A Photosensitive Polymeric Carrier with a Renewable Singlet Oxygen Reservoir Regulated by Two NIR Beams for Enhanced Antitumor Phototherapy

Small, Journal Year: 2021, Volume and Issue: 17(29)

Published: June 18, 2021

Abstract Photodynamic therapy (PDT), which utilizes photosensitizer to convert molecular oxygen into singlet ( 1 O 2 ) upon laser irradiation ablate tumors, will exacerbate the already shortage of most solid tumors and is thus self‐limiting. Herein, a sophisticated photosensitive polymeric material (An‐NP) that allows sustained generation sufficient supply during entire phototherapy engineered by alternatively applying PDT photothermal (PTT) controlled two NIR beams. In addition generates , An‐NP consists other key components: molecularly designed anthracene derivative capable trapping/releasing with superior reversibility dye J‐aggregate superb performance. Thus, in 655 nm laser‐triggered process, abundant extra being trapped via conversion EPO‐NP; while subsequent 785 laser‐driven PTT converted EPO‐NP undergoes thermolysis liberate captured regenerates An‐NP. The intratumoral level can be replenished cycle for next round generate . working principle efficacy are preliminarily demonstrated living cells tumor‐bearing mice, respectively.

Language: Английский

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Light-mediated Activation/Deactivation Control and in vitro ADMETox Profiling of a Donepezil-like Dual AChE/MAO-B Inhibitor

European Journal of Pharmaceutical Sciences, Journal Year: 2025, Volume and Issue: unknown, P. 107066 - 107066

Published: March 1, 2025

The possibility to control the effects of drugs in time and space represents an ideal condition for developing safer more personalized therapies against different disorders. In this context, photopharmacology has paved way use light modulation activity. Our interest is directed photo-switchable molecules, capable interconverting between two isoforms upon irradiation. We recently reported compound 1, a donepezil-like based on 2-benzylidenindan-1-one structure, as dual AChE MAO-B inhibitor, which can be converted into E- (active form) Z- (about tenfold less active diastereoisomers by irradiating with UV-vis light. Aiming at identifying compounds remarkable activity physiological conditions, we herein report fine characterization 1 PBS solutions. First, evaluated its ability act photoswitch comparing solution organic solvents (e.g. methanol), demonstrating that wavelength UV range (330 nm) convert Z-diastereoisomer, while visible (400 allows interconversion from Z E both media. Along photoinducible behavior, investigated passive diffusion across cellular membrane PAMPA experiments, plasma microsomal stability, binding proteins. Interestingly, results such studies suggested could persist blood circulation long time, desirable application photopharmacological therapies. Cytotoxicity highlighted potential our prototypic lead photodrug neurodegenerative disorders, deserving advance molecular optimization further vitro vivo characterization.

Language: Английский

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Principles and Design of Molecular Tools for Sensing and Perturbing Cell Surface Receptor Activity

Chemical Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 25, 2025

Cell-surface receptors are vital for controlling numerous cellular processes with their dysregulation being linked to disease states. Therefore, it is necessary develop tools study and the signaling pathways they control. This Review broadly describes molecular approaches that enable 1) visualization of determine localization distribution; 2) sensing receptor activation permanent readouts as well in real time; 3) perturbing activity mimicking receptor-controlled learn more about these processes. Together, have provided valuable insight into fundamental biology helped characterize therapeutics target receptors.

Language: Английский

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Hypothesis-Driven, Structure-Based Design in Photopharmacology: The Case of eDHFR Inhibitors

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(6), P. 4798 - 4817

Published: March 8, 2022

Photopharmacology uses light to regulate the biological activity of drugs. This precise control is obtained through incorporation molecular photoswitches into bioactive molecules. A major challenge for photopharmacology rational design photoswitchable drugs that show light-induced activation. Computer-aided drug an attractive approach toward more effective, targeted design. Herein, we critically evaluated different structure-based approaches with Escherichia coli dihydrofolate reductase (eDHFR) as a case study. Through iterative examination our hypotheses, progressively tuned azobenzene-based, eDHFR inhibitors in five design–make–switch–test–analyze cycles. Targeting hydrophobic subpocket enzyme and specific salt bridge only thermally metastable cis-isomer emerged most promising strategy. We identified three could be activated upon irradiation reached potencies low-nanomolar range. Above all, this systematic study provided valuable insights future endeavors photopharmacology.

Language: Английский

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Photochromic Fentanyl Derivatives for Controlled μ‐Opioid Receptor Activation

Chemistry - A European Journal, Journal Year: 2022, Volume and Issue: 28(63)

Published: July 28, 2022

Photoswitchable ligands as biological tools provide an opportunity to explore the kinetics and dynamics of clinically relevant μ-opioid receptor. These can potentially activate or deactivate receptor when desired by using light. Spatial temporal control activity allows for application in a diverse range investigations. have been developed this work, modelled on known agonist fentanyl, with aim expanding current "toolbox" fentanyl photoswitchable ligands. In doing so, that change geometry (isomerize) upon exposure light, varying photophysical biochemical properties. This variation properties could be valuable further studying functional significance

Language: Английский

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Systematic modifications of substitution patterns for property tuning of photoswitchable asymmetric azobenzenes

Organic & Biomolecular Chemistry, Journal Year: 2022, Volume and Issue: 20(20), P. 4204 - 4214

Published: Jan. 1, 2022

Systematic investigations of substituted azobenzenes uncovered photoswitches that thermally relax in minutes, suitable for biological applications.

Language: Английский

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Tuning Proapoptotic Activity of a Phosphoric‐Acid‐Tethered Tetraphenylethene by Visible‐Light‐Triggered Isomerization and Switchable Protein Interactions for Cancer Therapy

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 61(36)

Published: July 11, 2022

We herein report a phosphoric-acid-substituted tetraphenylethene (T-P) capable of adapting its geometric configuration and biological activity to the microenvironment upon light irradiation for apoptosis modulation. Different from most ultraviolet-responsive isomerization, T-P undergoes cis-trans isomerization under visible irradiation, which is biocompatible thus photo-modulation possible in living biosystems. By using alkaline phosphatase (ALP) albumin as dual targets, isomers display different protein binding selectivity, cancer-cell internalization efficiency apoptosis-inducing ability. The proapoptotic was found be kinetically controlled by enzymatic reaction with ALP regulated co-existing albumin. Motivated these findings, two-way modulation effect on-demand boosting anticancer efficacy were realized vitro vivo endogenous proteins multiple non-invasive switching stimuli.

Language: Английский

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All-in-One Photoactivated Inhibition of Butyrylcholinesterase Combined with Luminescence as an Activation and Localization Indicator: Carbon Quantum Dots@Phosphonate Hybrids

Nanomaterials, Journal Year: 2023, Volume and Issue: 13(17), P. 2409 - 2409

Published: Aug. 25, 2023

Photopharmacology is a booming research area requiring new generation of agents possessing simultaneous functions photoswitching and pharmacophore. It important that any practical implementation photopharmacology ideally requires spatial control the medicinal treatment zone. Thus, advances in study substances meeting all listed requirements will lead to breakthrough coming years. In this study, CQDs@phosphonate nanohybrids are presented for first time combine biocompatible nontoxic luminescent carbon quantum dots (CQDs) with photoactive phosphonate enabling inhibition butyrylcholinesterase (BChE), which prognostic marker numerous diseases. The conjunction these components hybrids maintains provides enhancement BChE inhibition. After laser irradiation wavelength 266 nm, demonstrate drastic increase from 38% up almost 100% luminescence decrease. All hybrid properties demonstrated not only vitro experiments but also complex biological samples, i.e., chicken breast. most achievement demonstration characterized by remarkable combination all-in-one photopharmacology: (i) bioactivity toward inhibition, (ii) strong change degree as result irradiation, an indicator (iii) state, (iv) localization on surface sample.

Language: Английский

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Kinetic mechanism of Na+-coupled aspartate transport catalyzed by GltTk

Communications Biology, Journal Year: 2021, Volume and Issue: 4(1)

Published: June 17, 2021

Abstract It is well-established that the secondary active transporters Glt Tk and Ph catalyze coupled uptake of aspartate three sodium ions, but insight in kinetic mechanism transport fragmentary. Here, we systematically measured rates proteoliposomes containing purified , derived rate equation for a which two ions bind before another after aspartate. Re-analysis existing data on using this allowed determination turnover number (0.14 s −1 ), without need error-prone protein quantification. To overcome complication may adopt right-side-out or inside-out membrane orientations upon reconstitution, thereby confounding analysis, employed rapid method synthetic nanobodies to inactivate one population. Oppositely oriented proteins showed same kinetics, consistent with use an identical gating element both sides membrane. Our work underlines value bona fide experiments reveal mechanistic features Na + -aspartate symport cannot be observed detergent solution. Combined previous pre-equilibrium binding studies, full structurally characterized SLC1A family now emerging.

Language: Английский

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Photopharmacology of Ion Channels through the Light of the Computational Microscope

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(21), P. 12072 - 12072

Published: Nov. 8, 2021

The optical control and investigation of neuronal activity can be achieved carried out with photoswitchable ligands. Such compounds are designed in a modular fashion, combining known ligand the target protein photochromic group, as well an additional electrophilic group for tethered design strategy optimized by including structural data. In addition to experimental structures, computational methods (such homology modeling, molecular docking, dynamics enhanced sampling techniques) provide insights guide photoswitch understand observed light-regulated effects. This review discusses application such structure-based ligands targeting voltage- ligand-gated ion channels. Structural mapping may help identify residues near binding pocket amenable mutagenesis covalent attachment. Modeling complex shed light on different activities two isomers effect site-directed mutations binding, channel subtype selectivity. examples presented here show how integration modeling data greatly facilitate optimization. Recent advances biology, both computational, expected further strengthen this rational photopharmacology approach.

Language: Английский

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