Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China.
School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui 230026, China.
Nucleic Acids Res. 2020 Sep 25;48(17):9986-9994. doi: 10.1093/nar/gkaa693.
Telomeric DNA, whose length homeostasis is closely correlated with immortality of cancer cells, is regarded as a molecular clock for cellular lifespan. Regarding the capacity in forming G-quadruplex, G-rich 3'-overhang (G-overhang) has been considered as an attractive anticancer target. However, it is still challenging to precisely target telomeric G-overhang with current ligands because of the polymorphism of G-quadruplexes in cells. Herein, we construct a telomeric G-overhang-specific near-infrared-traceable DNA nano-hydrolase, which is composed of four parts: (i) dexamethasone for targeting cell nuclei; (ii) complementary DNA for hybridizing with G-overhang; (iii) multinuclear Ce(IV) complexes for hydrolyzing G-overhang; and (iv) upconversion nanoparticles for real-time tracking. The multivalent targeted DNA nano-hydrolase can be traced to precisely digest telomeric G-overhang, which contributes to telomeric DNA shortening and thereby causes cell aging and apoptosis. The anticancer treatment is further proved by in vivo studies. In this way, this design provides a telomeric G-overhang-specific eradication strategy based on a non-G-quadruplex targeting manner.
端粒 DNA 的长度平衡与其癌细胞的永生密切相关，被视为细胞寿命的分子钟。由于细胞中 G-四链体的多态性，富含 G 的 3'-突出端（G-突出端）被认为是一种有吸引力的抗癌靶标。然而，由于当前配体难以精确靶向端粒 G-突出端，因此仍然具有挑战性。在此，我们构建了一种端粒 G-突出端特异性近红外可追踪 DNA 纳米水解酶，它由四部分组成：（i）地塞米松用于靶向细胞核；（ii）与 G-突出端杂交的互补 DNA；（iii）多核 Ce（IV）配合物用于水解 G-突出端；（iv）上转换纳米粒子用于实时跟踪。多价靶向 DNA 纳米水解酶可以精确追踪并消化端粒 G-突出端，导致端粒 DNA 缩短，从而引起细胞衰老和凋亡。体内研究进一步证明了这种抗癌治疗方法。通过这种方式，该设计提供了一种基于非 G-四链体靶向方式的端粒 G-突出端特异性消除策略。
