Multimodal Precision Imaging of Pulmonary Nanoparticle Delivery in Mice: Dynamics of Application, Spatial Distribution, and Dosimetry

Yang, Lin; Gradl, Regine; Dierolf, Martin; Möller, Winfried; Kutschke, David; Feuchtinger, Annette; Hehn, Lorenz; Donnelley, Martin; Günther, Benedikt; Achterhold, Klaus; Walch, Axel; Stoeger, Tobias; Razansky, Daniel; Pfeiffer, Franz; Morgan, Kaye S.; Schmid, Otmar

doi:10.1002/smll.201904112

Cited by 25 publications

(24 citation statements)

References 57 publications

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“…As these transport mechanisms operate within an intricate 3D airway network covering a breadth of length scales within a space-filling volume, combined with a wide range of gravitational orientations (e.g. apical vs. basal lung lobes), PM deposition patterns in the deep lungs are known to be complex and spatially heterogeneous [35,118,136,142]. Here, microfluidic acinar airway models have enabled seminal quantitative in vitro studies of aerosol (PM) deposition patterns under physiological breathing conditions providing for the first time, temporally-resolved tracking of airborne particle flight within alveolar cavities [143].…”

Section: Physiological Respiratory Airflows and Inhaled Aerosol Transportmentioning

confidence: 99%

Advanced human-relevant in vitro pulmonary platforms for respiratory therapeutics

Artzy‐Schnirman

Raviv

Flikshtain

et al. 2021

Advanced Drug Delivery Reviews

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Over the past years, advanced in vitro pulmonary platforms have witnessed exciting developments that are pushing beyond traditional preclinical cell culture methods. Here, we discuss ongoing efforts in bridging the gap between in vivo and in vitro interfaces and identify some of the bioengineering challenges that lie ahead in delivering new generations of human-relevant in vitro pulmonary platforms. Notably, in vitro strategies using foremost lung-on-chips and biocompatible "soft" membranes have focused on platforms that emphasize phenotypical endpoints recapitulating key physiological and cellular functions. We review some of the most recent in vitro studies underlining seminal therapeutic screens and translational applications and open our discussion to promising avenues of pulmonary therapeutic exploration focusing on liposomes. Undeniably, there still remains a recognized trade-off between the physiological and biological complexity of these novel in vitro lung models and their ability to deliver assays with throughput capabilities. The upcoming years are thus anticipated to see further developments in broadening the applicability of such in vitro systems and accelerating therapeutic exploration for drug discovery and translational medicine in treating respiratory disorders.

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Section: Physiological Respiratory Airflows and Inhaled Aerosol Transportmentioning

confidence: 99%

Advanced human-relevant in vitro pulmonary platforms for respiratory therapeutics

Artzy‐Schnirman

Raviv

Flikshtain

et al. 2021

Advanced Drug Delivery Reviews

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“…11,[38][39][40] However, this mode of administration was proved to generate an uneven pattern of deposition of the aerosol which could generate impairment to human transposition. 41 Contrarily, inhalation of an aerosol generated by a nebuliser resulted in a homogeneous deposition and, thus, an easier extrapolation to human. 42 This difference of deposition pattern between instillation and inhalation is well documented in nanotoxicology [43][44][45] and was also found in mechanically ventilated patients.…”

Section: Discussionmentioning

confidence: 99%

<p>Nebulised Gadolinium-Based Nanoparticles for a Multimodal Approach: Quantitative and Qualitative Lung Distribution Using Magnetic Resonance and Scintigraphy Imaging in Isolated Ventilated Porcine Lungs</p>

Montigaud¹,

Pourchez²,

Leclerc³

et al. 2020

IJN

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This study aims at determining lung distribution of gadolinium-based polysiloxane nanoparticles, AGuIX ® (small rigid platform-SRP), as a potential theranostic approach by the pulmonary route. Methods: First, the aerodynamic size distribution and the aerosol output rate were thoroughly characterized. Then, a multimodal approach using magnetic resonance (MR) and gamma-camera (GC) imaging allows to assess the deposition of the aerosolised nanoparticles in the respiratory tract using isolated ventilated porcine lungs. Results: The SRP has proven to be radiolabelled by radioisotope with a good yield. Crude SRP or radiolabelled ones showed the same aerodynamic size distribution and output as a conventional molecular tracer, as sodium fluoride. With MR and GC imaging approaches, the nebulised dose represented about 50% of the initial dose of nanoparticles placed in the nebuliser. Results expressed as proportions of the deposited aerosol showed approximately a regional aerosol deposition of 50% of the deposited dose in the lungs and 50% in the upper airways. Each technique assessed a homogeneous pattern of deposited nanoparticles in Lungs. MR observed a strong signal enhancement with the SRP, similar to the one obtained with a commonly used MRI contrast agent, gadoterate meglumine. Conclusion: As a known theranostic approach by intravenous administration, SRP appeared to be easily aerosolised with a conventional nebuliser. The present work proves that pulmonary administration of SRP is feasible in a human-like model and allows multimodal imaging with MR and GC imaging. This work presents the proof of concept of SRP nebulisation and aims to generate preclinical data for the potential clinical transfer of SRP for pulmonary delivery.

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“…Other related efforts are developing data, methods and tools which are useful for AOP development [ 24 , 25 , 26 ]. For example, the EU’s NanoSolveIT project is developing: (i) innovative modelling techniques and tools for nanoinformatics; (ii) an IATA to identify the specific characteristics of MNs that are responsible for adverse effects on human health or the environment; and (iii) in silico methods, models and tools which are useful for AOP development.…”

Section: Recent Progress With Aops For Nanosafetymentioning

confidence: 99%

Translating Scientific Advances in the AOP Framework to Decision Making for Nanomaterials

et al. 2020

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Much of the current innovation in advanced materials is occurring at the nanoscale, specifically in manufactured nanomaterials (MNs). MNs display unique attributes and behaviors, and may be biologically and physically unique, making them valuable across a wide range of applications. However, as the number, diversity and complexity of MNs coming to market continue to grow, assessing their health and environmental risks with traditional animal testing approaches is too time- and cost-intensive to be practical, and is undesirable for ethical reasons. New approaches are needed that meet current requirements for regulatory risk assessment while reducing reliance on animal testing and enabling safer-by-design product development strategies to be implemented. The adverse outcome pathway (AOP) framework presents a sound model for the advancement of MN decision making. Yet, there are currently gaps in technical and policy aspects of AOPs that hinder the adoption and use for MN risk assessment and regulatory decision making. This review outlines the current status and next steps for the development and use of the AOP framework in decision making regarding the safety of MNs. Opportunities and challenges are identified concerning the advancement and adoption of AOPs as part of an integrated approach to testing and assessing (IATA) MNs, as are specific actions proposed to advance the development, use and acceptance of the AOP framework and associated testing strategies for MN risk assessment and decision making. The intention of this review is to reflect the views of a diversity of stakeholders including experts, researchers, policymakers, regulators, risk assessors and industry representatives on the current status, needs and requirements to facilitate the future use of AOPs in MN risk assessment. It incorporates the views and feedback of experts that participated in two workshops hosted as part of an Organization for Economic Cooperation and Development (OECD) Working Party on Manufactured Nanomaterials (WPMN) project titled, “Advancing AOP Development for Nanomaterial Risk Assessment and Categorization”, as well as input from several EU-funded nanosafety research consortia.

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Multimodal Precision Imaging of Pulmonary Nanoparticle Delivery in Mice: Dynamics of Application, Spatial Distribution, and Dosimetry

Cited by 25 publications

References 57 publications

Advanced human-relevant in vitro pulmonary platforms for respiratory therapeutics

Advanced human-relevant in vitro pulmonary platforms for respiratory therapeutics

<p>Nebulised Gadolinium-Based Nanoparticles for a Multimodal Approach: Quantitative and Qualitative Lung Distribution Using Magnetic Resonance and Scintigraphy Imaging in Isolated Ventilated Porcine Lungs</p>

Translating Scientific Advances in the AOP Framework to Decision Making for Nanomaterials

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