Center of Nanoscience, Nanotechnology and Innovation - CeNano2I, Federal University of Minas Gerais - UFMG, Av. Antônio Carlos, 6627 - Belo Horizonte/MG, Brazil.
Biomater Sci. 2019 Apr 23;7(5):2102-2122. doi: 10.1039/c8bm01528g.
Glioblastoma is the most aggressive primary brain cancer, which has no cure yet. Emerging nanotheranostic alternatives such as magnetic iron oxide nanoparticles (MIONs) have great potential as multimodal cancer therapy mediators. They can act as nanocarriers of anticancer drugs and generate localized heat when exposed to an alternating magnetic field (AMF), resulting in combined effects of chemotherapy and magnetic hyperthermia therapy. Thus, we designed and synthesized novel MIONs directly through a co-precipitation method by a single step one-pot aqueous green process using carboxymethylcellulose (CMC) as a multifunctional, biocompatible and water-soluble biopolymer ligand (iron oxide nanoparticle-CMC, MION@CMC). They were bioconjugated via amide bonds with doxorubicin (DOX, an anticancer drug) forming nanohybrids (MION@CMC-DOX). The CMC, MION@CMC and MION@CMC-DOX nanoconjugates were comprehensively characterized by 1HNMR, FTIR, TEM/SAED/EDX, UV-visible, XRD, zeta potential (ZP) and DLS analyses. Moreover, cytotoxicity and cell killing activities of these nanoconjugates were assessed by in vitro biological assays. The nanoconjugates were incubated with glioma cells (U87), a magnetic hyperthermia (MHT) assay was performed for evaluating the activity against brain cancer cells and confocal laser scanning laser microscopy was used for bioimaging their cellular uptake pathways. The results showed that fairly monodisperse and water-soluble ultra-small iron oxide nanoparticles (Fe3O4) were synthesized (core size = 7 ± 2 nm) and stabilized by CMC producing negatively charged nanocolloids (-38 ± 3 mV, MION@CMC; hydrodynamic radius, HD = 38 ± 2 nm). The results confirmed the conjugation of MION@CMC with DOX by amide bonds, leading to the development of magnetopolymersome nanostructures (MION@CMC-DOX). The cell viability bioassays evidenced low toxicity of MION@CMC compared to the severe cytotoxicity of MION@CMC-DOX nanosystems mainly caused by the release of DOX. Under an alternating magnetic field, MION@CMC and MION@CMC-DOX systems demonstrated activity for killing U87 cancer cells due to the heat generated by hyperthermia. In addition, the MION@CMC-DOX bioconjugates showed significantly higher cell killing response when exposed to an AMF due to the combined chemotherapy effect of DOX release inside the cancer cells triggering apoptotic pathways.
胶质母细胞瘤是最具侵袭性的原发性脑癌，目前尚无治愈方法。新兴的纳米治疗替代物，如磁性氧化铁纳米粒子（MIONs），作为多模式癌症治疗介质具有巨大的潜力。它们可以作为抗癌药物的纳米载体，并在暴露于交变磁场（AMF）时产生局部热量，从而产生化疗和磁热疗的联合效应。因此，我们通过一步一步的一锅水相绿色过程，直接通过共沉淀法设计并合成了新型 MIONs，该过程使用羧甲基纤维素（CMC）作为多功能、生物相容和水溶性生物聚合物配体（氧化铁纳米粒子-CMC，MION@CMC）。它们通过酰胺键与阿霉素（DOX，一种抗癌药物）结合形成纳米杂化物（MION@CMC-DOX）。CMC、MION@CMC 和 MION@CMC-DOX 纳米复合物通过 1HNMR、FTIR、TEM/SAED/EDX、UV-可见、XRD、Zeta 电位（ZP）和 DLS 分析进行了综合表征。此外，通过体外生物学测定评估了这些纳米复合物的细胞毒性和细胞杀伤活性。将纳米复合物与神经胶质瘤细胞（U87）孵育，进行磁热疗（MHT）测定以评估对脑癌细胞的活性，并使用共聚焦激光扫描显微镜进行生物成像以研究其细胞摄取途径。结果表明，相当单分散和水溶性的超小氧化铁纳米粒子（Fe3O4）被合成（核尺寸=7±2nm）并由 CMC 稳定，产生带负电荷的纳米胶体（-38±3mV，MION@CMC；水动力半径，HD=38±2nm）。结果证实了 MION@CMC 通过酰胺键与 DOX 的结合，导致了磁聚合物囊泡纳米结构（MION@CMC-DOX）的发展。细胞活力生物测定结果表明，与 MION@CMC-DOX 纳米系统的严重细胞毒性相比，MION@CMC 的毒性较低，主要是由于 DOX 的释放。在交变磁场下，MION@CMC 和 MION@CMC-DOX 系统由于磁热产生的热量而表现出杀死 U87 癌细胞的活性。此外，由于 DOX 在癌细胞内释放引发凋亡途径，MION@CMC-DOX 生物偶联物在暴露于 AMF 时表现出更高的细胞杀伤反应。
