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PH-responsive and hyaluronic acid-functionalized metal-organic frameworks for therapy of osteoarthritis.

ABSTRACT: Drug therapy of osteoarthritis (OA) is limited by the short retention and lacking of stimulus-responsiveness after intra-articular (IA) injection. The weak acid microenvironment in joint provides a potential trigger for controlled drug release systems in the treatment of OA. Herein, we developed an pH-responsive metal?-?organic frameworks (MOFs) system modified by hyaluronic acid (HA) and loaded with an anti-inflammatory protocatechuic acid (PCA), designated as MOF@HA@PCA, for the therapy of OA. Results demonstrated that MOF@HA@PCA could smartly respond to acidic conditions in OA microenvironment and gradually release PCA, which could remarkably reduce synovial inflammation in both IL-1? induced chondrocytes and the OA joints. MOF@HA@PCA also down-regulated the expression of inflammatory markers of OA and promoted the expression of cartilage-specific makers. This work may provide a new insight for the design of efficient nanoprobes for precision theranostics of OA .

SUBMITTER: Xiong F

PROVIDER: S-EPMC7523381 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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pH-responsive and hyaluronic acid-functionalized metal-organic frameworks for therapy of osteoarthritis.

Xiong Feng F Qin Zainen Z Chen Haimin H Lan Qiumei Q Wang Zetao Z Lan Nihan N Yang Yuan Y Zheng Li L Zhao Jinmin J Kai Dan D

Journal of nanobiotechnology 20200929 1

Drug therapy of osteoarthritis (OA) is limited by the short retention and lacking of stimulus-responsiveness after intra-articular (IA) injection. The weak acid microenvironment in joint provides a potential trigger for controlled drug release systems in the treatment of OA. Herein, we developed an pH-responsive metal - organic frameworks (MOFs) system modified by hyaluronic acid (HA) and loaded with an anti-inflammatory protocatechuic acid (PCA), designated as MOF@HA@PCA, for the therapy of OA. ...[more]

PMID: 32993662

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Project description:A versatile approach to modify metal-organic framework nanoparticles (NMOFs) with nucleic acid tethers, using the "click chemistry" method is introduced. The nucleic acid-functionalized NMOFs are used to prepare stimuli-responsive carriers of loads (fluorescence probes or anti-cancer drugs). Two different stimuli-responsive nucleic acid-based NMOFs are presented. One system involves the preparation of pH-responsive NMOFs. The NMOFs are loaded with fluorophores or doxorubicin anti-cancer drug and locked in the NMOFs by pH-responsive DNA duplex capping units. At pH = 5.0 the capping units are unlocked, leading to the release of the loads. The AS1411 aptamer is conjugated to the locking units as the targeting unit for the nucleolin biomarker present in cancer cells. The pH-responsive doxorubicin-loaded NMOFs and, in particular, the AS1411 aptamer-modified pH-responsive NMOFs reveal selective, targeted, cytotoxicity toward MDA-MB-231 breast cancer cells. A second system involves the synthesis of NMOFs that are loaded with fluorophores or doxorubicin and capped with metal-ion-dependent DNAzyme/substrate complexes as locking units (metal ion = Mg2+ or Pb2+ ions). In the presence of the respective metal ions, the nucleic acid locking units are cleaved off, resulting in the release of the loads. Also, "smart" Mg2+-ion-dependent DNAzyme capped doxorubicin-loaded NMOFs are synthesized via the integration of the ATP aptamer sequence in the loop domain of the Mg2+-dependent DNAzyme. The unlocking of these NMOFs proceeds effectively only in the presence of ATP and Mg2+ ions, acting as cooperative triggers. As ATP is over-expressed in cancer cells, the "smart" carrier provides sense-and-treat functions. The "smart" ATP/Mg2+-triggered doxorubicin-loaded NMOFs reveal selective cytotoxicity toward MDA-MB-231 cancer cells. Beyond the use of the metal-ion-dependent DNAzymes as ion-responsive locks of drug-loaded NMOF carriers, the DNAzyme-capped fluorophore-loaded NMOFs are successfully applied as functional units for multiplexed ion-sensing and for the design of logic-gate systems.

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PH-responsive and hyaluronic acid-functionalized metal-organic frameworks for therapy of osteoarthritis.

Publications

pH-responsive and hyaluronic acid-functionalized metal-organic frameworks for therapy of osteoarthritis.

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