pH和miRNA响应性DNA-四面体/金属有机骨架共轭：功能性感官和治疗载体,ACS Nano

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pH和miRNA响应性DNA-四面体/金属有机骨架共轭：功能性感官和治疗载体
ACS Nano ( IF 15.8 ) Pub Date : 2021-03-31 , DOI: 10.1021/acsnano.0c09996
Pu Zhang ₁ , Yu Ouyang ₁ , Yang Sung Sohn ₂ , Rachel Nechushtai ₂ , Eli Pikarsky ₃ , Chunhai Fan ₄ , Itamar Willner ₁

Affiliation

介绍了由DNA四面体门锁定的载有药物的UiO-66金属-有机框架纳米颗粒NMOF组成的刺激响应性杂合结构的合成。混合系统将药物在多孔NMOF中的高负载能力与DNA四面体的有效细胞渗透特性结合在一起。核酸官能化的UiO-66 NMOF装有药物（阿霉素，DOX或喜树碱，CPT）或染料作为药物模型（若丹明6G或荧光素），并用于制备刺激反应性载体。在这项研究中，提出了两种不同的刺激反应性NMOF。一种系统引入了由pH响应DNA四面体锁定的载有药物的NMOF。在酸性pH值下，门控四面体通过i-基序结构的形成而与NMOF分离，导致NMOF解锁并释放毒品。此外，四面体门用AS1411适体系链修饰，这些将载药的NMOF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载有药物/染料并被microRNA（miRNA）响应的四面体（miRNA-21或miRNA-155）封闭的NMOF。在存在miRNA的情况下，miRNA反应性四面体与NMOF的解离导致NMOF的解锁和负载的释放。miRNA反应性四面体门控杂合载体的进一步发展包括以下内容。（i）通过适当改造miRNA门控单元，通过miRNA触发子的再生，核酸外切酶III（Exo III）扩增载体的解锁，并证明了所载药物的释放增强。（ii）通过应用miRNA-21响应的DNA四面体修饰的DOX加载的NMOF和miRNA-155响应的DNA四面体修饰的CPT加载的NMOF的混合物，多重miRNA-21 / miRNA-155决定了药物的释放被证明。与模拟DNA双链体修饰的NMOF相比，DNA四面体门控，载药NMOF渗透进入恶性MDA-MB-231乳腺癌细胞表现出更有效的细胞渗透。与非恶性上皮MCF-10A乳腺细胞相比，由于存在于癌细胞中的酸性pH或存在于MDA-MB-231恶性细胞中的miRNA-21，证明了对恶性细胞的有效和选择性的细胞毒性。（ii）通过应用miRNA-21响应的DNA四面体修饰的DOX加载的NMOF和miRNA-155响应的DNA四面体修饰的CPT加载的NMOF的混合物，多重miRNA-21 / miRNA-155决定了药物的释放被证明。与模拟DNA双链体修饰的NMOF相比，DNA四面体门控，载药NMOF渗透进入恶性MDA-MB-231乳腺癌细胞表现出更有效的细胞渗透。与非恶性上皮MCF-10A乳腺细胞相比，由于存在于癌细胞中的酸性pH或存在于MDA-MB-231恶性细胞中的miRNA-21，证明了对恶性细胞的有效和选择性的细胞毒性。（ii）通过应用miRNA-21响应的DNA四面体修饰的DOX加载的NMOF和miRNA-155反应的DNA四面体修饰的CPT加载的NMOF的混合物，多重miRNA-21 / miRNA-155决定了药物的释放被证明。与模拟DNA双链体修饰的NMOF相比，DNA四面体门控，载药NMOF渗透进入恶性MDA-MB-231乳腺癌细胞表现出更有效的细胞渗透。与非恶性上皮MCF-10A乳腺细胞相比，由于存在于癌细胞中的酸性pH或存在于MDA-MB-231恶性细胞中的miRNA-21，证明了对恶性细胞的有效和选择性的细胞毒性。与模拟DNA双链体修饰的NMOF相比，DNA四面体门控，载药NMOF渗透进入恶性MDA-MB-231乳腺癌细胞表现出更有效的细胞渗透。与非恶性上皮MCF-10A乳腺细胞相比，由于存在于癌细胞中的酸性pH或存在于MDA-MB-231恶性细胞中的miRNA-21，证明了对恶性细胞的有效和选择性的细胞毒性。与模拟DNA双链体修饰的NMOF相比，DNA四面体门控，载药NMOF渗透进入恶性MDA-MB-231乳腺癌细胞表现出更有效的细胞渗透。与非恶性上皮MCF-10A乳腺细胞相比，由于存在于癌细胞中的酸性pH或存在于MDA-MB-231恶性细胞中的miRNA-21，证明了对恶性细胞的有效和选择性的细胞毒性。

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pH- and miRNA-Responsive DNA-Tetrahedra/Metal–Organic Framework Conjugates: Functional Sense-and-Treat Carriers

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.

更新日期：2021-04-28

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