Macromolecules and Interfaces Institute, ‡School of Biomedical Engineering and Sciences, §Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, and ∥Department of Sustainable Biomaterials, Virginia Tech , Blacksburg, Virginia 24061, United States.
Biomacromolecules. 2014 May 12;15(5):1560-7. doi: 10.1021/bm401593n. Epub 2014 Apr 9.
Elongated nanoparticles have recently been shown to have distinct advantages over spherical ones in targeted drug delivery applications. In addition to their oblong geometry, their lack of cytotoxicity and numerous surface hydroxyl groups make cellulose nanocrystals (CNCs) promising drug delivery vectors. Herein we report the synthesis of folic acid-conjugated CNCs for the targeted delivery of chemotherapeutic agents to folate receptor-positive cancer cells. Folate receptor-mediated cellular binding/uptake of the conjugate was demonstrated on human (DBTRG-05MG, H4) and rat (C6) brain tumor cells. Folate receptor expression of the cells was verified by immunofluorescence staining. Cellular binding/uptake of the conjugate by DBTRG-05MG, H4, and C6 cells was 1452, 975, and 46 times higher, respectively, than that of nontargeted CNCs. The uptake mechanism was determined by preincubation of the cells with the uptake inhibitors chlorpromazine or genistein. DBTRG-05MG and C6 cells internalized the conjugate primarily via caveolae-mediated endocytosis, whereas H4 cells internalized the conjugate primarily via clathrin-mediated endocytosis.
近年来，研究表明，在靶向药物输送应用中，长形纳米颗粒比球形纳米颗粒具有明显的优势。除了它们的长形几何形状外，其缺乏细胞毒性和众多表面羟基基团使得纤维素纳米晶体（CNC）成为有前途的药物输送载体。在此，我们报告了叶酸偶联的 CNC 的合成，用于将化疗药物靶向递送至叶酸受体阳性癌细胞。在人（DBTRG-05MG、H4）和大鼠（C6）脑肿瘤细胞上证明了通过叶酸受体介导的细胞结合/摄取该偶联物。通过免疫荧光染色验证了细胞中叶酸受体的表达。DBTRG-05MG、H4 和 C6 细胞对该偶联物的细胞结合/摄取分别比非靶向 CNC 高 1452、975 和 46 倍。通过用摄取抑制剂氯丙嗪或金雀异黄素预先孵育细胞来确定摄取机制。DBTRG-05MG 和 C6 细胞主要通过小窝蛋白介导的内吞作用内化该偶联物，而 H4 细胞主要通过网格蛋白介导的内吞作用内化该偶联物。
