Development and evaluation of a new modular nanotransporter for drug delivery into nuclei of pathological cells expressing folate receptors

Drug Des Devel Ther. 2017 Apr 26;11:1315-1334. doi: 10.2147/DDDT.S127270. eCollection 2017.


Purpose: Modular nanotransporters (MNTs) are artificial multifunctional systems designed to facilitate receptor-specific transport from the cell surface into the cell nucleus through inclusion of polypeptide domains for accomplishing receptor binding and internalization, as well as sequential endosomal escape and nuclear translocation. The objective of this study was to develop a new MNT targeted at folate receptors (FRs) for precise delivery of therapeutic cargo to the nuclei of FR-positive cells and to evaluate its potential, particularly for delivery of therapeutic agents (eg, the Auger electron emitter 111In) into the nuclei of target cancer cells.

Methods: A FR-targeted MNT was developed by site-specific derivatization of ligand-free MNT with maleimide-polyethylene glycol-folic acid. The ability of FR-targeted MNT to accumulate in target FR-expressing cells was evaluated using flow cytometry, and intracellular localization of this MNT was assessed using confocal laser scanning microscopy of cells. The cytotoxicity of the 111In-labeled FR-targeted MNT was evaluated on HeLa and U87MG cancer cell lines expressing FR. In vivo micro-single-photon emission computed tomography/CT imaging and antitumor efficacy studies were performed with intratumoral injection of 111In-labeled FR-targeted MNT in HeLa xenograft-bearing mice.

Results: The resulting FR-targeted MNT accumulated in FR-positive HeLa cancer cell lines specifically and demonstrated the ability to reach its target destination - the cell nuclei. 111In-labeled FR-targeted MNT demonstrated efficient and specific FR-positive cancer cell eradication. A HeLa xenograft in vivo model revealed prolonged retention of 111In delivered by FR-targeted MNT and significant tumor growth delay (up to 80% growth inhibition).

Conclusion: The FR-targeted MNT met expectations of its ability to deliver active cargo into the nuclei of target FR-positive cells efficiently and specifically. As a result of this finding the new FR-targeted MNT approach warrants broad evaluation.

Keywords: cancer; folic acid; indium-111; nuclear delivery; radionuclide therapy.

MeSH terms

  • Animals
  • Cell Nucleus / metabolism*
  • Cell Proliferation / drug effects
  • Drug Carriers / chemistry
  • Drug Delivery Systems*
  • Female
  • Folic Acid / metabolism
  • Folic Acid Transporters / metabolism*
  • HeLa Cells
  • Humans
  • Indium Radioisotopes
  • Maleimides / chemistry
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Nanostructures / chemistry*
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / metabolism*
  • Neoplasms, Experimental / pathology*
  • Polyethylene Glycols / chemistry
  • Tumor Cells, Cultured


  • Drug Carriers
  • Folic Acid Transporters
  • Indium Radioisotopes
  • Maleimides
  • maleimide
  • Polyethylene Glycols
  • Folic Acid