Nanoscale Metal-Organic Framework with an X-ray Triggerable Prodrug for Synergistic Radiotherapy and Chemotherapy.

As heavy-metal-based nanoscale metal-organic frameworks (nMOFs) are excellent radiosensitizers for radiotherapy via enhanced energy deposition and reactive oxygen species (ROS) generation, we hypothesize that nMOFs with covalently conjugated and X-ray triggerable prodrugs can harness the ROS for on-demand release of chemotherapeutics for chemoradiotherapy. Herein, we report the design of a novel nMOF, Hf-TP-SN, with an X-ray-triggerable 7-ethyl-10-hydroxycamptothecin (SN38) prodrug for synergistic radiotherapy and chemotherapy. Upon X-ray irradiation, electron-dense Hf12 secondary building units serve as radiosensitizers to enhance hydroxyl radical generation for the triggered release of SN38 via hydroxylation of the 3,5-dimethoxylbenzyl carbonate followed by 1,4-elimination, leading to 5-fold higher release of SN38 from Hf-TP-SN than its molecular counterpart. As a result, Hf-TP-SN plus radiation induces significant cytotoxicity to cancer cells and efficiently inhibits tumor growth in colon and breast cancer mouse models.

Zinc cyclic di-AMP nanoparticles target and suppress tumours via endothelial STING activation and tumour-associated macrophage reinvigoration.

The clinical utility of stimulator of interferon genes (STING) agonists has been limited due to poor tumour-targeting and unwanted toxicity following systemic delivery. Here we describe a robust tumour-targeted STING agonist, ZnCDA, formed by the encapsulation of bacterial-derived cyclic dimeric adenosine monophosphate (CDA) in nanoscale coordination polymers. Intravenously injected ZnCDA prolongs CDA circulation and efficiently targets tumours, mediating robust anti-tumour effects in a diverse set of preclinical cancer models at a single dose. Our findings reveal that ZnCDA enhances tumour accumulation by disrupting endothelial cells in the tumour vasculature. ZnCDA preferentially targets tumour-associated macrophages to modulate antigen processing and presentation and subsequent priming of an anti-tumour T-cell response. ZnCDA reinvigorates the anti-tumour activity of both radiotherapy and immune checkpoint inhibitors in immunologically 'cold' pancreatic and glioma tumour models, offering a promising combination strategy for the treatment of intractable human cancers.

Monte Carlo Simulation-Guided Design of a Thorium-Based Metal-Organic Framework for Efficient Radiotherapy-Radiodynamic Therapy.

High-Z metal-based nanoscale metal-organic frameworks (nMOFs) with photosensitizing ligands can enhance radiation damage to tumors via a unique radiotherapy-radiodynamic therapy (RT-RDT) process. Here we report Monte Carlo (MC) simulation-guided design of a Th-based nMOF built from Th6 -oxo secondary building units and 5,15-di(p-benzoato)porphyrin (DBP) ligands, Th-DBP, for enhanced RT-RDT. MC simulations revealed that the Th-lattice outperformed the Hf-lattice in radiation dose enhancement owing to its higher mass attenuation coefficient. Upon X-ray or γ-ray radiation, Th-DBP enhanced energy deposition, generated more reactive oxygen species, and induced significantly higher cytotoxicity to cancer cells over the previously reported Hf-DBP nMOF. With low-dose X-ray irradiation, Th-DBP suppressed tumor growth by 88 % in a colon cancer and 97 % in a pancreatic cancer mouse model.

Tumor-Activatable Nanoparticles Target Low-Density Lipoprotein Receptor to Enhance Drug Delivery and Antitumor Efficacy.

The binding of plasma proteins to nanomedicines is widely considered detrimental to their delivery to tumors. Here, the design of OxPt/SN38 nanoparticle containing a hydrophilic oxaliplatin (OxPt) prodrug in a coordination polymer core and a hydrophobic cholesterol-conjugated SN38 prodrug on the lipid shell for active tumor targeting is reported. OxPt/SN38 hitchhikes on low-density lipoprotein (LDL) particles, concentrates in tumors via LDL receptor-mediated endocytosis, and selectively releases SN38 and OxPt in acidic, esterase-rich, and reducing tumor microenvironments, leading to 6.0- and 4.9-times higher accumulations in tumors over free drugs. By simultaneously crosslinking DNA and inhibiting topoisomerase I, OxPt/SN38 achieved 92-98% tumor growth inhibition in five colorectal cancer tumor models and prolonged mouse survival by 58-80 days compared to free drug controls in three human colorectal cancer tumor models without causing serious side effects. The study has uncovered a novel nanomedicine strategy to co-deliver combination chemotherapies to tumors via active targeting of the LDL receptor.

Dimensional Reduction Enhances Photodynamic Therapy of Metal-Organic Nanophotosensitizers.

Herein we report that dimensional reduction from three-dimensional nanoscale metal-organic frameworks (nMOFs) to two-dimensional nanoscale metal-organic layers (nMOLs) increases the frequency of encounters between photosensitizers and oxygen and facilitates the diffusion of singlet oxygen from the nMOL to significantly enhance photodynamic therapy. The nMOFs and nMOLs share the same M12-oxo (M = Zr, Hf) secondary building units and 5,15-di-p-benzoatoporphyrin (DBP) ligands but exhibit three-dimensional and two-dimensional topologies, respectively. Molecular dynamics simulations and experimental studies revealed that the nMOLs with a monolayer morphology enhanced the generation of reactive oxygen species and exhibited over an order of magnitude higher cytotoxicity over the nMOFs. In a mouse model of triple-negative breast cancer, Hf-DBP nMOL showed 49.1% more tumor inhibition, an 80% higher cure rate, and 16.3-fold lower metastasis potential than Hf-DBP nMOF.

Synergistic checkpoint-blockade and radiotherapy-radiodynamic therapy via an immunomodulatory nanoscale metal-organic framework.

Checkpoint blockade elicits durable responses in immunogenic cancers, but it is largely ineffective in immunologically 'cold' tumours. Here we report the design, synthesis and performance of a bismuth-based nanoscale metal-organic framework that modulates the immunological and mechanical properties of the tumour microenvironment for enhanced radiotherapy-radiodynamic therapy. In mice with non-immunogenic prostate and pancreatic tumours irradiated with low X-ray doses, the intratumoural injection of the radiosensitizer mediated potent outcomes via the repolarization of immunosuppressive M2 macrophages into immunostimulatory M1 macrophages, the reduction of the concentration of intratumoural transforming growth factor beta (TGF-ß) and of collagen density, and the inactivation of cancer-associated fibroblasts. When intravenously injected in combination with checkpoint-blockade therapy, the radiosensitizer mediated the reversal of immunosuppression in primary and distant tumours via the systemic reduction of TGF-ß levels, which led to the downregulation of collagen expression, the stimulation of T-cell infiltration in the tumours and a robust abscopal effect. Nanoscale radiosensitizers that stimulate anti-tumour immunity and T-cell infiltration may enhance the therapeutic outcomes of checkpoint blockade in other tumour types.

A Substrate-Binding Metal-Organic Layer Selectively Catalyzes Photoredox Ene-Carbonyl Reductive Coupling Reactions.

Intermolecular photoredox ene-carbonyl reductive coupling reactions typically have low product selectivity owing to competing dimerization and/or reduction of ketyl radicals. Herein, we report a metal-organic layer (MOL), Hf-Ir-OTf, as a bifunctional photocatalyst for selective photoredox reductive coupling of ketones or aldehydes with electron-deficient alkenes. Composed of iridium-based photosensitizers (Ir-PSs) and triflated Hf12 clusters, Hf-Ir-OTf uses Lewis acidic Hf sites to bind and activate electron-deficient alkenes to accept ketyl radicals generated by adjacent Ir-PSs, thereby suppressing undesired dimerization and reduction of ketyl radicals to enhance the selectivity for the cross-coupling products. The MOL-catalyzed reductive coupling reaction accommodates a variety of olefinic substrates and tolerates reducible groups, nicely complementing current methods for cross-coupling reactions.

Reprogramming of Neutrophils as Non-canonical Antigen Presenting Cells by Radiotherapy-Radiodynamic Therapy to Facilitate Immune-Mediated Tumor Regression.

Ineffective antigen cross-presentation in the tumor microenvironment compromises the generation of antitumor immune responses. Radiotherapy-radiodynamic therapy (RT-RDT) with nanoscale metal-organic frameworks (nMOFs) induces robust adaptive immune responses despite modest activation of canonical antigen presenting dendritic cells. Here, using transplantable and autochthonous murine tumor models, we demonstrate that RT-RDT induces antitumor immune responses via early neutrophil infiltration and reprogramming. Intravenous or intratumoral injection of nMOFs recruited peripheral CD11b+Ly6G+CD11c- neutrophils into tumors. The activation of nMOFs by low-dose X-rays significantly increased the population of CD11b+Ly6G+CD11c+ hybrid neutrophils with upregulated expression of the co-stimulatory molecules CD80 and CD86 as well as major histocompatibility complex class II molecules. Thus, nMOF-enabled RT-RDT reshapes a favorable tumor microenvironment for antitumor immune responses by reprogramming tumor-infiltrating neutrophils to function as non-canonical antigen presenting cells for effective cross-presentation of tumor antigens.

Monte Carlo Simulations Reveal New Design Principles for Efficient Nanoradiosensitizers Based on Nanoscale Metal-Organic Frameworks.

Nanoscale metal-organic frameworks (nMOFs) have recently been shown to provide better radiosensitization than solid nanoparticles (NPs) when excited with X-rays. Here, a Monte Carlo simulation of different radiosensitization effects by NPs and nMOFs using a lattice model consisting of 3D arrays of nanoscale secondary building units (SBUs) is reported. The simulation results reveal that lattices outperform solid NPs regardless of radiation sources or particle sizes via enhanced scatterings of photons and electrons within the lattices. Optimum dose enhancement can be achieved by tuning SBU size and inter-SBU distance.

Nanoscale Metal-Organic Framework Confines Zinc-Phthalocyanine Photosensitizers for Enhanced Photodynamic Therapy.

The performance of photodynamic therapy (PDT) depends on the solubility, pharmacokinetic behaviors, and photophysical properties of photosensitizers (PSs). However, highly conjugated PSs with strong reactive oxygen species (ROS) generation efficiency tend to have poor solubility and aggregate in aqueous environments, leading to suboptimal PDT performance. Here, we report a new strategy to load highly conjugated but poorly soluble zinc-phthalocyanine (ZnP) PSs in the pores of a Hf12-QC (QC = 2″,3'-dinitro-[1,1':4',1";4″,1'"-quaterphenyl]-4,4'"-dicarboxylate) nanoscale metal-organic framework to afford ZnP@Hf-QC with spatially confined ZnP PSs. ZnP@Hf-QC avoids aggregation-induced quenching of ZnP excited states to significantly enhance ROS generation upon light irradiation. With higher cellular uptake, enhanced ROS generation, and better biocompatibility, ZnP@Hf-QC mediated PDT exhibited an IC50 of 0.14 µM and achieved exceptional antitumor efficacy with >99% tumor growth inhibition and 80% cure rates on two murine colon cancer models.

Rational Construction of an Artificial Binuclear Copper Monooxygenase in a Metal-Organic Framework.

Artificial enzymatic systems are extensively studied to mimic the structures and functions of their natural counterparts. However, there remains a significant gap between structural modeling and catalytic activity in these artificial systems. Herein we report a novel strategy for the construction of an artificial binuclear copper monooxygenase starting from a Ti metal-organic framework (MOF). The deprotonation of the hydroxide groups on the secondary building units (SBUs) of MIL-125(Ti) (MIL = Matériaux de l'Institut Lavoisier) allows for the metalation of the SBUs with closely spaced CuI pairs, which are oxidized by molecular O2 to afford the CuII2(µ2-OH)2 cofactor in the MOF-based artificial binuclear monooxygenase Ti8-Cu2. An artificial mononuclear Cu monooxygenase Ti8-Cu1 was also prepared for comparison. The MOF-based monooxygenases were characterized by a combination of thermogravimetric analysis, inductively coupled plasma-mass spectrometry, X-ray absorption spectroscopy, Fourier-transform infrared spectroscopy, and UV-vis spectroscopy. In the presence of coreductants, Ti8-Cu2 exhibited outstanding catalytic activity toward a wide range of monooxygenation processes, including epoxidation, hydroxylation, Baeyer-Villiger oxidation, and sulfoxidation, with turnover numbers of up to 3450. Ti8-Cu2 showed a turnover frequency at least 17 times higher than that of Ti8-Cu1. Density functional theory calculations revealed O2 activation as the rate-limiting step in the monooxygenation processes. Computational studies further showed that the Cu2 sites in Ti8-Cu2 cooperatively stabilized the Cu-O2 adduct for O-O bond cleavage with 6.6 kcal/mol smaller free energy increase than that of the mononuclear Cu sites in Ti8-Cu1, accounting for the significantly higher catalytic activity of Ti8-Cu2 over Ti8-Cu1.

Nanoscale Metal-Organic Layers Detect Mitochondrial Dysregulation and Chemoresistance via Ratiometric Sensing of Glutathione and pH.

Mitochondrial dysregulation controls cell death and survival by changing endogenous molecule concentrations and ion flows across the membrane. Here, we report the design of a triply emissive nanoscale metal-organic layer (nMOL), NA@Zr-BTB/F/R, for sensing mitochondrial dysregulation. Zr-BTB nMOL containing Zr6 secondary building units (SBUs) and 2,4,6-tris(4-carboxyphenyl)aniline (BTB-NH2) ligands was postsynthetically functionalized to afford NA@Zr-BTB/F/R by exchanging formate capping groups on the SBUs with glutathione(GSH)-selective (2E)-1-(2'-naphthyl)-3-(4-carboxyphenyl)-2-propen-1-one (NA) and covalent conjugation of pH-sensitive fluorescein (F) and GSH/pH-independent rhodamine-B (R) to the BTB-NH2 ligands. Cell imaging demonstrated NA@Zr-BTB/F/R as a ratiometric sensor for mitochondrial dysregulation and chemotherapy resistance via GSH and pH sensing.

Sequential Treatment of Bioresponsive Nanoparticles Elicits Antiangiogenesis and Apoptosis and Synergizes with a CD40 Agonist for Antitumor Immunity.

The combination of antiangiogenesis and chemotherapy regimens with cancer immunotherapy has the potential to synergistically boost antitumor immunity. Herein, we report the construction of two bioresponsive nanoparticles, namely, Podo-NP and CbP-NP, comprising prodrugs of podophyllotoxin (Podo) and carboplatin, respectively. Sequential treatment with esterase-responsive Podo-NP, redox-sensitive CbP-NP, and a CD40 agonist promotes antitumor T cell response. Podo-NP suppresses angiogenesis by preventing proliferation and migration of endothelial cells, sprouting of neovessels, formation of tubules, and stabilization of newly formed vessels. Vascular endothelial growth factor blockade and endostatin stimulation normalize tortuous tumor vasculatures to allow efficient infiltration of effector immune cells. Subsequent treatment with CbP-NP arrests the cell-division cycle and elicits the apoptosis of tumor cells. CD40 agonist activates antigen-presenting cells to process the released tumor-associated antigens from dying tumor cells, thus reversing immunosuppressive tumor microenvironments. Sequential delivery of antiangiogenic and chemotherapeutic agents with bioresponsive NPs activates tumor microenvironments and synergizes with CD40 agonist to regress transplanted tumors and inhibit disseminated tumors in a lung cancer mouse model.

Metal-Organic Layers Hierarchically Integrate Three Synergistic Active Sites for Tandem Catalysis.

We report the design of a bifunctional metal-organic layer (MOL), Hf12 -Ru-Co, composed of [Ru(DBB)(bpy)2 ]2+ [DBB-Ru, DBB=4,4'-di(4-benzoato)-2,2'-bipyridine; bpy=2,2'-bipyridine] connecting ligand as a photosensitizer and Co(dmgH)2 (PPA)Cl (PPA-Co, dmgH=dimethylglyoxime; PPA=4-pyridinepropionic acid) on the Hf12 secondary building unit (SBU) as a hydrogen-transfer catalyst. Hf12 -Ru-Co efficiently catalyzed acceptorless dehydrogenation of indolines and tetrahydroquinolines to afford indoles and quinolones. We extended this strategy to prepare Hf12 -Ru-Co-OTf MOL with a [Ru(DBB)(bpy)2 ]2+ photosensitizer and Hf12 SBU capped with triflate as strong Lewis acids and PPA-Co as a hydrogen transfer catalyst. With three synergistic active sites, Hf12 -Ru-Co-OTf competently catalyzed dehydrogenative tandem transformations of indolines with alkenes or aldehydes to afford 3-alkylindoles and bisindolylmethanes with turnover numbers of up to 500 and 460, respectively, illustrating the potential use of MOLs in constructing novel multifunctional heterogeneous catalysts.

Metal-Organic Frameworks Integrate Cu Photosensitizers and Secondary Building Unit-Supported Fe Catalysts for Photocatalytic Hydrogen Evolution.

We report here the synthesis of a series of metal-organic frameworks (MOFs), FeX@Zr6-Cu, comprising cuprous photosensitizing linkers (Cu-PSs) and catalytically active FeII centers supported on secondary building units (SBUs) for photocatalytic H2 evolution. Close proximity (∼1 nm) between Cu-PS and SBU-supported Fe sites and stabilization of Fe sites by periodically ordered SBUs led to exceptionally high H2 evolution activity for FeX@Zr6-Cu, with turnover numbers of up to 33 700 and turnover frequencies of up to 880 h-1. Photocatalytic H2 evolution activities of FeX@Zr6-Cu correlate with the lability of X counteranions, suggesting that open coordination environments of Fe sites generated by labile X groups facilitate the formation of Fe-hydride intermediates before hydrogen evolution. This work highlights the potential of using MOFs to integrate Earth-abundant components for solar energy utilization.

Cerium-Based Metal-Organic Layers Catalyze Hydrogen Evolution Reaction through Dual Photoexcitation.

Cerium-based materials such as ceria are increasingly used in catalytic reactions. We report here the synthesis of the first Ce-based metal-organic layer (MOL), Ce6-BTB, comprising Ce6 secondary building units (SBUs) and 1,3,5-benzenetribenzoate (BTB) linkers, and its functionalization for photocatalytic hydrogen evolution reaction (HER). Ce6-BTB was postsynthetically modified with photosensitizing [(MBA)Ir(ppy)2]Cl or [(MBA)Ru(bpy)2]Cl2 (MBA = 2-(5'-methyl-[2,2'-bipyridin]-5-yl)acetate, ppy = 2-phenylpyridine, bpy = 2,2'-bipyridine) to afford Ce6-BTB-Ir or Ce6-BTB-Ru MOLs, respectively. The proximity of photosensitizing ligands and Ce6 SBUs in the MOLs facilitates electron transfer to drive photocatalytic HER under visible light with turnover numbers of 1357 and 484 for Ce6-BTB-Ir and Ce6-BTB-Ru, respectively. Photophysical and electrochemical studies revealed a novel dual photoexcitation pathway whereby the excited photosensitizers in the MOL are reductively quenched and then transfer electrons to Ce6 SBUs to generate CeIII centers, which are further photoexcited to CeIII* species for HER.

Metal-Organic Framework with Dual Active Sites in Engineered Mesopores for Bioinspired Synergistic Catalysis.

Here we report the design of an enzyme-inspired metal-organic framework (MOF), 1-OTf-Ir, by installing strong Lewis acid and photoredox sites in engineered mesopores. Al-MOF (1), with mixed 2,2'-bipyridyl-5,5-dicarboxylate (dcbpy) and 1,4-benzenediacrylate (pdac) ligands, was oxidized with ozone and then triflated to generate strongly Lewis acidic Al-OTf sites in the mesopores, followed by the installation of [Ir(ppy)2(dcbpy)]+ (ppy = 2-phenylpyridine) sites to afford 1-OTf-Ir with both Lewis acid and photoredox sites. 1-OTf-Ir effectively catalyzed reductive cross-coupling of N-hydroxyphthalimide esters or aryl bromomethyl ketones with vinyl- or alkynyl-azaarenes to afford new azaarene derivatives. 1-OTf-Ir enabled catalytic synthesis of anticholinergic drugs Pheniramine and Chlorpheniramine.

Multistep Engineering of Synergistic Catalysts in a Metal-Organic Framework for Tandem C-O Bond Cleavage.

Cleavage of strong C-O bonds without breaking C-C/C-H bonds is a key step for catalytic conversion of renewable biomass to hydrocarbon feedstocks. Herein we report multistep sequential engineering of orthogonal Lewis acid and palladium nanoparticle (NP) catalysts in a metal-organic framework (MOF) built from (Al-OH)n secondary building units and a mixture of 2,2'-bipyridine-5,5'-dicarboxylate (dcbpy) and 1,4-benzenediacrylate (pdac) ligands (1) for tandem C-O bond cleavage. Ozonolysis of 1 selectively removed pdac ligands to generate Al2(OH)(OH2) sites, which were subsequently triflated with trimethylsilyl triflate to afford strongly Lewis acidic sites for dehydroalkoxylation. Coordination of Pd(MeCN)2Cl2 to dcbpy ligands followed by in situ reduction produced orthogonal Pd NP sites in 1-OTf-PdNP as the hydrogenation catalyst. The selective and precise transformation of 1 into 1-OTf-PdNP was characterized step by step using powder X-ray diffraction, transmission electron microscopy, thermogravimetric analysis, inductively coupled plasma mass spectrometry, infrared spectroscopy, and X-ray absorption spectroscopy. The hierarchical incorporation of orthogonal Lewis acid and Pd NP active sites endowed 1-OTf-PdNP with outstanding catalytic performance in apparent hydrogenolysis of etheric, alcoholic, and esteric C-O bonds to generate saturated alkanes via a tandem dehydroalkoxylation-hydrogenation process under relatively mild conditions. The reactivity of C-O bonds followed the trend of tertiary carbon > secondary carbon > primary carbon. Control experiments demonstrated the heterogeneous nature and recyclability of 1-OTf-PdNP and its superior catalytic activity over the homogeneous counterparts. Sequential engineering of multiple catalytic sites in MOFs thus presents a unique opportunity to address outstanding challenges in sustainable catalysis.

Metal-Organic Frameworks Significantly Enhance Photocatalytic Hydrogen Evolution and CO2 Reduction with Earth-Abundant Copper Photosensitizers.

We report here the design of two multifunctional metal-organic frameworks (MOFs), mPT-Cu/Co and mPT-Cu/Re, comprising cuprous photosensitizers (Cu-PSs) and molecular Co or Re catalysts for photocatalytic hydrogen evolution (HER) and CO2 reduction (CO2RR), respectively. Hierarchical organization of Cu-PSs and Co/Re catalysts in these MOFs facilitates multielectron transfer to drive HER and CO2RR under visible light with an HER turnover number (TON) of 18 700 for mPT-Cu/Co and a CO2RR TON of 1328 for mPT-Cu/Re, which represent a 95-fold enhancement over their homogeneous controls. Photophysical and electrochemical investigations revealed the reductive quenching pathway in HER and CO2RR catalytic cycles and attributed the significantly improved performances of MOFs over their homogeneous counterparts to enhanced electron transfer due to close proximity between Cu-PSs and active catalysts and stabilization of Cu-PSs and molecular catalysts by the MOF framework.