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

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

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.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Autoradiography
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Electrophoresis, Polyacrylamide Gel
  • ErbB Receptors / metabolism
  • Female
  • Folate Receptors, GPI-Anchored / metabolism
  • Humans
  • Indium Radioisotopes / chemistry*
  • Melanocyte-Stimulating Hormones / pharmacology
  • Melanoma, Experimental / pathology
  • Mice, Inbred C57BL
  • Nanoparticles / chemistry*
  • Receptors, Melanocortin / metabolism
  • Tomography, Emission-Computed, Single-Photon
  • Tomography, X-Ray Computed

Substances

  • Antineoplastic Agents
  • Folate Receptors, GPI-Anchored
  • Indium Radioisotopes
  • Receptors, Melanocortin
  • Melanocyte-Stimulating Hormones
  • ErbB Receptors