Development of 177Lu-DN(C19)-CXCR4 Ligand Nanosystem for Combinatorial Therapy in Pancreatic Cancer
Por:
Trujillo-Nolasco M., Cruz-Nova P., Ferro-Flores G., Gibbens-Bandala B., Morales-Avila E., Aranda-Lara L., Vargas M., Ocampo-García B.
Publicada:
1 ene 2021
Resumen:
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-PDESd 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.
Filiaciones:
Departamento de Materials Radiactivos, Instituto Nacional de Investigaciones Nucleares, Carretera México-Toluca S/N, Ocoyoacac, Estado de México, 52750, Mexico
Facultad de Química, Universidad Autónoma del Estado de México, Paseo Tollocan S/N, Toluca, Estado de México, 50180, Mexico
Facultad de Medicina, Universidad Autónoma del Estado de México, Toluca, 50180 Estado de México, Mexico
Departamento de Biomedicina Molecular. Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Av. I.P.N., Ciudad de México, 07360
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