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Recent preclinical and clinical studies have highlighted the improved outcomes of combination radiotherapy and immunotherapy. Concurrently, the development of high-Z metallic nanoparticles as radiation dose enhancers has been explored to widen the therapeutic window of radiotherapy and potentially enhance immune activation. In this study, folate-modified hafnium-based metal-organic frameworks (HfMOF-PEG-FA) are evaluated in combination with imiquimod, a TLR7 agonist, as a well-defined interferon regulatory factor (IRF) stimulator for local antitumor immunotherapy. The enhancement of radiation dose deposition by HfMOF-PEG-FA and subsequent generation of reactive oxygen species (ROS) deregulates cell proliferation and increases apoptosis. HfMOF-PEG-FA loaded with imiquimod (HfMOF-PEG-FA@IMQ) increases DNA double-strand breaks and cell death, including apoptosis, necrosis, and calreticulin exposure, in response to X-ray irradiation. Treatment with this multipronged therapy promotes IRF stimulation for subsequent interferon production within tumor cells themselves. The novel observation is reported that HfMOF itself increases TLR7 expression, unexpectedly pairing immune agonist and receptor upregulation in a tumor intrinsic manner, and supporting the synergistic effect observed with the γH2AX assay. T-cell analysis of CT26 tumors following intratumoral administration of HfMOF-PEG-FA@IMQ with radiotherapy reveals a promising antitumor response, characterized by an increase in CD8+ and proliferative T cells.
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Interferón Tipo I , Estructuras Metalorgánicas , Neoplasias , Humanos , Imiquimod/farmacología , Receptor Toll-Like 7/agonistas , Estructuras Metalorgánicas/farmacología , Hafnio/metabolismo , Regulación hacia Arriba , Interferón Tipo I/farmacología , Neoplasias/tratamiento farmacológico , Neoplasias/radioterapia , Línea Celular TumoralRESUMEN
Nanoparticle characterization and in vitro data on the effects of combined PARP inhibition and DNA damage by chemoradiation are shown. This data accompanies the research article "Fucoidan-coated nanoparticles target radiation-induced P-selectin to enhance chemoradiotherapy in murine colorectal cancer" (DuRoss et al., 2021) Additional characterization of the physiochemical properties of nanoscale metal organic frameworks (nMOFs) comprised of hafnium and 1,4-dicarboxybenzene (Hf-BDC) loaded with temozolomide (TMZ) and talazoparib (Tal) are presented. Toxicity data of the drug-loaded nMOF coated with fucoidan (TT@Hf-BDC-Fuco) in colorectal cancer cells, CT-26, from alamarBlue-based chemoradiation experiments are shown. Experimental methods for the nanoparticle characterization and cell-based assays of the nMOF formulation are presented.
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X-ray radiation is commonly employed in clinical practice for diagnostic and therapeutic applications. Over the past decade, developments in nanotechnology have led to the use of high-Z elements as the basis for innovative new treatment platforms that enhance the clinical efficacy of X-ray radiation. Nanoscale metal-frameworks (nMOFs) are coordination networks containing organic ligands that have attracted attention as therapeutic platforms in oncology and other areas of medicine. In cancer therapy, X-ray activated, high-Z nMOFs have demonstrated potential as radiosensitizers that increase local radiation dose deposition and generation of reactive oxygen species (ROS). This minireview summarizes current research on high-Z nMOFs in cancer theranostics and discusses factors that may influence future clinical application.
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Neoplasias , Humanos , Estructuras Metalorgánicas , Nanoestructuras , Neoplasias/diagnóstico , Neoplasias/terapia , Medicina de Precisión , Rayos XRESUMEN
Colorectal cancer (CRC) is a leading cause of cancer-related death for both men and women, highlighting the need for new treatment strategies. Advanced disease is often treated with a combination of radiation and cytotoxic agents, such as DNA damage repair inhibitors and DNA damaging agents. To optimize the therapeutic window of these multimodal therapies, advanced nanomaterials have been investigated to deliver sensitizing agents or enhance local radiation dose deposition. In this study, we demonstrate the feasibility of employing an inflammation targeting nanoscale metal-organic framework (nMOF) platform to enhance CRC treatment. This novel formulation incorporates a fucoidan surface coating to preferentially target P-selectin, which is over-expressed or translocated in irradiated tumors. Using this radiation stimulated delivery strategy, a combination PARP inhibitor (talazoparib) and chemotherapeutic (temozolomide) drug-loaded hafnium and 1,4-dicarboxybenzene (Hf-BDC) nMOF was evaluated both in vitro and in vivo. Significantly, these drug-loaded P-selectin targeted nMOFs (TT@Hf-BDC-Fuco) show improved tumoral accumulation over multiple controls and subsequently enhanced therapeutic effects. The integrated radiation and nanoformulation treatment demonstrated improved tumor control (reduced volume, density, and growth rate) and increased survival in a syngeneic CRC mouse model. Overall, the data from this study support the continued investigation of radiation-priming for targeted drug delivery and further consideration of nanomedicine strategies in the clinical management of advanced CRC.
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Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/radioterapia , Nanopartículas/química , Selectina-P/genética , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Quimioradioterapia/efectos adversos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Modelos Animales de Enfermedad , Sistemas de Liberación de Medicamentos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Hafnio/farmacología , Humanos , Ratones , Ftalazinas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Polisacáridos/química , Polisacáridos/farmacología , Tolerancia a Radiación/efectos de los fármacos , Tolerancia a Radiación/genética , Temozolomida/farmacologíaRESUMEN
X-ray radiotherapy is a common method of treating cancerous tumors or other malignant lesions. The side effects of this treatment, however, can be deleterious to patient quality of life if critical tissues are affected. To potentially lower the effective doses of radiation and negative side-effects, new classes of nanoparticles are being developed to enhance reactive oxygen species production during irradiation. This report presents the synthesis and radiotherapeutic efficacy evaluation of a new nanoparticle formulation designed for this purpose, composed of a CaF2 core, mesoporous silica shell, and polyethylene glycol coating. The construct was additionally doped with Tb and Eu during the CaF2 core synthesis to prepare nanoparticles (NPs) with X-ray luminescent properties for potential application in fluorescence imaging. The mesoporous silica shell was added to provide the opportunity for small molecule loading, and the polyethylene glycol coating was added to impart aqueous solubility and biocompatibility. The potential of these nanomaterials to act as radiosensitizers for enhancing X-ray radiotherapy was supported by reactive oxygen species generation assays. Further, in vitro experiments indicate biocompatibility and enhanced cellular damage during X-ray radiotherapy.
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In this report, we describe the X-ray luminescent properties of two lanthanide-based nanoscale metal-frameworks (nMOFs) and their potential as novel platforms for optical molecular imaging techniques such as X-ray excited radioluminescence (RL) imaging. Upon X-ray irradiation, the nMOFs display sharp tunable emission peaks that span the visible to near-infrared spectral region (â¼400-700 nm) based on the identity of the metal (Eu, Tb, or Eu/Tb). Surface modification of the nMOFs with polyethylene glycol (PEG) resulted in nanoparticles with enhanced aqueous stability that demonstrated both cyto- and hemo-compatibility important prerequisites for biological applications. Importantly, this is the first report to document and investigate the radioluminescent properties of lanthanide nMOFs. Taken together, the observed radioluminescent properties and low in vitro toxicity demonstrated by the nMOFs render them promising candidates for in vivo translation.
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Elementos de la Serie de los Lantanoides/química , Estructuras Metalorgánicas , Imagen Multimodal , Nanopartículas/química , Neoplasias/diagnóstico por imagen , Polietilenglicoles/químicaRESUMEN
While the advancement of clinical radiotherapy was driven by technological innovations throughout the 20th century, continued improvement relies on rational combination therapies derived from biological insights. In this review, we highlight the importance of combination radiotherapy in the era of precision medicine. Specifically, we survey and summarize the areas of research where improved understanding in cancer biology will propel the field of radiotherapy forward by allowing integration of novel nanotechnology-based treatments.
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Nanomedicina , Neoplasias/radioterapia , Animales , Terapia Combinada , Humanos , Inmunoterapia , Neoplasias/tratamiento farmacológicoRESUMEN
Chemoradiation is an effective combined modality therapeutic approach that utilizes principles of spatial cooperation to combat the adaptability associated with cancer and to potentially expand the therapeutic window. Optimal therapeutic efficacy requires intelligent selection and refinement of radiosynergistic pharmaceutical agents, enhanced delivery methods, and temporal consideration. Here, a monodisperse sub-20 nm mixed poloxamer micelle (MPM) system was developed to deliver hydrophobic drugs intravenously, in tandem with ionizing radiation. This report demonstrates in vitro synergy and enhanced radiosensitivity when two molecularly targeted DNA repair inhibitors, talazoparib and buparlisib, are encapsulated and combined with radiation in a 4T1 murine breast cancer model. Evaluation of in vivo biodistribution and toxicity exhibited no reduction in particle accumulation upon radiation and a lack of both acute and chronic toxicities. In vivo efficacy studies suggested the promise of combining talazoparib, buparlisib, and radiation to enhance survival and control tumor growth. Tissue analysis suggests enhanced DNA damage leading to apoptosis, thus increasing efficacy. These findings highlight the challenges associated with utilizing clinically relevant inclusion criteria and treatment protocols because complete tumor regression and extended survival were masked by an aggressively metastasizing model. As with clinical treatment regimens, the findings here establish a need for further optimization of this multimodal platform.
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Aminopiridinas/farmacología , Neoplasias de la Mama , Quimioradioterapia , Daño del ADN , Morfolinas/farmacología , Ftalazinas/farmacología , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Línea Celular Tumoral , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Micelas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
S-Nitrosothiols (RSNOs) such as S-nitrosoglutathione (GSNO) are known to produce nitric oxide (NO) through thermal, photolytic, and metal ion-promoted pathways, which has led to their increasing use as exogenous sources of therapeutic NO. Despite the burgeoning NO release applications for RSNOs, their susceptibility to metal-promoted decomposition has rarely been examined in a uniform manner through the specific measurement of NO release. In this study, the ability of various transition and post-transition metal ions to promote NO release from GSNO was surveyed by chemiluminescence-based NO detection. Substantial NO formation (>10-fold increase relative to GSNO baseline) was detected after the addition of Cu2+, Au3+, Pd2+, Pt2+, and V3+. Modest increases were observed in the cases of Co2+, Hf4+, Fe2+, Fe3+, Mn2+, Hg2+, Ni2+, Ag+, Sn2+, and Zr4+, while no effect was evident for Al3+, Cr3+, Pb2+, Sc3+, and Zn2+. It was further observed that In+ compounds initiate the apparent NO-forming decomposition of GSNO, while In0 and In3+ are inactive, indicating that In+ exerts a previously unknown effect on GSNO.
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Indio/química , Donantes de Óxido Nítrico/química , Óxido Nítrico/síntesis química , S-Nitrosoglutatión/químicaRESUMEN
BACKGROUND: Management of hemostasis is a key challenge during extracorporeal life support (ECLS). Metal organic frameworks are being investigated for use as nitric oxide (NO) catalysts for incorporation into ECLS circuitry to prevent thrombosis at the blood-biomaterial interface. A specific metal organic framework, CuBTTri, has been shown to accelerate NO release from bioavailable donors like S-nitrosoglutathione (GSNO). We hypothesized that CuBTTri would reduce thrombus formation in whole blood (WB) and inhibit platelet aggregation. METHODS: CuBTTri particles were added to WB and analyzed by thromboelastography. Biostable metal-based frameworks (MIL-100, Zeolite USY) were added to blood as controls, in addition to a saline vehicle control. Reaction time (R), clot formation time (K), alpha-angle, clot strength (MA), and percent fibrinolysis (LY30/LY60) were recorded. The effect of CuBTTri on platelet aggregation was assessed in WB and platelet-rich plasma (PRP), both with and without addition of GSNO. RESULTS: CuBTTri significantly prolonged R and K and decreased alpha-angle and MA relative to the metal framework controls. Dose escalation results suggest that the control metal-based particles induce thrombus formation, as R and K were significantly reduced compared with the saline control; however, this did not occur in the CuBTTri group. LY30/LY60 were elevated in the CuBTTri group versus saline (p = 0.014) but were not different from metal framework controls. CuBTTri alone and with GSNO reduced platelet aggregation in WB (p < 0.0001), whereas GSNO alone had no effect. In PRP, GSNO and CuBTTri inhibited platelet aggregation separately, and together decreased aggregation by 35% relative to GSNO alone (p = 0.004). CONCLUSIONS: CuBTTri reduced thrombus formation and inhibited platelet aggregation. CuBTTri enhanced platelet inhibition with GSNO, which was consistent with reports that CuBTTri accelerates NO release from endogenous NO donors. This initial characterization of CuBTTri demonstrated its potential as an antithrombogenic agent to be further evaluated with incorporation into ECLS circuitry.
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Oxigenación por Membrana Extracorpórea/efectos adversos , Estructuras Metalorgánicas/farmacología , Agregación Plaquetaria/fisiología , Trombosis/prevención & control , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Fibrinolíticos/farmacología , Hemostasis/fisiología , Humanos , Estructuras Metalorgánicas/química , Óxido Nítrico/metabolismo , S-Nitrosoglutatión/metabolismo , Tromboelastografía/métodosRESUMEN
Cu-BTTri (H3BTTri = 1,3,5-tris[1H-1,2,3-triazol-5-yl]benzene) is a water-stable, copper-based metal-organic framework (MOF) that exhibits the ability to generate therapeutic nitric oxide (NO) from S-nitrosothiols (RSNOs) available within the bloodstream. Immobilization of Cu-BTTri within a polymeric membrane may allow for localized NO generation at the blood-material interface. This work demonstrates that Cu-BTTri can be incorporated within hydrophilic membranes prepared from poly(vinyl alcohol) (PVA), a polymer that has been examined for numerous biomedical applications. Following immobilization, the ability of the MOF to produce NO from the endogenous RSNO S-nitrosoglutathione (GSNO) is not significantly inhibited. Poly(vinyl alcohol) membranes containing dispersions of Cu-BTTri were tested for their ability to promote NO release from a 10 µM initial GSNO concentration at pH 7.4 and 37 °C, and NO production was observed at levels associated with antithrombotic therapeutic effects without significant copper leaching (<1%). Over 3.5 ± 0.4 h, 10 wt % Cu-BTTri/PVA membranes converted 97 ± 6% of GSNO into NO, with a maximum NO flux of 0.20 ± 0.02 nmol·cm-2·min-1. Furthermore, it was observed for the first time that Cu-BTTri is capable of inducing NO production from GSNO under aerobic conditions. At pH 6.0, the NO-forming reaction of 10 wt % Cu-BTTri/PVA membrane was accelerated by 22%, while an opposite effect was observed in the case of aqueous copper(II) chloride. Reduced temperature (20 °C) and the presence of the thiol-blocking reagent N-ethylmaleimide (NEM) impair the NO-forming reaction of Cu-BTTri/PVA with GSNO, with both conditions resulting in a decreased NO yield of 16 ± 1% over 3.5 h. Collectively, these findings suggest that Cu-BTTri/PVA membranes may have therapeutic utility through their ability to generate NO from endogenous substrates. Moreover, this work provides a more comprehensive analysis of the parameters that influence Cu-BTTri efficacy, permitting optimization for potential medical applications.
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Alcohol Polivinílico/química , Estructuras Metalorgánicas , Óxido Nítrico , Donantes de Óxido Nítrico , Cloruro de PoliviniloRESUMEN
The development of extracorporeal devices for organ support has been a part of medical history and progression since the late 1900s. These types of technology are primarily used and developed in the field of critical care medicine. Unfractionated heparin, discovered in 1916, has really been the only consistent form of thromboprophylaxis for attenuating or even preventing the blood-biomaterial reaction that occurs when such technologies are initiated. The advent of regional anticoagulation for procedures such as continuous renal replacement therapy and plasmapheresis have certainly removed the risks of systemic heparinization and heparin effect, but the challenges of the blood-biomaterial reaction and downstream effects remain. In addition, regional anticoagulation cannot realistically be applied in a system such as extracorporeal membrane oxygenation because of the high blood flow rates needed to support the patient. More recently, advances in the technology itself have resulted in smaller, more compact extracorporeal life support (ECLS) systems that can-at certain times and in certain patients-run without any form of anticoagulation. However, the majority of patients on ECLS systems require some type of systemic anticoagulation; therefore, the risks of bleeding and thrombosis persist, the most devastating of which is intracranial hemorrhage. We provide a concise overview of the primary and alternate agents and monitoring used for thromboprophylaxis during use of ECLS. In addition, we explore the potential for further biomaterial and technologic developments and what they could provide when applied in the clinical arena.
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Anticoagulantes/administración & dosificación , Oxigenación por Membrana Extracorpórea/métodos , Trombosis/prevención & control , Anticoagulantes/efectos adversos , Oxigenación por Membrana Extracorpórea/efectos adversos , Hemorragia/inducido químicamente , Heparina/administración & dosificación , Humanos , Hemorragias Intracraneales/inducido químicamente , Trombosis/etiologíaRESUMEN
Epithelial ovarian cancer (EOC) is the most prevalent form of ovarian cancer and has the highest mortality rate. Novel insight into EOC is required to minimize the morbidity and mortality rates caused by recurrent, drug resistant disease. Although numerous studies have evaluated genome instability in EOC, none have addressed the putative role chromosome instability (CIN) has in disease progression and drug resistance. CIN is defined as an increase in the rate at which whole chromosomes or large parts thereof are gained or lost, and can only be evaluated using approaches capable of characterizing genetic or chromosomal heterogeneity within populations of cells. Although CIN is associated with numerous cancer types, its prevalence and dynamics in EOC is unknown. In this study, we assessed CIN within serial samples collected from the ascites of five EOC patients, and in two well-established ovarian cancer cell models of drug resistance (PEO1/4 and A2780s/cp). We quantified and compared CIN (as measured by nuclear areas and CIN Score (CS) values) within and between serial samples to glean insight into the association and dynamics of CIN within EOC, with a particular focus on resistant and recurrent disease. Using quantitative, single cell analyses we determined that CIN is associated with every sample evaluated and further show that many EOC samples exhibit a large degree of nuclear size and CS value heterogeneity. We also show that CIN is dynamic and generally increases within resistant disease. Finally, we show that both drug resistance models (PEO1/4 and A2780s/cp) exhibit heterogeneity, albeit to a much lesser extent. Surprisingly, the two cell line models exhibit remarkably similar levels of CIN, as the nuclear areas and CS values are largely overlapping between the corresponding paired lines. Accordingly, these data suggest CIN may represent a novel biomarker capable of monitoring changes in EOC progression associated with drug resistance.
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Inestabilidad Cromosómica/genética , Resistencia a Antineoplásicos/genética , Neoplasias Ováricas/tratamiento farmacológico , Línea Celular Tumoral , Inestabilidad Cromosómica/efectos de los fármacos , Femenino , Heterogeneidad Genética/efectos de los fármacos , Humanos , Hibridación Fluorescente in Situ , Estadificación de Neoplasias , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Platino (Metal)/administración & dosificación , Análisis de la Célula IndividualRESUMEN
It has been previously demonstrated that copper-based metal-organic frameworks (MOFs) accelerate formation of the therapeutically active molecule nitric oxide (NO) from S-nitrosothiols (RSNOs). Because RSNOs are naturally present in blood, this function is hypothesized to permit the controlled production of NO through use of MOF-based blood-contacting materials. The practical implementation of MOFs in this application typically requires incorporation within a polymer support, yet this immobilization has been shown to impair the ability of the MOF to interact with the NO-forming RSNO substrate. Here, the water-stable, copper-based MOF H3[(Cu4Cl)3-(BTTri)8] (H3BTTri = 1,3,5-tris(1H-1,2,3-triazol-5-yl)benzene), or Cu-BTTri, was incorporated within the naturally derived polysaccharide chitosan to form membranes that were evaluated for their ability to enhance NO generation from the RSNO S-nitrosoglutathione (GSNO). This is the first report to evaluate MOF-induced NO release from GSNO, the most abundant small-molecule RSNO. At a 20 µM initial GSNO concentration (pH 7.4 phosphate buffered saline, 37 °C), chitosan/Cu-BTTri membranes induced the release of 97 ± 3% of theoretical NO within approximately 4 h, corresponding to a 65-fold increase over the baseline thermal decomposition of GSNO. Furthermore, incorporation of Cu-BTTri within hydrophilic chitosan did not impair the activity of the MOF, unlike earlier efforts using hydrophobic polyurethane or poly(vinyl chloride). The reuse of the membranes continued to enhance NO production from GSNO in subsequent experiments, suggesting the potential for continued use. Additionally, the major organic product of Cu-BTTri-promoted GSNO decomposition was identified as oxidized glutathione via mass spectrometry, confirming prior hypotheses. Structural analysis by pXRD and assessment of copper leaching by ICP-AES indicated that Cu-BTTri retains crystallinity and exhibits no significant degradation following exposure to GSNO. Taken together, these findings provide insight into the function and utility of polymer/Cu-BTTri systems and may support the development of future MOF-based biomaterials.
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Óxido Nítrico/química , Quitosano , Cobre , Glutatión , Estructuras Metalorgánicas , S-NitrosoglutatiónRESUMEN
Nitric oxide (NO) occurs naturally in mammalian biochemistry as a critical signaling molecule and exhibits antithrombotic, antibacterial, and wound-healing properties. NO-forming biodegradable polymers have been utilized in the development of antithrombotic or antibacterial materials for biointerfacial applications, including tissue engineering and the fabrication of erodible coatings for medical devices such as stents. Use of such NO-forming polymers has frequently been constrained by short-term release or limited NO storage capacity and has led to the pursuit of new materials with improved NO release function. Herein, we report the development of an NO-releasing bioerodible coating prepared from poly[bis(3-mercapto-3-methylbut-1-yl glycinyl)phosphazene] (POP-Gly-MMB), a polyphosphazene based on glycine and the naturally occurring tertiary thiol 3-mercapto-3-methylbutan-1-ol (MMB). To evaluate the NO release properties of this material, the thiolated polymer POP-Gly-MMB-SH was applied as a coating to glass substrates and subsequently converted to the NO-forming S-nitrosothiol (RSNO) derivative (POP-Gly-MMB-NO) by immersion in a mixture of tert-butyl nitrite (t-BuONO) and pentane. NO release flux from the coated substrates was determined by chemiluminescence-based NO measurement and was found to remain in a physiologically relevant range for up to 2 weeks (6.5-0.090 nmol of NO·min-1·cm-2) when immersed in pH 7.4 phosphate-buffered saline (PBS) at 37 °C. Furthermore, the coating exhibited an overall NO storage capacity of 0.89 ± 0.09 mmol·g-1 (4.3 ± 0.6 µmol·cm-2). Erosion of POP-Gly-MMB-NO in PBS at 37 °C over 6 weeks results in 14% mass loss, and time-of-flight mass spectrometry (TOF-MS) was used to characterize the organic products of hydrolytic degradation as glycine, MMB, and several related esters. The comparatively long-term NO release and high storage capacity of POP-Gly-MMB-NO coatings suggest potential as a source of therapeutic NO for biomedical applications.
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Óxido Nítrico/química , Compuestos Organofosforados , Polímeros , S-NitrosotiolesRESUMEN
Metal-organic frameworks (MOFs) have demonstrated promise in biomedical applications as vehicles for drug delivery, as well as for the ability of copper-based MOFs to generate nitric oxide (NO) from endogenous S-nitrosothiols (RSNOs). Because NO is a participant in biological processes where it exhibits anti-inflammatory, antibacterial, and antiplatelet activation properties, it has received significant attention for therapeutic purposes. Previous work has shown that the water-stable MOF H3[(Cu4Cl)3-(BTTri)8] (H3BTTri = 1,3,5-tris(1H-1,2,3-triazol-5-yl)benzene), or CuBTTri, produces NO from RSNOs and can be included within a polymeric matrix to form NO-generating materials. While such materials demonstrate potential, the possibility of MOF degradation leading to copper-related toxicity is a concern that must be addressed prior to adapting these materials for biomedical applications. Herein, we present the first cytotoxicity evaluation of an NO-generating CuBTTri/polymer composite material using 3T3-J2 murine embryonic fibroblasts and primary human hepatocytes (PHHs). CuBTTri/polymer films were prepared from plasticized poly(vinyl chloride) (PVC) and characterized via PXRD, ATR-FTIR, and SEM-EDX. Additionally, the ability of the CuBTTri/polymer films to enhance NO generation from S-nitroso-N-acetylpenicillamine (SNAP) was evaluated. Enhanced NO generation in the presence of the CuBTTri/polymer films was observed, with an average NO flux (0.90 ± 0.13 nmol cm(-2) min(-1)) within the range associated with antithrombogenic surfaces. The CuBTTri/polymer films were analyzed for stability in phosphate buffered saline (PBS) and cell culture media under physiological conditions for a 4 week duration. Cumulative copper release in both cell media (0.84 ± 0.21%) and PBS (0.18 ± 0.01%) accounted for less than 1% of theoretical copper present in the films. In vitro cell studies performed with 3T3-J2 fibroblasts and PHHs did not indicate significant toxicity, providing further support for the potential implementation of CuBTTri-based materials in biomedical applications.
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Estructuras Metalorgánicas/química , Polímeros/química , Agua/química , Células 3T3 , Animales , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Hepatocitos/efectos de los fármacos , Humanos , Estructuras Metalorgánicas/farmacología , Ratones , S-Nitroso-N-Acetilpenicilamina/químicaRESUMEN
Nitric oxide (NO) is a unique bioactive molecule that performs multiple physiological functions and has been found to exhibit antithrombotic, antimicrobial, and wound-healing effects as an exogenous therapeutic agent. NO release from polymeric materials intended for use in biomedical applications has been established to reduce their thrombogenicity and decrease the likelihood of infection and inflammation that frequently produce medical complications. As a result, numerous NO-releasing polymers have been developed in an effort to utilize the beneficial properties of NO to improve the performance of implantable materials. The majority of synthetic NO-releasing biodegradable polymers that have been reported to date are polyesters, and there is significant interest in the development of new NO-releasing materials with improved or distinctive physicochemical characteristics. Polyphosphazenes are polymers with inorganic phosphorus-nitrogen backbones, and hydrolytically-sensitive derivatives with organic substituents have been prepared that degrade under physiological conditions. For this reason, biodegradable poly(organophosphazenes) are interesting candidate materials for applications such as tissue engineering, where the addition of NO release capability may be therapeutically useful. Herein, we report the first development and characterization of an NO-releasing poly(organophosphazene) from poly(ethyl S-methylthiocysteinyl-co-ethyl cysteinyl phosphazene) (POP-EtCys-SH). The thiolated polymer was synthesized from the reaction of poly(dichlorophosphazene) with ethyl S-methylthiocysteinate, followed by partial cleavage of the disulfide linkages to form free thiol groups. The conversion of thiol to the NO-releasing S-nitrosothiol functional group with tert-butyl nitrite resulted in a polymer (POP-EtCys-NO) with an average NO content of 0.55 ± 0.04 mmol g-1 that was found to release a total of 0.35 ± 0.02 mmol NO g-1 over 24 h under physiological conditions (37 °C, pH 7.4 phosphate buffered saline). Extracts obtained from both the thiolated and S-nitrosated polymers were not found to significantly impair the viability of human dermal fibroblasts or induce morphological changes, indicating that this cysteine-based polyphosphazene may possess potential utility as an NO-releasing biomaterial.
RESUMEN
Immobilization of metal-organic frameworks (MOFs) onto flexible polymeric substrates as secondary supports expands the versatility of MOFs for surface coatings for the development of functional materials. In this work, we demonstrate the deposition of copper(II) benzene-1,3,5-tricarboxylate (CuBTC) crystals directly onto the surface of carboxyl-functionalized cotton capable of generating the therapeutic bioagent nitric oxide (NO) from endogenous sources. Characterization of the CuBTC-cotton material by XRD, ATR-IR, and UV-vis indicate that CuBTC is successfully immobilized on the cotton fabric. In addition, SEM imaging reveals excellent surface coverage with well-defined CuBTC crystals. Subsequently, the CuBTC-cotton material was evaluated as a supported heterogeneous catalyst for the generation of NO using S-nitrosocysteamine as the substrate. The resulting reactivity is consistent with the activity observed for unsupported CuBTC particles. Overall, this work demonstrates deposition of MOFs onto a flexible polymeric material with excellent coverage as well as catalytic NO release from S-nitrosocysteamine at therapeutic levels.