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Engineering of Nebulized Metal-Phenolic Capsules for Controlled Pulmonary Deposition.

ABSTRACT: Particle-based pulmonary delivery has great potential for delivering inhalable therapeutics for local or systemic applications. The design of particles with enhanced aerodynamic properties can improve lung distribution and deposition, and hence the efficacy of encapsulated inhaled drugs. This study describes the nanoengineering and nebulization of metal-phenolic capsules as pulmonary carriers of small molecule drugs and macromolecular drugs in lung cell lines, a human lung model, and mice. Tuning the aerodynamic diameter by increasing the capsule shell thickness (from ≈100 to 200 nm in increments of ≈50 nm) through repeated film deposition on a sacrificial template allows precise control of capsule deposition in a human lung model, corresponding to a shift from the alveolar region to the bronchi as aerodynamic diameter increases. The capsules are biocompatible and biodegradable, as assessed following intratracheal administration in mice, showing >85% of the capsules in the lung after 20 h, but <4% remaining after 30 days without causing lung inflammation or toxicity. Single-cell analysis from lung digests using mass cytometry shows association primarily with alveolar macrophages, with >90% of capsules remaining nonassociated with cells. The amenability to nebulization, capacity for loading, tunable aerodynamic properties, high biocompatibility, and biodegradability make these capsules attractive for controlled pulmonary delivery.

SUBMITTER: Ju Y

PROVIDER: S-EPMC7080547 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Engineering of Nebulized Metal-Phenolic Capsules for Controlled Pulmonary Deposition.

Ju Yi Y Cortez-Jugo Christina C Chen Jingqu J Wang Ting-Yi TY Mitchell Andrew J AJ Tsantikos Evelyn E Bertleff-Zieschang Nadja N Lin Yu-Wei YW Song Jiaying J Cheng Yizhe Y Mettu Srinivas S Rahim Md Arifur MA Pan Shuaijun S Yun Gyeongwon G Hibbs Margaret L ML Yeo Leslie Y LY Hagemeyer Christoph E CE Caruso Frank F

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20200110 6

Particle-based pulmonary delivery has great potential for delivering inhalable therapeutics for local or systemic applications. The design of particles with enhanced aerodynamic properties can improve lung distribution and deposition, and hence the efficacy of encapsulated inhaled drugs. This study describes the nanoengineering and nebulization of metal-phenolic capsules as pulmonary carriers of small molecule drugs and macromolecular drugs in lung cell lines, a human lung model, and mice. Tunin ...[more]

PMID: 32195089

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Project description:BackgroundDexmedetomidine (Dex), a selective a2-adrenergic receptor agonist, has been previously reported to attenuate intrapulmonary shunt during one-lung ventilation (OLV) and to alleviate bronchoconstriction. However, the therapeutic effects of nebulized Dex on pulmonary shunt and lung mechanics during OLV have not been evaluated. Here we determine whether nebulized dexmedetomidine improved pulmonary shunt and lung mechanics in patients undergoing elective thoracic surgery in a prospective randomized controlled clinical trial.MethodsOne hundred and twenty-eight patients undergoing elective thoracoscopic surgery were included in this study and randomly divided into four groups: 0.9% saline (Placebo group), 0.5 µg/kg (Dex0.5 group), 1 µg/kg (Dex1 group) and 2 µg/kg (Dex2group) dexmedetomidine. After bronchial intubation, patients received different nebulized doses of dexmedetomidine (0.5 µg/kg, 1 µg/kg and 2 µg/kg) or 0.9% saline placebo during two-lung ventilation(TLV). OLV was initiated 15 min after bronchial intubation. Anesthesia was maintained with intravenous infusion of cisatracurium and propofol. Bispectral Index values were maintained within 40-50 by adjusting the infusion of propofol in all groups. Arterial blood gas samples and central venous blood gas samples were taken as follows: 15 min after bronchial intubation during two-lung ventilation (TLV15), after 30 and 60 min of OLV (OLV30and OLV60, respectively) and 15 min after reinstitution of TLV (ReTLV). Dynamic compliance was also calculated at TLV15, OLV30, OLV60 and ReTLV.ResultsDex decreased the requirement of propofol in a dose-dependent manner(P = 0.000). Heart rate (HR) and mean arterial pressure (MAP) displayed no significant difference among groups (P = 0.397 and 0.863). Compared with the placebo group, Dex administered between 0.5 and 2 µg/kg increased partial pressure of oxygen (PaO2) significantly at OLV30 and OLV60(P = 0.000); however, Dex administered between 1 and 2 µg/kg decreased pulmonary shunt fraction (Qs/Qt) at OLV30 and OLV60(P = 0.000). Compared with the placebo group, there were significant increases with dynamic compliance (Cdyn) after OLV in Dex0.5, Dex1 and Dex2group(P = 0.000). Conclusions. Nebulized dexmedetomidine improved oxygenation not only by decreasing pulmonary shunt but also by improving lung compliance during OLV, which may be effective in managing OLV.

Project description:ObjectivesRespiratory failure secondary to COVID-19 is associated with morbidity and mortality. Current anti-inflammatory therapies are effective but are given systemically and have significant side effects. Furosemide has anti-inflammatory properties, can be administered by inhalation, and is inexpensive. We investigated the efficacy of nebulized furosemide as an adjunctive therapy for COVID-19 respiratory failure.DesignA double-blind, randomized, placebo-controlled trial.SettingMulticenter ICU study.PatientsAdults requiring invasive mechanical ventilation secondary to COVID-19.InterventionPatients were randomized within 48 hours of intubation to receive inhaled furosemide or placebo until day 28, death, or liberation from mechanical ventilation.Measurements and main resultsThe study was stopped early due to waning incidence of COVID-19; 39 patients were available for analysis with mean ± sd age of 70.5 (10.8) years, Acute Physiology and Chronic Health Evaluation II 26.1 (7.8) and Fio2 60.0% (21.9). Baseline characteristics were similar between the groups. For the primary outcome of change in Pao2/Fio2 ratio between day 1 and day 6, it was +31.4 (83.5) in the furosemide arm versus +20.1 (92.8) in the control (p = 0.58). For secondary outcomes, furosemide versus control: 60-day mortality was 48% versus 71% (p = 0.20), hospital stay was 25.6 (21.9) versus 27.4 (25.0) days, p = 0.94 and VFD was 6.0 (9.1) versus 3.1 (7.1), p value of equals to 0.28. A post hoc analysis of the hierarchical composite outcome, alive and ventilator-free favored furosemide. There were no adverse events.ConclusionsIn this trial of inhaled furosemide for COVID-19 respiratory failure, differences in Pao2/Fio2 ratio to day 6 and other clinical outcomes were not significantly different, although the trial was underpowered due to early termination. Given the favorable profile of inhaled furosemide, further study is warranted in disease states where acute pulmonary inflammation contributes to the underlying pathophysiology.

Dataset Information

Engineering of Nebulized Metal-Phenolic Capsules for Controlled Pulmonary Deposition.

Publications

Engineering of Nebulized Metal-Phenolic Capsules for Controlled Pulmonary Deposition.

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