Low specificity and hypoxia-induced drug resistance are significant challenges in traditional cancer treatment. To enhance the anticancer efficacy, an injectable hydrogel system is developed through ...the formation of dynamic covalent bonds in hyaluronic acid, allowing for localized controlled release of drugs. This system also utilizes double-stranded DNA sequences for the intercalation delivery of the chemotherapeutic drug, enabling a multifaceted approach to therapy. Cisplatin not only serves as a chemotherapy drug but also acts as a catalyst for chemodynamic therapy (CDT) to initiate CDT cascades by creating hydrogen peroxide for the Fenton reaction. Hemoglobin, enclosed in PLGA nanoparticles, provides ferrous ions that react with hydrogen peroxide in an acidic environment, yielding hydroxyl radicals that induce cancer cell death. Additionally, oxygen released from hemoglobin mitigates hypoxia-induced chemoresistance, bolstering overall anticancer efficacy. Results demonstrate the shear-thinning properties and injectability of the hydrogel. Cisplatin elevates intracellular hydrogen peroxide levels in tumor cells, while hemoglobin efficiently releases ferrous ions and generates reactive oxygen species (ROS) in the presence of hydrogen peroxide. In in vitro and in vivo study, the combinational use of chemo- and chemodynamic therapies achieves a synergistic anticancer effect on combating glioblastoma. In summary, our CDT-based hydrogel, activated by endogenous cues and mediated by chemo drugs, spontaneously produces ROS and ameliorates the adverse tumor microenvironment with rational and selective antitumor strategies.
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•Cisplatin-activated chemodynamic cascades and hemoglobin-mediated Fenton reaction work synergistically and logically for antitumor effect.•Bioinspired hemoglobins serve as CDT agent for the Fenton reaction and deliver oxygen to reverse hypoxic microenvironment.•Cisplatin-based CDT is depth-independent treatment using endogenous stimuli to generate free radicals in site-specific manner.•This hydrogel system responds to the physiochemical-based surrounding changes with high-level control and precision.
Identification of the distinctive electron paramagnetic resonance signal at g = 2.03 in the yeast cells and liver of mice treated with carcinogens opened the discovery and investigation of the ...natural Fe(NO)2 motif in the form of dinitrosyliron complexes (DNICs). In this Viewpoint, a chronological collection of the benchmark for the study of DNIC demonstrates that the preceding study of its biological synthesis, storage, transport, transformation, and function related to NO physiology inspires the biomimetic study of structural and functional models supported by thiolate ligands to provide mechanistic insight at a molecular level. During the synthetic, spectroscopic, and theoretical investigations on the structure-to-reactivity relationship within DNICs, control of the Fe–NO bonding interaction and of the delivery of NO+/•NO/HNO/NO– by the supporting ligands and nuclearity evolves into the “redesign of the natural Fe(NO)2 motif” as a strategy to develop DNICs for NO-related biomedical application and therapeutic approach. The revolutionary transformation of covalent a Fe(NO)2 motif into a translational model for hydrogenase, triggered by the discovery of redox interconversion among {Fe(NO)2}9-L• ↔ {Fe(NO)2}9 ↔ {Fe(NO)2}10 ↔ {Fe(NO)2}10-L•−, echoes the preceding research journey on Fe/NiFe-hydrogenase and completes the development of an electrodeposited-film electrode for electrocatalytic water splitting. Through the 50-year journey, bioinorganic chemistry of DNIC containing the covalent Fe(NO)2 motif and noninnocent/labile NO ligands highlights itself as a unique metallocofactor to join the longitudinal study between biology/chemistry/biomedical application and the lateral study toward multielectron (photo/electro)catalysis for industrial application. This Viewpoint discloses the potential Fe(NO)2 motif awaiting continued contribution in order to emerge as a novel application in the next 50 years, whereas the parallel development of bioinorganic chemistry, guided by inspirational Nature, moves the science forward to the next stage in order to benefit the immediate needs for human activity.
Endogenous signals, namely nitric oxide (NO) and electrons, play a crucial role in regulating cell fate as well as the vascular and neuronal systems. Unfortunately, utilizing NO and electrical ...stimulation in clinical settings can be challenging due to NO's short half‐life and the invasive electrodes required for electrical stimulation. Additionally, there is a lack of tools to spatiotemporally control gas release and electrical stimulation. To address these issues, an “electromagnetic messenger” approach that employs on‐demand high‐frequency magnetic field (HFMF) to trigger NO release and electrical stimulation for restoring brain function in cases of traumatic brain injury is introduced. The system comprises a NO donor (poly(S‐nitrosoglutathione), pGSNO)‐conjugated on a gold yarn‐dynamos (GY) and embedded in an implantable silk in a microneedle. When subjected to HFMF, conductive GY induces eddy currents that stimulate the release of NO from pGSNO. This process significantly enhances neural stem cell (NSC) synapses' differentiation and growth. The combined strategy of using NO and electrical stimulation to inhibit inflammation, angiogenesis, and neuronal interrogation in traumatic brain injury is demonstrated in vivo.
An “electromagnetic messenger” approach utilizing high‐frequency magnetic fields (HFMF) to trigger nitric oxide (NO) release and electrical stimulation is developed for restoring brain function in traumatic brain injury. Upon exposure to HFMF, in vivo experiments demonstrated the combined strategy's effectiveness in inhibiting inflammation, angiogenesis, and neuronal interrogation in traumatic brain injury.
While immunotherapy has emerged as a promising strategy to treat glioblastoma multiforme (GBM), the limited availability of immunotherapeutic agents in tumors due to the presence of the blood–brain ...barrier (BBB) and immunosuppressive tumor microenvironment dampens efficacy. Nitric oxide (NO) plays a role in modulating both the BBB and tumor vessels and could thus be delivered to disrupt the BBB and improve the delivery of immunotherapeutics into GBM tumors. Herein, we report an immunotherapeutic approach that utilizes CXCR4-targeted lipid‑calcium-phosphate nanoparticles with NO donors (LCP-NO NPs). The delivery of NO resulted in enhanced BBB permeability and thus improved gene delivery across the BBB. CXCR4-targeted LCP-NO NPs delivered siRNA against the immune checkpoint ligand PD-L1 to GBM tumors, silenced PD-L1 expression, increased cytotoxic T cell infiltration and activation in GBM tumors, and suppressed GBM progression. Thus, the codelivery of NO and PD-L1 siRNA by these CXCR4-targeted NPs may serve as a potential immunotherapy for GBM.
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The short supply of donor corneas is exacerbated by the unsuitability of donors with insufficient endothelial cell density. Few studies have investigated promoting corneal endothelial cell ...proliferation to increase the endothelial cell density. We hypothesize that pre‐transplantation treatment of proliferative tissue‐cultivated corneas may increase corneal endothelial cell density. We observed that the airlift cultures were superior to immersion cultures with respect to both transparency and thickness. In this tissue culture system, we observed that lysophosphatidic acid increased the rabbit corneal endothelial cell density, number of BrdU‐positive cells and improve wound healing. We also observed an indirect effect of lysophosphatidic acid on corneal endothelial cell proliferation mediated by the stimulation of interleukin‐1β secretion from stromal cells. Human corneal tissues treated with lysophosphatidic acid or interleukin‐1β contained significantly more Ki‐67‐positive cells than untreated group. The lysophosphatidic acid‐ or interleukin‐1β‐treated cultured tissue remained hexagon‐shaped, with ZO‐1 expression and no evidence of the endothelial‐mesenchymal transition. Our novel protocol of tissue culture may be applicable for eye banks to optimize corneal grafting.
The employment of metal–organic framework (MOF)-based nanomaterials has been rapidly increasing in bioapplications owing to their biocompatibility, drug degradation, tunable porosity, and intrinsic ...biodegradability. This evidence suggests that the multifunctional bimetallic ions can behave as remarkable candidates for infection control and wound healing. In this study, bimetallic MOFs (Zn-HKUST-1 and FolA-Zn-HKUST-1) embedded with and without folic acid were synthesized and used for tissue sealing and repairing incisional wound sites in mice models. For comparison, HKUST-1 and FolA-HKUST-1 were also synthesized. The Brunauer–Emmett–Teller (BET) surface area measured for HKUST-1, FolA-HKUST-1, Zn-HKUST-1, and FolA-Zn-HKUST-1 from N2 isotherms was found to be 1868, 1392, 1706, and 1179 m2/g, respectively. The measurements of contact angle values for Zn-HKUST-1, FolA-HKUST-1, and Zn-FolA-HKUST-1 were identified as 4.95 ± 0.8, 43.6 ± 3.4, and 60.62 ± 2.0°, respectively. For topical application in wound healing, they display a wide range of healing characteristics, including antibacterial and enhanced wound healing rates. In addition, in vitro cell migration and tubulogenic potentials were evaluated. The significant reduction in the wound gap and increased expression levels for CD31, eNOS, VEGF-A, and Ki67 were observed from immunohistological analyses to predict the angiogenesis behavior at the incision wound site. The wound healing rate was analyzed in the excisional dermal wounds of diabetic mice model in vivo. On account of antibacterial potentials and tissue-repairing characteristics of Cu2+ and Zn2+ ions, designing an innovative mixed metal ion-based biomaterial has wide applicability and is expected to modulate the growth of various gradient tissues.
This retrospective cohort study was to assess the prognostic value of preoperative geriatric nutritional risk index (GNRI) on survival outcomes for patients with locally advanced oral squamous cell ...carcinoma (LAOSCC).
Patients with LAOSCC receiving upfront radical surgery at a single institute from January 2007 to February 2017 were enrolled. The primary outcomes in the study were 5-year overall survival (OS) and cancer-specific survival (CSS) rates, and a nomogram based on GNRI and other clinical-pathological factors was established for individualized OS prediction.
There were 343 patients enrolled in this study. The optimal cut-off value of GNRI was observed to be 97.8. Patients in the high-GNRI group (GNRI ≥97.8) had statistically significantly better outcomes in 5-year OS (74.7% vs. 57.2%, p = 0.001) and CSS (82.2% vs. 68.9%, p = 0.005) when compared with the low-GNRI group (GNRI <97.8). In Cox models, low GNRI remained an independent negative prognosticator of OS (HR: 1.6; 95% CI: 1.124–2.277; p = 0.009) and CSS (HR: 1.907; 95% CI: 1.219–2.984; p = 0.005). The c-index of the proposed nomogram, incorporating assorted clinicopathological factors and GNRI, had a statistically significant increase compared with the predictive nomogram constructed by the TNM staging system alone (0.692 vs. 0.637, p < 0.001).”
Preoperative GNRI is an independent prognostic factor of OS and CSS in patients with LAOSCC. A multivariate nomogram that includes GNRI may better help us to accurately estimate individual survival outcomes.
Bioavailability plays an important role in drug activity in the human body, as certain drug amounts should be present to elicit activity. However, low bioavailability of drugs leads to negligible use ...for human benefit. In this study, the diversely active neolignan, magnolol, was impregnated onto a Zr-based organometallic framework Uio-66(Zr) to increase its low bioavailability (4-5%) and to test its potential acute oral toxicity. Synthesis of Uio-66(Zr) was done through the solvothermal method while simple impregnation at different time points was used to incorporate magnolol. The loading capacity of Uio-66(Zr) at 36 h was found to be significantly higher at 72.16 ± 2.15% magnolol than in other incubation time. Based on the OECD 425 (limit test), toxicity was not observed at 2000 mg kg
dose of mag@Uio-66(Zr) in female Sprague Dawley rats. The area under the curve (AUC) at 0-720 min of mag@Uio-66(Zr) was significantly higher than the AUC of free magnolol. Moreover, relative bioavailability increased almost two-folds using Uio-66(Zr). Unconjugated magnolol was found in the liver, kidney, and brain of rats in all treatment groups. Collectively, Uio-66(Zr) provided a higher magnolol bioavailability when used as drug carrier. Thus, utilization of Uio-66(Zr) as drug carrier is of importance for maximal use for poorly soluble and lowly bioavailable drugs.
Release of the distinct NO redox‐interrelated forms (NO+, .NO, and HNO/NO−), derived from reaction of the dinitrosyl iron complex (DNIC) (NO)2Fe(C12H8N)2− (1) (C12H8N=carbazolate) and the ...substitution ligands (S2CNMe2)2, SC6H4‐o‐NHC(O)(C5H4N)2 ((PyPepS)2), and P(C6H3‐3‐SiMe3‐2‐SH)3 (P(SH)3), respectively, was demonstrated. In contrast to the reaction of (PyPepS)2 and DNIC 1 in a 1:1 stoichiometry that induces the release of an NO radical and the formation of complex PPNFe(PyPepS)2 (4), the incoming substitution ligand (S2CNMe2)2 triggered the transformation of DNIC 1 into complex (NO)Fe(S2CNMe2)2 (2) along with N‐nitrosocarbazole (3). The subsequent nitrosation of N‐acetylpenicillamine (NAP) by N‐nitrosocarbazole (3) to produce S‐nitroso‐N‐acetylpenicillamine (SNAP) may signify the possible formation pathway of S‐nitrosothiols from DNICs by means of transnitrosation of N‐nitrosamines. Protonation of DNIC 1 by P(SH)3 triggers the release of HNO and the generation of complex PPNFe(NO)P(C6H3‐3‐SiMe3‐2‐S)3 (5). In a similar fashion, the nucleophilic attack of the chelating ligand P(C6H3‐3‐SiMe3‐2‐SNa)3 (P(SNa)3) on DNIC 1 resulted in the direct release of NO− captured by (15NO)Fe(SPh)3−, thus leading to (15NO)(14NO)Fe(SPh)2−. These results illustrate one aspect of how the incoming substitution ligands ((S2CNMe2)2 vs. (PyPepS)2 vs. P(SH)3/P(SNa)3) in cooperation with the carbazolate‐coordinated ligands of DNIC 1 function to control the release of NO+, .NO, or NO− from DNIC 1 upon reaction of complex 1 and the substitution ligands. Also, these results signify that DNICs may act as an intermediary of NO in the redox signaling processes by providing the distinct redox‐interrelated forms of NO to interact with different NO‐responsive targets in biological systems.
Accept NO substitute! Incoming substitution ligands play a key role in modulating the generation of the distinct redox‐interrelated forms of NO (N‐nitrosocarbazole, .NO, and HNO/NO−) derived from reactions of the dinitrosyl iron complex (NO)2Fe(C12H8N)2− and ligands (S2CNMe2)2, (PyPepS)2, and P(C6H3‐3‐SiMe3‐2‐SH)3, respectively (see scheme).
Nitric oxide (NO) is an essential endogenous signaling molecule regulating multifaceted physiological functions in the (cardio)vascular, neuronal, and immune systems. Due to the short half-life and ...location-/concentration-dependent physiological function of NO, translational application of NO as a novel therapeutic approach, however, awaits a strategy for spatiotemporal control on the delivery of NO. Inspired by the magnetic hyperthermia and magneto-triggered drug release featured by Fe3O4 conjugates, in this study, we aim to develop a magnetic responsive NO-release material (MagNORM) featuring dual NO-release phases, namely, burst and steady release, for the selective activation of NO-related physiology and treatment of bacteria-infected cutaneous wound. After conjugation of NO-delivery Fe(μ-S-thioglycerol)(NO)22 with a metal–organic framework (MOF)-derived porous Fe3O4@C, encapsulation of obtained conjugates within the thermo-responsive poly(lactic-co-glycolic acid) (PLGA) microsphere completes the assembly of MagNORM. Through continuous/pulsatile/no application of the alternating magnetic field (AMF) to MagNORM, moreover, burst/intermittent/slow release of NO from MagNORM demonstrates the AMF as an ON/OFF switch for temporal control on the delivery of NO. Under continuous application of the AMF, in particular, burst release of NO from MagNORM triggers an effective anti-bacterial activity against both Gram-positive Staphylococcus aureus (S. aureus) and Gram-negative Escherichia coli (E. coli). In addition to the magneto-triggered bactericidal effect of MagNORM against E. coli-infected cutaneous wound in mice, of importance, steady release of NO from MagNORM without the AMF promotes the subsequent collagen formation and wound healing in mice.
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