State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, International Joint Laboratory for Advanced Fiber and Low-dimension Materials, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, P. R. China.
J Mater Chem B. 2019 Jan 14;7(2):277-285. doi: 10.1039/c8tb02723d. Epub 2018 Dec 12.
Design of powerful nanosystems to overcome multidrug resistance (MDR) for effective chemotherapy of cancer currently remains a great challenge. Herein, we report the development of a poly(amidoamine) (PAMAM) dendrimer/carbon dot nanohybrid for dual drug loading to overcome MDR and simultaneously monitor cancer cells via fluorescence imaging. First, blue-emitting carbon dots (CDs) were synthesized using sodium citrate as a carbon source via the hydrothermal method and used as a carrier to load the anticancer drug doxorubicin (DOX) through non-covalent interactions, thus forming CDs/DOX complexes. In parallel, PAMAM dendrimers of generation 5 (G5) were covalently modified by the targeting ligand cyclic arginine-glycine-aspartic (RGD) peptide and the drug efflux inhibitor d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). Then, through electrostatic interaction, functional dendrimers (G5-RGD-TPGS) were complexed with CDs/DOX complexes to form a dual drug-loaded nanohybrid system. The dual drug-loaded dendrimer/CD nanohybrids were well characterized. We showed that the nanohybrids possessed good colloidal stability and enabled significant inhibition of cancer cells due to the presence of TPGS, which can inhibit P-glycoprotein (P-gp) by decreasing ATP levels and increasing ROS levels; simultaneously, fluorescence imaging of cancer cells could be achieved in vitro due to the luminescence of CDs. In addition, the attached RGD ligands rendered the nanohybrid with targeting specificity to cancer cells expressing αβ integrin receptors. The developed dual drug-loaded dendrimer/CD nanohybrid may be used as a promising theranostic platform to overcome MDR for enhanced chemotherapy as well as for fluorescence imaging of cancer cells.
设计用于克服多药耐药性（MDR）的强大纳米系统，以实现癌症的有效化疗，目前仍然是一个巨大的挑战。在此，我们报告了一种聚（酰胺-胺）（PAMAM）树状大分子/碳点纳米杂化物的开发，用于双重药物加载以克服 MDR，并通过荧光成像同时监测癌细胞。首先，通过水热法使用柠檬酸钠作为碳源合成了发蓝光的碳点（CDs），并通过非共价相互作用用作载体来负载抗癌药物阿霉素（DOX），从而形成 CDs/DOX 复合物。同时，通过靶向配体环精氨酸-甘氨酸-天冬氨酸（RGD）肽和药物外排抑制剂 d-α-生育酚聚乙二醇 1000 琥珀酸（TPGS）对第五代（G5）PAMAM 树状大分子进行了共价修饰。然后，通过静电相互作用，功能化树状大分子（G5-RGD-TPGS）与 CDs/DOX 复合物复合，形成双重载药纳米杂化系统。对双重载药树突/CD 纳米杂化物进行了很好的表征。我们表明，由于 TPGS 的存在，纳米杂化物具有良好的胶体稳定性，并由于能够抑制 P-糖蛋白（P-gp）而显著抑制癌细胞，其通过降低 ATP 水平和增加 ROS 水平来抑制 P-gp；同时，由于 CDs 的发光，能够在体外实现癌细胞的荧光成像。此外，附着的 RGD 配体使纳米杂化物具有针对表达αβ整合素受体的癌细胞的靶向特异性。所开发的双重载药树突/CD 纳米杂化物可用作一种有前途的治疗学平台，以克服 MDR 以增强化疗以及癌细胞的荧光成像。
