Song Lei, Able Sarah, Johnson Errin, Vallis Katherine A
CR-UK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK.
Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK.
Nanotheranostics. 2017 Jun 8;1(3):232-243. doi: 10.7150/ntno.19952. eCollection 2017.
The successful use of targeted radionuclide therapy in the treatment of solid tumours may be limited by radioresistance, which necessitates delivery of a high dose of radioactivity. Nanoparticle (NP)-based delivery systems possess a large surface area for attachment of radioisotopes and so offer a solution to this challenge. However, tumour uptake may be limited by rapid hepatic clearance of NP via the mononuclear phagocyte system. Liver uptake is further compounded when epidermal growth factor (EGF) is used as a targeting ligand, as EGF-tagged NP bind the EGF receptor (EGFR), which is expressed to a moderate extent by hepatocytes. This report describes an indium-111 (In)-labelled PEGylated EGF-tagged gold (Au) NP (In-EGF-Au-PEG) and an effective strategy of coadministration of targeting ligand to address these issues. Direct attachment of EGF to the surface of Au NP did not compromise surface coating with long-chain PEG. experiments showed that In-EGF-Au-PEG targets EGFR-positive cancer cells (MDA-MB-468): >11% of radioactivity was internalised after incubation for 4 h. In studies accumulation of NP was observed in MDA-MB-468 xenografts and tumour uptake was enhanced by the coadministration of 15 µg of the unlabelled targeting ligand, EGF, to block hepatic EGFR. Uptake was 3.9% versus 2.8% injected dose/g (%ID/g) of tumour tissue with and without unlabelled EGF, respectively. Coadministration of EGF reduced liver uptake by 25.95% to 7.56 %ID/g. This suggests that the coadministration of unlabelled targeting ligand with radiolabelled PEGylated NP offers a promising strategy for targeting EGFR-positive cancer and for minimising liver uptake.
靶向放射性核素疗法在实体瘤治疗中的成功应用可能受到放射抗性的限制，这就需要给予高剂量的放射性物质。基于纳米颗粒（NP）的递送系统具有用于附着放射性同位素的大表面积，因此为这一挑战提供了解决方案。然而，肿瘤摄取可能会受到NP通过单核吞噬细胞系统快速肝清除的限制。当表皮生长因子（EGF）用作靶向配体时，肝脏摄取会进一步加剧，因为EGF标记的NP会结合表皮生长因子受体（EGFR），而肝细胞会适度表达该受体。本报告描述了一种铟-111（In）标记的聚乙二醇化EGF标记的金（Au）NP（In-EGF-Au-PEG）以及一种共同给药靶向配体以解决这些问题的有效策略。EGF直接附着于Au NP表面不会影响长链PEG的表面包被。实验表明，In-EGF-Au-PEG靶向EGFR阳性癌细胞（MDA-MB-468）：孵育4小时后，超过11%的放射性物质被内化。在研究中，观察到NP在MDA-MB-468异种移植瘤中积累，并且通过共同给药15μg未标记的靶向配体EGF来阻断肝脏EGFR，肿瘤摄取得到增强。分别给予和不给予未标记EGF时，肿瘤组织的摄取量分别为3.9%注射剂量/克（%ID/g）和2.8%ID/g。共同给药EGF可使肝脏摄取降低25.95%至7.56%ID/g。这表明未标记的靶向配体与放射性标记的聚乙二醇化NP共同给药为靶向EGFR阳性癌症和最小化肝脏摄取提供了一种有前景的策略。
