A Molecular Dynamics Study On Interactions Of Inhaled Nanoparticles With Pulmonary Surfactant

The large-scale production of nanomaterials has greatly increased the probability of human contact with nanoparticles.It has been widely accepted that nano-sized particles can enter the lungs through respiration and deposit in the alveoli or even reach all over the body through the blood circulation,causing lung diseases,which are extremely harmful to human health.Nevertheless,nanomaterials still have broad prospects in the field of biomedicine,especially in inhalation therapy.Exploring the uptake pathway of nanoparticles provides insight into the lung inhalation toxicity of nanoparticles and the potential for pulmonary administration.In the gas-liquid interface of the alveoli present in the layer of the like detergent,called pulmonary surfactant(PS),which can be converted by a complex topography reduce the surface tension of the alveoli.PS is the first biological barrier that constitutes host defense.Therefore,the inhaled nanoparticles will first interact with the PS,on the one hand,the microstructure,phase,and mechanical properties of the PS will be disturbed.On the other hand,its ability to penetrate the PS will contribute to the inhaled drug.Reasonable design of the carrier.In recent years,with the continuous development of computers and the greatly improvement of computing power,molecular simulation has become a powerful tool for studying nanobiology.In this paper,we will explore the interaction of different nanoparticles with the PS using molecular dynamics simulation.The main research contents are summarized as follows:(1)The interactions between SWCNTs(single walled carbon nanotubes)with different sizes and PSAt present,SWCNTs have been widely used in various fields of biomedicine,electronics,and materials.At the same time,large-scale production will inevitably expose it to the environment,puts human health at a high risk.As the front line of the innate host defense system,the pulmonary surfactant at the air-water interface of the lungs interacts with inhaled SWCNTs which in turn inevitably perturb the ultrastructure of the PS and affect its biophysical functions.Here,with molecular dynamics simulations,we demonstrate how the diameter and length of SWCNTs critically regulate their interactions with the PS.Compared to their diameters,the inhalation toxicity of SWCNTs was found to be largely affected by their lengths.Short SWCNTs with lengths comparable to the monolayer thickness are found to vertically insert into the PS with no indication of translocation,possibly leading to accumulation of SWCNTs in the PS with prolonged retention and increased inflammation potentials.The perturbation also comes from both forming water pores and increasing the PS compressibility.Longer SWCNTs are found to horizontally insert into the PS during inspiration,and they can be wrapped by PS during expiration via a tube diameterdependent self-rotation.The potential toxicity of longer SWCNTs comes from severe lipid depletion and the PS-rigidifying effect.Our research can explain the effects of SWCNTs on the structure,properties,and function of PS at a molecular level.(2)The interactions between SWCNTs with different surface patterning and PSThe surface modification has a very important influence on the interaction between nanomaterials and biomembranes.Therefore,the study of the interaction between SWCNTs with surface patterning and the PS during respiration can promote the safer and more efficient biomedical application.Here,by applying coarse-grained molecular dynamics,we probe how the inhaled SWCNTs with surface patterning interact with PS.For hydrophilic tubes,they can spontaneously translocate across PS,regardless of the tension.In contrast to SWCNTs with unique surface properties,the surface patterning of SWCNTs enhances their perturbation on PS.Under expansion,the PS translocation is frustrated via inducing ordered or disordered lipid rearrangement adhering on the patterned tube surface.Under compression,moreover,the lipid arrangements further self-adjust and grow into bilayers,which protrude along the tube surface and finally develop into a vesicle.The stripe width and stripe orientation,among other factors,are found to be the most important factors that determine whether and how the vesiculation takes place.The simulation work shows that the interaction path between SWCNTs and PS can be regulated by surface modification of nanotubes,thus providing theoretical guidance for future biological applications.(3)The interactions between lipid coated nanoparticles and PSBy performing molecular dynamics simulations,we study how the inhaled NPs interact with the PS,especially focusing on the transport of NPs of different properties aross the PS.While hydrophilic NPs directly translocate across the PS,transport of hydrophobic NPs is achieved via wrapping by the PS.When the hydrophilic NPs are decorated with lipid molecules(LCNPs),intriguingly,they are wrapped by the PS efficiently and with mild PS purturbation.Moreover,the formed structure is like a vesicle,which is likely to fuse with cell membranes to accomplish transport of hydrophilic NPs into the secondary organs.This behavior makes the LCNP as a prospective candidate in pulmonary nanodrug delivery.The effects of physical properties of LCNPs on their transport are investigated.Increasing the LCNP size promotes its wrapping by reducing the PS bending energy.The binding energy which drives the transport can be strengthened by increasing the lipid coating density and the lipid tail length,both of which also reduce the risk of PS rupture during the transport.These results should help understand how to better use surface decorations to achieve efficient pulmonary entry,which may provide useful guidelines for design of nanobased platforms for inhaled drug delivery.(4)The interactions between nanodroplets and PSWe demonstrate by molecular dynamics simulations the transport of nanodroplets across the PS being improved by lipid coating.In the absence of lipids,bare nanodroplets deposit at the PS layer to release drugs that can be directly translocated across the PS.The translocation is quicker under higher surface tensions but at the cost of opening pores that disrupt the ultrastructure of the PS layer.When the PS layer is compressed to lower surface tensions,the nanodroplet prompts collapse of the PS layer to induce severe PS perturbation.By coating the nanodroplet with lipids,the disturbance of the nanodroplet on the PS layer can be reduced.Moreover,the lipidcoated nanodroplet can be readily wrapped by the PS layer to form vesicular structures,which are expected to fuse with the cell membrane to release drugs into secondary organs.Properties of drug bioavailability,controlled drug release,and enzymatic tolerance in real systems could be improved by lipid coating on nanodroplets.Our results provide useful guidelines for the molecular design of nanodroplets as carriers for the pulmonary drug delivery.