Chemo-radiotherapy with 177Lu-PLGA(RGF)-CXCR4L for the targeted treatment of colorectal cancer

Pedro Cruz-Nova; Brenda Gibbens-Bandala; Alejandra Ancira-Cortez; Gerardo Ramírez-Nava; Clara Santos-Cuevas; Myrna Luna-Gutiérrez; Blanca Ocampo-García

doi:10.3389/fmed.2023.1191315

Chemo-radiotherapy with ¹⁷⁷Lu-PLGA(RGF)-CXCR4L for the targeted treatment of colorectal cancer

Front Med (Lausanne). 2023 Jun 12:10:1191315. doi: 10.3389/fmed.2023.1191315. eCollection 2023.

Authors

Pedro Cruz-Nova¹, Brenda Gibbens-Bandala¹, Alejandra Ancira-Cortez¹, Gerardo Ramírez-Nava², Clara Santos-Cuevas¹, Myrna Luna-Gutiérrez¹, Blanca Ocampo-García¹

Affiliations

¹ Departamento de Materiales Radiactivos, Instituto Nacional de Investigaciones Nucleares, Ocoyoacac, Estado de México, Mexico.
² Institute of Advanced Materials for Sustainable Manufacturing, Tecnológico de Monterrey, Mexico City, Mexico.

Abstract

Introduction: More than 1.9 million new cases of colorectal cancer and 935,000 deaths were estimated to have occurred worldwide in 2020. Therapies for metastatic colorectal cancer include cytotoxic chemotherapy and targeted therapies in multiple lines of treatment. Nevertheless, the optimal use of these agents has not yet been resolved. Regorafenib (RGF) is an Food and Drug Administration (FDA)-authorized multikinase inhibitor indicated for patients with metastatic colorectal cancer, non-responding to priority lines of chemotherapy and immunotherapy. Nanoparticles have been used in specific applications, such as site-specific drug delivery systems, cancer therapy, and clinical bioanalytical diagnostics. C-X-C Chemokine receptor type 4 (CXCR4) is the most widely-expressed chemokine receptor in more than 23 human cancer types, including colorectal cancer. This research aimed to synthesize and preclinically evaluate a targeted nanosystem for colorectal cancer chemo-radiotherapy using RGF encapsulated in Poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles coated with a CXCR4 ligand (CXCR4L) and ¹⁷⁷Lu as a therapeutic β-emitter.

Methods: Empty PLGA and PLGA(RGF) nanoparticles were prepared using the microfluidic method, followed by the DOTA and CXCR4L functionalization and nanoparticle radiolabeling with ¹⁷⁷Lu. The final nanosystem gave a particle size of 280 nm with a polydispersity index of 0.347. In vitro and in vivo toxicity effects were assessed using the HCT116 colorectal cancer cell line.

Results: ¹⁷⁷Lu-PLGA(RGF)-CXCR4L nanoparticles decreased cell viability and proliferation by inhibiting Erk and Akt phosphorylation and promoting apoptosis. Moreover, in vivo administration of ¹⁷⁷Lu-PLGA(RGF)-CXCR4L significantly reduced tumor growth in an HCT116 colorectal cancer xenograft model. The biokinetic profile showed hepatic and renal elimination.

Discussion: Data obtained in this research justify additional preclinical safety trials and the clinical evaluation of ¹⁷⁷Lu-PLGA(RGF)-CXCR4L as a potential combined treatment of colorectal cancer.

Keywords: 177Lu; CXCR4L; PLGA nanoparticles; Regorafenib; chemoradiotherapy; colorectal cancer.