Zhang Pu, Ouyang Yu, Sohn Yang Sung, Nechushtai Rachel, Pikarsky Eli, Fan Chunhai, Willner Itamar
Institute of Chemistry, Center for Nanoscience and Nanotechnology, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Institute of Life Science, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
ACS Nano. 2021 Apr 27;15(4):6645-6657. doi: 10.1021/acsnano.0c09996. Epub 2021 Mar 31.
The synthesis of stimuli-responsive hybrid structures composed of drug-loaded UiO-66 metal-organic framework nanoparticles, NMOFs, locked by DNA tetrahedra gates is presented. The hybrid systems combine the high loading capacity of drugs in the porous NMOFs and the effective cell permeation properties of the DNA tetrahedra. The nucleic acid-functionalized UiO-66 NMOFs are loaded with drugs (doxorubicin, DOX, or camptothecin, CPT) or with dyes as drug models (Rhodamine 6G or fluorescein) and used to prepare stimuli-responsive carriers. In this study, two different stimuli-responsive NMOFs are presented. One system introduces the drug-loaded NMOFs locked by pH-responsive DNA tetrahedra. At acidic pH values, the gating tetrahedra are dissociated from the NMOFs through the formation of i-motif structures, resulting in the unlocking of the NMOFs and the release of the drugs. In addition, the tetrahedra gates are modified with AS1411 aptamer tethers, and these target the drug-loaded NMOFs to nucleolin receptors overexpressed in certain malignant cells. A second system involves the preparation of NMOFs loaded with drugs/dyes and gated by the microRNA (miRNA)-responsive tetrahedra (miRNA-21 or miRNA-155). In the presence of miRNAs, the dissociation of miRNA-responsive tetrahedra from the NMOFs leads to the unlocking of the NMOFs and the release of the loads. Further developments of the miRNA-responsive tetrahedra-gated hybrid carriers include the following. (i) By appropriate engineering of the miRNA gating units, the exonuclease III (Exo III)-amplified unlocking of the carriers, through the regeneration of the miRNA triggers, and the enhanced release of the loaded drugs are demonstrated. (ii) By applying mixtures of miRNA-21-responsive DNA tetrahedra-gated DOX-loaded NMOFs and miRNA-155-responsive DNA tetrahedra-gated CPT-loaded NMOFs, the multiplexed miRNA-21/miRNA-155-dictated release of the drugs is demonstrated. As compared to the analog DNA duplex-modified NMOFs, DNA tetrahedra-gated, drug-loaded NMOFs permeation into malignant MDA-MB-231 breast cancer cells presents more effective cell permeation. Effective and selective cytotoxicity toward the malignant cells, as compared to nonmalignant epithelial MCF-10A breast cells, is demonstrated due to the acidic pH, present in cancer cells, or the miRNA-21, present in MDA-MB-231 malignant cells.
本文介绍了由载药的UiO-66金属有机框架纳米颗粒（NMOFs）组成的刺激响应性杂化结构的合成，该结构由DNA四面体门锁定。杂化系统结合了多孔NMOFs中药物的高负载能力和DNA四面体的有效细胞渗透特性。用核酸功能化的UiO-66 NMOFs负载药物（阿霉素，DOX，或喜树碱，CPT）或作为药物模型的染料（罗丹明6G或荧光素），并用于制备刺激响应性载体。在本研究中，展示了两种不同的刺激响应性NMOFs。一种系统引入了由pH响应性DNA四面体锁定的载药NMOFs。在酸性pH值下，门控四面体通过形成i-基序结构与NMOFs解离，导致NMOFs解锁并释放药物。此外，四面体门用AS1411适配体链修饰，这些适配体将载药NMOFs靶向某些恶性细胞中过表达的核仁素受体。第二种系统涉及制备负载药物/染料并由微小RNA（miRNA）响应性四面体（miRNA-21或miRNA-155）门控的NMOFs。在miRNA存在的情况下，miRNA响应性四面体与NMOFs的解离导致NMOFs解锁并释放负载物。miRNA响应性四面体门控杂化载体的进一步发展包括以下方面。（i）通过对miRNA门控单元进行适当的工程设计，证明了通过miRNA触发物的再生实现载体的核酸外切酶III（Exo III）放大解锁以及负载药物的增强释放。（ii）通过应用miRNA-21响应性DNA四面体门控的载DOX的NMOFs和miRNA-155响应性DNA四面体门控的载CPT的NMOFs的混合物，证明了药物的多重miRNA-21/miRNA-155指令释放。与类似的DNA双链修饰的NMOFs相比，DNA四面体门控的载药NMOFs渗透到恶性MDA-MB-231乳腺癌细胞中表现出更有效的细胞渗透。由于癌细胞中存在的酸性pH值或MDA-MB-231恶性细胞中存在的miRNA-21，与非恶性上皮MCF-10A乳腺癌细胞相比，对恶性细胞表现出有效的和选择性细胞毒性。
