Construction of Multiform Hollow-Structured Covalent Organic Frameworks via a Facile and Universal Strategy for Enhanced Sonodynamic Cancer Therapy.

The special structural morphology of hollow covalent organic frameworks (HCOFs) has an important influence on their applications. However, the rapid and precise control of morphology for HCOFs still remains largely challenging. Herein, we present a facile and universal two-step strategy based on solvent evaporation and oxidation of imine bond for the controllable synthesis of HCOFs. The strategy enables to prepare HCOFs in a greatly shortened reaction time and seven kinds of HCOFs are fabricated by the oxidation of imine bond via hydroxyl radicals (⋅OH) generated from Fenton reaction. Importantly, a fascinating library of HCOFs with diverse nanostructures, including bowl-like, yolk-shell, capsule-like and flower-like morphologies, has been ingeniously constructed. Owing to the large cavities, the obtained HCOFs are ideal candidates for drug delivery, which are employed to load five small molecule drugs, achieving the enhanced sonodynamic cancer therapy in vivo.

Double-activation of mitochondrial permeability transition pore opening via calcium overload and reactive oxygen species for cancer therapy.

BACKGROUND: Calcium ions (Ca2+) participates in various intracellular signal cascades and especially plays a key role in pathways relevant to cancer cells. Mitochondrial metabolism stimulated by calcium overload can trigger the opening of the mitochondrial permeability transition pore (MPTP), which leads to cancer cell death. METHODS: Herein, a mitochondrial pathway for tumour growth inhibition was built via the double-activation of MPTP channel. Fe2+ doped covalent organic frameworks (COF) was synthesised and applied as template to grow CaCO3 shell. Then O2 was storaged into Fe2+ doped COF, forming O2-FeCOF@CaCO3 nanocomposite. After modification with folic acid (FA), O2-FeCOF@CaCO3@FA (OFCCF) can target breast cancer cells and realize PDT/Ca2+ overload synergistic treatment. RESULTS: COF can induce the production of 1O2 under 650 nm irradiation for photodynamic therapy (PDT). Low pH and hypoxia in tumour microenvironment (TME) can activate the nanocomposite to release oxygen and Ca2+. The released O2 can alleviate hypoxia in TME, thus enhancing the efficiency of COF-mediated PDT. Abundant Ca2+ were released and accumulated in cancer cells, resulting in Ca2+ overload. Notably, the reactive oxygen species (ROS) and Ca2+ overload ensure the sustained opening of MPTP, which leads to the change of mitochondria transmembrane potential, the release of cytochrome c (Cyt c) and the activation of caspases 3 for cancer cell apoptosis. CONCLUSION: This multifunctional nanosystem with TME responded abilities provided a novel strategy for innovative clinical cancer therapy.

Covalent Organic Framework-Titanium Oxide Nanocomposite for Enhanced Sonodynamic Therapy.

Sonodynamic therapy (SDT) has attracted wide attention for its high tissue-penetration depth capacity. However, developing new kinds of sonosensitizers that are capable of generating large amounts of reactive oxygen species (ROS) still remains a challenge. Herein, covalent organic framework-titanium oxide nanoparticles (COF-TiO2 NPs) were successfully synthesized by using COF as a template. Under ultrasound (US) irradiation, large quantities of ROS can be generated, and compared with pure TiO2 NPs, the SDT performance of COF-TiO2 nanoparticles was significantly improved due to the narrower band gap. Both in vitro and in vivo experiments demonstrated the great tumor inhibitory effect via COF-TiO2-mediated SDT. This work broadens the biomedical applications of COF-based composites.

AgN3-Catalyzed Hydroazidation of Terminal Alkynes and Mechanistic Studies.

The hydroazidation of alkynes is the most straightforward way to access vinyl azides-versatile building blocks in organic synthesis. We previously realized such a fundamental reaction of terminal alkynes using Ag2CO3 as a catalyst. However, the high catalyst loading seriously limits its practicality, and moreover, the exact reaction mechanism remains unclear. Here, on the basis of X-ray diffraction studies on the conversion of silver salts, we report the identification of AgN3 as the real catalytic species in this reaction and developed a AgN3-catalyzed hydroazidation of terminal alkynes. AgN3 proved to be a highly robust catalyst, as the loading of AgN3 could be as low as 5 mol %, and such a small proportion of AgN3 is still highly efficient even at a 50 mmol reaction scale. Further, the combination of experimental investigations and theoretical calculations disclosed that the concerted addition mechanism via a six-membered transition state is more favored than the classical silver acetylide mechanism.

Copper-Doped Nanoscale Covalent Organic Polymer for Augmented Photo/Chemodynamic Synergistic Therapy and Immunotherapy.

Due to the specific tumor microenvironment (TME) and immunosuppressive state of cancer cells, conventional antitumor therapies face severe challenges, such as high rates of recurrence and metastasis. Herein, Cu-PPT nanoparticles were synthesized based on copper acetate, p-phenylenediamine, and 5,10,15,20-tetra-(4-aminophenyl)porphyrin via oxidative coupling reaction for the first time, and the resultant product was used for synergistic photothermal therapy (PTT), photodynamic therapy (PDT), and chemodynamic therapy (CDT). The polymer nanoparticles exhibited excellent photodynamic and photothermal effect with a photothermal conversion efficacy of 40.1% under 650 and 808 nm laser irradiation, respectively. Encapsulated Cu(I)/Cu(II) ions permitted Cu-PPT with glutathione (GSH) peroxidase-mimicking, catalase-mimicking, and Fenton-like activity to regulate TME. Depletion of overexpressed GSH would reduce antioxidant capacity, generated O2 could relieve hypoxia for enhancing PDT, and hyperthermia from PTT could promote the yield of ·OH. This multifunctional nanosystem with cascade reactions could inhibit tumor growth and activate immune responses effectively. By further combining with antiprogrammed death-ligand 1 (anti-PD-L1) checkpoint blockade therapy, distant tumor growth and cancer metastasis were successfully suppressed.

Yolk-Shell Structured Au Nanostar@Metal-Organic Framework for Synergistic Chemo-photothermal Therapy in the Second Near-Infrared Window.

Light-sensitive yolk-shell nanoparticles (YSNs) as remote-controlled and stimuli-responsive theranostic platforms provide an attractive method for synergistic cancer therapy. Herein, a kind of novel stimuli-responsive multifunctional YSNs has been successfully constructed by integrating star-shaped gold (Au star) nanoparticles as the second near-infrared (NIR-II) photothermal yolks and biodegradable crystalline zeolitic imidazolate framework-8 (ZIF-8) as the shells. In this platform, a chemotherapeutic drug (doxorubicin hydrochloride, DOX) was encapsulated into the cavity, which can show the behavior of controlled release due to the degradation process of ZIF-8 in the mildly acidic tumor microenvironment. Upon the 1064 nm (NIR-II biowindow) laser irradiation, gold nanostar@ZIF-8 (Au@MOF) nanoparticles exhibited outstanding synergistic anticancer effect based on their photothermal and promoted cargo release properties. Moreover, the strong NIR region absorbance endows the Au@MOF of NIR thermal imaging and photoacoustic (PA) imaging properties. This work contributes to design a stimuli-responsive "all-in-one" nanocarrier that realizes bimodal imaging diagnosis and chemo-photothermal synergistic therapy.

One-Pot Synthesis of DOX@Covalent Organic Framework with Enhanced Chemotherapeutic Efficacy.

Covalent organic frameworks (COFs) have attracted great attention across diverse research fields. However, only a few reports about the biomedical application of COFs are found in the literature. Attributed to the highly porous and tunable structure, as well as good thermal stability, COFs show great potential as drug carriers for chemotherapy. In this work, doxorubicin (DOX) was successfully in situ loaded into a COF by a one-pot method for the first time. The resultant DOX@COF platform exhibited high drug-loading capacity (32.1 wt %) and pH-responsive release property. In vitro and in vivo experiments demonstrated its good biocompatibility and enhanced antitumor efficacy.

Synthesis and integration of Fe-soc-MOF cubes into colloidosomes via a single-step emulsion-based approach.

Bottom-up fabrication of complex 3D hollow superstructures from nonspherical building blocks (BBs) poses a significant challenge for scientists in materials chemistry and physics. Spherical colloidal silica or polystyrene particles are therefore often integrated as BBs for the preparation of an emerging class of materials, namely colloidosomes (using colloidal particles for Pickering stabilization and fusing them to form a permeable shell). Herein, we describe for the first time a one-step emulsion-based technique that permits the assembly of metal-organic framework (MOF) faceted polyhedral BBs (i.e., cubes instead of spheres) into 3D hollow superstructures (or "colloidosomes"). The shell of each resultant hollow MOF colloidosome is constructed from a monolayer of cubic BBs, whose dimensions can be precisely controlled by varying the amount of emulsifier used in the synthesis.

Highly monodisperse M(III)-based soc-MOFs (M = In and Ga) with cubic and truncated cubic morphologies.

In this work, we carry out an investigation on shape-controlled growth of In(III)- and Ga(III)-based square-octahedral metal-organic frameworks (soc-MOFs). In particular, controllable crystal morphological evolution from simple cubes to complex octadecahedra has been achieved, and resultant highly uniform crystal building blocks promise new research opportunities for preparation of self-assembled MOF materials and related applications.

Self-generated etchant for synthetic sculpturing of Cu2O-Au, Cu2O@Au, Au/Cu2O, and 3D-Au nanostructures.

Structures of Gold: a simple transformative method for nanoscale sculpturing has been developed. Five different types of complex nanocomposites of cuprite and gold have been formed by using this self-etching approach.

Single-walled carbon nanohorns-based smart nanotheranostic: From phototherapy to enzyme-activated fluorescence imaging-guided photodynamic therapy.

Phototheranostics, a local non-invasive approach that integrates light-based diagnostics and therapeutics, enables precise treatment using nanotheranostic agents with minimal damage to normal tissues. However, ensuring high-efficiency ablation of cancer cells using phototheranostics for one time irradiation is highly challenging. Herein, we designed and synthesized a single-walled carbon nanohorns-based nanotheranostic agent, HA-IR808-SWNHs, by loading IR808, a photosensitizer, conjugated hyaluronic acid (HA) with an amide bond on the surface of single-walled carbon nanohorns (SWNHs) through noncovalent π-π interaction by the sonication method. The HA in HA-IR808-SWNHs improves the water dispersibility of SWNHs and endows SWNHs with targeting capabilities. Importantly, overexpressed endogenous hyaluronidase in cancer cells actively disassembles HA-IR808-SWNHs, forming small HA-IR808 fragments. The fragments exhibit a strong fluorescence signal and can be used to guide programmed photodynamic therapy for sequentially eliminating the residual living cancer cells. The current study confirms that HA-IR808-SWNHs is an endogenous enzyme-responsive nanotheranostic agent that can be employed to precisely track and ablate residual cancer cells in a spatiotemporal manner. The results strengthen the understanding of SWNH functionalization and expand its potential biomedical application, especially in cancer theranostics.

Facile Synthesis of a Cubic Porphyrin-Based Covalent Organic Framework for Combined Breast Cancer Therapy.

A cubic porphyrin-based covalent organic framework (COF) named CTP with excellent hydrophilicity was prepared with a facile method for the first time. Different from the conventional methods for the synthesis of porphyrin-based COFs, this facile strategy has greatly shortened the reaction time under mild conditions. Linking the porphyrin monomer into the COF overcame its poor solubility and biocompatibility and also narrowed the band gap owing to the formation of the π-conjugation structure. The improved biocompatibility and narrowed band gap enabled CTP to be an excellent sonosensitizer with an enhanced sonodynamic effect. Moreover, CTP could also effectively realize photothermal conversion under external irradiation due to the extended conjugated structure. This work developed a novel synthesis method for COFs and employed a COF as a sonosensitizer for the first time, which not only provided a new strategy to improve the efficiency of organic sonosensitizers but also inspired us to design more functional COFs for versatile applications.

Multifunctional carbon monoxide nanogenerator as immunogenic cell death drugs with enhanced antitumor immunity and antimetastatic effect.

The limited effect of immune checkpoint blockade (ICB) immunotherapy is subjected to the immuno-suppressive tumor microenvironment (TME). It is still a challenge to reverse the immune-suppressive state in clinical cancer therapy. Immunogenic cell death (ICD) is a way for inducing the therapeutical tumor immune system. In this work, carbon monoxide (CO) gas therapy is used to boost antitumor immunity for tumor control, metastasis and recurrence prevention. Briefly, CO2-g-C3N4-Au@ZIF-8@F127 (CCAZF) is proposed to integrate gas therapy and immunotherapy into a photocatalytic nanogenerator for overcoming the limitations of monotherapy. CCAZF exhibits a highly effective light-controllable release behavior of CO, which gradually aggravates the oxidative stress in tumor cells to induce ICD. With the induction of ICD, CO therapy enhances immune responses and enables efficient immune cells activated. When combined with ICB, CCAZF displays an enhanced immune effect, which mediates the regression of primary and distal tumors. This strategy of in-situ photocatalytic CO therapy furthest avoids the toxicity from CO leakage and provides a new method to design novel ICD inducers.

Synthesis of porphyrin-incorporating covalent organic frameworks for sonodynamic therapy.

Porphyrin-incorporating covalent organic frameworks were synthesized at room temperature. The resulting products with uniform morphology and excellent crystallinity exhibited good singlet oxygen generation ability. Both in vitro and in vivo experiments demonstrated the significant antitumor efficiency via sonodynamic therapy.

Facile synthesis of Fe-baicalein nanoparticles for photothermal/chemodynamic therapy with accelerated FeIII/FeII conversion.

Fe2+-baicalein-polyethylene glycol (Fe-BaP) nanoparticles were synthesized by a room temperature wet chemical method via coordination between Fe2+ and baicalein. Fe-BaP possessed high photothermal conversion efficiency (η = 45.6%) and excellent antitumor efficacy was achieved with the synergistic photothermal/chemodynamic tumor therapy.

Urchin-Shaped Metal Organic/Hydrogen-Bonded Framework Nanocomposite as a Multifunctional Nanoreactor for Catalysis-Enhanced Synergetic Therapy.

Ultrasound (US)-induced sonodynamic therapy (SDT) is an efficient and precise method against tumor, and the integration of multiple cancer therapies has been proved as a promising strategy for better therapeutic effects. Herein, for the first time, a multifunctional nanoreactor has been fabricated by integrating Fe-MIL-88B-NH2, PFC-1, and glucose oxidase (GOx) to form urchin-like Fe-MIL-88B-NH2@PFC-1-GOx (MPG) nanoparticles as Fenton's reagent, a sonosensitizer, and a tumor microenvironment (TME) modulator. In detail, MPG can generate •OH for chemodynamic therapy (CDT) and deplete glutathione (GSH) to alleviate the antioxidant ability of cancer cells. Moreover, catalase (CAT)-like MPG can react with H2O2 to generate O2 for relieving hypoxia in TME, enhancing GOx-catalyzed glucose oxidation to produce H2O2 and gluconic acid. Then, the regenerated H2O2 can promote the Fenton reaction to achieve GOx catalysis-enhanced CDT. Owing to its large π-electron conjugated system, MPG also serves as an ideal sonosensitizer, realizing a burst generation of 1O2 under US irradiation for efficient SDT. Therefore, the tumor treatment will be notably enhanced by MPG-based synergetic CDT/SDT/starvation therapy via a series of cascade reactions. Overall, this work develops a versatile nanoreactor with improved tumor treatment effectiveness and broadens the application prospects of porous materials in the field of biomedical research.

Conferring Ti-Based MOFs with Defects for Enhanced Sonodynamic Cancer Therapy.

The development of highly efficient, multifunctional, and biocompatible sonosensitizer is still a priority for current sonodynamic therapy (SDT). Herein, a defect-rich Ti-based metal-organic framework (MOF) (D-MOF(Ti)) with greatly improved sonosensitizing effect is simply constructed and used for enhanced SDT. Compared with the commonly used sonosensitizer TiO2 , D-MOF(Ti) results in a superior reactive oxygen species (ROS) yield under ultrasound (US) irradiation due to its narrow bandgap, which principally improves the US-triggered electron-hole separation. Meanwhile, due to the existence of Ti3+ ions, D-MOF(Ti) also exhibits a high level of Fenton-like activity to enable chemodynamic therapy. Particularly, US as the excitation source of SDT can simultaneously enhance the Fenton-like reaction to achieve remarkably synergistic outcomes for oncotherapy. More importantly, D-MOF(Ti) can be degraded and metabolized out of the body after completion of its therapeutic functions without off-target toxicity. Overall, this work identifies a novel Ti-familial sonosensitizer harboring great potential for synergistic sonodynamic and chemodynamic cancer therapy.

Synthesis, morphological control, and antibacterial properties of hollow/solid Ag2S/Ag heterodimers.

Ag(2)S and Ag are important functional materials that have received considerable research interest in recent years. In this work, we develop a solution-based synthetic method to combine these two materials into hollow/solid Ag(2)S/Ag heterodimers at room temperature. Starting from monodisperse Cu(2)O solid spheres, CuS hollow spheres can be converted from Cu(2)O through a modified Kirkendall process, and the obtained CuS can then be used as a solid precursor for preparation of the Ag(2)S/Ag heterodimers through ion exchange and photo-assisted reduction. We have found that formation of the Ag(2)S/Ag heterodimers is instantaneous, and the size of Ag nanocrystals on the hollow spheres of Ag(2)S can be controlled by changing the concentration and power of reducing agents in the synthesis. The growth of Ag nanoparticles on hollow spheres of Ag(2)S in the dimers is along the [111] direction of the silver crystal; the light absorption properties have also been investigated. Furthermore, coupling or tripling of Ag(2)S/Ag heterodimers into dumbbell-like trimers ((Ag(2)S)(2)/Ag, linear) and triangular tetramers ((Ag(2)S)(3)/Ag, coplanar) can also be attained at 60 degrees C by adding the bidentate ligand ethylenediamine as a cross-linking agent. To test the applicability of this highly asymmetric dipolar composite, photocatalytic inactivation of Escherichia coli K-12 in the presence of the as-prepared Ag(2)S/Ag heterodimers has been carried out under UV irradiation. The added Ag(2)S/Ag heterodimers show good chemical stability under prolonged UV irradiation, and no appreciable solid dissolution is found. Possible mechanisms regarding the enhanced antibacterial activity have also been addressed.

Highly ordered self-assemblies of submicrometer Cu2O spheres and their hollow chalcogenide derivatives.

Highly ordered superlattices assembled from transition metal oxide/sulfide submicrometer particles are difficult to prepare due to lack of monodisperse primary building blocks. In this work, we have successfully synthesized monodisperse Cu(2)O spheres with diameters in the submicrometer regime of 130-135 nm. Using the as-prepared Cu(2)O spheres as solid precursor, uniform hollow CuS and CuSe derivatives have also been synthesized in solution media. More importantly, a range of two-dimensional and three-dimensional superlattices of Cu(2)O, CuS, and CuSe solid/hollow spheres have been assembled for the first time. Without assistance of conventional sacrificing solid templates, the degree of ordering achieved in these superlattices is comparable to those reported for well-studied silica and polystyrene beads. The realization of these self-assembled superlattices may provide a new way of thin film design and fabrication for this class of photosensitive semiconducting materials using their prefabricated building blocks.

A covalent organic framework as a nanocarrier for synergistic phototherapy and immunotherapy.

As traditional cancer treatment methods, photodynamic therapy (PDT) and photothermal therapy (PTT) can eliminate primary tumors, but they cannot inhibit extensive tumor metastasis and local recurrence. Herein, in order to prevent intermolecular accumulation and improve photostability, indocyanine green (ICG) is spontaneously adsorbed onto a covalent organic framework (COF) with high affinity through π-π conjugation, and then chicken ovalbumin (OVA) is coated on the surface of COF@ICG via an electrostatic interaction force. The resultant COF@ICG@OVA can ablate primary tumors under 650 nm and 808 nm laser irradiation due to its high photothermal conversion efficiency (η = 35.75%) and ability to produce reactive oxygen species (ROS). Tumor-associated antigens are also produced after combinational PTT/PDT therapy. By further combining with anti-PD-L1 checkpoint blockade therapy, it can effectively eliminate primary tumors and inhibit the metastasis of cancer cells by generating strong immune responses. Taken together, COF@ICG@OVA nanoparticles offer an efficient synergistic therapeutic modality for the treatment of tumor metastasis.