Adsorption features of various inorganic materials for the drug removal from water and synthetic urine medium: A multi-technique time-resolved in situ investigation

Pharmaceutical active compounds, including hundreds of different substances, are counted among the emerging contaminants in waterbodies, whose presence raises a growing concern for the ecosystem. Drugs are metabolized and excreted mainly through urine as an unchanged active ingredient or in the form of metabolites. These emerging contaminants are not effectively removed with the technologies currently in use, making them a relevant environmental problem. This study proposes the treatment of urine and water at the source that can allow an easier removal of dissolved drugs and metabolites. The treatment of synthetic urine, with dissolved ibuprofen as a model compound, by adsorption, using various classes of inorganic materials, such as clays, hierarchical zeolites and ordered mesoporous silica (MCM-41), is presented. A multi-technique approach involving X-ray powder diffraction, solid-state NMR, UV-Vis and Raman spectroscopies was employed to investigate the adsorption process in inorganic adsorbents. Moreover, the uptake, the ensuing competition, the efficiency and selectivity as well as the packing of the model compound in ordered mesoporous silica during the incipient wetness impregnation process were all thoroughly monitored by a novel approach, involving combined complementary time-resolved in situ1 H and13 C MAS NMR spectroscopy as well as X-ray powder diffraction

Fingerprinting the hydration products of hydraulic binders using snapshots from time-resolved in situ multinuclear mas nmr spectroscopy

The very early hydration behavior of a hydraulic binder phase, ye'elimite, Ca4Al6O12SO4, in the absence and in the presence of calcium sulfate, has been investigated. A time-resolved in situ multinuclear magic angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopic suite involving 1H and 27Al MAS as well as two-dimensional 27Al multiple quantum MAS (MQMAS) experiments has been employed to detect the transient species and to govern the sequence of hydration reactions and the subsequent formation of the hydration products. The results of the study show that the rates of formation of ye'elimite hydration products vary substantially according to the absence or the presence of calcium sulfate. Hydrated calcium sulfoaluminate phases such as ettringite and monosulfate as well as aluminum hydroxide gel have been detected during the various stages of hydration. The direct observation of various transient species during the hydration stages of calcium aluminates and calcium sulfoaluminates illustrates the potential of a newly designed time-resolved in situ 1H MAS NMR experimental approach for fingerprinting phases and offers significant advantages over other established techniques in detecting transient species

Hybrid Injectable Sol-Gel Systems Based on Thermo-Sensitive Polyurethane Hydrogels Carrying pH-Sensitive Mesoporous Silica Nanoparticles for the Controlled and Triggered Release of Therapeutic Agents

Injectable therapeutic formulations locally releasing their cargo with tunable kinetics in response to external biochemical/physical cues are gaining interest in the scientific community, with the aim to overcome the cons of traditional administration routes. In this work, we proposed an alternative solution to this challenging goal by combining thermo-sensitive hydrogels based on custom-made amphiphilic poly(ether urethane)s (PEUs) and mesoporous silica nanoparticles coated with a self-immolative polymer sensitive to acid pH (MSN-CS-SIP). By exploiting PEU chemical versatility, Boc-protected amino groups were introduced as PEU building block (PEU-Boc), which were then subjected to a deprotection reaction to expose pendant primary amines along the polymer backbone (PEU-NH2, 3E18 -NH2/gPEU–NH2) with the aim to accelerate system response to external acid pH environment. Then, thermo-sensitive hydrogels were designed (15% w/v) showing fast gelation in physiological conditions (approximately 5 min), while no significant changes in gelation temperature and kinetics were induced by the Boc-deprotection. Conversely, free amines in PEU-NH2 effectively enhanced and accelerated acid pH transfer (pH 5) through hydrogel thickness (PEU-Boc and PEU-NH2 gels covered approximately 42 and 52% of the pH delta between their initial pH and the pH of the surrounding buffer within 30 min incubation, respectively). MSN-CS-SIP carrying a fluorescent cargo as model drug (MSN-CS-SIP-Ru) were then encapsulated within the hydrogels with no significant effects on their thermo-sensitivity. Injectability and in situ gelation at 37°C were demonstrated ex vivo through sub-cutaneous injection in rodents. Moreover, MSN-CS-SIP-Ru-loaded gels turned out to be detectable through the skin by IVIS imaging. Cargo acid pH-triggered delivery from PEU-Boc and PEU-NH2 gels was finally demonstrated through drug release tests in neutral and acid pH environments (in acid pH environment approximately 2-fold higher cargo release). Additionally, acid-triggered payload release from PEU-NH2 gels was significantly higher compared to PEU-Boc systems at 3 and 4 days incubation. The herein designed hybrid injectable formulations could thus represent a significant step forward in the development of multi-stimuli sensitive drug carriers. Indeed, being able to adapt their behavior in response to biochemical cues from the surrounding physio-pathological environment, these formulations can effectively trigger the release of their payload according to therapeutic needs

Hybrid injectable sol-gel systems based on thermo-sensitive polyurethane hydrogels carrying pH-sensitive mesoporous silica nanoparticles for the controlled and triggered release of therapeutic agents.

Injectable therapeutical formulations locally releasing their cargo with tunable kinetics in response to external biochemical/physical cues are gaining interest in the scientific community, with the aim to overcome the cons of traditional administration routes. In this work, we proposed an alternative solution to this challenging goal by combining thermosensitive hydrogels based on custom-made amphiphilic poly(ether urethane)s (PEUs) and mesoporous silica nanoparticles coated with a self-immolative polymer sensitive to acid pH (MSN-CS-SIP). By exploiting PEU chemical versatility, Boc-protected amino groups were introduced as PEU building block (PEU-Boc), which were then subjected to a deprotection reaction to expose pendant primary amines along the polymer backbone (PEU-NH2, 3E18 NH2/gPEU-NH2) with the aim to accelerate system response to external acid pH environment. Then, thermo-sensitive hydrogels were designed (15% w/v) showing fast gelation in physiological conditions (approximately 5 min), while no significant changes in gelation temperature and kinetics were induced by the Boc-deprotection. Conversely, free amines in PEU-NH2 effectively enhanced and accelerated acid pH transfer (pH 5) through hydrogel thickness (PEU-Boc and PEUNH2 gels covered approximately 42 and 52% of the pH delta between their initial pH and the pH of the surrounding buffer within 30 min incubation, respectively). MSN-CS-SIP carrying a fluorescent cargo as model drug (MSN-CS-SIP-Ru) were then encapsulated within the hydrogels with no significant effects on their thermo-sensitivity. Injectability and in situ gelation at 37�C were demonstrated ex vivo through sub-cutaneous injection. Hybrid Hydrogels for pH-Triggered Release in rodents. Moreover, MSN-CS-SIP-Ru-loaded gels turned out to be detectable through the skin by IVIS imaging. Cargo acid pH-triggered delivery from PEU-Boc and PEUNH2 gels was finally demonstrated through drug release tests in neutral and acid pH environments (in acid pH environment approximately 2-fold higher cargo release). Additionally, acid-triggered payload release from PEU-NH2 gels was significantly higher compared to PEU-Boc systems at 3 and 4 days incubation. The herein designed hybrid injectable formulations could thus represent a significant step forward in the development of multi-stimuli sensitive drug carriers. Indeed, being able to adapt their behavior in response to biochemical cues from the surrounding physio-pathological environment, these formulations can effectively trigger the release of their payload according to therapeutic needs

Locally delivered antistaphylococcal lysin exebacase or CF-296 is active in methicillin-resistant <i>Staphylococcus aureus</i> implant-associated osteomyelitis

Introduction: Staphylococcus aureus is the most common cause of orthopedic infections and can be challenging to treat, especially in the presence of a foreign body. The antistaphylococcal lysins exebacase and CF-296 have rapid bactericidal activity, a low propensity for resistance development, and synergize with some antibiotics. Methods: Rabbit implant-associated osteomyelitis was induced by drilling into the medial tibia followed by locally delivering exebacase, CF-296, or lysin carrier. A titanium screw colonized with methicillin-resistant S. aureus (MRSA) IDRL-6169 was inserted. Intravenous daptomycin or saline was administered and continued daily for 4 d. On day 5, rabbits were euthanized, and the tibiae and implants were collected for culture. Results were reported as log10 colony forming units (cfu) per gram of bone or log10 cfu per implant, and comparisons among the six groups were performed using the Wilcoxon rank sum test. Results: Based on implant and bone cultures, all treatments resulted in significantly lower bacterial counts than those of controls (P≤0.0025). Exebacase alone or with daptomycin as well as CF-296 with daptomycin were more active than daptomycin alone (P≤0.0098) or CF-296 alone (P≤0.0154) based on implant cultures. CF-296 with daptomycin was more active than either CF-296 alone (P=0.0040) or daptomycin alone (P=0.0098) based on bone cultures. Conclusion: Local delivery of either exebacase or CF-296 offers a promising complement to conventional antibiotics in implant-associated infections.</p

Exebacase for Staphylococcus aureus bloodstream infection and endocarditis

BACKGROUND: Novel therapeutic approaches are critically needed for Staphylococcus aureus bloodstream infections (BSI), particularly for methicillin-resistant S. aureus (MRSA). Exebacase, a first-in-class antistaphylococcal lysin, is a direct lytic agent that is rapidly bacteriolytic, eradicates biofilms, and synergizes with antibiotics. METHODS: In this superiority-design study, we randomly assigned 121 patients with S. aureus BSI/endocarditis to receive a single dose of exebacase or placebo. All patients received standard-of-care antibiotics. The primary efficacy endpoint was clinical outcome (responder rate) at Day 14. RESULTS: Clinical responder rates at Day 14 were 70.4% and 60.0% in the exebacase + antibiotics and antibiotics alone groups, respectively (difference=10.4, 90% CI [-6.3, 27.2], p-value=0.31), and were 42.8 percentage points higher in the pre-specified exploratory MRSA subgroup (74.1% vs. 31.3%, difference=42.8, 90% CI [14.3, 71.4], ad hoc p value=0.01). Rates of adverse events (AEs) were similar in both groups. No AEs of hypersensitivity to exebacase were reported. Thirty-day all-cause mortality rates were 9.7% and 12.8% in the exebacase + antibiotics and antibiotics alone groups, respectively, with a notable difference in MRSA (3.7% vs. 25.0%, difference= -21.3, 90% CI [-45.1, 2.5], ad hoc p-value=0.06). Among MRSA patients in the United States, median length-of-stay was 4-days shorter and 30-day hospital readmission rates were 48 percentage points lower in the exebacase-treated group compared with antibiotics alone. CONCLUSIONS: This study establishes proof-of-concept for exebacase and direct lytic agents as potential therapeutics and supports conduct of a confirmatory study focused on exebacase to treat MRSA BSI