
authors.lastname: Yakubovskaya
authors.affiliation: Laboratory of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences; Department of Biophysics, Biological Faculty, Lomonosov Moscow State University.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Sobolev
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001345:Autoradiography; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004591:Electrophoresis, Polyacrylamide Gel; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D058973:Folate Receptors, GPI-Anchored / Q000378:metabolism; D006801:Humans; D007205:Indium Radioisotopes / Q000737:chemistry*; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology; D008546:Melanoma, Experimental / Q000473:pathology; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry*; D044101:Receptors, Melanocortin / Q000378:metabolism; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed
chemical_list: D000970:Antineoplastic Agents; D058973:Folate Receptors, GPI-Anchored; D007205:Indium Radioisotopes; D044101:Receptors, Melanocortin; D009074:Melanocyte-Stimulating Hormones; D066246:ErbB Receptors
keywords: Auger electrons; cancer; melanoma; nuclear delivery; radionuclide therapy