The use of metal-organic frameworks (MOFs) in biomedical applications has greatly expanded over the past decade due to the precision tunability, high surface areas, and high loading capacities of MOFs. Specifically, MOFs are being explored for a wide variety of drug delivery applications. Initially, MOFs were used for delivery of small-molecule pharmaceuticals; however, more recent work has focused on macromolecular cargos, such as proteins and nucleic acids. Here, we review the historical application of MOFs for drug delivery, with a specific focus on the available options for designing MOFs for specific drug delivery applications. These options include choices of MOF structure, synthetic method, and drug loading. Further considerations include tuning, modifications, biocompatibility, cellular targeting, and uptake. Altogether, this Review aims to guide MOF design for novel biomedical applications.

Metal-Organic Frameworks for Drug Delivery: A Design Perspective.

Chemodynamic therapy (CDT), a novel cancer therapeutic strategy defined as the treatment using Fenton or Fenton-like reaction to produce •OH in the tumor region, was first proposed by Bu, Shi, and co-workers in 2016. Recently, with the rapid development of Fenton and Fenton-like nanomaterials, CDT has attracted tremendous attention because of its unique advantages: 1) It is tumor-selective with low side effects; 2) the CDT process does not depend on external field stimulation; 3) it can modulate the hypoxic and immunosuppressive tumor microenvironment; 4) the treatment cost of CDT is low. In addition to the Fe-involved CDT strategies, the Fenton-like reaction-mediated CDT strategies have also been proposed, which are based on many other metal elements including copper, manganese, cobalt, titanium, vanadium, palladium, silver, molybdenum, ruthenium, tungsten, cerium, and zinc. Moreover, CDT has been combined with other therapies like chemotherapy, radiotherapy, phototherapy, sonodynamic therapy, and immunotherapy for achieving enhanced anticancer effects. Besides, there have also been studies that extend the application of CDT to the antibacterial field. This review introduces the latest advancements in the nanomaterials-involved CDT from 2018 to the present and proposes the current limitations as well as future research directions in the related field.

Chemodynamic Therapy via Fenton and Fenton-Like Nanomaterials: Strategies and Recent Advances.

The rapid development of nanotechnology offers a variety of potential therapeutic strategies for cancer treatment. High atomic element nanomaterials are often utilized as radiosensitizers due to their unique photoelectric decay characteristics. Among them, gold nanoparticles (GNPs) are one of the most widely investigated and are considered to be an ideal radiosensitizers for radiotherapy due to their high X-ray absorption and unique physicochemical properties. Over the last few decades, multi-disciplinary studies have focused on the design and optimization of GNPs to achieve greater dosing capability and higher therapeutic effects and highlight potential mechanisms for radiosensitization of GNPs. Although the radiosensitizing potential of GNPs has been widely recognized, its clinical translation still faces many challenges. This review analyses the different roles of GNPs as radiosensitizers in cancer radiotherapy and summarizes recent advances. In addition, the underlying mechanisms of GNP radiosensitization, including physical, chemical and biological mechanisms are discussed, which may provide new directions for the optimization and clinical transformation of next-generation GNPs.

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Gold Nanoparticles as Radiosensitizers in Cancer Radiotherapy.

Strict conditions such as hypoxia, overexpression of glutathione (GSH), and high concentration of hydrogen peroxide (H2O2) in the tumor microenvironment (TME) limit the therapeutic effects of reactive oxygen species (ROS) for photodynamic therapy (PDT), chemodynamic therapy (CDT), and sonodynamic therapy (SDT). Here we fabricated a biocatalytic Janus nanocomposite (denoted as UPFB) for ultrasound (US) driven SDT and 808 nm near-infrared (NIR) light mediated PDT by combining core-shell-shell upconversion nanoparticles (UCNPs, NaYF4:20%Yb,1%Tm@NaYF4:10%Yb@NaNdF4) and a ferric zirconium porphyrin metal organic framework [PCN-224(Fe)]. Our design not only substantially overcomes the inefficient PDT effect arising from the inadequate Forster resonance energy transfer (FRET) process from UCNPs (donor) to MOFs (acceptor) with only NIR laser irradiation, but also promotes the ROS generation via GSH depletion and oxygen supply contributed by Fe3+ ions coordinated in UPFB as a catalase-like nanozyme. Additionally, the converted Fe2+ from the foregoing process can achieve CDT performance under acidic conditions, such as lysosomes. Meanwhile, UPFB linked with biotin exhibits a good targeting ability to rapidly accumulate in the tumor region, verified by fluorescence imaging and T2-weighted magnetic resonance imaging (MRI). In a word, it is believed that the synthesis and antitumor detection of UPFB heterostructures render them suitable for application in cancer therapeutics.

Upconverted Metal-Organic Framework Janus Architecture for Near-Infrared and Ultrasound Co-Enhanced High Performance Tumor Therapy.

Chemodynamic therapy is an emerging tumor therapeutic strategy. However, the anticancer effects are greatly limited by the strong acidity requirements for effective Fenton-like reaction, and the inevitably "off-target" toxicity. Herein, we develop an acidity-unlocked nanoplatform (FePt@FeOx @TAM-PEG) that can accurately perform the high-efficient and tumor-specific catalysis for anticancer treatment, through dual pathway of cyclic amplification strategy. Notably, the pH-responsive peculiarity of tamoxifen (TAM) drug allows for the catalytic activity of FePt@FeOx to be "turn-on" in acidic tumor microenvironments, while keeping silence in neutral condition. Importantly, the released TAM within cancer cells is able to inhibit mitochondrial complex I, leading to the upregulated lactate content and thereby the accumulated intracellular H+ , which can overcome the intrinsically insufficient acidity of tumor. Through the positive feedback loop, large amount of active FePt@FeOx nanocatalyzers are released and able to access to the endogenous H2 O2 , exerting the improved Fenton-like reaction within the more acidic condition. Finally, such smart nanoplatform enables self-boosting generation of reactive oxygen species (ROS) and induces strong intracellular oxidative stress, leading to the substantial anticancer outcomes in vivo, which may provide a new insight for tumor-specific cascade catalytic therapy and reducing the "off-target" toxicity to surrounding normal tissues.

An Acidity-Unlocked Magnetic Nanoplatform Enables Self-Boosting ROS Generation through Upregulation of Lactate for Imaging-Guided Highly Specific Chemodynamic Therapy

The incorporation of new modalities into chemotherapy greatly enhances the anticancer efficacy combining the merits of each treatment, showing promising potentials in clinical translations. Herein, a hybrid nanomedicine (Au/FeMOF@CPT NPs) is fabricated using metal-organic framework (MOF) nanoparticles and gold nanoparticles (Au NPs) as building blocks for cancer chemo/chemodynamic therapy. MOF NPs are used as vehicles to encapsulate camptothecin (CPT), and the hybridization by Au NPs greatly improves the stability of the nanomedicine in a physiological environment. Triggered by the high concentration of phosphate inside the cancer cells, Au/FeMOF@CPT NPs effectively collapse after internalization, resulting in the complete drug release and activation of the cascade catalytic reactions. The intracellular glucose can be oxidized by Au NPs to produce hydrogen dioxide, which is further utilized as chemical fuel for the Fenton reaction, thus realizing the synergistic anticancer efficacy. Benefitting from the enhanced permeability and retention effect and sophisticated fabrications, the blood circulation time and tumor accumulation of Au/FeMOF@CPT NPs are significantly increased. In vivo results demonstrate that the combination of chemotherapy and chemodynamic therapy effectively suppresses the tumor growth, meantime the systemic toxicity of this nanomedicine is greatly avoided.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/advs.202001060

A Nanomedicine Fabricated from Gold Nanoparticles‐Decorated Metal–Organic Framework for Cascade Chemo/Chemodynamic Cancer Therapy

Two important features are required for promising radiosensitizers: one is selective tumor cell targeting to enhance the therapeutic outcome via lethal DNA damage and the other is rapid clearance to enable excellent biocompatibility for potential clinical application. Herein, ultrasmall gold nanoparticles (Au NPs) with diameter smaller than 5 nm were prepared and covered with a multifunctional peptide to endow them with selective tumor cell uptake capability. Combined with X-ray irradiation, the responsive Au NPs demonstrated superior radio-sensitizing toxicity and rapid renal clearance in vivo. Methods: A responsive peptide (Tat-R-EK) consists of three build blocks were used: a cell and even nuclear penetrating block derived from human immunodeficiency virus-1 transactivator of transcription protein (Tat), an cathepsin B cleavable linker, and a zwitterionic antifouling block. Ultrasmall Au NPs were prepared and then covered by the peptide via the Au-S bonds between gold and thiol groups from cysteine. The morphology, colloidal stability and the responsiveness of obtained Au@Tat-R-EK NPs were studied using transmittance electron microscopy and dynamic laser scattering. The selective cancer cell uptake and accumulation of Au@Tat-R-EK NPs in cancer tissue were studied via ICP-MS in vitro and in vivo, respectively. The cytotoxicity of Au@Tat-R-EK NPs on HepG2 cancer cells was evaluated in terms of cell viability, DNA damage, intracellular reactive oxygen species generation, and apoptosis analysis. Finally, the biocompatibility and tumor destruction ability against orthotopic LM3 liver cancers were verified in vivo. Results: Multifunctional peptide modified ultrasmall Au NPs were successfully prepared. The Au NPs exhibited enough colloidal stability and cathepsin B-responsive surface change, leading to selectively uptake by cancer cells in vitro and accumulation to tumor sites in vivo. Combined with X-ray irradiation, the responsive Au NPs demonstrated superior radio-sensitizing cytotoxicity in vitro and therapeutic outcome on mouse liver cancer in vivo. The ultrasmall size enables rapid clearance of the Au NPs, guarantees the biocompatibility in vivo for potential clinical applications. Conclusion: Some obstacles faced by the Au NPs-based radiotherapy, such as short circulation half-life, non-specific distribution, slow clearance and low radio-sensitizing effect, were effective solved through rational design of the smart nanomedicine. This work provides new insight in designing tumor microenvironment-responsive nanomedicine in cancer radiotherapy.

Tumor microenvironment-responsive multifunctional peptide coated ultrasmall gold nanoparticles and their application in cancer radiotherapy.

Clinical trials confirm the combination of indoleamine 2,3-dioxygenase (IDO) blockade and immunogenic chemotherapy represents a brilliant future in cancer therapy. However, it remains challenging to precisely activate chemo-immunotherapy in situ to avoid side effects from the systemic administrations and reverse the poor immunogenicity and immunosuppressive microenvironment in tumor sites. Herein, a hybrid nanomedicine ("RPMANB NPs") to co-deliver an IDO inhibitor (NLG919) and a chemotherapeutic prodrug to amplify the therapeutic benefits are designed. Attributed to the delicate surface engineering, the RPMANB NPs possess excellent pharmacokinetics and tumor accumulation. The loaded NLG919 are released inside cancer tissues/cells due to the collapse of the metal-organic framework platform triggered by the highly concentrated phosphate, reversing the immunosuppressive tumor microenvironment by suppressing IDO activity. The potent chemotherapeutic drug is precisely activated through a highly efficient plasmon-driven catalysis in the presence of near-infrared light, eliciting antitumor immunity by triggering immunogenic cell death and avoiding side effects through in situ activation of chemotherapy. In vivo studies demonstrate that the chemo-immunotherapy greatly suppresses the tumor growth by promoting intratumoral accumulation of cytotoxic T lymphocytes and downregulating regulatory T cells. This work establishes a robust delivery platform to overcome the current obstacles of tumor treatments by combining precisely activatable chemotherapy with immunotherapy.

Plasmon-Driven Catalytic Chemotherapy Augments Cancer Immunotherapy through Induction of Immunogenic Cell Death and Blockage of IDO Pathway.

Lymphoepithelioma-like intrahepatic cholangiocarcinoma (LEL-ICC) is an uncommon lesion. Less than 100 cases of hepatic LELC, including IEL-HCC (hepatocellular carcinoma) and IEL-ICC, have been described, and the understanding of the LELC is very limited. We report the case of a 75-year-old woman with LEL-ICC. She complained of finding a lesion located in the left lateral liver during her last check-up 2 years ago. The contrast-enhanced abdominal computed tomography (CT) scan revealed a low-density mass located in the left lateral liver with an estimated magnitude of 20×16 mm. The magnetic resonance imaging (MRI) demonstrated two T2 high-signal intensity foci in the left lateral liver, with similar size and signal manifestation in the arterial and portal venous phases. The patient underwent laparoscopic left lateral hepatectomy. The postoperative pathological and immunohistochemical examination findings allowed for the definitive diagnosis. A literature review indicated that a geriatric Asian female with a single lesion located in the liver should consider the possibility of LEL-ICC. An Epstein-Barr virus (EBV) infection might play a crucial role in the tumorigenesis of LEL-ICC, and surgical resection was the first choice for treating LEL-ICC.

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Lymphoepithelioma-like intrahepatic cholangiocarcinoma with Epstein-Barr virus infection: report of a rare case

Background: For high morbidity rate but lack of early accurate screening, hepatocellular cancer (HCC) manifests as the fourth leading cause of cancer related death worldwide. Accumulating evidence demonstrated that a series of long noncoding RNA (lncRNA) have strong association with pathogenesis and clinical evaluation of HCC. LINC01554, one kind of lncRNA, has been found specifically enriched in liver tissue. However, the relationship between LINC01554 expression and HCC tumorigenesis remains unclear. Methods: The relative LINC01554 expression was measured in HCC tissues of 138 patients and several HCC cell lines using quantitative real-time PCR. Patients were grouped according to individual LINC01554 expression. Then, the potential association between LINC01554 expression in HCC tissues and clinical characteristics as well as prognostic information of patients was evaluated. Results: Compared to correspongding adjacent liver tissues, the LINC01554 expression in HCC was significantly down-regulated (P=0.001). And its expression levels in HCC cell lines were also remarkably lower than that in normal human hepatocyte cell line (P<0.001). Besides, the expression level of LINC01554 was significantly related to tumor size, multiple lesions, TNM stages, tumor recurrence rate as well as long-term survival in HCC patients (P<0.05). Conclusion: The research revealed that LINC01554 was down-regulated in HCC and it could be used for the accurate diagnosis and prognostic prediction of HCC patients.

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Sitong Zhang

Papers

A Nanomedicine Fabricated from Gold Nanoparticles‐Decorated Metal–Organic Framework for Cascade Chemo/Chemodynamic Cancer Therapy

Tumor microenvironment-responsive multifunctional peptide coated ultrasmall gold nanoparticles and their application in cancer radiotherapy.

Plasmon-Driven Catalytic Chemotherapy Augments Cancer Immunotherapy through Induction of Immunogenic Cell Death and Blockage of IDO Pathway.

Lymphoepithelioma-like intrahepatic cholangiocarcinoma with Epstein-Barr virus infection: report of a rare case

Down-regulation of Long Non-coding RNA LINC01554 in Hepatocellular Cancer and its Clinical Significance.