Department of Chemistry, School of Basic Sciences, Indian Institute of Technology Indore, Simrol, Khandwa Road, Indore 453552, India.
Department of Chemistry, University of Cincinnati, Cincinnati, Ohio 45221, United States.
ACS Appl Bio Mater. 2022 Jan 17;5(1):190-204. doi: 10.1021/acsabm.1c01041. Epub 2021 Dec 28.
Despite being the most common component of numerous metalloenzymes in the human body, zinc complexes are still under-rated as chemotherapeutic agents. Herein, the present study opens up a key route toward enhanced chemotherapy with the help of two Zn complexes (ZnMBC) synthesized alongside Mannich base ligands to upsurge biological potency. Further, well-established mesoporous silica nanoparticles (MSNs) have been chosen as carriers of the titled metallodrugs in order to achieve anticancer drug delivery. A pH-sensitive additive, namely, chitosan (CTS) conjugated with biotin is tagged to MSNs for the targeted release of core agents inside tumors selectively. In general, CTS blocks ZnMBC inside the mesopores of MSNs, and biotin acts as a targeting ligand to improve tumor-specific cellular uptake. CTS-biotin surface decoration significantly enhanced the cellular uptake of ZnMBC through endocytosis. A panel of four human cancer cell lines has revealed that ZnMBC (/)@MSNs-CTS-biotin nanoparticles (NPs) exhibits unprecedented enhanced cytotoxicity toward cancer cells with IC values ranging from 6.5 to 28.8 μM through induction of apoptosis. NPs also possess great selectivity between normal and cancer cells despite this potency. Two-photon-excited imaging of normal (HEK) and cancer (HeLa) cells has been performed to confirm the biased drug delivery. Also, NP-induced apoptosis was found to be dependent on targeting DNA and ROS generation. Moreover, a lower range of LD values (153.6-335.5 μM) were observed upon treatment zebrafish embryos with NPs . Because of the anatomical similarity to the human heart, the heart rate of NP-treated zebrafish has been analyzed in assessing the cardiac functions, which is in favor of the early clinical trials of ZnMBC (/)@MSNs-CTS-biotin candidates for their further evaluation as a chemotherapeutic and chemopreventive agent toward human cancers, especially adenocarcinoma.
尽管锌是人体中许多金属酶最常见的组成部分，但锌配合物作为化疗药物的作用仍然被低估。在本研究中，通过合成两种与曼尼希碱配体一起合成的锌配合物（ZnMBC），帮助开辟了增强化疗的关键途径，从而提高生物效力。此外，选择了成熟的介孔硅纳米粒子（MSNs）作为标题金属药物的载体，以实现抗癌药物的递药。选择了一种 pH 敏感的添加剂，即与生物素偶联的壳聚糖（CTS），标记在 MSNs 上，以便在肿瘤内选择性地释放核心药物。一般来说，CTS 会阻止 ZnMBC 进入 MSNs 的介孔中，而生物素则作为靶向配体来提高肿瘤特异性细胞摄取。CTS-生物素表面修饰通过内吞作用显著增强了 ZnMBC 的细胞摄取。一组四种人类癌细胞系表明，ZnMBC（/）@MSNs-CTS-生物素纳米粒子（NPs）通过诱导细胞凋亡，对癌细胞表现出前所未有的增强的细胞毒性，IC 值范围为 6.5 至 28.8 μM。尽管具有这种效力，但 NPs 对正常细胞和癌细胞也具有很大的选择性。对正常（HEK）和癌细胞（HeLa）进行了双光子激发成像，以确认偏向性药物递药。此外，还发现 NP 诱导的细胞凋亡依赖于靶向 DNA 和 ROS 的产生。此外，在用 NPs 处理斑马鱼胚胎时，观察到较低的 LD 值范围（153.6-335.5 μM）。由于与人类心脏的解剖相似性，分析了 NP 处理后的斑马鱼的心率，以评估心脏功能，这有利于 ZnMBC（/）@MSNs-CTS-生物素候选物的早期临床试验，以评估其作为人类癌症，特别是腺癌的化疗和化学预防药物的进一步评估。
