Light-triggered Nitric Oxide Release Research Articles

Biomimetic Activation of N-Nitrosamides with Red Light-Triggered Nitric Oxide Release via Mediated Electron Transfer.

Mediated electron transfer (MET) is fundamental to many biological functions, including cellular respiration, photosynthesis, and enzymatic catalysis. However, leveraging the MET process to enable the release of therapeutic gases has been largely unexplored. Herein, we report the bio-inspired activation of a series of UV-absorbing N-nitrosamide derivatives (NOA) under red light exposure, enabling the quantitative release of nitric oxide (NO) gasotransmitter via an MET process. The cornerstone of our design is the covalent linkage of a 2,4-dinitroaniline moiety, which acts as an electron mediator to the N-nitrosamide groups. This facilitates efficient electron transfer from the excited palladium(II) meso-tetraphenyltetrabenzoporphyrin (PdTPTBP) photocatalyst and the selective activation of NOA. Our approach has been validated with distinct photocatalysts and various N-nitrosamides, including those derived from carbamates, amides, and ureas. Notably, the modulation of the linker length between the electron mediator and N-nitrosamide groups serves as a regulatory mechanism for controlling NO release kinetics. Moreover, this biomimetic NO release platform demonstrates effective operation under both normoxic and hypoxic conditions, and it enables localized delivery of NO under physiological conditions, exhibiting significant anticancer efficacy within the phototherapeutic window and enhanced selectivity towards tumor cells.

Dual photoresponsive & water-triggered nitric oxide releasing materials based on rhodium-based metal-organic polyhedra.

The exogenous administration of nitric oxide (NO) is considered a potential therapeutic treatment against a great variety of diseases due to its significant role in multiple physiological functions. Due to the gaseous nature, short lifetime and dose- and tissue-dependent activity of this molecule, the development of new administration procedures is required to control the NO delivery in terms of dosage, timing, and location. In this work, we propose a new molecular material based on robust metal-organic polyhedra (MOPs) for controlled NO release. We select dirhodium paddlewheel complex-based cuboctahedral MOPs (RhMOP), in which NO can chemically coordinate to the open-metal sites at the axial sites of dirhodium paddlewheel moieties. We further prepare amorphous coordination polymer particles (CPPs) by connecting RhMOP with bis(imidazole) linkers at the external axial sites. Both molecular MOPs and polymeric CPPs show relevant NO payloads and the release of NO can be triggered by two different stimuli: light and humidity. We show that imidazole ligands coordinating to the external axial sites of the paddlewheel moieties tune the light-triggered NO release property. We further demonstrate that the size and the extrinsic pores of CPPs are important for enhanced NO release.

Photostimulated Extended Nitric Oxide (NO) Release from Water-Soluble Block Copolymer to Enhance Antibacterial Activity.

N-Nitrosamines are well established motifs to release nitric oxide (NO) under photoirradiation. Herein, a series of amphiphilic N-nitrosamine-based block copolymers (BCPx-NO) are developed to attain controlled NO release under photoirradiation (365 nm, 3.71 mW/cm2). The water-soluble BCPx-NO forms micellar architecture in aqueous medium and exhibits a sustained NO release of 92-160 μM within 11.5 h, which is 36.8-64.0% of the calculated value. To understand the NO release mechanism, a small molecular NO donor (NOD) resembling the NO releasing functional motif of BCPx-NO is synthesized, which displays a burst NO release in DMSO within 2.5 h. The radical nature of the released NO is confirmed by electron paramagnetic resonance (EPR) spectroscopy. The gradual NO release from micellar BCPx-NO enhances antibacterial activity over NOD and exhibits a superior bactericidal effect on Gram-positive Staphylococcus aureus. In relation to biomedical applications, this work offers a comprehensive insight into tuning light-triggered NO release to improve antibacterial activity.

NIR-Triggered On-Demand Nitric Oxide Release for Enhanced Synergistic Phototherapy of Hypoxic Tumor.

Hypoxia of tumor microenvironments is a major factor restricting tumor treatment, which causes progression and metastasis of tumor. The hypoxic tumor microenvironment not only makes the traditional treatment method, such as chemotherapy, ineffective but also hinders the O2-dependent treatments, such as photodynamic therapy (PDT). Recently, stimuli-responsive nitric oxide (NO) donors have attracted extensive research interest in hypoxic tumor treatment because the NO release process is O2-independent. Besides, NO can distribute more uniformly than drug molecules and more widely than the PDT-generated active species due to its strong diffusion ability (200 μm in cells) and long lifetime (2 s in cells). Encouraged by these advantages, a near infrared light-triggered NO release polymeric nanoplatform (P1-CapNO NPs) was constructed by a thermally sensitive NO release unit, a photothermal unit, and a hydrophilic polyethylene glycol unit. P1-CapNO NPs possess strong absorption in the NIR region (the wavelength of maximal absorption peak was 790 nm with a molar absorption coefficient of 2.4 × 105 M-1 cm-1), great photothermal conversion efficiency (23.8%), and NO release ability (the released NO concentration can reach 1.3 μM) under 808 nm laser irradiation. Owing to these advantages, the great synergistic antitumor effect can be achieved in vitro and in vivo even under the hypoxic environment. The synergistic therapeutic strategy in this work could bypass the obstacles caused by hypoxia in tumor treatment and provide a reference for building a NO-involved therapeutic platform.

PHMB modified photothermally triggered nitric oxide release nanoplatform for precise synergistic therapy of wound bacterial infections

Bacterial infection has been considered as a significant obstacle for wound healing. Nitric oxide (NO), as a novel alternative for antibiotics, has emerged as a promising antibacterial agent. However, the precise spatiotemporal controlled release of NO still remains a major challenge. Herein, a near-infrared (NIR) light triggered NO release nanoplatform (designated as PB-NO@PDA-PHMB) with enhanced broad-spectrum antibacterial and anti-biofilm properties was constructed. Given that PB-NO@PDA-PHMB has strong absorption in the NIR region and exhibits excellent photothermal effect, it can rapidly trigger NO release by NIR irradiation. PB-NO@PDA-PHMB can effectively contact and capture bacteria, and then exhibit synergistic effect of photothermal and gas therapy. In vitro and in vivo experiments indicated that PB-NO@PDA-PHMB exhibited excellent biocompatibility, satisfactory synergistic antibacterial efficacy and the capability of accelerating wound healing. Under NIR irradiation (808 nm, 1 W cm−2, 7 min), PB-NO@PDA-PHMB (80 μg mL−1) achieved 100% bactericidal activity against both Gram-negative bacteria Escherichia coli (E. coli) and Gram-positive bacteria Staphyloccocus aureus (S. aureus), removed 58.94% of S. aureus biofilm. Therefore, this all-in-one antibacterial nanoplatform with high NIR responsiveness provides a promising antibiotic-free strategy for bacterial infection treatment.

Light-triggered nitric oxide release and structure transformation of peptide for enhanced intratumoral retention and sensitized photodynamic therapy

Tumor-targeted delivery of nanomedicine is of great importance to improve therapeutic efficacy of cancer and minimize systemic side effects. Unfortunately, nowadays the targeting efficiency of nanomedicine toward tumor is still quite limited and far from clinical requirements. In this work, we develop an innovative peptide-based nanoparticle to realize light-triggered nitric oxide (NO) release and structural transformation for enhanced intratumoral retention and simultaneously sensitizing photodynamic therapy (PDT). The designed nanoparticle is self-assembled from a chimeric peptide monomer, TPP-RRRKLVFFK-Ce6, which contains a photosensitive moiety (chlorin e6, Ce6), a β-sheet-forming peptide domain (Lys-Leu-Val-Phe-Phe, KLVFF), an oligoarginine domain (RRR) as NO donor and a triphenylphosphonium (TPP) moiety for targeting mitochondria. When irradiated by light, the constructed nanoparticles undergo rapid structural transformation from nanosphere to nanorod, enabling to achieve a significantly higher intratumoral accumulation by 3.26 times compared to that without light irradiation. More importantly, the conversion of generated NO and reactive oxygen species (ROS) in a light-responsive way to peroxynitrite anions (ONOO−) with higher cytotoxicity enables NO to sensitize PDT in cancer treatment. Both in vitro and in vivo studies demonstrate that NO sensitized PDT based on the well-designed transformable nanoparticles enables to eradicate tumors efficiently. The light-triggered transformable nanoplatform developed in this work provides a new strategy for enhanced intratumoral retention and improved therapeutic outcome.

Near-infrared light-triggered nitric oxide release combined with low-temperature photothermal therapy for synergetic antibacterial and antifungal

In recent years, nitric oxide (NO) has been widely studied as a non-drug resistant antimicrobial agent, but the issue of low NO loading capacity as well as premature leakage during transportation limit its further application. Herein, we have developed a BNN6-loading molybdenum disulfide (MoS2) nanoflowers denoted PEG-MoS2-BNN6 with near-infrared light-triggered NO release and hyperthermia properties to realize the antibacterial and antifungal capability. The PEG-MoS2-BNN6 was synthesized by grafting polyethylene glycol (PEG) to MoS2 nanoflowers and the NO donor BNN6 was subsequently loaded via hydrophobic interaction. The incorporation of PEG can effectively improve the biocompatibility of MoS2. Moreover, BNN6 achieves a high payload thanks to the layered nanoflower structure of PEG-MoS2. Under the 808 ​nm laser irradiation for 10 ​min, the obtained PEG-MoS2-BNN6 could not only generate heat locally for low-temperature photothermal therapy (PTT) but also activate the decomposition of BNN6 to release NO. Notably, the simultaneously generated NO and gentle hyperthermia could trigger great antimicrobial effects against both S. aureus and Candida albicans, which effectively solved the limitations of monotherapy. Overall, this nanoplatform with low-temperature PTT/NO synergistic effects provides a new strategy to solve bacterial and fungal infections, which is promising in biomedical application in the future.

Retraction: Light-triggered nitric oxide release and targeted fluorescence imaging in tumor cells developed from folic acid-graft-carboxymethyl chitosan nanospheres.

Retraction of ‘Light-triggered nitric oxide release and targeted fluorescence imaging in tumor cells developed from folic acid-graft-carboxymethyl chitosan nanospheres’ by Rijun Gui et al., RSC Adv., 2014, 4, 30129–30136, DOI: 10.1039/C4RA03034F.

Synthesis and evaluation of novel O2-derived diazeniumdiolates as photochemical and real-time monitoring nitric oxide delivery agents

3, a new photochemical theranostic agent, wherein light-triggered nitric oxide release can be controlled and real-time monitored at the cellular level.

Assembled magnetic nanoparticles for photosensitive nitric oxide release and turn-on fluorescence detection in situ

Under electrostatic interactions, polyethylenimine-stabilized Fe3O4 magnetic nanoparticles were assembled with photosensitive nitric oxide (NO) donors (Fe4S3(NO7−)), RBS) and CuFL complex consisting of fluorescein derivatives (FL) and CuII to prepare Fe3O4–CuFL–RBS nanocomposites. The as-prepared nanocomposites exhibited weak fluorescence and hardly any release of NO upon light irradiation of 480 nm. The nanocomposites enabled NO release due to RBS photolysis under 365 nm light irradiation, while the released NO could in situ conjugate with CuFL to form FL–NO complex based on N-nitrosate reaction, which was verified by fluorescence increase responses of FL–NO (excited at 480 nm). Thus, Fe3O4–CuFL–RBS nanocomposites realized light-triggered NO release and turn-on fluorescence detection of NO in situ.

Retracted Article: Light-triggered nitric oxide release and targeted fluorescence imaging in tumor cells developed from folic acid-graft-carboxymethyl chitosan nanospheres

This article reported the synthesis of CMC–FA–RBS(CQD) nanospheres and studied their potential applications for NO release and fluorescence imaging.

Visible light-triggered nitric oxide release from near-infrared fluorescent nanospheric vehicles.

Bifunctional Ag2S QDs@CS-RBS nanospheres with ultralow toxicity for biomedical use were fabricated. These are capable of releasing NO under irradiation of visible light and emitting in near-infrared (NIR) region fluorescence excited by NIR laser under physiological environment. Glutathiose (GSH)-capped Ag2S QDs were synthesized and encapsulated by chitosan (CS) to form NIR fluorescent Ag2S QDs@CS nanospheres. A type of iron/sulfur/-nitrosyl cluster, Roussin's black salt anion Fe4S3(NO)7(-) (RBS) was conjugated with the Ag2S QDs@CS to obtain Ag2S QDs@CS-RBS nanospheres. A variety of characterization methods were employed to analyze the nanospheres. In vitro cell imaging and in vivo mice imaging experiments demonstrated that the Ag2S QDs@CS-RBS nanospheres could emit readily observable NIR fluorescence and deliver NO in living cells and small animals. The NIR imaging of the Ag2S QDs@CS nanospheres would not interfere with the light-triggered NO release from them, as the excitation lasers needed for these two functions are in different wavelength regions. This work provides new perspectives for the application of multifunctional nano-structured materials in diagnostics and bioimaging.

Ag2S Quantum Dots Conjugated Chitosan Nanospheres toward Light-Triggered Nitric Oxide Release and Near-Infrared Fluorescence Imaging

Nanoscaled light-triggered nitric oxide (NO) delivery vehicles with the ability of near-infrared (NIR) fluorescence imaging was presented, which consisted of chitosan (CS)-based S-nitrosothiols (SNO) and encapsulated silver sulfide quantum dots (Ag2S QDs). CS-SNO compounds that bore NO-storing functional groups were prepared via amino modification of chitosan. Water-soluble Ag2S QDs were synthesized and conjugated with the CS-SNO compounds with the aid of ethylenediaminetetraacetic acid (EDTA). The biocompatible Ag2S-CS-SNO nanospheres, with dimension of ∼117 nm, exhibited bright NIR fluorescence and satisfactory photostability under NIR irradiation. The Ag2S-CS-SNO nanospheres could release NO under irradiation of UV or visible light at physiological pH and temperature yet would hardly release NO if NIR irradiation was applied. Cell imaging was successfully performed, demonstrating that the Ag2S-CS-SNO nanospheres could emit readily observable NIR fluorescence and release NO in living cells. The NIR fluorescence imaging of the Ag2S-CS-SNO nanospheres did not interfere with the light-triggered NO release from them, which would provide new perspectives for the application of multifunctional nanostructured materials in diagnostics and imaging.

Conjugating S-Nitrosothiols with Glutathiose Stabilized Silver Sulfide Quantum Dots for Controlled Nitric Oxide Release and Near-Infrared Fluorescence Imaging

Light-controllable nitric oxide (NO) delivery nanoparticles with the capability of near-infrared (NIR) fluorescence imaging were reported. Water-dispersible Ag2S quantum dots (QDs) were synthesized via a one-pot procedure using reduced glutathiose (GSH) as both sulfur source and stabilizer. S-nitrosothiols (RSNOs) were conjugated with the GSH stabilized Ag2S QDs at the amino groups of the GSH, leading to Ag2S-GSH-SNO nanoparticles with dimension of ~5.5 nm. The biocompatible Ag2S-GSH-SNO nanoparticles could release NO under UV or visible irradiation and emit NIR fluorescence under NIR excitation for bioimaging at physiological pH and temperature, yet could hardly release NO when NIR irradiation was applied. In vitro cell imaging and mice imaging experiments demonstrated that the Ag2S-GSH-SNO nanoparticles could emit readily observable NIR fluorescence and release NO in living cells and small animals. The NIR fluorescence imaging of the Ag2S-GSH-SNO nanoparticles would not interfere with the light-triggered NO release from them, as the excitation lights needed for these two functions were in different wavelength regions. This work provides new perspectives for the application of multifunctional nanostructured materials in diagnostics and imaging.