RESEARCH

Next-generation
Molecular Theranostics Lab

Project

Highlight

Highlight

HOME > RESEARCH > Highlight
Lutetium Texaphyrin–Celecoxib Conjugate as a Potential Immuno-Photodynamic Therapy Agent, J. Am. Chem. Soc. 19434-19448, 146, 28, 2024
  • Immuno-photodynamic therapy (IPDT) has emerged as a new modality for cancer treatment. Novel photosensitizers can help achieve the promise inherent in IPDT, namely, the complete eradication of a tumor without recurrence. We report here a small molecule photosensitizer conjugate, LuCXB. This IPDT agent integrates a celecoxib (cyclooxygenase-2 inhibitor) moiety with a near-infrared absorbing lutetium texaphyrin photocatalytic core. In aqueous environments, the two components of LuCXB are self-associated through inferred donor–acceptor interactions. A consequence of this intramolecular association is that upon photoirradiation with 730 nm light, LuCXB produces superoxide radicals (O2–•) via a type I photodynamic pathway; this provides a first line of defense against the tumor while promoting IPDT. For in vivo therapeutic applications, we prepared a CD133-targeting, aptamer-functionalized exosome-based nanophotosensitizer (Ex-apt@LuCXB) designed to target cancer stem cells. Ex-apt@LuCXB was found to display good photosensitivity, acceptable biocompatibility, and robust tumor targetability. Under conditions of photoirradiation, Ex-apt@LuCXB acts to amplify IPDT while exerting a significant antitumor effect in both liver and breast cancer mouse models. The observed therapeutic effects are attributed to a synergistic mechanism that combines antiangiogenesis and photoinduced cancer immunotherapy.
Early onset diagnosis in Alzheimer’s disease patients via amyloid-β oligomers-sensing probe in cerebrospinal fluid. Nat. Commun. 1004, 15, 2024.
  • Amyloid-β (Aβ) oligomers are implicated in the onset of Alzheimer’s disease (AD). Herein, quinoline-derived half-curcumin-dioxaborine (Q-OB) fluorescent probe was designed for detecting Aβ oligomers by finely tailoring the hydrophobicity of the biannulate donor motifs in donor-π-acceptor structure. Q-OB shows a great sensing potency in dynamically monitoring oligomerization of Aβ during amyloid fibrillogenesis in vitro. In addition, we applied this strategy to fluorometrically analyze Aβ self-assembly kinetics in the cerebrospinal fluids (CSF) of AD patients. The fluorescence intensity of Q-OB in AD patients’ CSF revealed a marked change of log (I/I0) value of 0.34 ± 0.13 (cognitive normal), 0.15 ± 0.12 (mild cognitive impairment), and 0.14 ± 0.10 (AD dementia), guiding to distinguish a state of AD continuum for early diagnosis of AD. These studies demonstrate the potential of our approach can expand the currently available preclinical diagnostic platform for the early stages of AD, aiding in the disruption of pathological progression and the development of appropriate treatment strategies.
Photocatalytic Superoxide Radical Generator that Induces Pyroptosis in Cancer Cells. J. Am. Chem. Soc. 11326-11337, 25, 144, 2022.
  • Pyroptosis, a newly characterized form of immunogenic cell death, is attracting increasing attention as a promising approach to cancer immunotherapy. However, biocompatible strategies to activate pyroptosis remain rare. Here, we show that a photocatalytic superoxide radical (O2–•) generator, NI-TA, triggers pyroptosis in cancer cells. NI-TA was designed to take advantage of an intramolecular triplet-ground state splitting energy modulation approach. Detailed studies revealed that the pyroptosis triggered by NI-TA under conditions of photoexcitation proceeds through a caspase-3/gasdermin E (GSDME) pathway rather than via canonical processes involving caspase-1/gasdermin-D (GSDMD). NI-TA was found to function via a partial-O2-recycling mode of action and to trigger cell pyroptosis and provide for effective cancer cell ablation even under conditions of hypoxia (≤2% O2). In the case of T47D 3D multicellular spheroids, good antitumor efficiency and stemness inhibition are achieved. This work highlights how photocatalytic chemistry may be leveraged to develop effective pyroptosis-inducing agents.
Harnessing GLUT1 Targeted Pro-oxidant Ascorbate for Synergistic Phototherapeutics. Angew. Chem. Int. Ed. e202110832, 61, 2022.
  • Despite extensive efforts to realize effective photodynamic therapy (PDT), there is still a lack of therapeutic approaches concisely structured to mitigate the major obstacles of PDT in clinical applications. Herein, we report a molecular strategy exploiting ascorbate chemistry to enhance the efficacy of PDT in cancer cells overexpressing glucose transporter 1 (GLUT1). AA-EtNBS, a 5-O-substituted ascorbate–photosensitizer (PS) conjugate, undergoes a reversible structural conversion of the ascorbate moiety in the presence of reactive oxygen species (ROS) and glutathione (GSH), thereby promoting its uptake in GLUT1-overexpressed KM12C colon cancer cells and perturbing tumor redox homeostasis, respectively. Due to the unique pro-oxidant role of ascorbate in tumor environments, AA-EtNBS effectively sensitized KM12C cancer cells prior to PS-mediated generation of superoxide radicals under near-infrared (NIR) illumination. AA-EtNBS successfully exhibited GLUT1-targeted synergistic therapeutic efficacy during PDT both in vitro and in vivo. Therefore, this study outlines a promising strategy employing ascorbate both as a targeting unit for GLUT1-overexpressed cancer cells and redox homeostasis destruction agent, thereby enhancing therapeutic responses towards anticancer treatment when used in conjunction with conventional PDT.
DNA Damage Response Targeting Mitochondrial Induced Multifunctional Prodrug Strategy for Self-defensive Tumor Therapy. Angew. Chem. Int. Ed. e202117075, 61, 2022.
  • We report a novel multifunctional construct, M1, designed explicitly to target the DNA damage response in cancer cells. M1 contains both a floxuridine (FUDR) and protein phosphatase 2A (PP2A) inhibitor combined with a GSH-sensitive linker. Further conjugation of the triphenylphosphonium moiety allows M1 to undergo specific activation in the mitochondria, where mitochondria-mediated apoptosis is observed. Moreover, M1 has enormous effects on genomic DNA ascribed to FUDR\'s primary function of impeding DNA/RNA synthesis combined with diminishing PP2A-activated DNA repair pathways. Importantly, mechanistic studies highlight the PP2A obtrusion in FUDR/5-fluorouracil (5-FU) therapy and underscore the importance of its inhibition to harbor therapeutic potential. HCT116 cell xenograft-bearing mice that have a low response rate to 5-FU show a prominent effect with M1, emphasizing the importance of DNA damage response targeting strategies using tumor-specific microenvironment-activatable systems.
A small molecule strategy for targeting cancer stem cells in hypoxic microenvironments and preventing tumorigenesis. J. Am. Chem. Soc. 14115–14124, 35, 143, 2021.
  • Breast cancer consists of heterogenic subpopulations, which determine the prognosis and response to chemotherapy. Among these subpopulations, a very limited number of cancer cells are particularly problematic. These cells, known as breast cancer stem cells (BCSCs), are thought responsible for metastasis and recurrence. They are thus major contributor to the unfavorable outcomes seen for many breast cancer patients. BCSCs are more prevalent in the hypoxic niche. This is an oxygen-deprived environment that is considered crucial to their proliferation, stemness, and self-renewal but also one that makes BCSCs highly refractory to traditional chemotherapeutic regimens. Here we report a small molecule construct, AzCDF, that allows the therapeutic targeting of BCSCs and which is effective in normally refractory hypoxic tumor environments. A related system, AzNap, has been developed that permits CSC imaging. Several design elements are incorporated into AzCDF, including the CAIX inhibitor acetazolamide (Az) to promote localization in MDA-MB-231 CSCs, a dimethylnitrothiophene subunit as a hypoxia trigger, and a 3,4-difluorobenzylidene curcumin (CDF) as a readily released therapeutic payload. This allows AzCDF to serve as a hypoxia-liable molecular platform that targets BCSCs selectively which decreases CSC migration, retards tumor growth, and lowers tumorigenesis rates as evidenced by a combination of in vitro and in vivo studies. To the best of our knowledge, this is the first time a CSC-targeting small molecule has been shown to prevent tumorigenesis in an animal model.
Nanoscale materials-based platforms for the treatment of bone-related diseases. Matter (Cell Press), 2727–2764, 4, 2021.
  • Owing to the high density of bone tissue and the complex and highly hierarchical structure, drugs used for the treatment of bone-related diseases are often not effectively concentrated at the site of the lesion. Generally, the therapeutic effect is unsatisfactory, and the long-term use of drugs causes adverse effects. Therefore, it is of great importance to explore nanotherapeutic platforms to improve bone-targeting capabilities and provide controlled release performance on demand to enhance therapeutic effects. This review aims to (1) summarize various types of recently developed nanotherapeutic platforms; (2) present representative material strategies for applying nanoplatforms for treating bone diseases based on a deeper knowledge of the biophysical structure and material-chemical composition of human osteology, and the awareness of disease pathogenesis and progression; and (3) summarize the typical multifunctional systems through a suitable combination of different cues for enhancing the treatment efficacy.
An Ethacrynic Acid‐Brominated BODIPY Photosensitizer (EA‐BPS) Construct Enhances the Lethality of Reactive Oxygen Species in Hypoxic Tumor‐Targeted Photodynamic Therapy. Angew.Chem. Int. Ed. 2021, 60, 3196 –3204.
  • Despite being a clinically approved intervention for cancer, photodynamic therapy (PDT) still suffers from limitations. Prime among these is a therapeutic response that is mostly oxygen dependent. This limits the utility of PDT in treating hypoxic tumors since lower levels of cytotoxic reactive oxygen species (ROS) are generated in regions of low oxygen tension. Glutathione‐pi (GST‐pi) is a key enzyme that militates against ROS‐mediated apoptosis. We report herein a new construct, EA‐BPS, that contains both a brominated BODIPY photosensitizer (BPS) and an ethacrynic acid (EA) GST‐pi inhibitor. Photoirradiation of EA‐BPS induces a synergistic antitumor effect that results from the combination of ROS production and GST‐pi inhibition. Relative to BPS alone, an enhanced cell‐killing effect is seen under hypoxic conditions both in vitro and in vivo. We conclude that by making better use of the available oxygen in tumor environments, improved therapeutic PDT outcomes should be achievable even under hypoxic conditions.
Fluorescent Diagnostic Probes in Neurodegenerative Diseases
  • Neurodegenerative diseases are debilitating disorders that feature progressive and selective loss of function or structure of anatomically or physiologically associated neuronal systems. Both chronic and acute neurodegenerative diseases are associated with high morbidity and mortality along with the death of neurons in different areas of the brain; moreover, there are few or no effective curative therapy options for treating these disorders. There is an urgent need to diagnose neurodegenerative disease as early as possible, and to distinguish between different disorders with overlapping symptoms that will help to decide the best clinical treatment. Recently, in neurodegenerative disease research, fluorescent‐probe‐mediated biomarker visualization techniques have been gaining increasing attention for the early diagnosis of neurodegenerative diseases. A survey of fluorescent probes for sensing and imaging biomarkers of neurodegenerative diseases is provided. These imaging probes are categorized based on the different potential biomarkers of various neurodegenerative diseases, and their advantages and disadvantages are discussed. Guides to develop new sensing strategies, recognition mechanisms, as well as the ideal features to further improve neurodegenerative disease fluorescence imaging are also explored.
Mitochondrial Relocation of a Common Synthetic Antibiotic: A Non-genotoxic Approach to Cancer Therapy. Chem 2021, 6, 1408–141
  • Tumor recurrence as a result of therapy-induced nuclear DNA lesions is a major issue in cancer treatment. Currently, only a few examples of potentially non-genotoxic drugs have been reported. Mitochondrial re-localization of ciprofloxacin, one of the most commonly prescribed synthetic antibiotics, is reported here as a new approach. Conjugation of ciprofloxacin to a triphenyl phosphonium group (giving lead Mt-CFX) is used to enhance the concentration of ciprofloxacin in the mitochondria of cancer cells. The localization of Mt-CFX to the mitochondria induces oxidative damage to proteins, mtDNA, and lipids. A large bias in favor of mtDNA damage over nDNA was seen with Mt-CFX, contrary to classic cancer chemotherapeutics. Mt-CFX was found to reduce cancer growth in a xenograft mouse model and proved to be well tolerated. Mitochondrial re-localization of antibiotics could emerge as a useful approach to generating anticancer leads that promote cell death via the selective induction of mitochondrially mediated oxidative damage.
  RTP Live