The application of nanotechnology, molecular biotechnologies, and nano-sciences for medical purposes has been termed nanomedicine, a promising growing area of medical research. The aim of this paper is to provide an overview of and discuss nanotechnology applications in the early epochs of life, from transplacental transfer to neonatal/pediatric conditions. Diagnostic and therapeutic applications, mainly related to the respiratory tract, the neurosensory system, and infections, are explored and discussed. Preclinical studies show promising results for a variety of conditions, including for the treatment of pregnancy complications and fetal, neonatal, and pediatric diseases. However, given the complexity of the functions and interactions between the placenta and the fetus, and the complex and incompletely understood determinants of tissue growth and differentiation during early life, there is a need for much more data to confirm the safety and efficacy of nanotechnology in this field.
The phases are characterized by morphogenesis of the conducting airways, formation of alveoli (the terminal regions of the lungs where gas exchange occurs), differentiation of cells with region-specific functions of the lung (such as protection from foreign substances), efficient movement of air into and out of the lung, and efficient gas exchange at the alveolar–capillary interface. These processes are finely regulated by a complex network of cell signals, cell-derived molecules, hormones, and genetic expression.
One of the key components of the respiratory system is pulmonary surfactant. Pulmonary surfactant covers and stabilizes the alveoli and has peculiar biophysical properties, including the reduction of alveolar superficial tension and defense against microorganisms and toxic substances.
Surface tension is the force that develops at the interface between two or more fluids or between fluids and a solid wall. The forces of cohesion that act between the molecules of a fluid mean that those on the outer surface are subjected to a resulting force directed inwards; there is therefore a tendency of molecular stray from the limit surface of the liquid, which tends to contract and assume the minimum possible extent.
In the lungs, there is an interface between the liquid that covers the alveolar walls and the gas at their internal. Again, the surface liquid layer tends to contract and expel the air outwards, resulting in the collapse of the alveoli. The pressure generated within the alveoli due to surface tension is called collapse pressure and, according to Laplace’s law, is directly proportional to twice the surface tension and inversely proportional to the radius of the alveoli. Thus, the increase in surface tension determines an increment in the collapse pressure of the alveoli. In the physiological lung, surface tension is greatly reduced by the presence of surfactant, a mixture of different phospholipids, proteins, and ions produced by type II alveolar epithelial cells that cover about 10% of the area of the alveolar walls. Surfactant production begins at around the 20th week of gestation and reaches significant amounts in the amniotic fluid only after the 28th week [11].
The main components of surfactant are phospholipid dipalmitoylphosphatidylcholine, apoproteins, and calcium ions (see below). The tensioactive capacity lies in the amphibious dipalmitoylphosphatidylcholine at the liquid–gas interface. The absence of surfactant can lead to atelectasis (collapse of the alveoli) and respiratory insufficiency. Quantitatively, the surface tension of normal liquids covering the alveoli without surfactants is 50 dine/cm; this decreases to 5–30 dine/cm with surfactant. Consequently, the collapse pressure for medium-sized alveoli (r = 100 µm) falls from about 18 to 4 cm H2O.
To summarize, lung surfactant has important functions:
Moreover, surfactant can be used as a shuttle for the delivery of drugs and nanocarriers. Pulmonary surfactant is composed of approximately 90% lipids and 10% proteins. Four proteins—SP-A, -B, -C, and -D—are important for surfactant functions. SP-A and SP-D are large hydrophilic glycoproteins involved in pulmonary host defense through binding to inhaled particles and pathogens. SP-B and SP-C are smaller hydrophobic proteins that regulate the very low surface tension observed in the lung. The expression of surfactant proteins is regulated by genetic and environmental factors, including inflammation [12][13].
Interactions between surfactant and nanoparticles depend on the physico-chemical properties of the nanoparticles and also on the molecular composition, dynamic surface phase behavior, and monolayer biomechanics of the pulmonary surfactant [14][15][16]. The interaction between nanoparticles and surfactant has been studied with different methods. Hu et al. [14] showed that many factors, including surface charge, degree of hydrophobicity, and acquisition of a lipoprotein corona from endogenous surfactant, influence nanoprotein adsorption and blood stream translocation. Hydrophobic nanoparticles, such as carbon-based nanomaterials, can be retained at the surfactant lining layer and can lead to increased inflammation. Hydrophilic nanoparticles can be used for systemic drug delivery due to their rapid absorption and translocation to other organs and tissues. Anionic nanoparticles may inhibit the biophysical function of pulmonary surfactant by binding to surfactant proteins and interfering with their functions. Cationic nanoparticles may be taken up by cells and may cause acute toxicity. Therefore, neutral nanoparticles might be the safest option for pulmonary drug delivery.
In experimental models, some authors reported that hydrophilic nanomaterials (halloysite and bentonite) induced concentration-dependent damage on surfactant phospholipid function [17]. The shape and porous structure of nanoparticles are important factors to consider.
Other authors found that nanoparticles have different effects on lung inflammation and function depending on their metal properties: compared to non-metal nanoparticles (which elicit a dose-dependent inflammatory effect), silver nanoparticles do not induce significant inflammation, but only change in lung elastance [18][19].
On the other hand, the interaction between nanoparticles and surfactant may offer important therapeutic advantages: delivering drugs or nanoparticles in combination with surfactant can improve drug stability and prevent degradation and clearance in vivo, thereby allowing the delivery of macromolecular drugs. For example, nanovesicles carrying antibiotics have been successfully tested in animal models and clinical trials are ongoing [20][21]. Other potential applications include the diagnosis and therapy of different pulmonary diseases, vaccines, and cancer therapy.
Surfactant itself (animal-derived or synthetic) is an established therapy for respiratory distress syndrome, particularly among newborns: the administration of this drug is invasive, as it requires endotracheal instillation through a tube or a catheter. However, this maneuver can be associated with lung function deterioration and long-term complications among infants, and studies aimed at finding the most convenient method of administration are ongoing [22][23]. Other potential applications include the diagnosis and therapy of different pulmonary diseases, vaccines, and cancer therapy. Some authors designed inhalable nanoparticles mimicking some of the lipid components of surfactant [24]. Hopefully, technological advancement in this field will eventually lead to the production of inhalable surfactant preparations, and invasive surfactant administration will eventually be overcome.
Respiratory tract infections are among the most frequent worldwide and represent one of the most important causes of death in childhood. Antimicrobial resistance is a major challenge, as it results in increased morbidity and mortality worldwide. Since the development of new antimicrobials is expensive and has scarce success, one strategy to overcome this issue could be the application of synthetic products with antimicrobial properties. Moreover, newborns and young children have still immature metabolic pathways that can result in increased drug toxicity and poorly known drug interactions, potentially resulting in transient or persistent adverse events. Polymers with intrinsic antimicrobial effects or that can be conjugated with antimicrobials might replace antimicrobials. A comprehensive review of these compounds has been recently published [25]. Furthermore, nanomodified endotracheal tubes have been shown to reduce bacterial adhesion on the inner surface of the tube itself and potentially reduce the likelihood of ventilator-acquired infections [26].
Lower airway inflammation can be the result of different diseases and is often characterized by neutrophil leukocytes recruitment. Current therapies locally administered have low efficacy as multiple systems reduce drug availability, i.e., hydrophobicity and clearance by local defense systems. Some authors developed a delivery platform that takes advantage of the extracellular proteolysis of a microgel to deliver nanoparticle-embedded hydrophobic drugs to neutrophils and then to the lower airways [27]. In another study, Vij et al. successfully tested, in animal models, the efficacy of a PEGylated immuno-conjugated PLGA-nanoparticle to selectively deliver a drug to neutrophil cells [28].
Furthermore, the delivery of siRNAs to endothelial cells has been investigated in animal models for the treatment of pulmonary inflammatory conditions and other diseases [29].
Asthma is a common chronic inflammatory disease of the lungs starting in childhood and is characterized by intermittent airway obstruction, bronchial hyper-reactivity, and chronic airway inflammation. Diagnostic tests include the measurement of lung exhaled air flow and characteristics by means of specific instruments, i.e., spirometers. The electronic nose (E-nose) is a novel device based on nanosensors capable of detecting specific volatile organic compounds in exhaled gas, thus confirming an asthma diagnosis and allowing stratification and subtype characterization [30]. Asthma therapy relies mainly on the inhalation of certain drugs; however, poor deposition of the inhaled drug in the lung presents a challenge for the effectiveness of therapy. Drug nanoformulations are currently being evaluated following promising preclinical studies [31][32][33].
Concerning respiratory function monitoring and diagnostics, Bhattacharjee et al. [34] developed a point-of-care testing device consisting of a mouthpiece, paper-sensor, micro-heater assemblage, and monitoring unit which could facilitate the diagnosis of chronic obstructive lung diseases. The sensor was developed by depositing gold and cadmium sulfide nanoparticles on a paper surface in which the former enhanced the electrical and thermal conductivities while the latter allowed high precision humidity sensing.
Clinical studies are needed in order to assess the safety and efficacy of nanoparticles as drug carriers for respiratory and systemic conditions.
Ocular System
This entry is adapted from the peer-reviewed paper 10.3390/app10124323