Department of Radiology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, P. R. China and State Key Laboratory of Bioelectronics, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering & Collaborative Innovation Centre of Suzhou Nano Science and Technology, Southeast University, Nanjing 210096, P. R. China.
State Key Laboratory of Bioelectronics, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering & Collaborative Innovation Centre of Suzhou Nano Science and Technology, Southeast University, Nanjing 210096, P. R. China.
J Mater Chem B. 2020 Feb 7;8(5):895-907. doi: 10.1039/c9tb02521a. Epub 2020 Jan 7.
Since its launch in 1997, rituximab (RTX) has extensively improved the treatment of CD20-positive follicular and diffuse large B cell non-Hodgkin lymphoma (NHL). The application of RTX is limited usually by the failed therapy because of resistance. Iron oxide nanomaterials have been explored for cancer detection and treatment in recent years. In this study, a multivalent nanoprobe comprising one FeO nanoparticle and several RTX antibodies was constructed for the targeted imaging and enhanced treatment of NHL. Poly(ethylene glycol) (PEG)-coated FeO nanoparticles were fabricated via a thermal decomposition method and ligand exchange. RTX was conjugated onto the surface of the FeO-PEG nanoparticles to form FeO-PEG-nAb (n = 2, 5 or 8) multivalent nanoprobes. These multivalent nanoprobes, with a core size of approximately 11 nm and a hydrodynamic diameter of about 22 nm, showed colloidal stability in buffer solution. The r2 relaxation rate of FeO-PEG-nAb was similar to that of FeO-PEG (309 ± 3.08 mM s). The specificity of nanoprobes for CD20-positive Raji cells was assessed on a clinical magnetic resonance imaging scanner. The receptor binding site of one multivalent nanoprobe was more than that of one RTX, exhibiting valence-dependent induction of Raji cell apoptosis, and this effect could be enhanced by complement activation from blood serum added. A similar activity was observed in vivo in a NHL xenograft model. The multivalent nanoprobe treatment significantly reduced tumor burden and enhanced survival in comparison to the RTX group. Our studies demonstrate that the appropriate design and preparation of anticancer antibody-nanoparticle conjugates enable the generation of improved anticancer nanomedicines and could thus provide an efficient cancer theranostic strategy.
自 1997 年问世以来，利妥昔单抗（RTX）已广泛改善了 CD20 阳性滤泡性和弥漫性大 B 细胞非霍奇金淋巴瘤（NHL）的治疗效果。但是，由于耐药性，RTX 的应用通常受到失败治疗的限制。近年来，氧化铁纳米材料已被用于癌症的检测和治疗。在这项研究中，构建了一种由一个 FeO 纳米颗粒和几个 RTX 抗体组成的多价纳米探针，用于 NHL 的靶向成像和增强治疗。通过热分解法和配体交换制备了聚乙二醇（PEG）包覆的 FeO 纳米颗粒。RTX 被共轭到 FeO-PEG 纳米颗粒的表面上，形成 FeO-PEG-nAb（n = 2、5 或 8）多价纳米探针。这些多价纳米探针的核大小约为 11nm，水动力直径约为 22nm，在缓冲溶液中表现出胶体稳定性。FeO-PEG-nAb 的 r2 弛豫率与 FeO-PEG（309±3.08mM s）的弛豫率相似。在临床磁共振成像扫描仪上评估了纳米探针对 CD20 阳性 Raji 细胞的特异性。一个多价纳米探针的受体结合位点多于一个 RTX，表现出对 Raji 细胞凋亡的价态依赖性诱导，并且这种效应可以通过添加血清中的补体激活来增强。在 NHL 异种移植模型中也观察到了类似的体内活性。与 RTX 组相比，多价纳米探针治疗显著降低了肿瘤负担并提高了存活率。我们的研究表明，适当设计和制备抗癌抗体-纳米颗粒缀合物能够产生改进的抗癌纳米药物，从而为癌症治疗提供了一种有效的策略。
