Wu Tiantian, Huang Hai, Sheng Yaping, Shi Hongdong, Min Yuanzeng, Liu Yangzhong
CAS Key Laboratory of Soft Matter Chemistry, CAS High Magnetic Field Laboratory, Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China.
J Mater Chem B. 2018 Feb 21;6(7):1011-1017. doi: 10.1039/c7tb03132g. Epub 2018 Feb 6.
Targeted delivery of anticancer drugs that selectively accumulate in malignant cells could enhance drug efficacy and reduce side effects of conventional chemotherapy. In this work, we designed a single domain antibody (nanobody) based drug delivery system for targeted delivery of anticancer drugs. An anti-EGFR nanobody (Nb) was constructed with a C-tag and a Q-tag for site specific modifications under physiological conditions. The site specific PEGylation of the nanobody was achieved via a transglutaminase catalyzed reaction through the coupling of the Q-tag with PEG-NH. As a proof of concept, the PEGylated nanobody was tethered to HSA coated upconversion nanoparticles (UCNPs) through the C-tag, and an anticancer drug, doxorubicin (DOX), was loaded. Results showed that the Nb-conjugated drug delivery system exhibits superior specificity to the EGFR positive tumor cells. The drug delivery system is highly accumulated in the EGFR positive tumor cells (A431), whereas there was no detectable accumulation in the EGFR negative cells (MCF-7). Consequently, the drug loaded particles demonstrated significantly higher anti-proliferation to A431 cells than to MCF-7 cells. This work provides an effective approach for site-specific modification of nanobodies for the construction of targeted drug delivery systems.
能够选择性地在恶性细胞中积累的抗癌药物靶向递送系统，可提高药物疗效并降低传统化疗的副作用。在本研究中，我们设计了一种基于单域抗体（纳米抗体）的药物递送系统用于抗癌药物的靶向递送。构建了一种带有C标签和Q标签的抗表皮生长因子受体（EGFR）纳米抗体，以便在生理条件下进行位点特异性修饰。通过转谷氨酰胺酶催化反应，使纳米抗体通过Q标签与聚乙二醇-氨基（PEG-NH）偶联，实现纳米抗体的位点特异性聚乙二醇化。作为概念验证，通过C标签将聚乙二醇化纳米抗体连接到白蛋白包被的上转换纳米颗粒（UCNP）上，并负载抗癌药物阿霉素（DOX）。结果表明，纳米抗体偶联的药物递送系统对EGFR阳性肿瘤细胞具有卓越的特异性。该药物递送系统在EGFR阳性肿瘤细胞（A431）中高度积累，而在EGFR阴性细胞（MCF-7）中未检测到积累。因此，载药颗粒对A431细胞的抗增殖作用明显高于对MCF-7细胞的作用。这项工作为纳米抗体的位点特异性修饰以构建靶向药物递送系统提供了一种有效方法。
