Towards the Identification of an In Vitro Tool for Assessing the Biological Behavior of Aerosol Supplied Nanomaterials.

Luisana Di Cristo,Yuri Volkov,Adriele Prina-Mello,Mattia Aleardi,Karen Mc Quillan,Dania Movia,Ciaran Maguire

doi:10.3390/ijerph15040563

Abstract

Nanoparticles (NP)-based inhalation systems for drug delivery can be administered in liquid form, by nebulization or using pressurized metered dose inhalers, and in solid form by means of dry powder inhalers. However, NP delivery to the lungs has many challenges including the formulation instability due to particle-particle interactions and subsequent aggregation, causing poor deposition in the small distal airways and subsequent alveolar macrophages activity, which could lead to inflammation. This work aims at providing an in vitro experimental design for investigating the correlation between the physico-chemical properties of NP, and their biological behavior, when they are used as NP-based inhalation treatments, comparing two different exposure systems. By means of an aerosol drug delivery nebulizer, human lung cells cultured at air–liquid interface (ALI) were exposed to two titanium dioxide NP (NM-100 and NM-101), obtained from the JRC repository. In parallel, ALI cultures were exposed to NP suspension by direct inoculation, i.e., by adding the NP suspensions on the apical side of the cell cultures with a pipette. The formulation stability of NP, measured as hydrodynamic size distributions, the cell viability, cell monolayer integrity, cell morphology and pro-inflammatory cytokines secretion were investigated. Our results demonstrated that the formulation stability of NM-100 and NM-101 was strongly dependent on the aggregation phenomena that occur in the conditions adopted for the biological experiments. Interestingly, comparable biological data between the two exposure methods used were observed, suggesting that the conventional exposure coupled to ALI culturing conditions offers a relevant in vitro tool for assessing the correlation between the physico-chemical properties of NP and their biological behavior, when NP are used as drug delivery systems.

Highlights

The human body has a number of portals of entry available for drug administration, namely, the lungs, the gastrointestinal tract, the circulatory system, and the skin [1]
In supplemented cell culture medium, NM-100 showed a more mono-dispersed population as compared to NM-101, as indicated by the PDI values. These data demonstrated that differences in the formulation stability of those two materials exist under the experimental conditions used in this study
Our and suspension exposure in cultures of human lung lung cells grown in conditions, can be used for studying the correlation between the physicocells grown in air–liquid interface (ALI) conditions, can be used for studying the correlation between the physico-chemical chemical properties of NP, as determinants of the formulation and the biological behavior properties of NP, as determinants of the formulation stability, andstability, the biological behavior of NP, when of are used as drug delivery systems administrated by means of a nebulizer

Summary

Introduction

The human body has a number of portals of entry available for drug administration, namely, the lungs (inhalation), the gastrointestinal tract (digestion), the circulatory system (intravenous injection), and the skin (transdermal administration) [1]. The lung, with its huge internal surface of ca. 150 m2 , is an extremely attractive route for drug delivery, as it provides advantages for both. Res. Public Health 2018, 15, 563; doi:10.3390/ijerph15040563 www.mdpi.com/journal/ijerph

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