ISMO (UMR 8214), University Paris-Saclay, University Paris Sud, CNRS, F-91405 Orsay Cedex, France.
Nanotechnology. 2020 Mar 27;31(13):135102. doi: 10.1088/1361-6528/ab5d82. Epub 2019 Nov 29.
Radiotherapy is one of the main treatments used to fight cancer. A major limitation of this modality is the lack of selectivity between cancerous and healthy tissues. One of the most promising strategies proposed in this last decade is the addition of nanoparticles with high-atomic number to enhance radiation effects in tumors. Gold nanoparticles (AuNPs) are considered as one of the best candidates because of their high radioenhancing property, simple synthesis and low toxicity. Ultra small AuNPs (core size of 2.4 nm and hydrodynamic diameter of 4.5 nm) covered with dithiolated diethylenetriaminepentaacetic acid (Au@DTDTPA) are of high interest because of their properties to bind MRI active or PET active compounds at their surface, to concentrate in some tumors and be eliminated via renal clearance thanks to their small size. These key figures make Au@DTDTPA the best candidate to develop image-guided radiotherapy. Surprisingly the capacity of the nanoparticles to penetrate cells, an important issue to predict radioenhancement, has not been established yet. Here, we report the uptake dynamics, internalization routes and excretion dynamics of Au@DTDTPA nanoparticles in various cancer cell lines including glioblastoma (U87-MG), chordoma (UM-Chor1), cervix (HeLa), prostate (PC3), and pancreatic (BxPC-3) cell lines as well as fibroblasts (Dermal fibroblasts). This study demonstrates a strong cell line dependence of the nanoparticle uptake and excretion dynamics. Different pathways of cell internalization evidenced here explain this dependence. As a major finding, the retention of Au@DTDTPA nanoparticles was found to be higher in cancer cells than in fibroblasts. This result strengthens the strategy of using nanoagents to improve tumor selectivity of radiation treatments. In particular Au@DTDTPA nanoparticles are good candidates to improve the treatment of radioresitant gliobastoma, pancreatic and prostate cancer in particular. In conclusion, the variability of cell-to-nanoparticle interaction is a new parameter to consider in the choice of nanoagents in a combined treatment.
放射疗法是治疗癌症的主要方法之一。这种方法的一个主要局限性是缺乏对癌细胞和健康组织的选择性。在过去十年中提出的最有前途的策略之一是添加具有高原子数的纳米粒子来增强肿瘤中的辐射效应。金纳米粒子（AuNPs）因其高放射增强特性、简单的合成和低毒性而被认为是最佳候选者之一。由二硫代二乙三胺五乙酸（DTDTPA）覆盖的超小 AuNPs（核大小为 2.4nm，水动力直径为 4.5nm）由于其在表面结合 MRI 活性或 PET 活性化合物、在某些肿瘤中浓缩以及通过其小尺寸通过肾脏清除而被消除的能力而引起了极大的关注。这些关键特性使 Au@DTDTPA 成为开发图像引导放射治疗的最佳候选者。令人惊讶的是，纳米颗粒穿透细胞的能力——预测放射增强的一个重要问题——尚未确定。在这里，我们报告了 Au@DTDTPA 纳米颗粒在各种癌细胞系（包括神经胶质瘤（U87-MG）、脊索瘤（UM-Chor1）、宫颈（HeLa）、前列腺（PC3）和胰腺（BxPC-3）细胞系以及成纤维细胞（真皮成纤维细胞）中的摄取动力学、内化途径和排泄动力学。这项研究表明，纳米颗粒的摄取和排泄动力学具有很强的细胞系依赖性。这里证明的不同细胞内化途径解释了这种依赖性。作为一个主要发现，发现 Au@DTDTPA 纳米颗粒在癌细胞中的保留率高于成纤维细胞。这一结果加强了使用纳米剂来提高放射治疗肿瘤选择性的策略。特别是，Au@DTDTPA 纳米颗粒是改善对放射抗拒性神经胶质瘤、胰腺和前列腺癌特别是治疗的良好候选者。总之，细胞与纳米颗粒相互作用的可变性是在联合治疗中选择纳米剂时需要考虑的新参数。
