Institute of Chemistry, Center for Nanoscience and Nanotechnology, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Nanoscale. 2018 Mar 8;10(10):4650-4657. doi: 10.1039/c8nr00193f.
Amino-triphenyl dicarboxylate-bridged Zr metal-organic framework nanoparticles (NMOFs), 100-130 nm, are modified with a nucleic acid complementary to the VEGF aptamer. The nucleic acid-functionalized NMOFs were loaded with the anti-cancer drug doxorubicin (or Rhodamine 6G as a drug model), and the loaded NMOFs were capped by hybridization with the VEGF aptamer that yielded VEGF-responsive duplex nucleic acid gates. In the presence of VEGF, a biomarker over-expressed in cancer cells, selective unlocking of the gates proceeds through the formation of VEGF/aptamer complexes, resulting in the release of the loads. In addition, the VEGF aptamer locking units were conjugated to the AS1411 aptamer sequence that binds to nucleolin receptors associated with cancer cells, resulting in the construction of cancer-cell targeted VEGF-responsive doxorubicin-loaded NMOFs. The different drug-loaded stimuli-responsive NMOFs reveal selective permeation into MDA-MB-231 breast cancer cells, compared to their incorporation into normal MCF-10A breast cells, with a two-fold enhanced incorporation into the MDA-MB-231 cells of the AS1411 aptamer-functionalized NMOFs. Cytotoxicity experiments revealed impressive selective apoptosis of the doxorubicin-loaded NMOFs towards the MDA-MB-231 cancer cells compared to the normal MCF-10A breast cells. A 55% and 70% MDA-MB-231 cell apoptosis was observed upon subjecting the cells to the VEGF aptamer and the VEGF aptamer/AS1411 aptamer conjugate-caged NMOFs, respectively, for a time-interval of three days, where only <10% apoptosis of the MCF-10A cells was observed under similar conditions.
氨基三苯二羧酸桥联 Zr 金属有机骨架纳米粒子（NMOFs），100-130nm，通过与与 VEGF 适体互补的核酸进行修饰。核酸功能化的 NMOFs 负载抗癌药物阿霉素（或作为药物模型的罗丹明 6G），并用 VEGF 适体进行杂交封闭负载的 NMOFs，得到对 VEGF 有响应的双链核酸门。在 VEGF 的存在下，VEGF 是一种在癌细胞中过度表达的生物标志物，通过形成 VEGF/适体复合物选择性解锁门，导致负载物的释放。此外，VEGF 适体锁定单元与结合核仁素受体的 AS1411 适体序列缀合，构建了针对癌细胞的 VEGF 响应性阿霉素负载 NMOFs。与正常 MCF-10A 乳腺细胞相比，不同负载药物的刺激响应性 NMOFs 选择性渗透进入 MDA-MB-231 乳腺癌细胞，并且与正常 MCF-10A 乳腺细胞相比，AS1411 适体功能化 NMOFs 对 MDA-MB-231 细胞的掺入增加了两倍。细胞毒性实验表明，与正常 MCF-10A 乳腺细胞相比，负载阿霉素的 NMOFs 对 MDA-MB-231 癌细胞具有显著的选择性凋亡作用。当将细胞暴露于 VEGF 适体和 VEGF 适体/AS1411 适体缀合笼 NMOFs 中 3 天时，分别观察到 MDA-MB-231 细胞的 55%和 70%凋亡，而在类似条件下，仅观察到 MCF-10A 细胞的<10%凋亡。
