Coimbra Chemistry Centre (CQC), Department of Chemistry, University of Coimbra, Rua Larga, 3004-535 Coimbra, Portugal.
Nanoscale. 2018 Apr 19;10(15):7238-7249. doi: 10.1039/c7nr08442k.
Fluoropyrimidines, such as 5-fluorouracil (5-FU) and related prodrugs, are considered one of the most successful agents in the treatment of colorectal cancer, yet poor specificity and tumor cell resistance remain the major limiting bottlenecks. Here, we exploited for the first time the ability of two DNA nanoscaffolds, a DNA tetrahedron (Td) and rectangle DNA origami, to incorporate 5-fluoro-2'-deoxyuridine (FdUn) oligomers. In addition, cholesterol moieties were synthetically attached to Td and DNA origami staples to enhance cellular uptake. DNA nanostructures functionalized with FdUn exhibited an enhanced cytotoxicity and higher ability to trigger apoptosis in colorectal cancer cells relative to conventional 5-FU and FdU, especially having cholesterol as an internalization helper. The cholesterol content mostly correlates with the increase of the FdUn nanostructure cytotoxicity. DNA nanoscaffolds bearing FdUn were able to circumvent the low sensitivity of colorectal cancer cells towards 5-FU. Both DNA nanostructures attained a comparable cytotoxic effect yet Td displays higher antiproliferative action. The ability to reduce the proliferation of cancer cells is mainly related to the concentration of DNA nanostructures. The present work suggests that self-assembled DNA nanoparticles are privileged vehicles for delivering fluoropyrimidines, opening new avenues to the development of promising therapeutics for cancer treatment.
氟嘧啶类药物，如 5-氟尿嘧啶（5-FU）及其相关前体药物，被认为是治疗结直肠癌最成功的药物之一，但特异性差和肿瘤细胞耐药性仍是主要的限制瓶颈。在这里，我们首次利用两种 DNA 纳米支架，即 DNA 四面体（Td）和矩形 DNA 折纸，来整合 5-氟-2'-脱氧尿嘧啶（FdUn）寡聚物。此外，胆固醇部分被合成连接到 Td 和 DNA 折纸支架上，以增强细胞摄取。与传统的 5-FU 和 FdU 相比，功能化的 FdUn 的 DNA 纳米结构表现出增强的细胞毒性和更高的诱导结直肠癌细胞凋亡的能力，尤其是具有胆固醇作为内化辅助剂。胆固醇含量与 FdUn 纳米结构细胞毒性的增加大多相关。携带 FdUn 的 DNA 纳米支架能够规避结直肠癌细胞对 5-FU 的低敏感性。两种 DNA 纳米结构都具有相当的细胞毒性作用，但 Td 显示出更高的抗增殖作用。减少癌细胞增殖的能力主要与 DNA 纳米结构的浓度有关。本研究表明，自组装的 DNA 纳米颗粒是递氟化嘧啶类药物的有优势载体，为开发用于癌症治疗的有前途的治疗方法开辟了新途径。
