Nanoscale Metal–Organic Frameworks for Real-Time Intracellular pH Sensing in Live Cells

Real-time measurement of intracellular pH in live cells is of great importance for understanding physiological/pathological processes and developing intracellular drug delivery systems. We report here the first use of nanoscale metal–organic frameworks (NMOFs) for intracellular pH sensing in live cells. Fluorescein isothiocyanate (FITC) was covalently conjugated to a UiO NMOF to afford F-UiO NMOFs with exceptionally high FITC loadings, efficient fluorescence, and excellent ratiometric pH-sensing properties. Upon rapid and efficient endocytosis, F-UiO remained structurally intact inside endosomes. Live cell imaging studies revealed endo- and exocytosis of F-UiO and endosome acidification in real time. Fluorescently labeled NMOFs thus represent a new class of nanosensors for intracellular pH sensing and provide an excellent tool for studying NMOF–cell interactions

A Chlorin-Based Nanoscale Metal–Organic Framework for Photodynamic Therapy of Colon Cancers

We report here the rational design of the first chlorin-based nanoscale metal–organic framework (NMOF), DBC-UiO, with much improved photophysical properties over the previously reported porphyrin-based NMOF, DBP-UiO. Reduction of the DBP ligands in DBP-UiO to the DBC ligands in DBC-UiO led to a 13 nm red shift and an 11-fold increase in the extinction coefficient of the lowest-energy Q band. While inheriting the crystallinity, stability, porosity, and nanoplate morphology of DBP-UiO, DBC-UiO sensitizes more efficient ¹O₂ generation and exhibits significantly enhanced photodynamic therapy (PDT) efficacy on two colon cancer mouse models as a result of its improved photophysical properties. Both apoptosis and immunogenic cell death contributed to killing of cancer cells in DBC-UiO-induced PDT

Nanoscale Metal–Organic Frameworks for Real-Time Intracellular pH Sensing in Live Cells

Real-time measurement of intracellular pH in live cells is of great importance for understanding physiological/pathological processes and developing intracellular drug delivery systems. We report here the first use of nanoscale metal–organic frameworks (NMOFs) for intracellular pH sensing in live cells. Fluorescein isothiocyanate (FITC) was covalently conjugated to a UiO NMOF to afford F-UiO NMOFs with exceptionally high FITC loadings, efficient fluorescence, and excellent ratiometric pH-sensing properties. Upon rapid and efficient endocytosis, F-UiO remained structurally intact inside endosomes. Live cell imaging studies revealed endo- and exocytosis of F-UiO and endosome acidification in real time. Fluorescently labeled NMOFs thus represent a new class of nanosensors for intracellular pH sensing and provide an excellent tool for studying NMOF–cell interactions

Nanoscale Metal–Organic Framework for Highly Effective Photodynamic Therapy of Resistant Head and Neck Cancer

Photodynamic therapy (PDT) is an effective anticancer procedure that relies on tumor localization of a photosensitizer followed by light activation to generate cytotoxic reactive oxygen species (e.g., ¹O₂). Here we report the rational design of a Hf–porphyrin nanoscale metal–organic framework, DBP–UiO, as an exceptionally effective photosensitizer for PDT of resistant head and neck cancer. DBP–UiO efficiently generates ¹O₂ owing to site isolation of porphyrin ligands, enhanced intersystem crossing by heavy Hf centers, and facile ¹O₂ diffusion through porous DBP–UiO nanoplates. Consequently, DBP–UiO displayed greatly enhanced PDT efficacy both <i>in vitro</i> and <i>in vivo</i>, leading to complete tumor eradication in half of the mice receiving a single DBP–UiO dose and a single light exposure. NMOFs thus represent a new class of highly potent PDT agents and hold great promise in treating resistant cancers in the clinic

Nanoscale Metal–Organic Frameworks for the Co-Delivery of Cisplatin and Pooled siRNAs to Enhance Therapeutic Efficacy in Drug-Resistant Ovarian Cancer Cells

Ovarian cancer is the leading cause of death among women with gynecological malignancies. Acquired resistance to chemotherapy is a major limitation for ovarian cancer treatment. We report here the first use of nanoscale metal–organic frameworks (NMOFs) for the co-delivery of cisplatin and pooled small interfering RNAs (siRNAs) to enhance therapeutic efficacy by silencing multiple drug resistance (MDR) genes and resensitizing resistant ovarian cancer cells to cisplatin treatment. UiO NMOFs with hexagonal-plate morphologies were loaded with a cisplatin prodrug and MDR gene-silencing siRNAs (Bcl-2, P-glycoprotein [P-gp], and survivin) via encapsulation and surface coordination, respectively. NMOFs protect siRNAs from nuclease degradation, enhance siRNA cellular uptake, and promote siRNA escape from endosomes to silence MDR genes in cisplatin-resistant ovarian cancer cells. Co-delivery of cisplatin and siRNAs with NMOFs led to an order of magnitude enhancement in chemotherapeutic efficacy <i>in vitro</i>, as indicated by cell viability assay, DNA laddering, and Annexin V staining. This work shows that NMOFs hold great promise in the co-delivery of multiple therapeutics for effective treatment of drug-resistant cancers

Mitochondria-Targeted Nanosystem Enhances Radio–Radiodynamic–Chemodynamic Therapy on Triple Negative Breast Cancer

Radiodynamic therapy (RDT), which produces 1O2 and other reactive oxygen species (ROS) in response to X-rays, can be used in conjunction with radiation therapy (RT) to drastically lower X-ray dosage and reduce radio resistance associated with conventional radiation treatment. However, radiation–radiodynamic therapy (RT–RDT) is still impotent in a hypoxic environment in solid tumors due to its oxygen-dependent nature. Chemodynamic therapy (CDT) can generate reactive oxygen species and O2 by decomposing H2O2 in hypoxic cells and thus potentiate RT–RDT to achieve synergy. Herein, we developed a multifunctional nanosystem, AuCu-Ce6-TPP (ACCT), for RT–RDT–CDT. Ce6 photosensitizers were conjugated to AuCu nanoparticles via Au–S bonds to realize radiodynamic sensitization. Cu can be oxidized by H2O2 and catalyze the degradation of H2O2 to generate •OH through the Fenton-like reaction to realize CDT. Meanwhile, the degradation byproduct oxygen can alleviate hypoxia while Au can consume glutathione to increase the oxidative stress. We then attached mercaptoethyl-triphenylphosphonium (TPP-SH) to the nanosystem, targeting ACCT to mitochondria (colocalization Pearson coefficient 0.98) to directly disrupt mitochondrial membranes and more efficiently induce apoptosis. We confirmed that ACCT efficiently generates 1O2 and •OH upon X-ray irradiation, resulting in strong anticancer efficacy in both normoxic and hypoxic 4T1 cells. The down-regulation of hypoxia-inducible factor 1α expression and reduction of intracellular H2O2 concentrations suggested that ACCT could significantly alleviate hypoxia in 4T1 cells. ACCT-enhanced RT–RDT–CDT can successfully shrink or remove tumors in radioresistant 4T1 tumor-bearing mice upon 4 Gy of X-ray irradiation. Our work thus presents a new strategy to treat radioresistant hypoxic tumors

Electron Crystallography Reveals Atomic Structures of Metal–Organic Nanoplates with M₁₂(μ₃‑O)₈(μ₃‑OH)₈(μ₂‑OH)₆ (M = Zr, Hf) Secondary Building Units

Nanoscale metal–organic frameworks (nMOFs) have shown tremendous potential in cancer therapy and biomedical imaging. However, their small dimensions present a significant challenge in structure determination by single-crystal X-ray crystallography. We report here the structural determination of nMOFs by rotation electron diffraction (RED). Two isostructural Zr- and Hf-based nMOFs with linear biphenyldicarboxylate (BPDC) or bipyridinedicarboxylate (BPYDC) linkers are stable under intense electron beams to allow the collection of high-quality RED data, which reveal a MOF structure with M₁₂(μ₃-O)₈(μ₃-OH)₈(μ₂-OH)₆ (M = Zr, Hf) secondary building units (SBUs). The nMOF structures differ significantly from their UiO bulk counterparts with M₆(μ₃-O)₄(μ₃-OH)₄ SBUs and provide the foundation for clarifying the structures of a series of previously reported nMOFs with significant potential in cancer therapy and biological imaging. Our work clearly demonstrates the power of RED in determining nMOF structures and elucidating the formation mechanism of distinct nMOF morphologies

Synergistic Assembly of Heavy Metal Clusters and Luminescent Organic Bridging Ligands in Metal–Organic Frameworks for Highly Efficient X‑ray Scintillation

We have designed two metal–organic frameworks (MOFs) to efficiently convert X-ray to visible-light luminescence. The MOFs are constructed from M₆(μ₃-O)₄(μ₃-OH)₄(carboxylate)₁₂ (M = Hf or Zr) secondary building units (SBUs) and anthracene-based dicarboxylate bridging ligands. The high atomic number of Zr and Hf in the SBUs serves as effective X-ray antenna by absorbing X-ray photons and converting them to fast electrons through the photoelectric effect. The generated electrons then excite multiple anthracene-based emitters in the MOF through inelastic scattering, leading to efficient generation of detectable photons in the visible spectrum. The MOF materials thus serve as efficient X-ray scintillators via synergistic X-ray absorption by the metal-cluster SBUs and optical emission by the bridging ligands

Nanoscale Metal–Organic Frameworks for Ratiometric Oxygen Sensing in Live Cells

We report the design of a phosphorescence/fluorescence dual-emissive nanoscale metal–organic framework (NMOF), R-UiO, as an intracellular oxygen (O₂) sensor. R-UiO contains a Pt­(II)-porphyrin ligand as an O₂-sensitive probe and a Rhodamine-B isothiocyanate ligand as an O₂-insensitive reference probe. It exhibits good crystallinity, high stability, and excellent ratiometric luminescence response to O₂ partial pressure. <i>In vitro</i> experiments confirmed the applicability of R-UiO as an intracellular O₂ biosensor. This work is the first report of a NMOF-based intracellular oxygen sensor and should inspire the design of ratiometric NMOF sensors for other important analytes in biological systems

Chlorin-Based Nanoscale Metal–Organic Framework Systemically Rejects Colorectal Cancers via Synergistic Photodynamic Therapy and Checkpoint Blockade Immunotherapy

Photodynamic therapy (PDT) can destroy local tumors and minimize normal tissue damage, but is ineffective at eliminating metastases. Checkpoint blockade immunotherapy has enjoyed recent success in the clinic, but only elicits limited rates of systemic antitumor response for most cancers due to insufficient activation of the host immune system. Here we describe a treatment strategy that combines PDT by a new chlorin-based nanoscale metal–organic framework (nMOF), TBC-Hf, and a small-molecule immunotherapy agent that inhibits indoleamine 2,3-dioxygenase (IDO), encapsulated in the nMOF channels to induce systemic antitumor immunity. The synergistic combination therapy achieved effective local and distant tumor rejection in colorectal cancer models. We detected increased T cell infiltration in the tumor microenvironment after activation of the immune system with the combination of IDO inhibition by the small-molecule immunotherapy agent and immunogenic cell death induced by PDT. We also elucidated the underlying immunological mechanisms and revealed compensatory roles of neutrophils and B cells in presenting tumor-associated antigens to T cells in this combination therapy. We believe that nMOF-enabled PDT has the potential to significantly enhance checkpoint blockade cancer immunotherapy, affording clinical benefits for the treatment of many difficult-to-treat cancers