Controlled Release Of Nitric Oxide Research Articles

Construction of a multifunctional peptide nanoplatform for nitric oxide release and monitoring and its application in tumor-bearing mice

As a “star molecule”, nitric oxide (NO) either promotes or inhibits many physiological processes depending on its concentration. The in situ generation and monitoring of therapeutic gas molecules has been a problem that many researchers have been working to address due to the stochastic nature of gas molecule movement. There are still relatively few studies using short peptides as NO storage systems, and there are still challenges in monitoring NO release in situ with real-time imaging over long periods of time. In this work, a morphologically transformable NO release, diagnosis and treatment integrated multifunctional nanoplatform was fabricated. A new NO-activated probe (DPBTD) with emission in the first near infrared (NIR-I) region was encapsulated into the hydrophobic domains of Ac-KLVFFAL-NH2 peptide derivatives as a biosensor for NO release. Peptide scaffolds were endowed with the capacity of controlled NO release by the introduction of NO donor (organic nitrates). Interestingly, morphology of the nanoplatform could be transformed from one-dimensional (1D) nanowires to two-dimensional (2D) nanosheets via nanorods transition state under tip sonication, which was allowed for better cell uptake. Eventually, this nanocarrier was used for stimuli-responsive NO release, real-time imaging and treatment in tumor tissues of 4T1 tumor-bearing mice. This strategy expands the application potential of peptide-based nanomaterials and provides ideas for monitoring the progress of gas-mediated cancer therapy.

L-Arginine-Modified CoWO4 /FeWO4 S-Scheme Heterojunction Enhances Ferroptosis against Solid Tumor.

Ferroptosis has recently attracted much attention as an anti-tumor therapy. Evidence suggests that ferroptosis can induce oxidative stress and accumulation of lethal lipid peroxides in cancer cells, leading to cell damage. However, unsuitable pH, H2 O2 levels, and high glutathione (GSH) expression in the tumor microenvironment hinder the development of ferroptosis-mediated therapy. In this study, an l-arginine (l-arg)-modified CoWO4 /FeWO4 (CFW) S-scheme heterojunction is strategically designed and constructed for ultrasound (US)-triggered sonodynamic- and gas therapy-induced ferroptosis. CFW not only has excellent Fenton-catalytic activity, outstanding GSH consumption capacity, and excellent ability to overcome tumor hypoxia, but its S-scheme heterostructure can also avoid the rapid combination of electron (e) and hole (h+ ) pairs, thereby enhancing the sonodynamic effects. As a precursor of nitric oxide (NO), l-arg is modified on the surface of CFW (CFW@l-arg) to achieve controlled NO release under US irradiation, thereby enhancing ferroptosis. In addition, poly(allylamine hydrochloride) is further modified on the surface of CFW@l-arg to stabilize l-arg and achieve controllable NO release. Both in vitro and in vivo results demonstrate that such a multifunctional therapeutic nanoplatform can achieve high therapeutic efficacy through sonodynamic and gas therapy-enhanced ferroptosis. This designed oncotherapy nanoplatform provides new inspiration for ferroptosis-mediated therapy.

Nitric Oxide (NO) as a Reagent for Topochemical Framework Transformation and Controlled NO Release in Covalent Organic Frameworks

Covalent organic frameworks (COFs) have emerged as versatile platforms for the separation and storage of hazardous gases. Simultaneously, the synthetic toolbox to tackle the "COF trilemma" has been diversified to include topochemical linkage transformations and post-synthetic stabilization strategies. Herein, we converge these themes and reveal the unique potential of nitric oxide (NO) as a new reagent for the scalable gas-phase transformation of COFs. Using physisorption and solid-state nuclear magnetic resonance spectroscopy on 15N-enriched COFs, we study the gas uptake capacity and selectivity of NO adsorption and unravel the interactions of NO with COFs. Our study reveals the clean deamination of terminal amine groups on the particle surfaces by NO, exemplifying a unique surface passivation strategy for COFs. We further describe the formation of a NONOate linkage by the reaction of NO with an amine-linked COF, which shows controlled release of NO under physiological conditions. NONOate-COFs thus show promise as tunable NO delivery platforms for bioregulatory NO release in biomedical applications.

Carbon nanotubes as a nitric oxide nano-reservoir improved the controlled release profile in 3D printed biodegradable vascular grafts

Small diameter vascular grafts (SDVGs) are associated with a high failure rate due to poor endothelialization. The incorporation of a nitric oxide (NO) releasing system improves biocompatibility by using the NO effect to promote endothelial cell (EC) migration and proliferation while preventing bacterial infection. To circumvent the instability of NO donors and to prolong NO releasing, S-nitroso-N-acetyl-d-penicillamine (SNAP) as a NO donor was loaded in multi-walled carbon nanotubes (MWCNTs). Successful loading was confirmed with a maximum SNAP amount of ~ 5% (w/w) by TEM, CHNS analysis and FTIR spectra. SDVGs were 3D printed from polycaprolactone (PCL) and coated with a 1:1 ratio of polyethylene glycol and PCL dopped with different concentrations of SNAP-loaded matrix and combinations of MWCNTs-OH. Coating with 10% (w/w) SNAP-matrix-10% (w/w) SNAP-MWCNT-OH showed a diminished burst release and 18 days of NO release in the range of 0.5–4 × 10–10 mol cm−2 min−1 similar to the NO release from healthy endothelium. NO-releasing SDVGs were cytocompatible, significantly enhanced EC proliferation and migration and diminished bacterial viability. The newly developed SNAP-loaded MWCNT-OH has a great potential to develop NO releasing biomaterials with a prolonged, controlled NO release promoting in-situ endothelialization and tissue integration in vivo, even as an approach towards personalized medicine.

Ultrasound-Triggered Piezocatalysis for Selectively Controlled NO Gas and Chemodrug Release to Enhance Drug Penetration in Pancreatic Cancer.

Nitric oxide (NO) is drawing widespread attention in treating pancreatic ductal adenocarcinoma (PDAC) as a safe and therapeutically efficient technique through modulating the dense fibrotic stroma in the tumor microenvironment to enhance drug penetration. Considerable NO nanogenerators and NO releasing molecules have been developed to shield the systemic toxicity caused by free diffusion of NO gas. However, on-demand controlled release of NO and chemotherapy drugs at tumor sites remains a problem limited by the complex and dynamic tumor microenvironment. Herein, we present an ultrasound-responsive nanoprodrug of CPT-t-R-PEG2000@BaTiO3 (CRB) which encapsulates piezoelectric nanomaterials barium titanate nanoparticle (BaTiO3) with amphiphilic prodrug molecules that consisted of thioketal bond (t) linked chemotherapy drug camptothecin (CPT) and NO-donor l-arginine (R). Based on ultrasound-triggered piezocatalysis, BaTiO3 can continuously generate ROS in the hypoxic tumor environment, which induces a cascade of reaction processes to break the thioketal bond to release CPT and oxidize R to release NO, simultaneously delivering CPT and NO to the tumor site. It is revealed that CRB shows a uniform size distribution, prolonged blood circulation time, and excellent tumor targeting ability. Moreover, controlled release of CPT and NO were observed both in vitro and in vivo under the stimulation of ultrasound, which is beneficial to the depletion of dense stroma and subsequently enhanced delivery and efficacy of CPT. Taken together, CRB significantly increased the antitumor efficacy against highly malignant Panc02 tumors in mice through inhibiting chemoresistance, representing a feasible approach for targeted therapies against Panc02 and other PDAC.

Therapeutic Potency of NO Loaded into Anticancer Copper Metal-Organic Framework through Nonclassical Hydrogen Bonding.

Metal-organic frameworks (MOFs) are potential exogenous scaffolds for therapeutic nitric oxide (NO) delivery because they can store drug or bioactive gas molecules within pores or on active metal sites. Herein, we employed a Cu-MOF coordinated with glutarate (glu) and 1,2-bis(4-pyridyl)ethane (bpa) to obtain NO-loaded Cu-MOF (NO⊂Cu-MOF). NO loading transformed the space group of Cu-MOF from monoclinic C2/c to triclinic P-1 through nonclassical hydrogen bonding with glu and bpa. Cu-MOF showed good stability in deionized water and phosphate-buffered saline. NO⊂Cu-MOF released up to 1.10 μmol mg-1 NO over 14.6 h at 37 °C, which is suitable for therapeutic applications. NO⊂Cu-MOF showed moderate biocompatibility with L-929 cells and significant anticancer activity against HeLa cells, suggesting an apoptosis-mediated cell death mechanism. These insights into NO bonding modes with Cu-MOF that enable controlled NO release can inspire the design of functional MOFs as hybrid NO donors for drug delivery.

Guided Bone Regeneration with a Nitric‐Oxide Releasing Polymer Inducing Angiogenesis and Osteogenesis in Critical‐Sized Bone Defects

Synthetic scaffolds, as bone grafts, provide a favorable environment for the repair and growth of new bone tissue at defect sites. However, the lack of angio- and osteo-induction limits the usefulness of artificial scaffolds for bone regeneration. Nitric oxide (NO) performs essential roles in healing processes, such as regulating inflammation and addressing incomplete revascularization. In this study, a polymer capable of controlled NO release is developed to promote the osteogenic capacity in artificial scaffolds. The biological efficiency of the NO compound is assessed by its effect on pre-osteoblasts and macrophages in vitro and the extent of vascularization and bone formation in the calvaria defect model in vivo. The compound does not inhibit cell adhesion or proliferation. NO treatment significantly increases both alkaline phosphatase activity and mineralization in pre-osteoblasts. Macrophages treated with NO secrete high levels of anti-inflammatory factors and adopt the pro-regenerative phenotype. In the critical-sized defect model, the collagen scaffold containing the NO compound enhances neovascularization and bone formation. The developed NO-releasing system promotes osteogenesis and regeneration of damaged bone tissue. As the multiple functions of NO involve macrophage modulation and angiogenesis, such release systems may be valuable for guiding bone regeneration in critical-sized defects.

Nitric Oxide-Releasing Nanofibrous Scaffolds Based on Silk Fibroin and Zein with Enhanced Biodegradability and Antibacterial Properties.

Clinical applications of scaffolds and implants have been associated with bacterial infection resulting in impaired tissue regeneration. Nanofibers provide a versatile structure for both antimicrobial molecule delivery and tissue engineering. In this study, the nitric oxide (NO) donor molecule S-nitrosoglutathione (GSNO) and the natural biodegradable polymer zein (ZN) were combined with silk fibroin (SF) to develop antibacterial and biodegradable nanofibrous scaffolds for tissue engineering applications. The compatibility and intermolecular interactions of SF and ZN were studied using differential scanning calorimetry and Fourier transform infrared spectroscopy. The incorporation of ZN increased the hydrophobicity of the fibers and resulted in a more controlled and prolonged NO release profile lasting for 48 h. Moreover, the degradation kinetics of the fibers was significantly improved after blending with ZN. The results of tensile testing indicated that the addition of ZN and GSNO had a positive effect on the strength and stretchability of SF fibers and did not adversely affect their mechanical properties. Finally, due to the antibacterial properties of both NO and ZN, the SF-ZN-GSNO fibers showed a synergistically high antibacterial efficacy with 91.6 ± 2.5% and 77.5 ± 3.1% reduction in viability of adhered Staphylococcus aureus and Escherichia coli after 24 h exposure, respectively. The developed NO-releasing fibers were not only antibacterial but also non-cytotoxic and successfully enhanced the proliferation and growth of fibroblast cells, which was quantitatively studied by a CCK-8 assay and visually observed through fluorescent staining. Overall, SF-ZN-GSNO fibers developed in this study were biodegradable and highly antibacterial and showed great cytocompatibility with fibroblasts, indicating their promising potential for a range of tissue engineering and medical device applications.

Effects of the light-controlled nitric oxide donor “NORD-1” and light irradiation in rats with neurogenic erectile dysfunction

ABSTRACT Introduction Radical prostatectomy often causes erectile dysfunction (ED). This is considered to be due to surgery-induced nerve damage. Impairments in neurotransmission result in the release of nitric oxide (NO) in penile corpus cavernosum insufficiency. Therefore, phosphodiesterase-5 inhibitors are not necessarily effective for this type of ED. NO supplementation may be effective for this type of ED. However, NO acts on the whole body and thus may cause adverse effects. Recently, we have developed a light-controlled NO donor that enables spatially and temporally controlled NO release by light irradiation. Whether this type of NO donor is useful for neurogenic ED remains unknown. Objective We investigated whether this light-controlled NO donor “NORD-1” and light irradiation were effective for managing neurogenic ED in rats with bilateral cavernous nerve injury (BCNI). Methods We used eight-week-old male Wistar-ST rats. The rats were divided into four groups: Sham+SiR650 (control compound) (n=5), Sham+NORD-1 (n=5), BCNI+SiR650 (n=6), and BCNI+NORD-1 (n=6). Initially, sham or BCNI surgery was performed under anesthesia in each group. BCNI surgery was performed by crushing the bilateral cavernous nerves. Four weeks post-surgery, erectile function before and after the injection of each compound into the penile corpus cavernosum was evaluated based on the change in intracavernous pressure (ICP) under electrical stimulation of the cavernous nerve. The changes in ICP with and without light irradiation were also evaluated after the administration of each compound. Results Before administering each treatment without light irradiation, the ICP/mean arterial pressure (MAP) ratio under stimulation in the BCNI+SiR650 and BCNI+NORD-1 groups were lower than those in the Sham+SiR650 (P<0.01) and Sham+NORD-1 (P=0.06) groups. After the each treatment without light irradiation, the ICP/MAP ratio under stimulation in the Sham+NORD-1 group was slightly higher than that in the Sham+SiR650 group. However, the ICP/MAP ratio under stimulation in the BCNI+SiR650 and BCNI+NORD-1 groups remained significantly lower (P<0.05 and P<0.01, respectively). After the treatment with light irradiation, the ICP/MAP ratios under stimulation in the Sham+NORD-1 and BCNI+NORD-1 groups were significantly higher than those in the Sham+SiR650 (P<0.01) and BCNI+NORD-1 (P<0.01) groups, respectively. Conclusions The combination of NORD-1 and light irradiation may be useful for treating neurogenic ED, although its toxicity must be evaluated. Disclosure Work supported by industry: no.

Nitric Oxide Induces Immunogenic Cell Death and Potentiates Cancer Immunotherapy.

Tumor cells undergoing immunogenic cell death (ICD) release immunogenic damage-associated molecular patterns (DAMPs) to trigger a long-term protective antitumor response. ICD can be induced by certain pathogens, chemotherapeutics, and physical modalities. In this work, we demonstrate that a gaseous molecule, specifically nitric oxide (NO), can induce a potent ICD effect. NO exerts cytotoxic effects that are accompanied by the emission of DAMPs based on the endoplasmic reticulum stress and mitochondrial dysfunction pathways. Released DAMPs elicit immunological protection against a subsequent rechallenge of syngeneic tumor cells in immunocompetent mice. We prepare polynitrosated polyesters with high NO storage capacity through a facile polycondensation reaction followed by a postsynthetic modification. The polynitrosated polyesters-based NO nanogenerator (NanoNO) that enables efficient NO delivery and controlled NO release in tumors induces a sufficient ICD effect. In different immune-intact models of tumors, the NanoNO exhibits significant tumor growth suppression and increases the local dose of immunogenic signals and T cell infiltrations, ultimately prolonging survival. In addition, the NanoNO synergizes with the PD-1 blockade to prevent metastasis. We conclude not only that NO is a potent ICD inducer for cancer immunotherapy but also that it expands the range of ICD inducers into the field of gaseous molecules.

Near-infrared laser-controlled nitric oxide-releasing gold nanostar/hollow polydopamine Janus nanoparticles for synergistic elimination of methicillin-resistant Staphylococcus aureus and wound healing

Recently, nitric oxide (NO) has received increasing interest in combat against bacteria-induced infections because of its ability to sensitize and enhance the antibacterial effectiveness of many therapeutic approaches such as antibiotics. However, high-efficient loading and controlled release of NO remain a big challenge. In the present work, a type of gold nanostar/hollow polydopamine Janus nanostructure (GNS/HPDA JNPs) with precise near infrared (NIR)-controlled NO release property was fabricated using a facile seed-mediated method. Upon NIR laser irradiation, the NO-releasing GNS/HPDA JNPs (GNS/HPDA-BNN6) exhibited a synergistic photothermal and NO antibacterial effect by significantly inhibiting the growth and biofilm formation of both Gram-negative and Gram-positive bacterial strains, including methicillin-resistant Staphylococcus aureus (MRSA). An in-depth mechanism study revealed that two pathways were mainly involved in the synergistic photothermal and NO antibacterial effect. In one pathway, the synergistic effect severely destroyed the bacterial membrane by causing leakage of intracellular components such as DNA. In another pathway, the synergistic effect largely disturbed bacterial metabolism by regulating relative metabolic genes, followed by enhancing ROS generation to cause intracellular GSH depletion and DNA damage. More importantly, the synergistic effect significantly diminished the drug resistance of MRSA by downregulating the expression of the drug-resistant gene mecA and some relative multidrug efflux pumps (e.g., SepA and Tet38). An in vivo evaluation using a rat model with MRSA-infected wounds indicated that the synergistic photothermal and NO effect of GNS/HPDA-BNN6 can effectively eliminate MRSA from wounds, thereby alleviating inflammation and promoting wound healing. Statement of significanceMultidrug-resistant (MDR) bacteria have become a big threat to mankind, and therefore, the development of innovative antibacterial agents with high antibacterial efficiency is urgently required. Nanomaterial-mediated nitric oxide (NO) therapy is a promising strategy to effectively combat MDR bacteria through a synergistic antibacterial effect. Here, a gold nanostar/hollow polydopamine Janus nanostructure with precise near infrared (NIR) light-controlled NO release property (GNS/HPDA-BNN6) was developed. Both in vitro and in vivo evaluations demonstrated that GNS/HPDA-BNN6 could effectively eliminate methicillin-resistant Staphylococcus aureus (MRSA) from infected wounds and promote wound healing through a synergistic photothermal and NO therapeutic effect. Remarkably, the synergistic effect significantly diminished the drug resistance of MRSA by downregulating the expression of some drug-resistant genes and multidrug efflux pumps.

Functionalized boron nanosheets with near-infrared-triggered photothermal and nitric oxide release activities for efficient antibacterial treatment and wound healing promotion.

The spread of bacterial resistance is a rising serious threat to global public health, and has created an urgent need for the development of a new generation of antibacterial nano-agents to take the place of antibiotics. In this work, a multifunctional nanoplatform based on boron nanosheet (B NS)-coated quaternized chitosan (QCS) and the nitric oxide (NO) donor N,N'-di-sec-butyl-N,N'-dinitroso-1,4-phenylenediamine (BNN6) (B-QCS-BNN6) was prepared via a liquid-phase exfoliation and electrostatic adsorption method. The 2D B NSs could convert near-infrared (NIR) light into heat energy as well as assemble positively charged QCS and BNN6 to trap negatively charged bacteria, and the positive charge made it easily captured by bacteria, increasing the opportunities for NO diffusion to the bacterial surface. The B-QCS-BNN6 nanoplatform not only exhibited photothermal therapy (PTT) efficacy but could also control NO release precisely after stimulation with an 808 nm laser for the rapid and effective treatment of typical Gram-negative and Gram-positive bacteria. The enhanced PTT/NO antibacterial function achieved >99.9% inactivation of bacteria within 5 min. Furthermore, this synergetic antibacterial strategy could also be conveniently employed for highly efficient disinfection of a methicillin-resistant Staphylococcus aureus (MRSA) infected wound and promotion of the reconstruction of damaged tissues for in vivo MRSA-infected wound therapy.

S-nitrosoglutathione functionalized polydopamine nanoparticles incorporated into chitosan/gelatin hydrogel films with NIR-controlled photothermal/NO-releasing therapy for enhanced wound healing

Nitric oxide (NO) has aroused wide interest in the treating infected wounds due to its characteristic functionalities. However, its utilization is limited due to its volatile properties, high reactivity, direct potential toxicity, and byproducts of NO donors limited its application. Herein, endogenously NO donor S-nitrosoglutathione (GSNO) was connected covalently to polydopamine nanoparticles (PDA-GSNO NPs) to minimize the loss of NO in aqueous medium. Meanwhile, near-infrared (NIR)-controlled NO release and photothermal therapy (PTT) was obtained through the photothermal conversion by PDA. Then chitosan (CS)/gelatin (GE) biocomposite hydrogel films with preferable biocompatibility, surface hydrophilicity, hydroabsorptivity, and mechanical adhesive properties were constructed. By embedding PDA-GSNO NPs into the films, a multifunctional wound dressing was fabricated. Under NIR light irradiation, the combination of PTT, NO-releasing, and CS antibacterial agents can strengthen the in vitro antimicrobial efficacy and in vivo wound healing activities. Meanwhile, the obtained wound dressing presented good biocompatibility. This work outlines an approach for combating bacterial infections and demonstrating the possibility for synergistic NO-releasing wound healing.

Photo controlled release of nitric oxide (NO) from amphiphilic and nanoscale vesicles based ruthenium nitrosyl complex: NO release and cytotoxicity studies

Nitric oxide (NO) is an important gaseous signaling molecule. Precise spatiotemporal control release of NO for therapeutic applications is still challenging. We report herein a new amphiphilic and nano scale vesicles based NO-delivery platform that is capable of light-controlled NO release. 1.Ru-NO was incorporated into the lipid bilayers to form nanoscale vesicles (Lip-1.Ru-NO) to make it bio-compatible and 100% water soluble. The liposome Lip-1.Ru-NO gradually released NO in blue light over a period of 120 min, with relatively high efficiency as compared to 1.Ru-NO in CH3CN-water mixture. Amount of NO release from liposomes could be easily controlled and modulated by changing the concentration of 1.Ru-NO in nano scale vesicles. Light triggered controlled NO release, water solubility, and non-toxic nature of the complex before and after NO release are fulfilled by incorporation of amphiphilic ruthenium complex in to the vesicles surface.

Therapeutic Delivery of Nitric Oxide Utilizing Saccharide-Based Materials.

As a gasotransmitter, nitric oxide (NO) regulates physiological pathways and demonstrates therapeutic effects such as vascular relaxation, anti-inflammation, antiplatelet, antithrombosis, antibacterial, and antiviral properties. However, gaseous NO has high reactivity and a short half-life, so NO delivery and storage are critical questions to be solved. One way is to develop stable NO donors and the other way is to enhance the delivery and storage of NO donors from biomaterials. Most of the researchers studying NO delivery and applications are using synthetic polymeric materials, and they have demonstrated significant therapeutic effects of these NO-releasing polymeric materials on cardiovascular diseases, respiratory disease, bacterial infections, etc. However, some researchers are exploring saccharide-based materials to fulfill the same tasks as their synthetic counterparts while avoiding the concerns of biocompatibility, biodegradability, and sustainability. Saccharide-based materials are abundant in nature and are biocompatible and biodegradable, with wide applications in bioengineering, drug delivery, and therapeutic disease treatments. Saccharide-based materials have been implemented with various NO donors (like S-nitrosothiols and N-diazeniumdiolates) via both chemical and physical methods to deliver NO. These NO-releasing saccharide-based materials have exhibited controlled and sustained NO release and demonstrated biomedical applications in various diseases (respiratory, Crohn's, cardiovascular, etc.), skin or wound applications, antimicrobial treatment, bone regeneration, anticoagulation, as well as agricultural and food packaging. This review aims to highlight the studies in methods and progress in developing saccharide-based NO-releasing materials and investigating their potential applications in biomedical, bioengineering, and disease treatment.

Development of Nonheme {FeNO}7 Complexes Based on the Pyrococcus furiosus Rubredoxin for Red-Light-Controllable Nitric Oxide Release

Nitric oxide (NO) is an essential biological messenger, contributing a significant role in a diverse range of physiological processes. The light-controllable NO releasers are of great interest because of their potential as agents for NO-related research and therapeutics. Herein, we developed a pair of red-light-controllable NO releasers, pfRd-C9A-{FeNO}7 and pfRd-C42A-{FeNO}7 (pfRd = Pyrococcus furiosus rubredoxin), by constructing a nonheme {FeNO}7 center within the redesigned iron-sulfur protein scaffolds. While shown to be both air and thermally stable, these complexes are highly sensitive to red-light irradiation with temporal precision, which was confirmed by electron paramagnetic resonance spin trapping and Griess assay. The temporally controlled NO release from these complexes was also demonstrated in DNA cleavage assay. Overall, this study demonstrates that such a protein-based nonheme iron nitrosyl system could be a viable chemical tool for precise NO administration.

Glutathione-Responsive Biodegradable Nanoplatform with Endogenous Esterase-Triggered Nitric Oxide Release for Gas Therapy and Enhanced Chemotherapy.

The potential therapeutic effect of nitric oxide (NO) for cancers has received considerable attention as a "killer" that causes damage to mitochondria and DNA by oxidation or nitrosation. However, the fabrication of an intelligent and controllable NO release system has remained elusive in the desired location to realize selective cancer therapy. Herein, an intelligent endogenous esterase-triggered nitric oxide (NO) generator for synergetic cancer therapy is fabricated by integrating NO prodrug and doxorubicin (DOX) into a single glutathione (GSH)-responsive mesoporous silica nanoparticle (MPND). When the MPND is internalized into the cancer cell, the rupture of -S-S- bridges and the degradation of MPND occur in the tumor microenvironment with a high level of GSH, inducing the on-demand release of DOX. Importantly, the high endogenic esterase concentration can activate the prodrug to generate abundant NO, which further enhances the release performance of DOX. In vitro results verify that the release profiles of NO and DOX show the stimuli-responsive dependence of endogenic esterase and GSH, respectively, demonstrating the potential for on-demand release in the cancer cells. Consequently, MPND shows a high antitumor efficiency in MCF-7 cancer cells. Furthermore, using multicellular tumor spheroids to mimic in vivo experiment, MPND can enhance the tumor penetration and therapeutic effect for killing the deep tumor tissue at the central location. Therefore, the endogenous esterase-triggered NO nanogenerators may provide a potential alternative strategy to develop NO-relevant platforms for synergistic cancer therapy.

Prussian blue and collagen loaded chitosan nanofibers with NIR-controlled NO release and photothermal activities for wound healing

1 Prussian blue and collagen loaded chitosan electrospun nanofibers were fabricated. 2 The chitosan nanofibers possess NIR controlled NO release and PTT activities. 3 The nanofibers displayed synergetic antibacterial against E. coli and S. aureus . 4 The nanofibers promoted collagen deposition, cell growth, and epithelialization. 5 The nanofibers provide sufficient biosafety for wound healing. Nitric oxide (NO) has emerged as a potential wound therapeutic agent due to its pivotal role in the wound healing processes. Nevertheless, NO-based therapy for clinical applications is still restricted due to its gaseous state and short half-life. Here we exploited a wound dressing by incorporating sodium nitroprusside doped prussian blue nanoparticals and Type I collagen into the chitosan/poly(vinyl alcohol) nanofibers through the electrospinning method. This hybrid nanofibrous scaffold possess the excellent abilities of NIR controlled NO release, photothermal therapy, and imitation of extra-cellular matrix-like architecture. These synergistic effects could enhance their anti-bactericidal effects in vitro and furthermore accelerate wound healing in vivo when compared to control groups. Histological analysis demonstrated the scaffold could promote fibroblast growth and accelerate epithelialization. Moreover, no apparent histological toxicology and negligible damage to major organs were observed, which provided sufficient biosafety for in vivo application. These data indicate the fabricated hybrid nanofibrous scaffold could be used as an ideal candidate for accelerating wound healing and treating chronic wounds.

Multi-functional effects of a nitric oxide-conjugated copolymer for accelerating palatal wound healing

The damaged site of a palatal wound is difficult to repair and often remains unclosed due to failure of the healing process, which occurs in inadequate environments of the oral cavity. Nitric oxide (NO) has effective functions in repairing damaged tissues, but it has a limitation due to short lifetime and rapid diffusion. Here, we synthesize a donor to deliver exogenous NO gas and verify its therapeutic effect for the palatal wound healing, which is known to take longer for healing due to the poor environment of warm saliva containing millions of microbes. NO was incorporated into the synthetic polymer and the NO-donors were characterized based upon their ability to release NO. The NO donor not only reduced cytotoxicity but also increased migration and proliferation in gingival fibroblasts. Moreover, the angiogenic capacity was improved by NO-donor treatment. In the palatal wound model, the NO-treatment was involved in enhancing the biological responses associated with wound healing. This strategy suggests that treatment involving controlled NO release may have beneficial effects on palatal wound healing.

Photoacoustic Cavitation‐Ignited Reactive Oxygen Species to Amplify Peroxynitrite Burst by Photosensitization‐Free Polymeric Nanocapsules

AbstractPhotoacoustic (PA) technology can transform light energy into acoustic wave, which can be used for either imaging or therapy that depends on the power density of pulsed laser. Here, we report photosensitizer‐free polymeric nanocapsules loaded with nitric oxide (NO) donors, namely NO‐NCPs, formulated from NIR light‐absorbable amphiphilic polymers and a NO‐releasing donor, DETA NONOate. Controlled NO release and nanocapsule dissociation are achieved in acidic lysosomes of cancer cells. More importantly, upon pulsed laser irradiation, the PA cavitation can excite water to generate significant reactive oxygen species (ROS) such as superoxide radical (O2.−), which further spontaneously reacts with the in situ released NO to burst highly cytotoxic peroxynitrite (ONOO−) in cancer cells. The resultant ONOO− generation greatly promotes mitochondrial damage and DNA fragmentation to initiate programmed cancer cell death. Apart from PA imaging, PA cavitation can intrinsically amplify reactive species via photosensitization‐free materials for promising disease theranostics.