Self-Assembled Metal-Organic Framework Stabilized Organic Cocrystals for Biological Phototherapy.

Organic self-assembled co-crystals have garnered considerable attention due to their facile synthesis and intriguing properties, but supramolecular interactions restrict their stability in aqueous solution, which is especially important for biological applications. Herein, we report on the first biological application of aqueous dispersible self-assembled organic co-crystals via the construction of metal-organic framework (MOF) -stabilized co-crystals. In particular, we built an electron-deficient MOF with naphthalene diimide (NDI) as the ligand and biocompatible Ca2+ as the metal nodes. An electron donor molecule, pyrene, was encapsulated to form the host-guest MOF self-assembled co-crystal. We observed that such MOF structure leads to uniquely high-density ordered arrangement and the close intermolecular distance (3.47 Å) of the charge transfer pairs. Hence, the concomitant superior charge transfer interaction between pyrene/NDI can be attained and the resultant photothermal conversion efficiency of Py@Ca-NDI in aqueous solution can thus reach up to 41.8 %, which, to the best of our knowledge, is the highest value among the reported organic co-crystal materials; it is also much higher than that of the FDA approved photothermal agent ICG as well as most of the reported MOFs. Based on this realization, as a proof of concept, we demonstrated that such a self-assembled organic co-crystal platform can be used in biological applications that are exemplified via highly effective long wavelength light photothermal therapy.

Highly Crystalline Covalent Organic Frameworks Act as a Dual-Functional Fluorescent-Sensing Platform for Myricetin and Water, and Adsorbents for Myricetin.

Selective detection of active ingredients in complex samples has always been a crucial challenge because there are many disturbing compounds, especially structural analogues that interfere with the detection. In this work, a fluorescent covalent organic framework (named COF-TD), which can be used for the selective fluorescence detection and enrichment of myricetin from complex samples, was reported for the first time. The highly crystalline COF-TD with bright blue fluorescence was formed through a solution polymerization method by the condensation reaction between 4,4',4″-(1,3,5-triazine-2,4,6-triyl)trianiline and 2,5-dihydroxy-1,4-benzenedicarboxaldehyde. Due to spatial size selectivity, multisites hydrogen bonding, and π-π interaction, myricetin can quench the fluorescence of COF-TD with an inner filter effect (IFE) and static quenching mechanisms as well as can be enriched on COF-TD. Myricetin can observably eliminate the interference of other compounds and selectively quench the fluorescence of COF-TD with a limit of detection (LOD) of 0.30 µg·mL-1. The high adsorption ability of COF-TD (Q = 124.6 mg·g-1) to myricetin was also obtained. Finally, a sensing platform based on COF-TD for myricetin was successfully developed and applied for the detection of myricetin from vine teas. In addition, COF-TD also showed good water sensing ability and could be used effectively to detect water content in organic solvent (1-18% water in acetone, 0.5-5% water in acetonitrile, 1-4.5% water in ethyl acetate, v/v). To the best of our knowledge, this is the first report where COF-TD was used to detect water in a relatively wide concentration range. In all, this work provided dual-functional fluorescent COFs with the properties of an adsorbent, opening up new methodologies for the simple, selective, and enrichment detection method for myricetin.

Fabrication of a Kagomé-type MOF Membrane by Seeded Growth on Amino-functionalized Porous Al2 O3 Substrate.

In this study, we report an efficient fabrication method for the membrane of a metal-organic framework (MOF) (Kgm-OEt) which is one kind of kagomé-type MOF with a two-dimensional (2D) sheet structure having one-dimensional (1D) channels suitable for separation of H2 from other larger gases. The Kgm-OEt seed layer was created on an Al2 O3 substrate using layer-by-layer (LBL) growth, then a membrane was fabricated by secondary growth. The membrane on a 3-aminopropyltriethoxysilane (APTEs)-treated substrate obtained in this method was continuous and defect-free with the crystal orientation suitable for gas transportation, while the membrane grown on an unmodified substrate was loosely packed with unfavorable crystal orientation.

Selenium-engineered covalent organic frameworks for high-efficiency and long-acting cancer therapy.

A porphyrin-containing covalent organic framework (COF) was synthesized as a substrate for decorating selenium nanoparticles (Se NPs) via in situ reduction. Se NP-mediated therapy (SeT) was carried out in conjunction with photodynamic therapy (PDT) to provide an increased anticancer effect and remedy the constrained efficacy of PDT.

Zinc-Based Metal-Organic Frameworks in Drug Delivery, Cell Imaging, and Sensing.

The design and structural frameworks for targeted drug delivery of medicinal compounds and improved cell imaging have been developed with several advantages. However, metal-organic frameworks (MOFs) are supplemented tremendously for medical uses with efficient efficacy. These MOFs are considered as an absolutely new class of porous materials, extensively used in drug delivery systems, cell imaging, and detecting the analytes, especially for cancer biomarkers, due to their excellent biocompatibility, easy functionalization, high storage capacity, and excellent biodegradability. While Zn-metal centers in MOFs have been found by enhanced efficient detection and improved drug delivery, these Zn-based MOFs have appeared to be safe as elucidated by different cytotoxicity assays for targeted drug delivery. On the other hand, the MOF-based heterogeneous catalyst is durable and can regenerate multiple times without losing activity. Therefore, as functional carriers for drug delivery, cell imaging, and chemosensory, MOFs' chemical composition and flexible porous structure allowed engineering to improve their medical formulation and functionality. This review summarizes the methodology for fabricating ultrasensitive and selective Zn-MOF-based sensors, as well as their application in early cancer diagnosis and therapy. This review also offers a systematic approach to understanding the development of MOFs as efficient drug carriers and provides new insights on their applications and limitations in utility with possible solutions.

Ameliorative effect of a nano chromium metal-organic framework on experimental diabetic chronic kidney disease.

Metal-Organic Frameworks (MOFs) are a new class of crystalline porous structures which can be used as a novel structure in diverse fields of medical science. Several studies have shown that chromium supplementation can be effective in amelioration of biochemical parameters of diabetes and its renal complications. Therefore, a chromium-containing MOF (DIFc) was synthetized by nanochelating technology in the present study and then its effect on biochemical indices in diabetic rats was evaluated. Diabetes was induced by high-fat diet consumption and streptozotocin (35 mg/kg) injection and then the treatment started 8 weeks after disease induction and continued for 8 weeks. The results showed that DIFc treatment decreased HOMA-IR index, blood urea nitrogen, uric acid and malondialdehyde in plasma samples. This nano MOF also reduced albumin, malondialdehyde and 8-isoprostane in urine specimen, while it increased creatinine clearance. In conclusion, DIFc MOF demonstrated promising results in the present study, indicating that it can be developed and evaluated in future investigations with the aim of designing a novel agent for management of diabetes and its renal complications.

Rapid ultrasound-assisted microextraction of atorvastatin in the sample of blood plasma by nickel metal organic modified with alumina nanoparticles.

In the present work, nickel-1,4-benzenedioxyacetic acid was synthesized as a rod-like metal organic material and then modified with alumina nanoparticles to synthesize nickel metal organic modified-Al2 O3 nanoparticles. The material was found as an efficient sorbent for the enrichment of atorvastatin in human blood plasma. After the extraction of the sample of plasma by ultrasound-assisted dispersive solid phase extraction, high performance liquid chromatography-ultraviolet was used to determine the quantitatively pre-concentrated interest analyte. The conditions for optimum extraction were achieved by the optimization of the volume of eluent, dosage of the sorbent, and time of sonication. Solution pH of 7.0, 250 µL of ethanol, 45 mg of the sorbent, and 10 min of sonication time were the conditions for extracting the atorvastatin maximum recovery of higher than 97.0%. By using desirability function for the optimization of the process, the present method showed a response that was linear ranging from 0.2 to 800 ng/mL with regression coefficient of 0.999 in the plasma of human blood with a satisfactory detection limit of 0.05 ng/mL, while the precision of interday for the current method was found to be <5%. It can be concluded that dispersive solid phase extraction method is effective for the extraction of atorvastatin from human plasma samples (97.4-102%) due to its easy operation, simplicity, repeatability, and reliability.

Covalent Organic Framework-Based Nanocomposite for Synergetic Photo-, Chemodynamic-, and Immunotherapies.

Cancer deaths are mainly caused by tumor metastases. However, tumor ablation therapies can only target the primary tumor but not inhibit tumor metastasis. Herein, a multifunctional covalent organic framework (COF)-based nanocomposite is designed for synergetic photo-, chemodynamic- and immunotherapies. Specifically, the synthesized COF possesses the ability to produce singlet oxygen under the 650 nm laser irradiation. After being metallized with FeCl3, p-phenylenediamine is polymerized on the surface of COF with Fe3+ as the oxidant. The obtained poly(p-phenylenediamine) can be used for photothermal therapy. Meanwhile, the overexpressed H2O2 in the tumor would be further catalyzed and decomposed into hydroxyl radicals (•OH) by the Fe3+/Fe2+ redox couple via Fenton reaction. Intriguingly, the increase of temperature caused by photothermal therapy can accelerate the production of •OH. Moreover, the tumor-associated antigen induced a robust antitumor immune response and effectively inhibited tumor metastasis in the presence of anti-PD-L1 checkpoint blockade. Such a COF-based multifunctional nanoplatform provides an efficacious treatment strategy for both the primary tumor and tumor metastasis.

Post-synthesis strategy to integrate porphyrinic metal-organic frameworks with CuS NPs for synergistic enhanced photo-therapy.

Multifunctional nanotheranostic systems with both therapeutic and imaging functions are highly desired for the development of more effective and less toxic anti-tumor drugs. Herein, a simple but effective method is reported to fabricate a novel PCN-CuS-FA-ICG-based nanoplatform for dual-modal imaging-guided synergistic photothermal/photodynamic therapy. Porphyrinic metal-organic frameworks with CuS NPs are obtained in aqueous solution via a simple post-synthesis strategy. Furthermore, to obtain a more effective therapy, indocyanine green (ICG) was incorporated into the multifunctional theranostic platform to promote the photothermal therapeutic effect. The as-prepared PCN-CuS-FA-ICG not only exhibits an excellent 1O2 generation efficiency under 650 nm irradiation to achieve remarkable photodynamic cell killing, but also presents outstanding photothermal conversion under 808 nm irradiation to destroy tumor tissues by hyperthermia. In particular, the nanotherapeutic agent realized fluorescence and thermal imaging dual-modal imaging-guided cancer treatment. Meanwhile, in vivo experiments confirmed the evident accumulation of nanoparticles (NPs) at local tumors, and tumor growth was inhibited obviously via synergistic photothermal/photodynamic therapy with negligible side effects.

Assembly of Black Phosphorus Nanosheets and MOF to Form Functional Hybrid Thin-Film for Precise Protein Capture, Dual-Signal and Intrinsic Self-Calibration Sensing of Specific Cancer-Derived Exosomes.

As the emerging and noninvasive biomarkers, exosomes play an important role in cancer screening, cancer-related immune response, and the physiological process. The sensitive, specific, and efficient detection of cancer cell-derived exosomes is of significance for early cancer diagnosis of patients. This work developed a novel dual-signal and intrinsic self-calibration aptasensor of exosomes based on a functional hybrid thin-film platform. This platform was constructed via facile assembly of black phosphorus nanosheets (BPNSs) and ferrocene (Fc)-doped metal-organic frameworks (ZIF-67) on indium tin oxide (ITO) slice, followed by combining methylene blue (MB)-labeled single- strand DNA aptamer on ITO slice. The resultant aptamer-BPNSs/Fc/ZIF-67/ITO platform had dual redox-signal responses of MB (labeled on aptamer) and Fc (doped into ZIF-67). In the presence of specific cancer cell-derived exosomes, the redox current of MB regularly reduced and that of Fc (as reference) hardly changed. An intrinsic self-calibration aptasensor was achieved and enabled sensitive detection of exosomes, showing a limit of detection down to 100 particles mL-1. The aptasensor with a capability of precise protein capture can efficiently determine specific cancer cell-derived exosomes in practical human serum and plasma samples from healthy individuals and breast cancer patients. In light of excellent performances, this aptasensor can be expanded to multiple biomarkers from cell line exosomes and is beneficial for exploring advanced techniques for high-performance detection of exosomes derived from different types of cancer cells. This work promotes the development of current techniques for early cancer screening and clinical diagnosis.

A biomimetic MOF nanoreactor enables synergistic suppression of intracellular defense systems for augmented tumor ablation.

A homotypic cancer cell membrane camouflaged MOF-based nanoreactor with the photothermal-starvation effect has been developed for synergistic suppression of intracellular defensive systems for enhanced cancer treatment.

Metal-organic frameworks based fluorescent sensor array for discrimination of flavonoids.

Metal-organic frameworks (MOFs) are hotly investigated as a novel kind of fluorescent sensing materials in recent years. However, the application of MOF sensing to drug analysis is still very difficult yet, because the structural similarity among drug homolog-ues exceeds the discrimination ability of MOFs. Array sensing technique, which relies on the combined responses of a group of sensing materials, is a viable way to solve this problem. In this work, we chose five luminescent MOFs with different fluorophores to construct a fluorescent sensor array for the analysis of flavonoids. With the response pattern of these MOFs and the statistical methods of linear discriminant analysis and hierarchical cluster analysis, nine flavonoids with similar structures were correctly discriminated. By the combination with UV spectrum, our method could even realize the qualification and quantification of the flavonoid samples with unknown concentrations. This work is the first time of using MOFs to successfully distinguish multiple drug homolog-ues.

Smart All-in-One Thermometer-Heater Nanoprobe Based on Postsynthetical Functionalization of a Eu(III)-Metal-Organic Framework.

Real-time temperature feedback in tissue based on photothermal therapy is an urgent problem to be solved in cancer treatment. Herein, a smart all-in-one nanoprobe THA@Eu-NMOF@Fe/TA was designed and assembled by postsynthetical functionalization of an Eu(III)-based nanoscale metal-organic framework (Eu-NMOF) with a two-photon-absorbing ß-diketonate ligand 4,4,4-trifluoro-1-(9-hexylcarbazol-3-yl)-1,3-butanedione (HTHA) and Fe(III)/tannic acid assembly (Fe/TA). Such a functionalized material can simultaneously achieve the temperature-sensing and optical heating under a single beam of near-infrared (NIR) light. Under 808 nm laser excitation, real-time feedback of temperature by monitoring thermoresponsive fluorescence emission ratio ( I616/ I590) and fluorescence lifetime of Eu(III) ions were realized. Meantime, Fe/TA served as the photothermal agent and antibacterial agent to implement photothermal therapy (PTT) and antibacteria simultaneously. The functions of the nanoprobe were proved with ex vivo experiments, and the antibacterial activity against Gram-positive and Gram-negative bacteria of the probe was also elaborately evaluated. Our work paves a new avenue for engineering a new cancer treatment probe which can achieve real-time temperature sensing feedback during PTT and antibacterial process.

Preparation of a one-dimensional nanorod/metal organic framework Janus nanoplatform via side-specific growth for synergistic cancer therapy.

Janus nanoparticles (JNPs) have emerged in recent years as new compartmentalized colloids with two sides of different components, chemical properties or morphologies that have opened up a wide range of unique applications in biomedicine. Here, we explored a unique lactobionic acid (LA) modified metallic one-dimensional nanorod/metal organic framework (1D NR/MOF) JNP, the LA-gold NR/zeolitic imidazolate framework-8 (LA-AuNR/ZIF-8) JNP, for computed X-ray tomography (CT) image-guided liver cancer targeted synergistic chemo-photothermal theranostics. Taking advantage of the 1D nanostructure of the AuNRs, polyacrilic acid (PAA) was selectively attached to one side of the AuNRs for further growth of ZIF-8, and the exposed side of the AuNRs was modified with the targeting agent LA, thus realizing the drug loading and cancer specific targeting. In addition, the high contrast of Au makes the LA-AuNR/ZIF-8 JNPs suitable for CT image-guided cancer therapy. Furthermore, mice treated with doxorubicin (DOX) loaded LA-AuNR/ZIF-8 JNPs under near infrared (NIR) laser irradiation showed significant tumor inhibition, indicating the effective combination of pH and NIR stimuli response release, cancer specific targeting and synergistic chemotherapy and photothermal therapy.

Water Stable [Tb4] Cluster-Based Metal-Organic Framework as Sensitive and Recyclable Luminescence Sensor of Quercetin.

A novel 3D metal-organic framework (MOF){[Tb3(CBA)2(HCOO)(µ3-OH)4(H2O)]·2H2O·0.5DMF} n (S-1) was synthesized by the solvothermal method. The crystal structure indicates that [Tb4O4] cubane clusters self-assemble into an infinite chain by sharing vertex, which is further linked to adjacent chains through 1,1-cyclobutanedicarboxylic acid ligand (H2CBA), resulting in a honeycomb arrayed framework. S-1 possesses excellent water stability and still retains intact structure after exposure to water for 10 weeks or boiling water for 10 weeks. Interestingly, S-1 acts as a luminescence sensor to selectively and sensitively detect quercetin with the limit of detection (LOD) as low as 0.23 ppm (7.6 × 10-7 M). The relationship between relative luminescence intensity and concentration obeys linear in the range of 0-300 ppm (0-993 µM), which allows quantitative detection of quercetin. Importantly, S-1 can be reused at least six times with almost no change in luminescent intensity. Compared with the high performance liquid chromatography-mass spectrometry (HPLC-MS) method, S-1 was used to determine the content of quercetin in onionskin and apple peel samples with satisfactory results. Furthermore, a portable S-1 test paper is also developed and expected to be applied in practice. To our knowledge, S-1 is the first example of MOFs as luminescent sensor for quercetin.

Metal-Organic Framework as a Microreactor for in Situ Fabrication of Multifunctional Nanocomposites for Photothermal-Chemotherapy of Tumors in Vivo.

Metal-organic frameworks (MOFs) have been applied in chemotherapeutic drug loading for cancer treatment, but challenging for cases with large and malignant lesions. To overcome these difficulties, combinational therapies of chemotherapy and photothermal therapy (PTT) with potentially high selectivity and slight aggressiveness have drawn tremendous attention to treat various tumors. However, current MOF-based nanohybrids with photothermal agents involve tedious synthesis processes and heterogeneous structures. Herein, we employ MIL-53 as a microreactor to grow polypyrrole (PPy) nanoparticles in situ for the fabrication of PPy@MIL-53 nanocomposites. Fe3+ in MIL-53, as an intrinsic oxidizing agent, can oxidize the pyrrole monomer to generate PPy nanoparticles. The prepared PPy@MIL-53 nanocomposites integrate the intrinsic advantages of MOFs with high drug loading ability and magnetic resonance imaging (MRI) capacity, and PPy nanoparticles with outstanding PTT ability and excellent biocompatibility. The versatile PPy@MIL-53 nanocomposites with multiple functions displayed in vitro and in vivo synergism of photothermal-chemotherapy for cancer, potentially MRI-guided. The proposed MOF microreactor-based synthesis strategy shows a promising prospect in the fabrication of diverse multifunctional nanohybrids for tumor theranostics in vivo.

Facile synthesis of a metal-organic framework nanocarrier for NIR imaging-guided photothermal therapy.

The NIR dye cyanine (Cy) is one of the most significant phototherapy agents (PTAs) due to its strong NIR absorbance, high thermal conversion capacity and good safety. However, its clinic application is seriously limited owing to its inherent properties as an organic dye, including low solubility, poor selectivity, and fast clearance. Thus, herein, we embed Cy into the zeolitic imidazolate framework-8 (Cy@ZIF-8) for antitumor photothermal therapy (PTT). The obtained Cy@ZIF-8 NPs not only have good water solubility and excellent photostability, but also exhibit strong NIR absorbance and great photothermal conversion efficiency. Especially, the Cy@ZIF-8 NPs efficaciously inhibit tumor growth and possess outstanding NIR imaging capacity both in vitro and in vivo. This work demonstrates the theranostic value of Cy@ZIF-8 NPs for imaging-guided PTT therapy, and also encourages the further study of other PTAs@ZIF-8 composites for better anticancer PTT.

Synthesis and characterization of MIL-101(Cr) intercalated by polyaniline composite, doped with silica nanoparticles and its evaluation as an efficient solid-phase extraction sorbent.

A metal-organic framework/polyaniline composite was synthesized and doped with silica nanoparticles. The structure and morphology of the composite were characterized using Fourier transform infrared spectroscopy and scanning electron microscopy. It was packed inside a cartridge and evaluated for the solid-phase extraction of thymol and carvacrol, followed by gas chromatography with flame ionization detection measurement. The influence of the important experimental variables on the efficiency of the proposed method, including pH, ionic strength, volume of sample solution and type, and volume of eluent were studied and optimized. Under the optimal conditions, the relative standard deviations were found to be 3.8 and 9.8% for thymol and carvacrol, respectively, and the corresponding limits of detection were 0.1 and 1.0 ng/mL. The linear dynamic ranges for the calibration curves of the analytes were 10-10000 ng/mL, with determination coefficients (R2 ) > 0.993. The limits of quantifications were found to be 0.01 and 0.5 µg/mL, for thymol and carvacrol, respectively. The prepared nanocomposite sorbent was applied successfully to the extraction and determination of thymol and carvacrol in Lamiaceae plant extracts and a honey sample, with relative recoveries in the range of 90.28-122.0%.

Solid phase microextraction of phthalic acid esters from vegetable oils using iron (III)-based metal-organic framework/graphene oxide coating.

A hybrid composite featuring an iron-based metal-organic framework Material of Institute Lavoisier-88(Fe) and graphene oxide (MIL-88(Fe)/GO) was synthesized and used as the solid-phase microextraction (SPME) coating. The SPME fiber was prepared by covalent bonding of the MIL-88(Fe)/GO composite onto the stainless steel substrate. The fiber had a good durability and allowed >100 replicate extractions. The developed method, which combined the MIL-88(Fe)/GO coated fiber based SPME with gas chromatography-flame ionization detection (GC-FID), achieved low limits of detection (0.5-2.0 ng g-1, S/N = 3) and good linearity (r2 > 0.994) for the phthalic acid esters (PAEs) from various vegetable oil samples. The repeatability and fiber-to-fiber reproducibility were in the range of 4.0-9.1% and 5.7-11.4%, respectively. The method was successfully applied to the analysis of PAEs from vegetable oil samples with good recoveries (83.1-104.1%) and satisfactory precisions (RSDs < 10.5%), indicating that the MIL-88(Fe)/GO hybrid composite is a good coating material for the SPME of PAEs.

MOF based fluorescent assay of xanthine oxidase for rapid inhibitor screening with real-time kinetics monitoring.

The activity assay of xanthine oxidase (XO) is of great application value in clinical diagnosis because the abnormal level of this enzyme is related to a series of pathological states. In this work, a Zr based metal-organic framework (BTB-MOF) with stable photoluminescence in pure water and buffer solution was synthesized. The examination about the fluorescent responses of this material to xanthine and its oxidation product, uric acid, showed that, although both of them affected the emission of BTB-MOF in quenching form, the efficiencies presented much difference. Taking advantage of this feature, a fluorescent method was developed for the activity assay of XO, that is, BTB-MOF was added to the enzymatic oxidation system as a sensor to transduce the proceeding of the reaction real-timely to the signal of fluorescent intensity change. Our method can work under the interference of normal biologically related species, and precisely reflect XO activity in the range of 0.2-40 U L-1 (detection limit = 0.004 U L-1). With consecutive fluorescence intensity scan, this assay could be applied as a high speed screening method of XO inhibitors with the testing time of 1 min. This work shows the wide potential application of MOFs in enzyme analysis.