Achieving a "all in one" Fe/Tm-MOFs with controllable photothermal and catalytic performance for imaging-guided multi-modal synergetic therapy.

Targeting excess H2O2 in the tumor microenvironment, nanotheranostic agents for catalytic therapy are designed based on Fenton reaction, catalyzing H2O2 into oxygen and hydroxyl radical (OH). But the catalytic efficiency in tumor microenvironment is not satisfactory. In order to solve the problem, a series of bimetallic-dual ligands metal-organic frameworks Fe/Tm-MOFs were designed, that Fe3+ and Tm3+ as metalions, 2-methylimidazole and trimesic acid as ligands. Due to the doped Tm3+ in Fe/Tm-MOFs and the conjugated structures formed by two ligands, the rate of electron transfer was improved, thus promoting the generation of OH at some extent. In addition, the photothermal effect of Fe/Tm-MOFs further promotes the generation of OH, which was evidenced by the 3,3',5,5'-tetramethylbenzidine(TMB). Combining the drug loading and release capabilities of Fe/Tm-MOFs, synergetic therapy of photothermal/chemo-/catalytic therapy can be achieved. In vitro results reveal that DOX release behaviors are both pH- and thermal-responsive. In vivo anti-cancer results show that the tumors of mice almost disappeared within 10 days, which were injected with Fe/Tm-MOFs/DOX and irradiated with 808 nm for 10 min. Thus, an excellent therapeutic performance has been achieved. Besides, Fe/Tm-MOFs can serve as a multimodality bioimaging contrast agent, covering fluorescence imaging, photothermal imaging and magnetic resonance imaging. Thus, an all-in-one nanotheranostic agent is constructed, improving the catalytic efficiency and providing a novel method to design an efficient nanotheranostic agent.

"Dual-Key-and-Lock" dual drug carrier for dual mode imaging guided chemo-photothermal therapy.

Drug resistance and side effects are the two main problems of chemotherapy. In order to address these big challenges, p-PB@d-SiO2, which has the ability to co-deliver both the hydrophobic drug doxorubicin hydrochloride (DOX) and the hydrophilic drug ibuprofen (IBU), is constructed to achieve synergistic treatment. The drug-loaded nanoparticle consists of porous Prussian blue (p-PB) as the core and dendrimer-like SiO2 (d-SiO2) as the shell, which is further thiolated and coated with polyethylene glycol thiol (HS-PEG) to form the "Dual-Key-and-Lock" drug carrier p-PB@d-SiO2-SS-PEG. The locked drugs can only be released in the presence of cooperative triggers, i.e., a high glutathione concentration (the first key) and an acidic environment (the second key). The "dual key"-triggered release is much more significant in cancer lesions than in normal tissues, reducing side effects. Furthermore, cell viability experiments highlight the superior therapeutic efficacy of the dual-drug-loaded nanoparticles compared with the single-drug systems (60%, 73% and 86% vs. 56%, 68%, and 76% at 100, 200 and 500 µg mL-1, respectively). In vitro and in vivo experiments demonstrate the potential application of p-PB@d-SiO2-SS-PEG for dual-mode fluorescence and magnetic-resonance-imaging-guided chemo-photothermal therapy. The "Dual-Key-and-Lock" drug carrier system exhibits the "1 + 1 > 2" effect, demonstrating its excellent performance in synergy therapy for improved therapeutic efficiency and thereby reducing conventional drug resistance and side effects.

Synthesis of 'dual-key-and-lock' drug carriers for imaging and improved drug release.

In this work, a 'dual-key-and-lock' drug carrier was designed to respond to the tumor microenvironment (TME). A core-shell Fe-MOF@ZIF-8 was synthesized, with ZIF-8 as the shell (the first lock) to encapsulate catalase (CAT), and the Fe metal-organic framework (MOF) as the core (the second lock) to encapsulate the anticancer drug doxorubicin (DOX). Fe-MOF@ZIF-8 takes advantage of the TME-which includes a high concentration of H2O2, a weakly acidic environment and hypoxia-to achieve efficient cancer therapy. With the pH response, ZIF-8 and Fe-MOF are degraded in turn to release CAT and DOX, just like 'pH stimulation', as a key to open the two locks in turn. The released CAT reacts with the rich H2O2 in the tumor to produce O2 to regulate hypoxia, thereby improving the anticancer efficiency of the released DOX. The different cytotoxicity to L-02 cells and HeLa cells of Fe-MOF@ZIF-8 shows Fe-MOF@ZIF-8 is only harmful to cancer cells and is not harmful to normal cells. The reason is that the Fe2+/Fe3+ in Fe-MOF interact with the rich H2O2 in cancer cells to generate hydroxyl radicals (cOH), which is proved by the color of the solution of 3,3',5,5'-tetramethylbenzidine turning blue. After loading of the drug and CAT, Fe-MOF@ZIF-8 can release CAT, DOX and cOH in response to the TME, thus killing more HeLa cells. Therefore, synthesis of 'dual-key-and-lock' drug carriers responsive to the TME is a promising strategy for cancer treatment.

Acetaldehyde-modified-cystine functionalized Zr-MOFs for pH/GSH dual-responsive drug delivery and selective visualization of GSH in living cells.

In recent years, the construction of drug carriers that integrate diagnosis and treatment has become a new trend. In this article, a metal-organic framework (Zr-MOF) was synthesized and functionalized using acetaldehyde-modified-cystine (AMC) to form the functional drug carrier Zr-MOF/AMC which could be used to determine the concentration of glutathione (GSH) for cancer diagnosis, and to achieve pH/GSH dual-responsive release of methotrexate (MTX) for cancer therapy. The cleavage of the AMC disulfide bond by GSH generates two fluorescent molecules that produce strongly enhanced fluorescence, and the intensity is proportional to the GSH concentration. The green fluorescence of Zr-MOF/AMC in cancer cells proves that it can be applied in cell imaging to detect abnormal GSH concentrations for early diagnosis. In addition, MTX loaded on the Zr-MOF/AMC is released by the cleavage of the -S-S- and -C[double bond, length as m-dash]N- bonds at the high GSH concentration and low pH in cancer cells. This dual-responsive drug release helps to deliver drugs to cancer cells more precisely. All the experiments suggest that this novel type of pH/GSH dual-responsive Zr-MOF/AMC nanoparticle may serve as a new drug delivery system for cancer diagnosis and treatment.

Multifunctional drug carrier on the basis of 3d-4f Fe/La-MOFs for drug delivery and dual-mode imaging.

Multifunctional drug carriers for simultaneous imaging and drug delivery have emerged as an important new direction for the treatment of cancer. In this study, 3d-4f heterometallic Fe/La-MOFs, with excellent fluorescence and superior positive magnetic resonance imaging with high resolution, were synthesized successfully. The feasibility of Fe/La-MOFs for use in multifunctional drug delivery was demonstrated using doxorubicin hydrochloride (DOX) as the drug model. After modification with tunable amino modified silica layers, the drug loading increased to 150.2 mg g-1 from 23.9 mg g-1, and the pH responsive drug release climbed 80% from 10% upon regulating the pH from 5.8 to 7.4. T2-Weighted magnetic resonance imaging (MRI) and fluorescence optical imaging (FOI) both showed a clear concentration-dependent contrast enhancement, indicating potential application as a MRI/FOI dual mode imaging agent. In addition, the FOI of 4T1 cells loaded with Fe/La-MOFs demonstrated their capacity for imaging living cells. The particles were tracked by MRI, and the transverse relativity (r2) ranks among the highest reported for Fe3+complexes (100.49 mM-1 s-1). In summary, this is the first report on 3d-4f MOF particles displaying pH-responsive delivery and MRI/FOI dual mode imaging.

Controlled synthesis of up-conversion luminescent Gd/Tm-MOFs for pH-responsive drug delivery and UCL/MRI dual-modal imaging.

Using a facile one-step hydrothermal method, a series of metal-organic frameworks containing Gd/Tm (Gd/Tm-MOFs) were prepared successfully. Through the mutual activation of Gd3+ and Tm3+, Gd/Tm-MOFs showed unexpected excellent up-conversion luminescence (UCL) and a superior positive magnetic resonance image (MRI). Using doxorubicin hydrochloride (DOX) as a drug model, the feasibility of Gd/Tm-MOFs as a multifunctional drug carrier was demonstrated. Through modifying Gd/Tm-MOFs with uniform mesoporous silica (mSiO2) shells and folic acid (FA), the drug loading was improved up to 41.5 mg g-1, and pH responsive drug release increased to 64% from 12% by regulating the pH from 5.8 to 7.4. Also, the particles were tracked by MRI, and the second highest longitudinal relaxivity (r1) among the reported gadolinium complexes of 225.86 mM-1 s-1 was achieved. The cell imaging shows obvious blue and red luminescence under 980 nm laser excitation, and the up-conversion luminescence is unique because there is no autofluorescence from cells under 980 nm excitation. This indicates their promising application in the biological field. All the experiments indicate the promising application of Gd/Tm-MOFs in diagnosis and treatment.

A multifunctional composite Fe3O4/MOF/l-cysteine for removal, magnetic solid phase extraction and fluorescence sensing of Cd(ii).

Fe3O4/MOF (metal organic framework)/l-cysteine was synthesized and applied for the removal of Cd(ii) from wastewater. The adsorption kinetics and isotherms were investigated, and the results indicated that the adsorption obeyed the pseudo-second-order kinetic model and Langmuir isotherm. The maximum adsorption capacity was calculated to be 248.24 mg g-1. Fe3O4/MOF/l-cysteine was further applied to determine trace amounts of Cd(ii) in real water samples using ICP-AES (inductively coupled plasma-atomic emission spectroscopy) based on magnetic solid-phase extraction (MSPE). The determination limit was 10.6 ng mL-1. Additionally, Fe3O4/MOF/l-cysteine can also be used as a fluorescent sensor for "turn-off" detection of Cd(ii), and the detection limit was 0.94 ng mL-1.