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

ACS Nano. 2021 Apr 27;15(4):6645-6657. doi: 10.1021/acsnano.0c09996. Epub 2021 Mar 31.

Abstract

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.

Keywords: aptamer targeting; cancer cell; doxorubicin; drug release; multiplexed release; nanoparticles; stimuli-responsive.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA
  • Doxorubicin / pharmacology
  • Drug Carriers
  • Drug Delivery Systems
  • Hydrogen-Ion Concentration
  • Metal-Organic Frameworks*
  • MicroRNAs*
  • Nanoparticles*

Substances

  • Drug Carriers
  • Metal-Organic Frameworks
  • MicroRNAs
  • Doxorubicin
  • DNA