Tsoukalas Charalampos, Psimadas Dimitrios, Kastis George A, Koutoulidis Vassilis, Harris Adrian L, Paravatou-Petsotas Maria, Karageorgou Maria, Furenlid Lars R, Moulopoulos Lia A, Stamopoulos Dimosthenis, Bouziotis Penelope
Radiochemical Studies Laboratory, Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety, National Center for Scientific Research "Demokritos,", Athens, Greece.
Research Center of Mathematics, Academy of Athens, Athens, Greece.
Front Chem. 2018 Jun 20;6:224. doi: 10.3389/fchem.2018.00224. eCollection 2018.
Superparamagnetic iron oxide nanoparticles with well-integrated multimodality imaging properties have generated increasing research interest in the past decade, especially when it comes to the targeted imaging of tumors. Bevacizumab (BCZM) on the other hand is a well-known and widely applied monoclonal antibody recognizing VEGF-A, which is overexpressed in angiogenesis. The aim of this proof-of-concept study was to develop a dual-modality nanoplatform for targeted single photon computed emission tomography (SPECT) and magnetic resonance imaging (MRI) of tumor vascularization. Iron oxide nanoparticles (IONPs) have been coated with dimercaptosuccinic acid (DMSA), for consequent functionalization with the monoclonal antibody BCZM radiolabeled with Tc, via well-developed surface engineering. The IONPs were characterized based on their size distribution, hydrodynamic diameter and magnetic properties. cytotoxicity studies showed that our nanoconstruct does not cause toxic effects in normal and cancer cells. FeO-DMSA-SMCC-BCZM-Tc were successfully prepared at high radiochemical purity (>92%) and their stability in human serum and in PBS were demonstrated. cell binding studies showed the ability of the FeO-DMSA-SMCC-BCZM-Tc to bind to the VEGF-165 isoform overexpressed on M-165 tumor cells. The biodistribution studies in M165 tumor-bearing SCID mice showed high uptake in liver, spleen, kidney and lungs. The FeO-DMSA-SMCC-BCZM-Tc demonstrated quick tumor accumulation starting at 8.9 ± 1.88%ID/g at 2 h p.i., slightly increasing at 4 h p.i. (16.21 ± 2.56%ID/g) and then decreasing at 24 h p.i. (6.01 ± 1.69%ID/g). The tumor-to-blood ratio reached a maximum at 24 h p.i. (7), which is also the case for the tumor-to-muscle ratio (18). Initial pilot imaging studies on an experimental gamma-camera and a clinical MR camera prove our hypothesis and demonstrate the potential of FeO-DMSA-SMCC-BCZM-Tc for targeted dual-modality imaging. Our findings indicate that FeO-DMSA-SMCC-BCZM-Tc IONPs could serve as an important diagnostic tool for biomedical imaging as well as a promising candidate for future theranostic applications in cancer.
在过去十年中,具有良好整合的多模态成像特性的超顺磁性氧化铁纳米颗粒引发了越来越多的研究兴趣,尤其是在肿瘤的靶向成像方面。另一方面,贝伐单抗(BCZM)是一种广为人知且广泛应用的识别VEGF - A的单克隆抗体,VEGF - A在血管生成中过度表达。本概念验证研究的目的是开发一种用于肿瘤血管生成的靶向单光子计算机发射断层扫描(SPECT)和磁共振成像(MRI)的双模态纳米平台。通过成熟的表面工程技术,用二巯基琥珀酸(DMSA)包覆氧化铁纳米颗粒(IONPs),随后用用Tc标记的单克隆抗体BCZM进行功能化。基于其尺寸分布、流体动力学直径和磁性对IONPs进行了表征。细胞毒性研究表明,我们的纳米构建体在正常细胞和癌细胞中均未引起毒性作用。成功制备了具有高放射化学纯度(>92%)的FeO - DMSA - SMCC - BCZM - Tc,并证明了其在人血清和磷酸盐缓冲液(PBS)中的稳定性。细胞结合研究表明,FeO - DMSA - SMCC - BCZM - Tc能够与M - 165肿瘤细胞上过度表达的VEGF - 165异构体结合。在携带M165肿瘤的SCID小鼠中的生物分布研究表明,肝脏、脾脏、肾脏和肺中有高摄取。FeO - DMSA - SMCC - BCZM - Tc在注射后2小时开始迅速在肿瘤中蓄积,为8.9±1.88%ID/g,在注射后4小时略有增加(16.21±2.56%ID/g),然后在注射后24小时下降(6.01±1.69%ID/g)。肿瘤与血液的比率在注射后24小时达到最大值(约7),肿瘤与肌肉的比率也是如此(约18)。在实验性伽马相机和临床MR相机上进行的初步成像研究证实了我们的假设,并证明了FeO - DMSA - SMCC - BCZM - Tc在靶向双模态成像方面的潜力。我们的研究结果表明,FeO - DMSA - SMCC - BCZM - Tc IONPs可作为生物医学成像的重要诊断工具,也是未来癌症治疗诊断应用的有希望的候选者。