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An Ethacrynic Acid‐Brominated BODIPY Photosensitizer (EA‐BPS) Construct Enhances the Lethality of Reactive Oxygen Species in Hypoxic Tumor‐Targeted Photodynamic Therapy
  • 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
  • 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.
Targeting Heterogeneous Tumors Using a Multifunctional Molecular Prodrug, J. Am. Chem. Soc., 2019 (in press)
  • Reported here is a molecular construct (K1) designed to overcome hurdles associated with delivering active drugs to heterogeneous tumor environments. Construct K1 relies on two cancer environment triggers (GSH and H2O2) to induce prodrug activation. It releases an active drug form (SN38) under conditions of both oxidative and reductive stress in vitro. Specific uptake of K1 in COX-2 positive aggressive colon cancer cells (SW620 and LoVo) was seen, along with enhanced anticancer activity compared with the control agent SN-38. These findings are attributed to environmentally triggered drug release, as well as simultaneous scavenging of species giving rise to intracellular redox stress. K1 serves to downregulate various cancer survival signaling pathways (AKT, p38, IL-6, VEGF, and TNF-α) and upregulate an anti-inflammatory response (IL-10). Compared with SN-38 and DMSO as controls, K1 also displayed an improved in vivo therapeutic efficacy in a xenograft tumor regrowth model with no noticeable systematic toxicity at the administrated dose. We believe that the strategy described here presents an attractive approach to addressing solid tumors characterized by intratumoral heterogeneity.
"Harnessing Intramolecular Rotation to Enhance Two-photon Imaging of Aβ Plaques Through Minimizing Background Fluorescence" Angew. Chem. Int. Ed., 5648-5652, 58, 2019.
  • The aggregation of amyloid beta (Aβ) proteins in senile plaques is a critical event during the development of Alzheimer\'s disease, and the postmortem detection of Aβ‐rich proteinaceous deposits through fluorescent staining remains one of the most robust diagnostic tools. In animal models, fluorescence imaging can be employed to follow the progression of the disease, and among the different imaging methods, two‐photon microscopy (TPM) has emerged as one of the most powerful. To date, several near‐infrared‐emissive two‐photon dyes with a high affinity for Aβ fibrils have been developed, but there has often been a tradeoff between excellent two‐photon cross‐sections and large fluorescence signal‐to‐background ratios. In the current work, we introduced a twisted intramolecular charge state (TICT)‐based de‐excitation pathway, which results in a remarkable fluorescence increase of around 167‐fold in the presence of Aβ fibrils, while maintaining an excellent two‐photon cross section, thereby enabling high‐contrast ex vivo and in vivo TPM imaging. Overall, the results suggest that adopting TICT de‐excitation in two‐photon fluorophores may represent a general method to overcome the tradeoff between probe brightness and signal‐to‐background ratio.
"Chemiluminescent Probe for the In Vitro and In Vivo Imaging of Cancers Over-expressing NQO1" Angew. Chem. Int. Ed. 1739-1743, 58, 2019.
  • Activatable (turn‐on) probes that permit the rapid, sensitive, selective, and accurate identification of cancer‐associated biomarkers can help drive advances in cancer research. Herein, a NAD(P)H:quinone oxidoreductase‐1 (NQO1)‐specific chemiluminescent probe 1 is reported that allows the differentiation between cancer subtypes. Probe 1 incorporates an NQO1‐specific trimethyl‐locked quinone trigger moiety covalently tethered to a phenoxy‐dioxetane moiety through a para‐aminobenzyl alcohol linker. Bio‐reduction of the quinone to the corresponding hydroquinone results in a chemiluminescent signal. As inferred from a combination of in vitro cell culture analyses and in vivo mice studies, the probe is safe, cell permeable, and capable of producing a “turn‐on” luminescence response in an NQO1‐positive A549 lung cancer model. On this basis, probe 1 can be used to identify cancerous cells and tissues characterized by elevated NQO1 levels.
"Overcoming Drug Resistance by Targeting Cancer Bioenergetics with an Activatable Prodrug" Chem (Cell Press), 2370-2383, 4, 2018.
  • Nearly without exception, all known cancer chemotherapeutics elicit a resistance response over time. The resulting resistance is correlated with poor clinical outcomes. Here, we report an approach to overcoming resistance through reprogramming oncogene-directed alterations in mitochondrial metabolism before drug activation while simultaneously circumventing drug efflux pumps. Conjugate C1 increases cancer cell apoptosis and inhibits regrowth of drugresistant tumors, as inferred from efficacy studies carried out in human cancer cells and in Dox-resistant xenograft tumor models. It also displays minimal whole-animal toxicity. These benefits are ascribed to an ability to evade chemoresistance by switching cancer cell metabolism back to normal mitochondrial oxidative phosphorylation while helping target the active Dox to first the mitochondrion and then the nucleus.
"Rational Design of In Vivo Tau Tangle-Selective Near Infrared Fluorophores: Expanding the BODIPY Universe" J. Am. Chem. Soc., 2017, 139 (38), pp 13393–13403
  • The elucidation of the cause of Alzheimer’s disease remains one of the greatest questions in neurodegenerative research. The lack of highly reliable low-cost sensors to study the structural changes in key proteins during the progression of the disease is a contributing factor to this lack of insight. In the current work, we describe the rational design and synthesis of two fluorescent BODIPY-based probes, named Tau 1 and Tau 2. The probes were evaluated on the molecular surface formed by a fibril of the PHF6 (306VQIVYK311) tau fragment using molecular docking studies to provide a potential molecular model to rationalize the selectivity of the new probes as compared to a homologous Aβ-selective probe. The probes were synthesized in a few steps from commercially available starting products and could thus prove to be highly costeffective. We demonstrated the excellent photophysical properties of the dyes, such as a large Stokes shift and emission in the near-infrared window of the electromagnetic spectrum. The probes demonstrated a high selectivity for self-assembled microtubule-associated protein tau (Tau protein), in both solution and cell-based experiments. Moreover, the administration to an acute murine model of tauopathy clearly revealed the staining of self-assembled hyperphosphorylated tau protein in pathologically relevant hippocampal brain regions. Tau 1 demonstrated efficient blood−brain barrier penetrability and demonstrated a clear selectivity for tau tangles over Aβ plaques, as well as the capacity for in vivo imaging in a transgenic mouse model. The current work could open up avenues for the cost-effective monitoring of the tau protein aggregation state in animal models as well as tissue staining. Furthermore, these fluorophores could serve as the basis for the development of clinically relevant sensors, for example based on PET imaging.
"A mitochondria-targeted cryptocyanine-based photothermogenic photosensitizer" J. Am. Chem. Soc., 2017, 139 (29), pp 9972–9978
  • Cryptocyanine-based probes exhibit highly efficient photothermal conversion and represent a new class of photothermal agents for use in photothermal therapy (PTT). With the thermal susceptibility of mitochondria in mind, we have prepared a mitochondriatargeted, NIR-absorbing cryptocyanine probe (Mito-CCy) and evaluated its photophysical properties, photothermal conversion effici ncy, biological compatibility, cytotoxicity, and mitochondrial localization in HeLa cells. Upon subjecting 0.5 mL of a PBS buffer solution (10 mM, pH 7.4, containing 50% DMSO) of Mito-CCy (0.5 mM) to 730 nm laser irradiation at 2.3 W/cm2 , the temperature of the solution increased by 13.5 °C within 5 min. In contrast, the corresponding cryptocyanine (CCy) lacking the triarylphosphonium group gave rise to only an ∼3.4 °C increase in solution temperature under otherwise identical conditions. Mito-CCy also exhibited high cytotoxicity in HeLa cells when subject to photoirradiation. This light-induced cytotoxicity is attributed to the endogenous production of reactive oxygen species (ROS) induced under conditions of local heating. ROS are known to interfere with the mitochondrial defense system and to trigger apoptosis. By targeting the mitochondria, the present sensitizer-based photothermogenic approach is rendered more effective. As such, the system reported here represents the vanguard of what might be a new generation of organelle-targeted photothermal therapeutics.
"Overcoming the Limits of Hypoxia in Photodynamic Therapy: A Carbonic Anhydrase IX-Targeted Approach" J. Am. Chem. Soc., 2017, 139 (22), pp 7595–7602
  • A major challenge in photodynamic cancer therapy (PDT) is avoiding PDT-induced hypoxia, which can lead to cancer recurrence and progression through activation of various angiogenic factors and significantly reduce treatment outcomes. Reported here is an acetazolamide (AZ)-conjugated BODIPY photosensitizer (AZBPS) designed to mitigate the effects of PDT-based hypoxia by combining the benefits of anti-angiogenesis therapy with PDT. AZBPS showed specific affinity to aggressive cancer cells (MDA-MB231 cells) that overexpress carbonic anhydrase IX (CAIX). It displayed enhanced photocytotoxicity compared to a reference compound, BPS, which is an analogous PDT agent that lacks an acetazolamide unit. AZ-BPS also displayed an enhanced in vivo efficacy in a xenograft mouse tumor regrowth model relative to BPS, an effect attributed to inhibition of tumor angiogenesis by both PDT-induced ROS generation and CAIX knockdown. AZ-BPS was evaluated successfully in clinical samples collected from breast cancer patients. We thus believe that the combined approach described here represents an attractive therapeutic approach to targeting CAIX-overexpressing tumors.