Open Access

Application of nanotechnology in drug delivery systems for respiratory diseases (Review)

  • Authors:
    • Ming-Xin Luo
    • Shan Hua
    • Qi-Yun Shang
  • View Affiliations

  • Published online on: March 5, 2021     https://doi.org/10.3892/mmr.2021.11964
  • Article Number: 325
  • Copyright: © Luo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Respiratory disease is a common disease with a high incidence worldwide, which is a serious threat to human health, and is considered a societal and economic burden. The application of nanotechnology in drug delivery systems has created new treatments for respiratory diseases. Within this context, the present review systematically introduced the physicochemical properties of nanoparticles (NPs); reviewed the current research status of different nanocarriers in the treatment of respiratory diseases, including liposomes, solid lipid nanocarriers, polymeric nanocarriers, dendrimers, inorganic nanocarriers and protein nanocarriers; and discussed the main advantages and limitations of therapeutic nanomedicine in this field. The application of nanotechnology overcomes drug inherent deficiencies to a certain extent, and provides unlimited potential for the development of drugs to treat respiratory diseases. However, most of the related research work is in the preclinical experimental stage and safety assessment is still a challenging task. Future studies are needed to focus on the performance modification, molecular mechanism and potential toxicity of therapeutic nanomedicine.

Introduction

With the rise in air pollution levels, rapid changes in lifestyle and frequent outbreaks of microbial infections, the morbidity of respiratory diseases is increasing, particularly among children and the elderly population with weakened immune systems (1). Almost 4,000,000 people die from respiratory diseases every year worldwide (2). The main respiratory diseases include acute and chronic respiratory infections, lung cancer, asthma, chronic obstructive pulmonary disease, cystic fibrosis and tuberculosis (2). Although the current diagnostic and therapeutic techniques have improved, effective treatment of severe and chronic disease is still lacking (3,4). In addition, it is difficult for most drugs to reach the lower respiratory tract with adequate dose and minimum side effects. Therefore, there is an urgent need to efficiently and affordably enhance the quality of treatments for respiratory disease.

Nanoparticles (NPs) refer to particles ranging between 1 and 100 nm in size (5). Due to the increase in relative surface area and quantum effects, nanomaterials have special physical and chemical properties. The nanodrug delivery system is the application of nanotechnology in the pharmaceutical field, and has shown development prospects in targeted diagnosis and treatment, delaying drug release, improving drug solubility and availability, reducing drug side effects and overcoming barriers of the human body (6). The large contact surface area of airways is constructed by alveolar cells and goblet cells, whereas the main bronchiole cells consist of bronchial epithelial cells and Clara cells (mucus-producing cells). Alveolar type I epithelial cells and endothelial cells share a basement membrane. The air-blood barrier inside the lungs, with a size of 0.1–0.2 µm, is comprised of epithelial and endothelial tissue sharing the basement membrane (7). The thin barrier and high permeability of this membrane make the lungs an optimal site for systemic and local delivery of drugs. Furthermore, pulmonary delivery offers improved bioavailability, biocompatibility and distribution of drugs to lung sites (8). The development of nanotechnology brings a novel broad perspective for improving the effects of treatment and diagnosis of respiratory diseases.

However, the possible negative effects of NPs as drug carriers should also be considered. It is well known that the toxicity of inhaled NPs has a long history. For example, some NPs, similar to fine dusts and fibers in nature, may induce respiratory and cardiovascular diseases as environmental pollutants (9,10). Although these data cannot be directly transferred to inhaled therapeutic NPs, before practical application, different in vitro and in vivo methods should be used in preclinical research and clinical trials to systematically detect the interaction between nanomedicines and various components of the respiratory system. In this context, the present review summarizes the properties of NPs; discusses the research status and main points of different nanocarriers in drug delivery systems for respiratory diseases, such as lung cancer, asthma, chronic respiratory diseases, cystic fibrosis, tuberculosis and respiratory infection; and discusses the advantages and limitations of therapeutic nanomedicine in the field of respiratory diseases.

Application of NPs in respiratory systems

Characteristics of NPs for efficient respiratory disease treatment design

NPs can be inhaled, diffused into the respiratory tract and deposited in the alveoli, where they can approach and interact with the epithelial cells and pulmonary surfactant (PS) (11). The characteristics of NPs, including size, shape, surface charge and wettability, serve a critical role in understanding the interaction between NPs and organisms (12). Appropriate properties can not only facilitate their direct delivery to targeted tissues and cells, but also limit their adverse side effects by decreasing drug concentrations in other tissues of the body (13).

Size

Among the different characteristics of NPs, particle size is a remarkable characteristic. Inhaled NPs are deposited on the pulmonary airway mainly via diffusional displacement by the thermal motion between air molecules and the NPs (14). The nasopharyngeal and tracheobronchial deposition of NPs have been reported to be negatively correlated with their size (15). A previous animal study in pigs performed by Murgia et al (16) revealed that only extremely small carboxylated NPs (<100 nm) were able to penetrate into mucus. Compared with large NPs (>100 nm), NPs with smaller size (<30 nm) were more suitable at penetrating biological barriers, including the air-blood barriers.

After intranasal immunization of polystyrene particles (20–1,000 nm), Blank et al (17) compared the size-dependent cellular absorption of these particles on antigen-presenting cells at respiratory sites in BALB/c mice. In the trachea and lung parenchyma, most of the smaller particles (20 and 50 nm) were absorbed by dendritic cells (DCs) compared with larger ones (1,000 nm), and the smaller ones were also observed in lung-associated lymph nodes. However, the uptake of cells by alveolar macrophages did not depend on the size of particles and larger particles could easily be phagocytized by lung macrophages. In addition, Ghaffar et al (18) demonstrated that the cellular uptake of smaller polystyrene particles (50 nm) by DCs was better than that of larger ones (500 nm) through intratracheal administration in mice, which resulted in more active lymphatic transport, improved maturation of DCs and production of cytokines. Furthermore, NPs with smaller particle size had a higher surface/volume ratio and were more likely to aggregate than larger ones. The aggregation of NPs not only affects their deposition in the lung and association with PS, but also changes the clearance mechanisms of NPs.

Shape

Shape is another important property that affects the interaction of NPs and cells, and the fate of NPs in the human body. Previous studies reported that spherical particles were more conducive to cellular internalization than shaped particles (19,20). However, Gratton et al (21) reported that rod-shaped, cationic, cross-linked NPs modified with polyethylene glycol (PEG) were internalized at a higher rate than particles of other shapes (spheres, cylinders and cubes). In contrast, it was reported that gold nanospheres had better blood circulation and higher overall tumor accumulation rate than other shapes (nanodiscs, nanorods and nanocages) (22). Moreover, shape may also be involved in regulating the transport of NPs on the PS monolayer. A previous study revealed that NPs smaller than the thickness of the PS layer tended to be submerged and hardly transported through the PS layer, whereas NPs larger than the thickness of the lung surfactant layer tended to be encapsulated by the PS layer (23). The results of coarse-grained molecular dynamics simulations suggested that rod-like NPs exhibited stronger penetration and less adverse effects on the dipalmitoylphosphatidylcholine (DPPC) monolayer compared with other shapes (24,25).

Surface charge

The surface charge of NPs determines the interaction between NPs and anionic cell membranes. Since positively charged NPs have the potential to induce damage to cell membranes and organelles, nanocarriers with stronger positive charges may not be an ideal choice for drug delivery systems (26). For example, Mousseau and Berret (27) observed a stronger interaction between positively charged NPs and PS compared with negatively charged NPs in vitro, which resulted in the aggregation of NPs and reduced their transfer efficiency.

However, in some specific fields, positively charged NPs have shown obvious advantages. A previous study in mice revealed that cationic NPs were mostly associated with DCs, whereas anionic particles were mainly internalized by alveolar macrophages (28). It is possible that the different cellular uptake mechanisms of cationic and anionic NPs might lead to different immune effects following pulmonary administration. Through animal experiments in mice, Tada et al (29) demonstrated that cationic liposomes induced higher antigen-specific antibody levels compared with anionic and neutral liposomes. Similarly, Fromen et al (30) reported that cationic NPs (~37 mV) conjugated with model antigen ovalbumin induced a higher level of antigen-specific IgG and local mucosal IgA in the plasma and bronchoalveolar lavage fluid (BALF) of mice after pulmonary immunization. In addition, cationic NPs could produce a large number of CD4+ T cells and a high level of chemokines or cytokines, whereas negatively charged counterparts (~-38 mV) could not induce the same level of immunity response. Notably, positively charged cationic nanocarriers are widely used in drug delivery systems for gene therapy (31).

Wettability

The differences in wettability of NPs are often associated with different treatment outcomes. Hydrophobic NPs are deemed to interact more closely with the negatively charged cell membrane when compared with hydrophilic NPs. However, the hydrophobicity of NPs can mimic a danger signal to stimulate the immune system (32). Nanogels comprised of hydrophilic polymers [poly (sulfobetaine), PEG or poly (carboxybetaine)] were found to be effective in inhibiting immune responses after pulmonary administration, via a reduction in the degree of infiltration of inflammatory cells in the BALF and the expression of cytokines (TNF-α and IL-6) in a lipopolysaccharide (LPS)-induced inflammatory mouse model (33). Guzmán et al (34) reported that NPs incorporated into Langmuir monolayers of DPPC could alter the interfacial organization of the molecules. When compared with hydrophobic carbon black, hydrophilic silica had stronger influence on DPPC phase behavior.

Classification and advantages of NPs as drug delivery systems for treating respiratory diseases

NPs have great potential to be applied as pulmonary delivery systems for the diagnosis and treatment of local respiratory diseases and may even exert systemic actions, such as blood coagulation (35) and cardiovascular effects (36). Delivery of therapeutic drugs to target sites may be important for efficient treatment of tuberculosis, lung cancer, cystic fibrosis, and other acute and chronic respiratory infections. As early as 1654, an inhalation device was first designed by Bennet to produce opium vapor for cough treatment (37). The Food and Drug Administration (FDA) has already approved several materials as drug delivery systems, including liposomal, polymeric, dendrimers, inorganic and protein materials. More complex materials comprised of micelles, proteins, and a variety of inorganic or metallic materials are currently in development for assessment in clinical trials (38).

Liposomes

The application of liposomes as a drug delivery system has a significant impact on pharmacology. Liposomes are a class of lipid vesicles composed mainly of phospholipids and cholesterol. This colloidal form is comprised of a self-assembled lipid bilayer with amphiphilic domains, including an inner aqueous core and an outer shell of the lipid bilayer (39). According to the physical properties of the drug, liposomes can encapsulate drugs with different solubility in the water core or bilayer interface of the phospholipid bilayer, and enhance the solubility of the loaded drug through the co-solubility effect (37). The lipid bilayer of liposomes is similar to the composition of cell membranes in the body, which can not only reduce its toxicity, but can also enable liposomes to cross numerous biological barriers (40), thereby increasing absorption and ultimately enhancing the therapeutic effect of loaded drugs. In addition, liposomes can be used as carriers for other functional groups, such as targeted ligands, to create new properties for the delivery of therapeutic drugs (41). Furthermore, a previous study by Garbuzenko et al (42) tested a variety of nanomaterials to select the best inhalation carrier for anticancer drugs, and revealed that compared with non-lipid-based carriers, lipid-based nanocarriers had advantages in terms of accumulation and retention time in the lungs. Based on these advantages, liposomes became the earliest nanocarriers approved by the FDA in 1995, including liposome formulations of doxorubicin (DOX; Doxil®) (43) and amphotericin B (44). In the past few decades, nanomedicine based on the liposome delivery system has generated the interest of scientists and clinicians in different fields of respiratory diseases (Table I). For example, in an orthotopic mouse model of human lung A549 non-small cell lung cancer (NSCLC) cells, Garbuzenko et al (45) compared the effects of intravenous and intratracheal administration of liposome-encapsulated DOX, antisense oligonucleotides and small interfering RNA (siRNA) on lung cancer, and demonstrated that compared with systemic administration by intravenous injection, intratracheal administration resulted in much higher peak concentrations and longer retention time of three drugs in the lungs, which indicated that local intratracheal administration was better than systemic administration of the same drug. Similarly, Koshkina et al (46) proved that the pulmonary delivery of paclitaxel (PTX) in liposome aerosol formulations was more efficient than intravenous injection in mice. In a carbamate-induced lung tumor mouse model, Fritz et al (47) showed that clodronate encapsulated with liposomes reduced the number of macrophages by 50% after 4–6 weeks of treatment and significantly weakened the proliferative ability of tumor cells. Besides, a phase I clinical trial carried out by Wittgen et al (48) explored the application of cisplatin liposomal formulation in lung cancer. Their results indicated that this drug delivery system could enhance the drug accumulation and reduce the systemic side effects.

Table I.

Brief application of liposomes in drug delivery systems for the treatment of respiratory diseases.

Table I.

Brief application of liposomes in drug delivery systems for the treatment of respiratory diseases.

Author, yearColloidal systemApplicationObject of the studyDrug CharacteristicsMethod of administrationKey findings(Refs.)
Fritz et al, 2014LiposomesLung cancerMiceClodronateNAIntravenous injectionReduced the number of macrophages and attenuated the proliferation ability of tumor cells(47)
Garbuzenko et al, 2009LiposomesLung cancerOrthotopic mice model of human lung A549 NSCLC cellsDOX/ASO/siRNADOX: 130±10 nm; −10±2 mV; ASO: 130±10 nm; −10±2 mV; siRNA: >500 nm; 4±2 mV Intratracheal/intravenous administrationExtended the retention time of the drug in the lung and enhanced the efficacy of the drug(45)
Koshkina et al, 2001LiposomesLung cancerMicePTX230±170 nmAerosol/intravenous administrationReduced number of visible tumor foci on the lung surfaces, prolonged survival and enhanced the efficacy of the drug(46)
Wittgen et al, 2007LiposomesLung cancerPatients with lung carcinomaCisplatinNAInhalationEnhanced drug accumulation and reduced the systemic side effects(48)
Olivier et al, 2017LiposomesNTM lung diseasePatients with persistently positive NTM cultureAmikacinNAInhalationPromoted the negative conversion of sputum and induced lower toxicity(49)
Zhang et al, 2018Liposomes diseaseNTM lungTHP-1 human peripheral blood monocytes/ratAmikacin221±98 nmNose-only inhalationEffectively entered bacterial biofilms, improved cellular uptake of amikacin in macrophages and inhibited the distribution of amikacin to other tissues(50)
Chen et al, 2012LiposomesAsthmaRatSBS33–58 nmIntratracheal administrationIncreased the concentration and retention time of SBS in the lungs and displayed a longer anti-asthmatic effect than free SBS(53)
Konduri et al, 2005LiposomesAsthmaMiceBudesonideNAInhalationImproved lung inflammation and reduced the toxicity of inhaled steroid asthma drugs(52)
Ng et al, 2018LiposomesAsthmaBCI-NS1.1 cell lineCurcumin271.3±3.06 nm; PdI=0.512±0.003; −61.0±0.68 mVNAAnti-inflammatory effects on lipopolysaccharide-induced airway inflammation(54)
Komalla et al, 2020LiposomesChronic respiratory diseasesHuman epithelial virus-transformed cell line BEAS-2B/miceNA173.23±1.62 nm; PdI=0.13±0.01; −0.82±0.24 mVInjectionSuppressed pro-inflammatory cytokines, decreased eosinophil number and reduced airway hyperresponsiveness(55)
Okusanya et al, 2009LiposomesCystic fibrosisPatients with cystic fibrosis with chronic pseudomonal infectionAmikacinNAInhalationImproved lung function and reduced bacterial density in the lung(51)
Nahar et al, 2014Starch-coated magnetic liposomesPulmonary arterial hypertensionPASMCs/ratFasudil130.4±3.98 nm; PdI=0.05±0.04; −9.58±1.74 mVIntratracheal administrationEnhanced the absorption of PASMCs to liposomes; reduced the proliferation of PASMCs, and the optimized liposomes appeared to be safe; extended the half-life of magnetic liposomes(56)
Wijagkanalan et al, 2008Mannosylated liposomesAlveolar macrophage-related respiratory diseasesAlveolar macrophages and alveolar epithelial type II cells/ratNA90–125 nm; PdI=0.14–0.35; −9–15 mVIntratracheal administrationEnhanced the uptake of alveolar macrophages compared with bare-liposomes(57)
Cryan et al, 2006Octaarginine-coated liposomesRespiratory diseases in lungCalu-3 cellsDextrans213.4±44.3 nmNAIncreased intracellular targeting, improved cellular uptake and reduced drug toxicity(58)

[i] ASO, antisense oligonucleotides; DOX, doxorubicin; NA, not available; NSCLC, non-small cell lung cancer; NTM, nontuberculous mycobacterial; PASMCs, pulmonary arterial smooth muscle cells; PdI, polydispersity index; PTX, paclitaxel; siRNA, small interfering RNA; SBS, salbutamol sulfate; SLN, solid lipid nanocarrier.

Several types of antimicrobials for the treatment of airway infections can also be delivered by liposomes. A double-blind, randomized, phase II clinical trial conducted by Olivier et al (49) applied inhaled liposomal amikacin in the treatment of nontuberculous mycobacterial lung disease; the results revealed that the drug promoted the negative conversion of sputum and induced lower toxicity compared with parenteral amikacin. Similarly, Zhang et al (50) explored the efficacy of liposomal amikacin in nontuberculous mycobacteria both in vivo (rat model) and in vitro, and their results showed that this nanodrug could effectively enter bacterial biofilms, improve cellular uptake of amikacin in macrophages and inhibit the distribution of amikacin to other tissues. Additionally, through a randomized controlled clinical trial, Okusanya et al (51) reported that liposomal amikacin improved lung function and reduced bacterial density in the lung of patients with chronic Pseudomonas infection.

Furthermore, liposomal drug delivery systems have been applied to inflammatory respiratory diseases. For example, Konduri et al (52) investigated the effect of liposomal budesonide on the treatment of asthma using a mouse model; the results revealed that this drug delivery system significantly improved lung inflammation and reduced the toxicity of inhaled steroid asthma drugs. Chen et al (53) designed liposomes to encapsulate salbutamol sulfate (SBS) in aerosol form and demonstrated that the complexes exhibited longer anti-asthmatic effects than free SBS. Furthermore, Ng et al (54) demonstrated that liposome-encapsulated curcumin exerted an inhibitory effect on LPS-induced airway inflammation via cell experiments in vitro. A recent study performed by Komalla et al (55) through cell and animal experiments found that empty liposomes (UTS-001) could be used to treat chronic respiratory diseases by inhibiting epithelial pro-inflammatory cytokines and reducing the number of eosinophils.

In addition to simple liposomal nanocarriers, numerous groups have successfully modified liposomes to improve their properties, including cellular uptake, stability and targeting. For example, Nahar et al (56) demonstrated that starch-coated magnetic liposomes could be used as an inhalable carrier to deliver fasudil to treat pulmonary hypertension through in vitro cell experiments and rat animal models. In addition, a previous study reported that the cellular uptake of mannosylated liposomes by alveolar macrophages was higher compared with that of non-modified ones after intratracheal administration both in vivo and in vitro (57). Through in vitro experiments, Cryan et al (58) showed that octaarginine-coated liposomes could increase intracellular targeting, improve cellular uptake and reduce drug toxicity in airway cells.

Solid lipid nanocarriers (SLNs)

SLNs are another type of lipid-based material, which are slightly different from liposomes in structure. SLNs may represent an alternative to traditional carrier systems due to their numerous advantages, including targeted drug delivery, controlled-release, high drug stability, high drug loading, encapsulation of hydrophilic and lipophilic drugs, low carrier toxicity, avoidance of organic solvents in production (such as high-pressure homogenization) and large-scale industrial production (59,60). Nassimi et al (61) evaluated the toxicity of SLNs as potential nanocarriers in in vitro and ex vivo lung models, and their results showed that SLN20 (20% phospholipids included in particle lipid matrix) could be used as a safe pulmonary drug delivery system.

In the past few years, as a colloidal drug delivery system, SLNs have promoted the development of the treatment of respiratory diseases (Table II). For example, Videira et al (62) investigated the antitumor effect of PTX-loaded SLNs on lung cancer, and revealed that the pulmonary delivered nanodrug efficiently reduced cellular toxicity and suppressed the progression of lung metastases in vitro and in vivo. In addition, Castellani et al (63) designed SLN-encapsulated grape seed-derived proanthocyanidins to treat chronic respiratory diseases, and confirmed that the complex could inhibit oxidative stress and inflammation in airway epithelial cells through cell experiments and mouse models.

Table II.

Brief application of SLNs in drug delivery systems for the treatment of respiratory diseases.

Table II.

Brief application of SLNs in drug delivery systems for the treatment of respiratory diseases.

Author, yearColloidal systemApplicationObject of the studyDrug CharacteristicsMethod of administrationKey findings(Refs.)
Videira et al, 2012SLNLung cancerMXT-B2 tumor cells/ratPTX92.6±6.0 nm; PdI=0.106±0.030; −15.7±0.6 mVInhalationSuppressed the progression of lung metastases(62)
Castellani et al, 2018SLNChronic respiratory diseasesAirway epithelial cell line H441/miceGrape seed-derived proanthocyanidins243±24 nm; PdI=0.41–0.51; −14.5±1.0 mVSpray instillationDampened oxidative stress and inflammation of airway epithelial cells(63)
Maretti et al, 2019SLN modified with mannose derivativesTuberculosisJ774 murine macrophage cell lineRifampicin400±20 nm; PdI=0.43±0.09; −35.33±0.29 mVNAImproved the absorption capacity of macrophages for the encapsulated drugs(65)
Nimje et al, 2009Mannosylated SLNTuberculosisJ774 murine macrophage cell line/ratRifampicin389±2.3 nm; PdI=0.357; −11.7±0.8 mVIntravenous injectionTargeted delivery of rifampicin, increased the therapeutic effect and reduced the side effects of the drug(66)

[i] NA, not available; PdI, polydispersity index; PTX, paclitaxel; SLN, solid lipid nanocarrier.

Moreover, SLNs can be modified to improve their targeting ability, thereby increasing the accumulation of drugs in targeted sites and reducing systemic toxicity. For the treatment of tuberculosis (64), Maretti et al (65) used SLN modified with mannose derivatives as nanocarriers of rifampicin, and tested the anti-tuberculosis ability of the novel drug in J774 murine macrophage cells. Their results showed that SLNs modified with the surfactants (mannose derivatives) could improve the absorption capacity of macrophages for their encapsulated drugs. A similar study was carried out by Nimje et al (66), which revealed that mannose-conjugated SLNs could deliver rifampicin more effectively than bare-SLNs, which increased the therapeutic effect and reduced the side effects of the drug.

Polymeric nanocarriers

A polymer is a type of large molecule chemical compound, which is composed of numerous smaller homogeneous molecules. Polymers can be natural (albumin, gelatin, alginate, collagen, cyclodextrin and chitosan) or synthetic [poly-lactic-co-glycolic acid (PLGA), polyacrylates, polyethyleneimine (PEI), PEG, polyanhydrides and poly-l-lysine] (67). Polymers with particular biological and physicochemical advantages are used for the formulation of nanocarriers to deliver therapeutic and diagnostic drugs. Polymer-based nanocarriers can deliver different agents, which are inserted into the surface of the polymer or dispersed in the polymeric matrix (68).

Aliphatic polyesters are the most commonly used polymer nanocarriers due to their excellent biocompatibility, controlled-release properties and sufficient biodegradability under physiological conditions (69). Various forms of polymeric nanocarriers have been used in preclinical experiments for the treatment of respiratory diseases (Table III). Among them, PLGA has been approved by the FDA for use as a drug delivery system. Türeli et al (70) prepared PLGA NPs loaded with ciprofloxacin and tested their therapeutic effects on bacterial infection-induced cystic fibrosis in Calu-3 and CFBE41o cells. The results showed that the nanomedicine had high drug loading and permeability, which could not only achieve high and persistent local drug concentration, but also decrease the drug dose to reduce side effects. Through in vitro and in vivo experiments, Kim et al (71) revealed that the sustained-release inhalation system assembled by DOX and PLGA had high encapsulation efficiency and good nebulization ability, could effectively inhibit the growth of tumor cells and was suitable for the treatment of metastatic lung cancer. A previous study in guinea pigs performed by Pandey et al (72) showed that the encapsulation of PLGA prolonged the elimination half-life and average residence time of three anti-tuberculosis drugs, thereby increasing the bioavailability and reducing the frequency of administration. Besides, Tomoda et al (73) demonstrated that PLGA NPs loaded with TAS-103 enhanced drug toxicity to A549 lung cancer cells and increased the drug concentration in the lungs of rats. For gene transfer applications in the treatment of respiratory disease, PLGA is also considered a good choice. An in vitro study by Zou et al (74) reported that negatively charged bioadhesive PLGA NPs could be used as an efficient non-viral vector for gene therapy in the treatment of lung cancer.

Table III.

Brief application of polymeric nanocarriers in drug delivery systems for the treatment of respiratory diseases.

Table III.

Brief application of polymeric nanocarriers in drug delivery systems for the treatment of respiratory diseases.

Author, yearColloidal systemApplicationObject of the studyDrug CharacteristicsMethod of administrationKey findings(Refs.)
Türeli et al, 2017PLGACystic fibrosisCalu-3 cells and CF bronchial epithelial cells (CFBE41o)Ciprofloxacin190.4±28.6 nm; PdI=0.089NAHigh drug loading and permeability, achieved high and sustained local drug concentration, reduced drug dosage and side effects(70)
Kim et al, 2012PLGAMetastatic lung cancerB16F10 melanoma cells/miceDOX14.1±2.1 µmInhalationHigh encapsulation efficiency and good nebulization ability, inhibited the growth of tumor cells(71)
Pandey et al, 2003PLGATuberculosisGuinea pigsRifampicin, isoniazid and pyrazinamide1.88±0.11 µmInhalationProlonged the elimination half-life and average residence time, improved the bioavailability and reduced the frequency of administration(72)
Tomoda et al, 2009PLGALung cancerA549 NSCLC cells/ratTAS-103241.2 nmInhalationEnhanced the toxicity to cancer cells and increased the drug concentration in the lungs(73)
Zou et al, 2009Bioadhesive PLGALung cancerA549 NSCLC cellsDNA126±5 nm; PdI=0.105±0.004; −27.83±3.27 mVNAEfficient non-viral vector for gene therapy(74)
Melguizo et al, 2015PBCALung cancerA549 and LL/2 lung cancer cell lines/miceDOX~75 nm; PdI=0.064; −25 mVInjectionEnhanced the cellular uptake, improved the drug antitumor activity, and increased the survival rate of mice(79)
Howard et al, 2006ChitosanSystemic and mucosal diseaseNIH 3T3 cells, H1299 human lung carcinoma cells and murine peritoneal macrophages/micesiRNA176.4–319.4 nm; PdI=0.20–0.51; 18.8–31.1 mVNasal administrationHigh transfection efficiency(31)
Germershaus et al, 2008Trimethyl chitosan/PEGylated trimethyl chitosanLung cancerA549 NSCLC cellsDNA334/142 nm; 6.47±0.27/0.01± 0.02 mVNAImproved cellular uptake and transfection efficiency(84)

[i] DOX, doxorubicin; NA, not available; NSCLC, non-small cell lung cancer; PBCA, polybutylcyanoacrylate; PdI, polydispersity index; PEG, polyethylene glycol; PLGA, poly-lactic-co-glycolic acid; siRNA, small interfering RNA.

Although PLGA has numerous advantages, it also has several limitations as a pulmonary delivery system. For example, the slow degradation rate of PLGA may result in excessive accumulation of PLGA in the respiratory tract (75). The degradation rate of the drug depends on the composition and molecular weight of polymeric nanocarriers, and the release period varies from several weeks to several months. Moreover, continuous hydrolysis of PLGA may generate an acidic core within the drug delivery device, which lowers the pH of the microenvironment and damages pH-sensitive encapsulated proteins, such as peptides and proteins (76). Additionally, due to the extreme hydrophobicity of PLGA, the encapsulation efficiency of low-molecular-weight hydrophilic drugs may be undesirably low and the hydrophobic surface may cause rapid protein adsorption, leading to the clearance of PLGA by alveolar phagocytes (77).

Solutions have been applied to optimize the design and overcome the problems of PLGA delivery devices. To overcome the accumulation of PLGA carriers, several polymers with faster degradation rates have been synthesized for drug delivery. Polybutylcyanoacrylate (PBCA) is a noncytotoxic and biodegradable NP that can be used for pulmonary administration; in addition, it is pH-sensitive and can be catalyzed by enzymes (78). Compared with free DOX, in vitro and in vivo studies by Melguizo et al (79) revealed that PBCA-encapsulated DOX significantly enhanced the drug uptake of lung cancer cells, improved the antitumor activity of drugs and increased the survival rate of mice. Another approach is to use hydrophilic polymers to reduce accumulation of polymerics in the body. For stabilization of proteins within PLGA, pH-sensitive drugs could be pre-mixed with zinc or antacid excipients could be added to buffer the vehicle microclimate (80).

Polymers are important delivery carriers for nano-gene drugs in gene therapy of respiratory diseases; as well as the aforementioned modified PLGA, PEI is also a promising polymer for delivering recombinant genes to mammalian cells due to its high transfection efficiency, biocompatibility and biodegradability (81,82). This polymer with positively charged groups is able to closely interact with negatively charged genes. Similarly, chitosan is another nanocarrier commonly used in gene therapy for drug delivery. It is positively charged under neutral and acidic pH conditions and is a biodegradable polymer synthesized through the deacetylation of chitin (83). In 2006, Howard et al (31) synthesized a NP system composed of siRNA and chitosan, and revealed that the complex had high transfection efficiency in vitro and in vivo, and it was considered a potential genetic medicine for mucosal disease. Beyond that, in order to improve the transfection efficiency of gene drugs, a variety of improved polymer carriers based on chitosan have been proposed. Germershaus et al (84) compared the performance of chitosan, trimethyl chitosan and PEGylated trimethyl chitosan as DNA carriers, and the results showed that compared with unmodified chitosan, both modified forms of chitosan exhibited improved cellular uptake and transfection efficiency. In addition, the quaternization of chitosan could effectively inhibit the pH dependence and aggregation of DNA complexes, and PEGylation could further improve the stability of colloids.

Dendrimers

A dendrimer is a type of polymer nanostructure that is different from traditional polymers. It has a highly branched monodisperse three-dimensional structure. The multiple functional groups distributed on the surface of a dendrimer increase its versatility and biocompatibility as a nanocarrier (85). In addition, their external functional groups can be modified by other charged compounds through electrostatic interaction, and dendrimers with both hydrophobic and hydrophilic group structures can deliver a large number of drug molecules with different solubility (86). During the delivery process, the loaded drug can be combined with the functional groups on the surface of the dendrimer, or it can be wrapped in the molecular cavity of the dendrimer (87).

Based on these advantages, dendrimers have attracted the attention of researchers in the field of drug delivery due to their unique structural and physicochemical properties (Table IV). For example, a previous in vitro study by Bellini et al (88) reported that fourth-generation polyamidoamide (G4-PAMAM) dendrimers containing the anti-tuberculosis drug rifampicin had high stability under physiological pH conditions, and the PAMAM dendrimers could be used as a pH switch to rapidly release drugs in the acidic area of macrophages. Similarly, Rajabnezhad et al (89) synthesized different generations of PAMAM dendrimers encapsulating rifampicin to produce inhalable nanodrugs for the treatment of tuberculosis. Their results showed that compared with intravenous administration, third generation PAMAM dendrimers achieved sustained drug release, and significantly improved drug absorption and bioavailability. For the application of dendrimers in lung cancer, Conti et al (90) used an amine-terminated G4-PAMAM dendrimer (G4NH2) loaded with siRNA to decrease the expression of enhanced green fluorescent protein in a model of A549 cells, indicating that G4NH2-siRNA could not only target alveolar epithelial cells, but could also effectively silence the target gene. Furthermore, Zhong et al (91) explored the effect of a complex composed of DOX and carboxyl-terminated G4-PAMAM dendrimers in lung metastasis, and confirmed that compared with intravenous administration, the complex prolonged the accumulation and retention time of the drug in the lung and reduced systemic toxicity, thereby enhancing the efficacy of DOX on melanoma lung metastasis and increasing the survival rate of mice. In addition, dendrimers have been used to treat inflammatory respiratory diseases related to asthma. Through a mouse lung inflammation model, Inapagolla et al (92) revealed that G4-PAMAM conjugated with methylprednisolone (MP) might enhance the ability of MP to inhibit inflammation by prolonging the residence time of the drug within the lung.

Table IV.

Brief application of dendrimers in drug delivery systems for the treatment of respiratory diseases.

Table IV.

Brief application of dendrimers in drug delivery systems for the treatment of respiratory diseases.

AuthorColloidal systemApplicationObject of the studyDrug CharacteristicsMethod of administrationKey findings(Refs.)
Bellini et al, 2015G4-PAMAMTuberculosisNARifampicin2.03±0.02 nmNAHigh stability and rapid pH-dependent release(88)
Rajabnezhad et al, 2016G3-PAMAMTuberculosisRatRifampicin6.21±0.03 nmIntratracheal administrationSustained release, and improved drug absorption and bioavailability(89)
Conti et al, 2014G4-PAMAMLung cancerA549 NSCLC cellssiRNA254±52 nm; PdI=0.5±0.1; 33±3 mVNATargeted lung alveolar epithelial A549 cells and silenced target genes(90)
Zhong et al, 2016G4-PAMAMLung cancerMiceDOX4.7–9.7 nm; 13.8±7.0 mVIntratracheal administrationProlonged the accumulation and retention time, reduced the systemic toxicity and enhanced the efficacy of the drug(91)
Inapagolla et al, 2010G4-PAMAMAsthmaMice MethylprednisoloneNAInhalationProlonged the drug residence time, enhanced the ability of the drug to inhibit inflammation(92)

[i] DOX, doxorubicin; NA, not available; NSCLC, non-small cell lung cancer; PAMAM, polyamidoamide; PdI, polydispersity index; siRNA, small interfering RNA.

Inorganic nanocarriers

There are several types of inorganic substances that have been used to synthesize NPs, including gold, silica, iron oxide, alumina and titanium dioxide. Inorganic NP carriers possess several advantages, such as high biocompatibility, high delivery efficiency, high stability, magnetic properties and resistance to microbial degradation (93). Several iron oxide NPs have been approved by the European Union. Based on the plasmonic and magnetic characteristics of inorganic materials, they can also be used for diagnosis of respiratory diseases, such as positron emission tomography, computed tomography and magnetic resonance imaging (94). The external magnetic field can not only direct these magnetic NPs to the targeted sites, but also increase the temperature of these NPs (95). High temperature can induce apoptosis of target cells, including infected cells and cancer cells (86,96).

In addition to high-temperature-based targeted drug control, gold NPs (AuNPs), as typical inorganic NPs, are often used as nanocarriers in drug delivery systems for the treatment of respiratory diseases (Table V). For example, a previous study conducted by Chen et al (97) demonstrated that methotrexate (MTX)-AuNPs were more cytotoxic to tumor cell lines than free MTX, and MTX could inhibit tumor growth only when under AuNP encapsulation both in vitro and in vivo. Similarly, Brown et al (98) confirmed that AuNPs increased the toxicity of the antitumor drug oxaliplatin to lung cancer cell lines. Apart from the application in lung cancer treatment, Codullo et al (99) investigated the role of AuNP-loaded imatinib in the treatment of lung fibrosis through cell experiments and mouse models, and the results showed that the complex could significantly improve the anti-fibrotic efficacy of imatinib, thereby inhibiting the proliferation of fibroblasts and macrophages.

Table V.

Brief application of inorganic nanocarriers in drug delivery systems for the treatment of respiratory diseases.

Table V.

Brief application of inorganic nanocarriers in drug delivery systems for the treatment of respiratory diseases.

AuthorColloidal systemApplicationObject of the studyDrug CharacteristicsMethod of administrationKey findings(Refs.)
Chen et al, 2007AuNPLung cancerCancer cell lines (LL2, ML-1, MBT-2, TSGH 8301, TCC-SUP, J82, PC-3, HeLa)/miceMTX14.3 nm; −7.3±2.5 mVIntraperitoneal administrationHigh cytotoxicity toward numerous tumor cell lines, suppressed growth tumor(97)
Brown et al, 2010AuNPLung cancerCancer cell lines (A549, HCT116, HCT15, HT29, RKO)Oxaliplatin176±25 nm; 14±7.0 mVNAImproved the toxicity of drugs to cancer cells(98)
Codullo et al, 2019AuNPLung fibrosis and alveolar macrophages/miceLung fibroblastsImatinib21.25±2.461 nm; PdI=0.255±0.023; −46.3±2.842 mVIntratracheal instillationIncreased drug efficacy, inhibited proliferation of fibroblasts and macrophages(99)
Omlor et al, 2017PEGylated AuNP/citrated AuNPAsthmaMiceNA6 nm; −43 mV/9 nm; −51 mVIntranasal administrationInhibited both inflammatory infiltrates and airway hyperreactivity(101)
Park et al, 2014P-PEG-AuNP25Lung cancerCancer cell lines (A549, HeLa)DOX25 nmNAEnhanced cell death induction activity of the drug(102)

[i] AuNP, gold nanoparticle; DOX, doxorubicin; NA, not available; MTX, methotrexate; PdI, polydispersity index; PEG, polyethylene glycol.

Despite these advantages, drug delivery systems using metal NPs as carriers still have some limitations. For example, when administered by intravenous injection, positively charged AuNPs are easily combined with negatively charged serum proteins in the blood and form aggregates (96). Based on this defect, previous studies have proposed an improved solution, that is, PEG modification of the surface to prevent the aggregation of AuNPs and thus improve their stability during storage (100). Omlor et al (101) modified AuNPs with PEG and citrate to reduce airway inflammation in a mouse model. Furthermore, an in vitro study performed by Park et al (102) combined cell-penetrating peptides with PEG-AuNPs to enhance the cell death-inducing activity of the anticancer drug DOX. In addition, the potential concentration-dependent cytotoxicity and low excretion of inorganic nanocarriers also limit their clinical application to a certain extent. Therefore, systemic absorption and subsequent adverse events must be fully considered when designing and examining nanomedicine.

Protein nanocarriers

Protein NPs include a large number of classes, such as endogenous protein carriers conjugated with drugs, engineered proteins and combined platforms that rely on protein or peptide motifs for targeting delivery (103). Protein NPs have many advantages, including high biocompatibility and solubility, biodegradability, modifiability, controlled-release properties and targeted drug delivery (104). At present, a large number of preclinical experiments based on protein nanocarriers have been reported in the field of respiratory diseases, particularly for respiratory infection (Table VI). Among them are virus-like particles (VLPs), which are a type of protein NP assembled from viral proteins with diverse structures and functions (Table VI). The proteins of VLPs can be commercially expressed in numerous systems, such as prokaryotic systems (Escherichia coli) and eukaryotic systems (yeast and insect cells) (105). VLPs could be used as nanocarriers for vaccines to treat infectious respiratory diseases, such as influenza virus and respiratory syncytial virus (RSV) infection (106). For example, Coleman et al (107) proposed to use purified coronavirus spike protein NPs to load Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV) protein antigens for vaccination. The results showed that this strategy could produce high titers of antibodies in mouse models. Additionally, Smith et al (108) and Lee et al (109) used baculovirus vector and VLPs to combine with RSV fusion proteins to construct protein nanocarrier vaccines, respectively. The results demonstrated that in cotton rat and mouse models RSV replication was effectively inhibited in the lungs following intramuscular injection of vaccines, and nanocarriers promoted the immunogenicity of vaccines when compared with traditional formalin-inactivated RSV. In addition to the application of vaccination strategies, protein nanocarriers have been used in other respiratory diseases. A previous in vitro study confirmed that the encapsulation of apigenin with bovine serum albumin could inhibit lung injury induced by immune responses by enhancing antioxidant activity (110).

Table VI.

Brief application of protein nanocarriers in drug delivery systems for the treatment of respiratory diseases.

Table VI.

Brief application of protein nanocarriers in drug delivery systems for the treatment of respiratory diseases.

AuthorColloidal systemApplicationObject of the studyDrug CharacteristicsMethod of administrationKey findings(Refs.)
Coleman et al, 2014Purified coronavirus spike proteinVaccination strategiesMiceMERS-CoV and SARS-CoV protein antigens~25 nmIntramuscular injectionProduced high titer antibodies(107)
Smith et al, 2012Baculovirus vectorVaccination strategiesCotton ratRSV fusion proteins40 nmIntramuscular injectionInduced neutralizing serum antibodies and inhibited virus replication(108)
Lee et al, 2017VLPVaccination strategiesMiceRSV fusion proteins60–120 nmIntramuscular injectionInduced distinct innate and adaptive cellular subsets(109)
Pápay et al, 2017Bovine serum albuminPulmonary inflammationFranz cell apparatusApigenin376±7.824 nm; PdI=0.285±0.01; −19.20±0.818 mVNAEffective against oxidative stress-induced lung injury(110)

[i] MERS-CoV, Middle East respiratory syndrome coronavirus; NA, not available; PdI, polydispersity index; RSV, respiratory syncytial virus; SARS-CoV, severe acute respiratory syndrome coronavirus; VLP, virus-like particle.

The advantages and limitations of therapeutic nanomedicine in respiratory diseases

Inhaled administration is a non-invasive drug delivery route. The drug is delivered through the cavity of the respiratory tract and the mucous membrane to achieve local or systemic drug delivery. The special physiological structure of the lung determines the characteristics and advantages of inhaled administration. Firstly, pulmonary inhalation can achieve effective lung-targeted medication and maintain the biological activity of the drug, which is suitable for the treatment of common respiratory diseases, including asthma, emphysema and chronic bronchitis (111). Secondly, in contrast to other routes of administration, such as oral and intramuscular injection, pulmonary inhalation takes effect rapidly (112). Thirdly, pulmonary inhalation can avoid hepatic first-pass metabolism, decrease the dosage of administration and reduce systemic side effects (113).

Based on the basic advantages of pulmonary inhalation, the application of nanotechnology in drug delivery systems has further improved the efficacy of inhalation therapy for different respiratory diseases. In general, nanocarriers enhance cellular uptake and achieve therapeutic effects in the lungs with lower drug doses (70), enhance the solubility of drugs, particularly the delivery of hydrophobic molecules (37,86), enhance the stability of drugs under physiological conditions (88), achieve controlled-release to prevent the rapid elimination of drugs (72,91,92) and result in targeted drug delivery (57,66,90).

Although nanocarriers have promoted the development of drugs related to respiratory diseases, the potential toxicity of NPs to the lung microenvironment or systemic toxicity is also the focus of current nanomedicine research. It has been reported that the size, surface charge, polarity and degradability of NPs are typical characteristics related to toxicity (114). Previous studies have demonstrated that inhalation of nanomaterials <100 nm is usually related to chronic toxicity (115,116). Therefore, in terms of particle size, the drug development process needs to fully balance the efficacy and toxicity of the nanodrug. However, a previous study evaluated the effects of particles with different sizes (50–150 nm) and different materials (PEG-ylated lipid particles, polyvinyl acetate and polystyrene) on mice, and found that acute respiratory toxicity was independent of particle size and only hydrophobic materials caused inflammation (117). In addition, Dailey et al (118) compared non-biodegradable polymers and biodegradable polymers of the same size, and confirmed that NPs derived from biodegradable polymers produced less toxicity and inflammatory responses. Furthermore, the application of nanocarriers in pharmaceutical preparations may change the distribution behavior of the original drugs in the body, which may cause new unpredictable adverse reactions.

Briefly, in the process of developing nanomedicine for the treatment of respiratory diseases, it is necessary to systematically explore the interaction between the nanomedicine and the respiratory system, including in vitro and in vivo detection methods to measure the genotoxicity, cytotoxicity and tissue toxicity of the drug (119), in order to thoroughly examine the safety, tolerability and therapeutic effect of NPs in treatment. Although some preclinical studies have shown promising application prospects, the current clinical trials of nanomedicine related to respiratory diseases remain limited, and the clinically known applications of nanocarriers are liposomes (48,49) in nontuberculous mycobacterial lung disease and lung cancer, and PLGA in pulmonary arterial hypertension (120).

Conclusions

Nanotechnology has become an important tool to overcome the defects of drugs, and to enable them to target specific cells or tissues passively or actively. The present review summarized the applications and advantages of NPs as drug delivery vehicles in respiratory diseases, such as lung cancer, asthma, chronic respiratory diseases, cystic fibrosis, tuberculosis and respiratory infection. The combination of nanotechnology has further promoted the development of drugs for respiratory diseases based on the benefits of inhaled administration. However, although preclinical studies have shown broad development prospects, most relevant studies are still in the early stage of experimentation, and their clinical effects need to be further verified. Future studies should focus on the performance modification, molecular mechanism and potential toxicity of therapeutic nanomedicine in the process of treatment.

Acknowledgements

Not applicable.

Funding

No funding was received.

Availability of data and materials

Not applicable.

Authors' contributions

MXL wrote and revised the manuscript. SH contributed to the conception and design of the work. QYS contributed to the drafting of the article and literature search. MXL and QYS confirmed the authenticity of all the raw data. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Glossary

Abbreviations

Abbreviations:

ASO

antisense oligonucleotides

AuNPs

gold nanoparticles

DCs

dendritic cells

DOX

doxorubicin

DPPC

dipalmitoylphosphatidylcholine

FDA

Food and Drug Administration

LPS

lipopolysaccharide

MERS-CoV

Middle East respiratory syndrome coronavirus

MP

methylprednisolone

NPs

nanoparticles

NSCLC

non-small cell lung cancer

PAMAM

polyamidoamide

PBCA

polybutylcyanoacrylate

PEG

polyethylene glycol

PEI

polyethyleneimine

PLGA

poly-lactic-co-glycolic acid

PS

pulmonary surfactant

PTX

paclitaxel

SARS-CoV

severe acute respiratory syndrome coronavirus

SBS

salbutamol sulfate

siRNA

small interfering RNA

SLN

solid lipid nanocarriers

RSV

respiratory syncytial virus

VLPs

virus-like particles

References

1 

D'Amato G and Cecchi L: Effects of climate change on environmental factors in respiratory allergic diseases. Clin Exp Allergy. 38:1264–1274. 2008. View Article : Google Scholar : PubMed/NCBI

2 

Ferkol T and Schraufnagel D: The global burden of respiratory disease. Ann Am Thorac Soc. 11:404–406. 2014. View Article : Google Scholar : PubMed/NCBI

3 

Newman SP: Delivering drugs to the lungs: The history of repurposing in the treatment of respiratory diseases. Adv Drug Deliv Rev. 133:5–18. 2018. View Article : Google Scholar : PubMed/NCBI

4 

Chang LH and Rivera MP: Respiratory diseases: Meeting the challenges of screening, prevention, and treatment. N C Med J. 74:385–392. 2013.PubMed/NCBI

5 

Jeong J, Lee S, Kim SH, Han Y, Lee DK, Yang JY, Jeong J, Roh C, Huh YS and Cho WS: Evaluation of the dose metric for acute lung inflammogenicity of fast-dissolving metal oxide nanoparticles. Nanotoxicology. 10:1448–1457. 2016. View Article : Google Scholar : PubMed/NCBI

6 

Pison U, Welte T, Giersig M and Groneberg DA: Nanomedicine for respiratory diseases. Eur J Pharmacol. 533:341–350. 2006. View Article : Google Scholar : PubMed/NCBI

7 

Fröhlich E and Salar-Behzadi S: Toxicological assessment of inhaled nanoparticles: Role of in vivo, ex vivo, in vitro, and in silico studies. Int J Mol Sci. 15:4795–4822. 2014. View Article : Google Scholar : PubMed/NCBI

8 

Sung JC, Pulliam BL and Edwards DA: Nanoparticles for drug delivery to the lungs. Trends Biotechnol. 25:563–570. 2007. View Article : Google Scholar : PubMed/NCBI

9 

Bakand S, Hayes A and Dechsakulthorn F: Nanoparticles: A review of particle toxicology following inhalation exposure. Inhal Toxicol. 24:125–135. 2012. View Article : Google Scholar : PubMed/NCBI

10 

Donaldson K, Tran L, Jimenez LA, Duffin R, Newby DE, Mills N, MacNee W and Stone V: Combustion-derived nanoparticles: A review of their toxicology following inhalation exposure. Part Fibre Toxicol. 2:102005. View Article : Google Scholar : PubMed/NCBI

11 

Xu Y, Li S, Luo Z, Ren H, Zhang X, Huang F, Zuo YY and Yue T: Role of lipid coating in the transport of nanodroplets across the pulmonary surfactant layer revealed by molecular dynamics simulations. Langmuir. 34:9054–9063. 2018. View Article : Google Scholar : PubMed/NCBI

12 

Auria-Soro C, Nesma T, Juanes-Velasco P, Landeira-Viñuela A, Fidalgo-Gomez H, Acebes-Fernandez V, Gongora R, Parra MJA, Manzano-Roman R and Fuentes M: Interactions of nanoparticles and biosystems: Microenvironment of nanoparticles and biomolecules in nanomedicine. Nanomaterials (Basel). 9:13652019. View Article : Google Scholar

13 

Senapati S, Mahanta AK, Kumar S and Maiti P: Controlled drug delivery vehicles for cancer treatment and their performance. Signal Transduct Target Ther. 3:72018. View Article : Google Scholar : PubMed/NCBI

14 

Poh TY, Mohamed Ali NAB, Aogáin MM, Kathawala MH, Setyawati MI, Ng KW and Chotirmall SH: Inhaled nanomaterials and the respiratory microbiome: Clinical, immunological and toxicological perspectives. Part Fibre Toxicol. 15:462018. View Article : Google Scholar : PubMed/NCBI

15 

Oberdorster G, Elder A and Rinderknecht A: Nanoparticles and the brain: Cause for concern? J Nanosci Nanotechnol. 9:4996–5007. 2009. View Article : Google Scholar : PubMed/NCBI

16 

Murgia X, Pawelzyk P, Schaefer UF, Wagner C, Willenbacher N and Lehr CM: Size-Limited penetration of nanoparticles into porcine respiratory mucus after aerosol deposition. Biomacromolecules. 17:1536–1542. 2016. View Article : Google Scholar : PubMed/NCBI

17 

Blank F, Stumbles PA, Seydoux E, Holt PG, Fink A, Rothen-Rutishauser B, Strickland DH and von Garnier C: Size-Dependent uptake of particles by pulmonary antigen-presenting cell populations and trafficking to regional lymph nodes. Am J Respir Cell Mol Biol. 49:67–77. 2013. View Article : Google Scholar : PubMed/NCBI

18 

Ghaffar KA, Marasini N, Giddam AK, Batzloff MR, Good MF, Skwarczynski M and Toth I: The role of size in development of mucosal liposome-lipopeptide vaccine candidates against group a streptococcus. Med Chem. 13:22–27. 2016. View Article : Google Scholar : PubMed/NCBI

19 

Murugan K, Choonara YE, Kumar P, Bijukumar D, du Toit LC and Pillay V: Parameters and characteristics governing cellular internalization and trans-barrier trafficking of nanostructures. Int J Nanomedicine. 10:2191–2206. 2015.PubMed/NCBI

20 

Zhang L, Wang Y, Yang D, Huang W, Hao P, Feng S, Appelhans D, Zhang T and Zan X: Shape effect of nanoparticles on tumor penetration in monolayers versus spheroids. Mol Pharm. 16:2902–2911. 2019. View Article : Google Scholar : PubMed/NCBI

21 

Gratton SE, Ropp PA, Pohlhaus PD, Luft JC, Madden VJ, Napier ME and DeSimone JM: The effect of particle design on cellular internalization pathways. Proc Natl Acad Sci USA. 105:11613–11618. 2008. View Article : Google Scholar : PubMed/NCBI

22 

Black KC, Wang Y, Luehmann HP, Cai X, Xing W, Pang B, Zhao Y, Cutler CS, Wang LV, Liu Y and Xia Y: Radioactive 198Au-doped nanostructures with different shapes for in vivo analyses of their biodistribution, tumor uptake, and intratumoral distribution. ACS Nano. 8:4385–4394. 2014. View Article : Google Scholar : PubMed/NCBI

23 

Hu G, Jiao B, Shi X, Valle RP, Fan Q and Zuo YY: Physicochemical properties of nanoparticles regulate translocation across pulmonary surfactant monolayer and formation of lipoprotein corona. ACS Nano. 7:10525–10533. 2013. View Article : Google Scholar : PubMed/NCBI

24 

Lin X, Zuo YY and Gu N: Shape affects the interactions of nanoparticles with pulmonary surfactant. Sci China Mater. 58:28–37. 2015. View Article : Google Scholar : PubMed/NCBI

25 

Beck-Broichsitter M, Ruppert C, Schmehl T, Günther A and Seeger W: Biophysical inhibition of synthetic vs. Naturally-Derived pulmonary surfactant preparations by polymeric nanoparticles. Biochim Biophys Acta. 1838:474–481. 2014. View Article : Google Scholar : PubMed/NCBI

26 

Li J: Development of a QTsome lipid nanoparticle delivery platform for oligonucleotide therapeutics. The Ohio State University. 2018.

27 

Mousseau F and Berret JF: The role of surface charge in the interaction of nanoparticles with model pulmonary surfactants. Soft Matter. 14:5764–5774. 2018. View Article : Google Scholar : PubMed/NCBI

28 

Fromen CA, Rahhal TB, Robbins GR, Kai MP, Shen TW, Luft JC and DeSimone JM: Nanoparticle surface charge impacts distribution, uptake and lymph node trafficking by pulmonary antigen-presenting cells. Nanomedicine. 12:677–687. 2016. View Article : Google Scholar : PubMed/NCBI

29 

Tada R, Hidaka A, Kiyono H, Kunisawa J and Aramaki Y: Intranasal administration of cationic liposomes enhanced granulocyte-macrophage colony-stimulating factor expression and this expression is dispensable for mucosal adjuvant activity. BMC Res Notes. 11:4722018. View Article : Google Scholar : PubMed/NCBI

30 

Fromen CA, Robbins GR, Shen TW, Kai MP, Ting JP and DeSimone JM: Controlled analysis of nanoparticle charge on mucosal and systemic antibody responses following pulmonary immunization. Proc Natl Acad Sci U S A. 112:488–493. 2015. View Article : Google Scholar : PubMed/NCBI

31 

Howard KA, Rahbek UL, Liu X, Damgaard CK, Glud SZ, Andersen MØ, Hovgaard MB, Schmitz A, Nyengaard JR, Besenbacher F and Kjems J: RNA interference in vitro and in vivo using a novel chitosan/siRNA nanoparticle system. Mol Ther. 14:476–484. 2006. View Article : Google Scholar : PubMed/NCBI

32 

Fadeel B: Clear and present danger? Engineered nanoparticles and the immune system. Swiss Med Wkly. 142:w136092012.PubMed/NCBI

33 

Li B, Xie J, Yuan Z, Jain P, Lin X, Wu K and Jiang S: Mitigation of inflammatory immune responses with hydrophilic nanoparticles. Angew Chem Int Ed Engl. 57:4527–4531. 2018. View Article : Google Scholar : PubMed/NCBI

34 

Guzmán E, Ferrari M, Santini E, Liggieri L and Ravera F: Effect of silica nanoparticles on the interfacial properties of a canonical lipid mixture. Colloids Surf B Biointerfaces. 136:971–980. 2015. View Article : Google Scholar : PubMed/NCBI

35 

Borm PJ and Kreyling W: Toxicological hazards of inhaled nanoparticles-potential implications for drug delivery. J Nanosci Nanotechnol. 4:521–531. 2004. View Article : Google Scholar : PubMed/NCBI

36 

Oberdörster G, Oberdörster E and Oberdörster J: Nanotoxicology: An emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect. 113:823–839. 2005. View Article : Google Scholar : PubMed/NCBI

37 

Ngan CL and Asmawi AA: Lipid-Based pulmonary delivery system: A review and future considerations of formulation strategies and limitations. Drug Deliv Transl Res. 8:1527–1544. 2018. View Article : Google Scholar : PubMed/NCBI

38 

Patra JK, Das G, Fraceto LF, Campos EVR, Rodriguez-Torres MDP, Acosta-Torres LS, Diaz-Torres LA, Grillo R, Swamy MK, Sharma S, et al: Nano based drug delivery systems: Recent developments and future prospects. J Nanobiotechnology. 16:712018. View Article : Google Scholar : PubMed/NCBI

39 

Bulbake U, Doppalapudi S, Kommineni N and Khan W: Liposomal formulations in clinical use: An updated review. Pharmaceutics. 9:122017. View Article : Google Scholar

40 

Rudokas M, Najlah M, Alhnan MA and Elhissi A: Liposome delivery systems for inhalation: A critical review highlighting formulation issues and anticancer applications. Med Princ Pract. 25:60–72. 2016. View Article : Google Scholar : PubMed/NCBI

41 

Riaz MK, Riaz MA, Zhang X, Lin C, Wong KH, Chen X, Zhang G, Lu A and Yang Z: Surface functionalization and targeting strategies of liposomes in solid tumor therapy: A Review. Int J Mol Sci. 19:1952018. View Article : Google Scholar

42 

Garbuzenko OB, Mainelis G, Taratula O and Minko T: Inhalation treatment of lung cancer: The influence of composition, size and shape of nanocarriers on their lung accumulation and retention. Cancer Biol Med. 11:44–55. 2014.PubMed/NCBI

43 

Barenholz Y: Doxil®-the first FDA-approved nano-drug: lessons learned. J Control Release. 160:117–134. 2012. View Article : Google Scholar : PubMed/NCBI

44 

Rust DM and Jameson G: The novel lipid delivery system of amphotericin B: Drug profile and relevance to clinical practice. Oncol Nurs Forum. 25:35–48. 1998.PubMed/NCBI

45 

Garbuzenko OB, Saad M, Betigeri S, Zhang M, Vetcher AA, Soldatenkov VA, Reimer DC, Pozharov VP and Minko T: Intratracheal versus intravenous liposomal delivery of siRNA, antisense oligonucleotides and anticancer drug. Pharm Res. 26:382–394. 2009. View Article : Google Scholar : PubMed/NCBI

46 

Koshkina NV, Waldrep JC, Roberts LE, Golunski E, Melton S and Knight V: Paclitaxel liposome aerosol treatment induces inhibition of pulmonary metastases in murine renal carcinoma model. Clin Cancer Res. 7:3258–3262. 2001.PubMed/NCBI

47 

Fritz JM, Tennis MA, Orlicky DJ, Lin H, Ju C, Redente EF, Choo KS, Staab TA, Bouchard RJ, Merrick DT, et al: Depletion of tumor-associated macrophages slows the growth of chemically induced mouse lung adenocarcinomas. Front Immunol. 5:5872014. View Article : Google Scholar : PubMed/NCBI

48 

Wittgen BP, Kunst PW, van der Born K, van Wijk AW, Perkins W, Pilkiewicz FG, Perez-Soler R, Nicholson S, Peters GJ and Postmus PE: Phase I study of aerosolized SLIT cisplatin in the treatment of patients with carcinoma of the lung. Clin Cancer Res. 13:2414–2421. 2007. View Article : Google Scholar : PubMed/NCBI

49 

Olivier KN, Griffith DE, Eagle G, McGinnis JP II, Micioni L, Liu K, Daley CL, Winthrop KL, Ruoss S, Addrizzo-Harris DJ, et al: Randomized trial of liposomal amikacin for inhalation in nontuberculous mycobacterial lung disease. Am J Respir Crit Care Med. 195:814–823. 2017. View Article : Google Scholar : PubMed/NCBI

50 

Zhang J, Leifer F, Rose S, Chun DY, Thaisz J, Herr T, Nashed M, Joseph J, Perkins WR and DiPetrillo K: Amikacin liposome inhalation suspension (ALIS) penetrates non-tuberculous mycobacterial biofilms and enhances amikacin uptake into macrophages. Front Microbiol. 9:9152018. View Article : Google Scholar : PubMed/NCBI

51 

Okusanya OO, Bhavnani SM, Hammel J, Minic P, Dupont LJ, Forrest A, Mulder GJ, Mackinson C, Ambrose PG and Gupta R: Pharmacokinetic and pharmacodynamic evaluation of liposomal amikacin for inhalation in cystic fibrosis patients with chronic pseudomonal infection. Antimicrob Agents Chemother. 53:3847–3854. 2009. View Article : Google Scholar : PubMed/NCBI

52 

Konduri KS, Nandedkar S, Rickaby DA, Düzgüneş N and Gangadharam PR: The use of sterically stabilized liposomes to treat asthma. Methods Enzymol. 391:413–427. 2005. View Article : Google Scholar : PubMed/NCBI

53 

Chen X, Huang W, Wong BC, Yin L, Wong YF, Xu M and Yang Z: Liposomes prolong the therapeutic effect of anti-asthmatic medication via pulmonary delivery. Int J Nanomedicine. 7:1139–1148. 2012.PubMed/NCBI

54 

Ng ZY, Wong JY, Panneerselvam J, Madheswaran T, Kumar P, Pillay V, Hsu A, Hansbro N, Bebawy M, Wark P, et al: Assessing the potential of liposomes loaded with curcumin as a therapeutic intervention in asthma. Colloids Surf B Biointerfaces. 172:51–59. 2018. View Article : Google Scholar : PubMed/NCBI

55 

Komalla V, Allam VS, Kwok CL, Sheikholeslami B, Owen L, Jaffe A, Waters SA, Mohammad S, Oliver BG, Chen H and Haghi M: A phospholipid-based formulation for the treatment of airway inflammation in chronic respiratory diseases. Eur J Pharm Biopharm. 157:47–58. 2020. View Article : Google Scholar : PubMed/NCBI

56 

Nahar K, Absar S, Patel B and Ahsan F: Starch-coated magnetic liposomes as an inhalable carrier for accumulation of fasudil in the pulmonary vasculature. Int J Pharm. 464:185–195. 2014. View Article : Google Scholar : PubMed/NCBI

57 

Wijagkanalan W, Kawakami S, Takenaga M, Igarashi R, Yamashita F and Hashida M: Efficient targeting to alveolar macrophages by intratracheal administration of mannosylated liposomes in rats. J Control Release. 125:121–130. 2008. View Article : Google Scholar : PubMed/NCBI

58 

Cryan SA, Devocelle M, Moran PJ, Hickey AJ and Kelly JG: Increased intracellular targeting to airway cells using octaarginine-coated liposomes: In vitro assessment of their suitability for inhalation. Mol Pharm. 3:104–112. 2006. View Article : Google Scholar : PubMed/NCBI

59 

Uner M and Yener G: Importance of solid lipid nanoparticles (SLN) in various administration routes and future perspectives. Int J Nanomedicine. 2:289–300. 2007.PubMed/NCBI

60 

Bi R, Shao W, Wang Q and Zhang N: Solid lipid nanoparticles as insulin inhalation carriers for enhanced pulmonary delivery. J Biomed Nanotechnol. 5:84–92. 2009. View Article : Google Scholar : PubMed/NCBI

61 

Nassimi M, Schleh C, Lauenstein HD, Hussein R, Lübbers K, Pohlmann G, Switalla S, Sewald K, Müller M, Krug N, et al: Low cytotoxicity of solid lipid nanoparticles in in vitro and ex vivo lung models. Inhal Toxicol. 21:104–109. 2009. View Article : Google Scholar : PubMed/NCBI

62 

Videira M, Almeida AJ and Fabra A: Preclinical evaluation of a pulmonary delivered paclitaxel-loaded lipid nanocarrier antitumor effect. Nanomedicine. 8:1208–1215. 2012. View Article : Google Scholar : PubMed/NCBI

63 

Castellani S, Trapani A, Spagnoletta A, di Toma L, Magrone T, Di Gioia S, Mandracchia D, Trapani G, Jirillo E and Conese M: Nanoparticle delivery of grape seed-derived proanthocyanidins to airway epithelial cells dampens oxidative stress and inflammation. J Transl Med. 16:1402018. View Article : Google Scholar : PubMed/NCBI

64 

Bayón-Cordero L, Alkorta I and Arana L: Application of solid lipid nanoparticles to improve the efficiency of anticancer drugs. Nanomaterials (Basel). 9:4742019. View Article : Google Scholar

65 

Maretti E, Costantino L, Buttini F, Rustichelli C, Leo E, Truzzi E and Iannuccelli V: Newly synthesized surfactants for surface mannosylation of respirable SLN assemblies to target macrophages in tuberculosis therapy. Drug Deliv Transl Res. 9:298–310. 2019. View Article : Google Scholar : PubMed/NCBI

66 

Nimje N, Agarwal A, Saraogi GK, Lariya N, Rai G, Agrawal H and Agrawal GP: Mannosylated nanoparticulate carriers of rifabutin for alveolar targeting. J Drug Target. 17:777–787. 2009. View Article : Google Scholar : PubMed/NCBI

67 

Rytting E, Nguyen J, Wang X and Kissel T: Biodegradable polymeric nanocarriers for pulmonary drug delivery. Expert Opin Drug Deliv. 5:629–639. 2008. View Article : Google Scholar : PubMed/NCBI

68 

Marasini N, Haque S and Kaminskas LM: Polymer-Drug conjugates as inhalable drug delivery systems: A review. Curr Opin Colloid Interface Sci. 31:2017. View Article : Google Scholar : PubMed/NCBI

69 

Yang M, Yamamoto H, Kurashima H, Takeuchi H, Yokoyama T, Tsujimoto H and Kawashima Y: Design and evaluation of poly(DL-lactic-co-glycolic acid) nanocomposite particles containing salmon calcitonin for inhalation. Eur J Pharm Sci. 46:374–380. 2012. View Article : Google Scholar : PubMed/NCBI

70 

Türeli NG, Torge A, Juntke J, Schwarz BC, Schneider-Daum N, Türeli AE, Lehr CM and Schneider M: Ciprofloxacin-Loaded PLGA nanoparticles against cystic fibrosis P. Aeruginosa lung infections. Eur J Pharm Biopharm. 117:363–371. 2017. View Article : Google Scholar : PubMed/NCBI

71 

Kim I, Byeon HJ, Kim TH, Lee ES, Oh KT, Shin BS, Lee KC and Youn YS: Doxorubicin-Loaded highly porous large PLGA microparticles as a sustained- release inhalation system for the treatment of metastatic lung cancer. Biomaterials. 33:5574–5583. 2012. View Article : Google Scholar : PubMed/NCBI

72 

Pandey R, Sharma A, Zahoor A, Sharma S, Khuller GK and Prasad B: Poly (DL-lactide-co-glycolide) nanoparticle-based inhalable sustained drug delivery system for experimental tuberculosis. J Antimicrob Chemother. 52:981–986. 2003. View Article : Google Scholar : PubMed/NCBI

73 

Tomoda K, Ohkoshi T, Hirota K, Sonavane GS, Nakajima T, Terada H, Komuro M, Kitazato K and Makino K: Preparation and properties of inhalable nanocomposite particles for treatment of lung cancer. Colloids Surf B Biointerfaces. 71:177–182. 2009. View Article : Google Scholar : PubMed/NCBI

74 

Zou W, Liu C, Chen Z and Zhang N: Studies on bioadhesive PLGA nanoparticles: A promising gene delivery system for efficient gene therapy to lung cancer. Int J Pharm. 370:187–195. 2009. View Article : Google Scholar : PubMed/NCBI

75 

Dailey LA and Kissel T: New poly(lactic-co-glycolic acid) derivatives: Modular polymers with tailored properties. Drug Discov Today Technol. 2:7–13. 2005. View Article : Google Scholar : PubMed/NCBI

76 

Xu Y, Kim CS, Saylor DM and Koo D: Polymer degradation and drug delivery in PLGA-based drug-polymer applications: A review of experiments and theories. J Biomed Mater Res B Appl Biomater. 105:1692–1716. 2017. View Article : Google Scholar : PubMed/NCBI

77 

Fu J, Fiegel J, Krauland E and Hanes J: New polymeric carriers for controlled drug delivery following inhalation or injection. Biomaterials. 23:4425–4433. 2002. View Article : Google Scholar : PubMed/NCBI

78 

Fatemeh DRA, Shahmabadi HE, Abedi A, Alavi SE, Movahedi F, Esfahani MKM, Mehrizi TZ and Akbarzadeh A: Polybutylcyanoacrylate nanoparticles and drugs of the platinum family: Last status. Indian J Clin Biochem. 29:333–338. 2014. View Article : Google Scholar : PubMed/NCBI

79 

Melguizo C, Cabeza L, Prados J, Ortiz R, Caba O, Rama AR, Delgado ÁV and Arias JL: Enhanced antitumoral activity of doxorubicin against lung cancer cells using biodegradable poly(butylcyanoacrylate) nanoparticles. Drug Des Devel Ther. 9:6433–6444. 2015.PubMed/NCBI

80 

Choi WS, Murthy GG, Edwards DA, Langer R and Klibanov AM: Inhalation delivery of proteins from ethanol suspensions. Proc Natl Acad Sci USA. 98:11103–11107. 2001. View Article : Google Scholar : PubMed/NCBI

81 

Nam JP and Nah JW: Target gene delivery from targeting ligand conjugated chitosan-PEI copolymer for cancer therapy. Carbohydr Polym. 135:153–161. 2016. View Article : Google Scholar : PubMed/NCBI

82 

Zhao L, Li Y, Pei D, Huang Q, Zhang H, Yang Z, Li F and Shi T: Glycopolymers/PEI complexes as serum-tolerant vectors for enhanced gene delivery to hepatocytes. Carbohydr Polym. 205:167–175. 2019. View Article : Google Scholar : PubMed/NCBI

83 

B. Thapa and R. Narain; 1-Mechanism current challenges new approaches for non viral gene delivery, : Ravin Narain, Polymers and Nanomaterials for Gene Therapy. Woodhead Publishing; 2016, pp. 1–27

84 

Germershaus O, Mao S, Sitterberg J, Bakowsky U and Kissel T: Gene delivery using chitosan, trimethyl chitosan or polyethylenglycol-graft-trimethyl chitosan block copolymers: Establishment of structure-activity relationships in vitro. J Control Release. 125:145–154. 2008. View Article : Google Scholar : PubMed/NCBI

85 

Mehta M, Deeksha, Tewari D, Gupta G, Awasthi R, Singh H, Pandey P, Chellappan DK, Wadhwa R, Collet T, et al: Oligonucleotide therapy: An emerging focus area for drug delivery in chronic inflammatory respiratory diseases. Chem Biol Interact. 308:206–215. 2019. View Article : Google Scholar : PubMed/NCBI

86 

Ahmad J, Akhter S, Rizwanullah Md, Amin S, Rahman M, Ahmad MZ, Rizvi MA, Kamal MA and Ahmad FJ: Nanotechnology-Based inhalation treatments for lung cancer: State of the art. Nanotechnol Sci Appl. 8:55–66. 2015.PubMed/NCBI

87 

Mendes LP, Pan J and Torchilin VP: Dendrimers as nanocarriers for nucleic acid and drug delivery in cancer therapy. Molecules. 22:14012017. View Article : Google Scholar

88 

Bellini RG, Guimarães AP, Pacheco MA, Dias DM, Furtado VR, de Alencastro RB and Horta BAC: Association of the anti-tuberculosis drug rifampicin with a PAMAM dendrimer. J Mol Graph Model. 60:34–42. 2015. View Article : Google Scholar : PubMed/NCBI

89 

Rajabnezhad S, Casettari L, Lam JK, Nomani A, Torkamani MR, Palmieri GF, Rajabnejad MR and Darbandi MA: Pulmonary delivery of rifampicin microspheres using lower generation polyamidoamine dendrimers as a carrier. Powder Technol. 291:366–374. 2016. View Article : Google Scholar

90 

Conti DS, Brewer D, Grashik J, Avasarala S and da Rocha SR: Poly(amidoamine) dendrimer nanocarriers and their aerosol formulations for siRNA delivery to the lung epithelium. Mol Pharm. 11:1808–1822. 2014. View Article : Google Scholar : PubMed/NCBI

91 

Zhong Q, Bielski ER, Rodrigues LS, Brown MR, Reineke JJ and da Rocha SR: Conjugation to poly(amidoamine) dendrimers and pulmonary delivery reduce cardiac accumulation and enhance antitumor activity of doxorubicin in lung metastasis. Mol Pharm. 13:2363–2375. 2016. View Article : Google Scholar : PubMed/NCBI

92 

Inapagolla R, Guru BR, Kurtoglu YE, Gao X, Lieh-Lai M, Bassett DJP and Kannan RM: In vivo efficacy of dendrimer-methylprednisolone conjugate formulation for the treatment of lung inflammation. Int J Pharm. 399:140–147. 2010. View Article : Google Scholar : PubMed/NCBI

93 

Mehta M, Deeksha, Sharma N, Vyas M, Khurana N, Maurya PK, Singh H, de Jesus TPA, Dureja H, Chellappan DK, et al: Interactions with the macrophages: An emerging targeted approach using novel drug delivery systems in respiratory diseases. Chem Biol Interact. 304:10–19. 2019. View Article : Google Scholar : PubMed/NCBI

94 

Cortajarena AL, Ortega D, Ocampo SM, Gonzalez-García A, Couleaud P, Miranda R, Belda-Iniesta C and Ayuso-Sacido A: Engineering iron oxide nanoparticles for clinical settings. Nanobiomedicine (Rij). 1:22014. View Article : Google Scholar : PubMed/NCBI

95 

Motomura K, Ishitobi M, Komoike Y, Koyama H, Noguchi A, Sumino H, Kumatani Y, Inaji H, Horinouchi T and Nakanishi K: SPIO-Enhanced magnetic resonance imaging for the detection of metastases in sentinel nodes localized by computed tomography lymphography in patients with breast cancer. Ann Surg Oncol. 18:3422–3429. 2011. View Article : Google Scholar : PubMed/NCBI

96 

Yhee JY, Im J and Nho RS: Advanced therapeutic strategies for chronic lung disease using nanoparticle-based drug delivery. J Clin Med. 5:822016. View Article : Google Scholar

97 

Chen YH, Tsai CY, Huang PY, Chang MY, Cheng PC, Chou CH, Chen DH, Wang CR, Shiau AL and Wu CL: Methotrexate conjugated to gold nanoparticles inhibits tumor growth in a syngeneic lung tumor model. Mol Pharm. 4:713–722. 2007. View Article : Google Scholar : PubMed/NCBI

98 

Brown SD, Nativo P, Smith JA, Stirling D, Edwards PR, Venugopal B, Flint DJ, Plumb JA, Graham D and Wheate NJ: Gold nanoparticles for the improved anticancer drug delivery of the active component of oxaliplatin. J Am Chem Soc. 132:4678–4684. 2010. View Article : Google Scholar : PubMed/NCBI

99 

Codullo V, Cova E, Pandolfi L, Breda S, Morosini M, Frangipane V, Malatesta M, Calderan L, Cagnone M, Pacini C, et al: Imatinib-Loaded gold nanoparticles inhibit proliferation of fibroblasts and macrophages from systemic sclerosis patients and ameliorate experimental bleomycin-induced lung fibrosis. J Control Release. 310:198–208. 2019. View Article : Google Scholar : PubMed/NCBI

100 

Zhang J, Mou L and Jiang X: Surface chemistry of gold nanoparticles for health-related applications. Chem Sci. 11:923–936. 2020. View Article : Google Scholar

101 

Omlor AJ, Le DD, Schlicker J, Hannig M, Ewen R, Heck S, Herr C, Kraegeloh A, Hein C, Kautenburger R, et al: Local effects on airway inflammation and systemic uptake of 5 nm PEGylated and citrated gold nanoparticles in asthmatic mice. Small. 13:10022017. View Article : Google Scholar

102 

Park H, Tsutsumi H and Mihara H: Cell-Selective intracellular drug delivery using doxorubicin and α-helical peptides conjugated to gold nanoparticles. Biomaterials. 35:3480–3487. 2014. View Article : Google Scholar : PubMed/NCBI

103 

Bhaskar S and Lim S: Engineering protein nanocages as carriers for biomedical applications. NPG Asia Mater. 9:e3712017. View Article : Google Scholar : PubMed/NCBI

104 

Syomin BV and Ilyin YV: Virus-Like particles as an instrument of vaccine production. Mol Biol. 53:323–334. 2019. View Article : Google Scholar : PubMed/NCBI

105 

Bobo D, Robinson KJ, Islam J, Thurecht KJ and Corrie SR: Nanoparticle-Based medicines: A review of FDA-approved materials and clinical trials to date. Pharm Res. 33:2373–2387. 2016. View Article : Google Scholar : PubMed/NCBI

106 

Renukaradhya GJ, Narasimhan B and Mallapragada SK: Respiratory nanoparticle-based vaccines and challenges associated with animal models and translation. J Controll Release. 219:622–631. 2015. View Article : Google Scholar

107 

Coleman CM, Liu YV, Mu H, Taylor JK, Massare M, Flyer DC, Smith GE and Frieman MB: Purified coronavirus spike protein nanoparticles induce coronavirus neutralizing antibodies in mice. Vaccine. 32:3169–3174. 2014. View Article : Google Scholar : PubMed/NCBI

108 

Smith G, Raghunandan R, Wu Y, Liu Y, Massare M, Nathan M, Zhou B, Lu H, Boddapati S, Li J, et al: Respiratory syncytial virus fusion glycoprotein expressed in insect cells form protein nanoparticles that induce protective immunity in cotton rats. PLoS One. 7:e508522012. View Article : Google Scholar : PubMed/NCBI

109 

Lee YT, Ko EJ, Kim KH, Hwang HS, Lee Y, Kwon YM, Kim MC, Lee YN, Jung YJ and Kang SM: Cellular immune correlates preventing disease against respiratory syncytial virus by vaccination with virus-like nanoparticles carrying fusion proteins. J Biomed Nanotechnol. 13:84–98. 2017. View Article : Google Scholar : PubMed/NCBI

110 

Pápay ZE, Kósa A, Böddi B, Merchant Z, Saleem IY, Zariwala MG, Klebovich I, Somavarapu S and Antal I: Study on the pulmonary delivery system of apigenin-loaded albumin nanocarriers with antioxidant activity. J Aerosol Med Pulm Drug Deliv. 30:274–288. 2017. View Article : Google Scholar : PubMed/NCBI

111 

Labiris NR and Dolovich MB: Pulmonary drug delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol. 56:588–599. 2003. View Article : Google Scholar : PubMed/NCBI

112 

Patton JS, Fishburn CS and Weers JG: The lungs as a portal of entry for systemic drug delivery. Proc Am Thorac Soc. 1:338–344. 2004. View Article : Google Scholar : PubMed/NCBI

113 

Shen AM and Minko T: Pharmacokinetics of inhaled nanotherapeutics for pulmonary delivery. J Control Release. 326:222–244. 2020. View Article : Google Scholar : PubMed/NCBI

114 

Scherließ R: Future of nanomedicines for treating respiratory diseases. Expert Opin Drug Deliv. 16:59–68. 2019. View Article : Google Scholar : PubMed/NCBI

115 

Oberdörster G: Safety assessment for nanotechnology and nanomedicine: Concepts of nanotoxicology. J Intern Med. 267:89–105. 2010. View Article : Google Scholar : PubMed/NCBI

116 

Ferreira AJ, Cemlyn-Jones J and Cordeiro CR: Nanoparticles, nanotechnology and pulmonary nanotoxicology. Rev Port Pneumol. 19:28–37. 2013. View Article : Google Scholar : PubMed/NCBI

117 

Jones MC, Jones SA, Riffo-Vasquez Y, Spina D, Hoffman E, Morgan A, Patel A, Page C, Forbes B and Dailey LA: Quantitative assessment of nanoparticle surface hydrophobicity and its influence on pulmonary biocompatibility. J Control Release. 183:94–104. 2014. View Article : Google Scholar : PubMed/NCBI

118 

Dailey LA, Jekel N, Fink L, Gessler T, Schmehl T, Wittmar M, Kissel T and Seeger W: Investigation of the proinflammatory potential of biodegradable nanoparticle drug delivery systems in the lung. Toxicol Appl Pharmacol. 215:100–108. 2006. View Article : Google Scholar : PubMed/NCBI

119 

Zhang WF, Zhou HY, Chen XG, Tang SH and Zhang JJ: Biocompatibility study of theophylline/chitosan/beta-cyclodextrin microspheres as pulmonary delivery carriers. J Mater Sci Mater Med. 20:1321–1330. 2009. View Article : Google Scholar : PubMed/NCBI

120 

Nakamura K, Matsubara H, Akagi S, Sarashina T, Ejiri K, Kawakita N, Yoshida M, Miyoshi T, Watanabe A, Nishii N and Ito H: Nanoparticle-Mediated drug delivery system for pulmonary arterial hypertension. J Clin Med. 6:482017. View Article : Google Scholar

Related Articles

Journal Cover

May-2021
Volume 23 Issue 5

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Luo M, Hua S and Shang Q: Application of nanotechnology in drug delivery systems for respiratory diseases (Review). Mol Med Rep 23: 325, 2021
APA
Luo, M., Hua, S., & Shang, Q. (2021). Application of nanotechnology in drug delivery systems for respiratory diseases (Review). Molecular Medicine Reports, 23, 325. https://doi.org/10.3892/mmr.2021.11964
MLA
Luo, M., Hua, S., Shang, Q."Application of nanotechnology in drug delivery systems for respiratory diseases (Review)". Molecular Medicine Reports 23.5 (2021): 325.
Chicago
Luo, M., Hua, S., Shang, Q."Application of nanotechnology in drug delivery systems for respiratory diseases (Review)". Molecular Medicine Reports 23, no. 5 (2021): 325. https://doi.org/10.3892/mmr.2021.11964