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使用Lu-PLGA(RGF)-CXCR4L进行化疗放疗以靶向治疗结直肠癌。

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

作者信息

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

机构信息

Departamento de Materiales Radiactivos, Instituto Nacional de Investigaciones Nucleares, Ocoyoacac, Estado de México, Mexico.

Institute of Advanced Materials for Sustainable Manufacturing, Tecnológico de Monterrey, Mexico City, Mexico.

出版信息

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

DOI:10.3389/fmed.2023.1191315
PMID:37378300
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10292846/
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 Lu 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 Lu. The final nanosystem gave a particle size of 280 nm with a polydispersity index of 0.347. and toxicity effects were assessed using the HCT116 colorectal cancer cell line.

RESULTS

Lu-PLGA(RGF)-CXCR4L nanoparticles decreased cell viability and proliferation by inhibiting Erk and Akt phosphorylation and promoting apoptosis. Moreover, administration of Lu-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 Lu-PLGA(RGF)-CXCR4L as a potential combined treatment of colorectal cancer.

摘要

引言

2020年全球估计有超过190万例新发结直肠癌病例和93.5万例死亡。转移性结直肠癌的治疗方法包括多线治疗中的细胞毒性化疗和靶向治疗。然而，这些药物的最佳使用方法尚未确定。瑞戈非尼（RGF）是一种美国食品药品监督管理局（FDA）批准的多激酶抑制剂，适用于对一线化疗和免疫治疗无反应的转移性结直肠癌患者。纳米颗粒已用于特定应用，如位点特异性药物递送系统、癌症治疗和临床生物分析诊断。C-X-C趋化因子受体4（CXCR4）是在包括结直肠癌在内的23种以上人类癌症类型中表达最广泛的趋化因子受体。本研究旨在合成并在临床前评估一种靶向纳米系统，用于结直肠癌的化学放疗，该系统使用包裹在聚（D，L-乳酸-共-乙醇酸）（PLGA）纳米颗粒中的RGF，该纳米颗粒涂有CXCR4配体（CXCR4L），并使用镥作为治疗性β发射体。

方法

采用微流控法制备空白PLGA和PLGA（RGF）纳米颗粒，然后进行DOTA和CXCR4L功能化以及纳米颗粒用镥进行放射性标记。最终的纳米系统粒径为280nm，多分散指数为0.347。使用HCT116结直肠癌细胞系评估其毒性作用。

结果

镥-PLGA（RGF）-CXCR4L纳米颗粒通过抑制Erk和Akt磷酸化并促进凋亡来降低细胞活力和增殖。此外，给予镥-PLGA（RGF）-CXCR4L可显著降低HCT116结直肠癌异种移植模型中的肿瘤生长。生物动力学曲线显示有肝脏和肾脏清除。

讨论

本研究获得的数据证明有必要进行额外的临床前安全性试验以及对镥-PLGA（RGF）-CXCR4L作为结直肠癌潜在联合治疗方法的临床评估。

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