Development of 177Lu-DN(C19)-CXCR4 Ligand Nanosystem for Combinatorial Therapy in Pancreatic Cancer

J Biomed Nanotechnol. 2021 Feb 28;17(2):263-278. doi: 10.1166/jbn.2021.3016.

Abstract

Pancreatic cancer is highly lethal and has a poor prognosis. The most common alteration during the formation of pancreatic tumors is the activation of KRAS (Kirsten rat sarcoma 2 viral oncogene homolog) oncogene. As a new therapeutic strategy, the C19 molecule ((2S)-N-(2,5-dichlorophenyl)-2-[(3,4-dimethoxyphenyl)-methylamine]propanamide) blocks the KRAS-membrane association in cancer cells. In addition, the chemokine receptor CXCR4 is overexpressed in pancreatic cancer. In this research, a new dendrimer-based nanoradiopharmaceutical (177Lu-DN(C19)-CXCR4L) encapsulating C19 and functionalized to target CXCR4 receptors is proposed as both, a targeted radiotherapy system (lutetium-177) and an oncotherapeutic approach by the stabilization of KRAS4b-PDESδ complex to produce dual-specific therapy in pancreatic cancer. 177The Lu-DN(C19)-CXCR4L was synthesized and characterized, C19 was encapsulated with 81% efficiency, the final nanosystem rendered a particle size of 67 nm and the specific uptake in pancreatic cell lines was demonstrated. The major cytotoxic effect was observed in the KRAS-dependent and radioresistant cell line Mia PaCa-2, which expresses a high density of CXCR4 receptors. The radiation dose of 3 Gy/Bq decreased viability to 7%, and this effect was attributed to the presence of C19. A synergistic effect (radio and chemotherapy) capable of reducing viability in pancreatic cancer cells through apoptotic mechanisms was demonstrated. Thus, 177Lu-DN(C19)-CXCR4L nanoradiopharmaceutical is efficacious in pancreatic cancer cell lines overexpressing the CXCR4 receptor.

MeSH terms

  • Cell Line, Tumor
  • Humans
  • Ligands
  • Pancreatic Neoplasms* / drug therapy
  • Pancreatic Neoplasms* / genetics
  • Receptors, CXCR4* / genetics
  • Signal Transduction

Substances

  • CXCR4 protein, human
  • Ligands
  • Receptors, CXCR4