CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK.
Nanoscale. 2018 Jun 7;10(22):10596-10608. doi: 10.1039/c7nr09606b.
Radiolabelled, drug-loaded nanoparticles may combine the theranostic properties of radionuclides, the controlled release of chemotherapy and cancer cell targeting. Here, we report the preparation of poly(lactic-co-glycolic acid) (PLGA) nanoparticles surface conjugated to DTPA-hEGF (DTPA = diethylenetriaminepentaacetic acid, hEGF = human epidermal growth factor) and encapsulating the ruthenium-based DNA replication inhibitor and radiosensitizer Ru(phen)2(tpphz)2+ (phen = 1,10-phenanthroline, tpphz = tetrapyridophenazine) Ru1. The functionalized PLGA surface incorporates the metal ion chelator DTPA for radiolabelling and the targeting ligand for EGF receptor (EGFR). Nanoparticles radiolabelled with 111In are taken up preferentially by EGFR-overexpressing oesophageal cancer cells, where they exhibit radiotoxicity through the generation of cellular DNA damage. Moreover, nanoparticle co-delivery of Ru1 alongside 111In results in decreased cell survival compared to single-agent formulations; an effect that occurs through DNA damage enhancement and an additive relationship between 111In and Ru1. Substantially decreased uptake and radiotoxicity of nanoparticles towards normal human fibroblasts and oesophageal cancer cells with normal EGFR levels is observed. This work demonstrates nanoparticle co-delivery of a therapeutic radionuclide plus a ruthenium-based radiosensitizer can achieve combinational and targeted therapeutic effects in cancer cells that overexpress EGFR.
放射性标记、载药纳米颗粒可将放射性核素的治疗诊断特性、化疗药物的控释和癌细胞靶向作用结合在一起。在此，我们报告了聚（乳酸-共-乙醇酸）（PLGA）纳米颗粒表面与 DTPA-hEGF（DTPA=二乙三胺五乙酸，hEGF=人表皮生长因子）相连，并包载基于钌的 DNA 复制抑制剂和放射增敏剂 Ru(phen)2(tpphz)2+（phen=1,10-邻菲啰啉，tpphz=四吡嗪并苯）Ru1 的制备。功能化的 PLGA 表面整合了用于放射性标记的金属离子螯合剂 DTPA 和用于表皮生长因子受体（EGFR）的靶向配体。用 111In 放射性标记的纳米颗粒优先被 EGFR 过表达的食管癌细胞摄取，在这些细胞中通过产生细胞 DNA 损伤表现出放射毒性。此外，与单药制剂相比，Ru1 与 111In 共同递药会导致细胞存活率降低；这种作用通过 DNA 损伤增强和 111In 与 Ru1 之间的附加关系发生。在正常表达 EGFR 的正常人成纤维细胞和食管癌细胞中，观察到纳米颗粒的摄取和放射毒性明显降低。这项工作证明，治疗性放射性核素与基于钌的放射增敏剂的纳米颗粒共递药可在过度表达 EGFR 的癌细胞中实现联合和靶向治疗效果。
