key: cord-0967936-3tayscyw
authors: Ibarra-Sánchez, Luis Ángel; Gámez-Méndez, Ana; Martínez-Ruiz, Manuel; Nájera-Martínez, Erik Francisco; Morales-Flores, Brando Alan; Melchor-Martínez, Elda M.; Sosa-Hernández, Juan Eduardo; Parra-Saldívar, Roberto; Iqbal, Hafiz M.N.
title: Nanostructures for drug delivery in respiratory diseases therapeutics: Revision of current trends and its comparative analysis
date: 2022-03-05
journal: J Drug Deliv Sci Technol
DOI: 10.1016/j.jddst.2022.103219
sha: 474d168a2cd59964c976751f4ecda21ec46c6d50
doc_id: 967936
cord_uid: 3tayscyw

Respiratory diseases are leading causes of death and disability in developing and developed countries. The burden of acute and chronic respiratory diseases has been rising throughout the world and represents a major problem in the public health system. Acute respiratory diseases include pneumonia, influenza, SARS-CoV-2 and MERS viral infections; while chronic obstructive pulmonary disease (COPD), asthma and, occupational lung diseases (asbestosis, pneumoconiosis) and other parenchymal lung diseases namely lung cancer and tuberculosis are examples of chronic respiratory diseases. Importantly, chronic respiratory diseases are not curable and treatments for acute pathologies are particularly challenging. For that reason, the integration of nanotechnology to existing drugs or for the development of new treatments potentially benefits the therapeutic goals by making drugs more effective and exhibit fewer undesirable side effects to treat these conditions. Moreover, the integration of different nanostructures enables improvement of drug bioavailability, transport and delivery compared to stand-alone drugs in traditional respiratory therapy. Notably, there has been great progress in translating nanotechnology-based cancer therapies and diagnostics into the clinic; however, researchers in recent years have focused on the application of nanostructures in other relevant pulmonary diseases as revealed in our database search. Furthermore, polymeric nanoparticles and micelles are the most studied nanostructures in a wide range of diseases; however, liposomal nanostructures are recognized to be some of the most successful commercial drug delivery systems. In conclusion, this review presents an overview of the recent and relevant research in drug delivery systems for the treatment of different pulmonary diseases and outlines the trends, limitations, importance and application of nanomedicine technology in treatment and diagnosis and future work in this field.

In this review, to analyze the trends in drug delivery for different nanostructures, a revision using the database ScienceDirect and the meta searcher Google Scholar.

Using the keywords: "drug delivery", "nanostructure", "respiratory diseases"; in combination with common names for drug delivery nanostructures (i.e. "polymeric nanoparticles", "micelles", "dendrimers", etc.), the most relevant research articles for Polymeric nanoparticles ("polymeric" OR "polymer") AND "nanoparticles" AND "drug delivery" AND "(respiratory diseases" OR "lung diseases") 43 15 Polymeric micelles ("polymeric" OR "polymer") AND "micelles" AND "drug delivery" AND "(respiratory diseases" OR "lung diseases") 39 15 Liposomes "liposomes" AND "drug delivery" AND "(respiratory diseases" OR "lung diseases") 20 7

Lipid based nanoparticles ("nanostructured lipid carrier" OR "solid lipid nanoparticles") AND "drug delivery" AND ("respiratory diseases" OR "lung diseases")

There are various routes of administration available, each of which has associated advantages and disadvantages. The route by which drugs enter the body has an impact on drug onset of action, the duration of that action, the bioavailability, and the intensity of the effect (Jin et al., 2015) . It was proposed by Boroujerdi to classify the administration routes into four categories; the first category consists of administration routes that enable the drug to contact various organs, and these organs can provide The lung possesses pulmonary-specific pharmacokinetic processes, including:

deposition and clearance (A general scheme of particle deposition, elimination and clearance paths are presented in Figure 2 ) . (1) Following inhalation nanoparticles travel along the respiratory tract where they can suffer deposition in the different regions of the lungs, this deposition depends on inhalation flow, device characteristics, but mainly depends on the particle size of the formulation, for example, particles over 10 μm will tend to impact the initial parts of the throat and most of the particles will not reach the deep lungs, while particles between 1 to 3 μm the transport mechanism is complex. One of the predominant mechanisms of clearance is through alveolar macrophages. Finally, it is important to consider that nanoparticle pharmacokinetics is an elaborate process that is influenced by drug formulation, particle size, particle physicochemical characteristics, type of device, and patient-related factors . 

Nanomedicine is a promising field and relatively new, it proposes that the combination between nanotechnology and biological systems can obtain new interactions that can be further exploited when compared with microscale materials (Boisseau & Loubaton, 2011) . Specifically, in terms of drug delivery, nanomedicine is promising that the use of nanomaterials can improve the delivery of poorly soluble 

Polymeric nanoparticles (PNPs) consider two types of structures, nanospheres that are dense polymeric matrices where the drug is supported within the matrix and nanocapsules that are hollow and the drug is contained inside the matrix, they can vary from 5 to 1000 nm, even when the range of obtained PNPs vary from 100- 

Polymeric micelles are composed of a two-layer structure; they have an internal core provided by the hydrophobic part of the block copolymer; and the outer shell also Complexed dendrimers have been shown to induce antiangiogenic responses in cancer models in vivo. Lipid nanoparticles can cross the blood-brain barrier making them useful for diagnosis and therapy for brain tumors.

As mentioned before, various surface modifications can be achieved on different nanostructures and conventional anti-tumor chemical drugs can be loaded into different nanocarriers in order to improve the pharmacological efficacy to target cancerous cells. It is important that both, researchers and clinicians take into account J o u r n a l P r e -p r o o f these specific characteristics in an effort to study and select the best option in a clinical setting. 

Liposomes are phospholipid vesicles with a spherical shape and can be produced itself; the major limitation in this study was the low load efficiency of pirfenidone into the liposomes due to its low solubility in water, however a strategy to improve the loading can be to change the conditions in the process of fabrication of the liposomes, like using a different pH as a gradient to improve the drug loading. 

In 

Dendrimers are synthetic macromolecules with characteristics like high branching points, 3D shape, and globular structure at the nanoscale size. They have a characteristic structure containing three principal stages: a core consisting of a single atom or molecule; then from the core emanate some branches, formed from repeated units that are connected by at least one branch connection, this creates radial concentric layers called "generations'', and there are various terminal functional groups usually are located at the surface of the dendrimers, and they determine the properties of the structure (Kesharwani et al., 2014) . The most representative characteristic of dendrimers is their tree-like structure resulting from the branch connections. In size, dendrimers are small structures that vary from 1 to 

Exosomes passive loading which broadly consists in exposing the donor cell to a therapeutic or diagnostic molecule while the exosome is formed so the drug is loaded during exosomes formation, or the active loading were drugs are loaded once the exosomes are formed, they are submitted to a physical process to promote the drug diffusion into the exosome (Luan et al., 2017) . But once the exosomes were passively charged, or even before an active charge method, exosomes must be isolated from the rest of the components present in the medium. To achieve this multiple techniques of isolation exist, such as differential centrifugation, filtration, chromatography, and polymer precipitation (Batrakova & Kim, 2015) . Exosomes fabrication methods and schematic representation is shown in Figure 9 .

J o u r n a l P r e -p r o o f As mentioned before, to obtain exosomes necessary for drug delivery purposes, two main processes are needed, the isolation of exosomes from the cellular medium that contains them, and the loading of the exosomes with the therapeutic agent. The most common method used for exosome isolation is differential ultracentrifugation, nuclear factor erythroid 2-related factor 2, MTT= 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, H1299= nonsmall human lung carcinoma cells, A549= adenocarcinomic human alveolar basal epithelial cells, MRC9= Medical Research

Council cell strain-9.

To develop functional DDS systems that can be applied in the clinical stage is necessary to complete a series of steps. These steps can be resumed in three major stages: (1) preclinical trials, (2) clinical trials, and (3) industrial production. Every step is crucial for the proper development of DDS that can be commercially available.

Each step has certain components of interest that are discussed in further subsections.

Preclinical development can be defined as those studies where a new drug delivery platform is proposed, in this step the nanostructured is experimentally fabricated, followed by physicochemical characterization, to then finally be tested in vitro and/or in vivo. In this step, the selection of the drug, type of nanostructure and the materials are the basic concepts. In spite of this, there are a wide number of variables that need to be measured and considered.

The selection of the fabrication method highly influences the physicochemical and biological properties but is also important to consider the reproducibility of the 

In Table 8 There Table 9 we show examples of inhalable products available on the market until 2020. 

The main objective of this review is to understand the tendencies, advances, and limitations of research for novel DDS therapy in pulmonary diseases. As can be seen in Table 1 Table 1 in second place, the lipidic structures such as liposomes and LBNPs, these types of structures have a good balance between pharmaceutical properties and ease of production; yet, liposomes are the most studied lipidic DDS, many authors have attributed their success due to their similarity to the cellular membrane in composition, allowing them to have good biocompatibility and cellular uptake (Bruch et al., 2019) . In third place from Table 1 is placed the exosomes technology, these relatively new DDS are naturally produced by cells, and this could give them the highest biocompatibility and biodegradability among the reviewed structures. On the other hand, the loading and isolation J o u r n a l P r e -p r o o f techniques could be limiting its scalability and translation to the markets (Patil et al., 2020) ; all things considered, it can be expected an increase in the number of publications in exosome research for next years. Dendrimers are the structure with the least number of publications in the period reviewed, despite their fabricacion is well-known, and there are many companies that produces dendrimers at large scale, their role in DDS can be limited by their biocompatibility; terminal groups in dendrimers can be highly reactive, this make them cytotoxic structures by their own, which can be desired in the treatment of cancer, but a critical concern in many other diseases. Nonetheless, this can be a desirable feature giving dendrimers a great capacity to be surface-modified and increase its biocompatibilty and safety (Gothwal et al., 2020) .

In summary on disease applications, it can be noticed that most of the research in DDS for lung therapy is focused on cancer treatment, this can be attributed to the high numbers of deaths by lung and bronchial cancer and the constant increase of patients with cancer every year (Siegel, et al., 2021) . Also, tuberculosis has gained interest due to the constant increment in drug resistant cases. This disease has been challenging to treat during many years, this gave the opportunity to DDS research to focus on new treatments for tuberculosis (Simmons et al., 2018) . In contrast, many other relevant lung diseases such as cystic fibrosis, asthma, COPD, and, caused by pathogens (with exception of SARS-CoV-2 due to the urgency of the current pandemic) are studied (Melchor-Martínez et al., 2021). Therefore, there is an important need for more research beyond lung cancer, even tuberculosis still being poorly studied in comparison with lung cancer therapy. (Gaul et al., 2018) . Despite the advantages, different biological barriers must be circumvented to successfully deliver the drug into the desired action site, which can be a specific lung section or specific cell type.

For example, particle deposition (which is not strictly a biological barrier, but is in fact a physical barrier) is one of the main challenges to solve in order to successfully deposit the DDS. The aerodynamic properties of particles will define the site where most of them will deposit, thus, the aerodynamic properties must be modified depending on the respiratory tract section of interest for the therapeutic (commonly for respiratory diseases, the deep lung region is the relevant site for therapy).

Size-dependent deposition of inhaled particles represents an important challenge for nanoparticle delivery systems. The most important parameter for lung deposition of inhaled particles is the particle size, characterized by the aerodynamic diameter.

Previous studies have shown that nanoparticles (in the range of 1-5 µm) show a high degree of deep lung deposition while smaller particles can be exhaled and bigger particles will tend to deposit in the outer regions of the respiratory tract (Carvalho et al., 2011) . Therefore, the design of DDS for lung delivery is usually a constant trade-off between the excellent aerodynamic properties of particles at the microscale, against the increased cellular uptake and bioavailability of nanoscale particles. Some studies have explored different techniques to overcome this challenge without sacrificing any of the properties mentioned before, for example bulking loaded nanoparticles using bulking agents such as mannitol and trehalose can increase the aerodynamic diameter of particles to reach an appropriate scale for optimal deposition and keeping the size of the original nanoparticles (Keil et al., 2019) . Microencapsulation, as the name implies, looks for generating nanoparticles for drug delivery and then being encapsulated inside microparticles of some easily degradable material that once microparticles reach the lung tissue it begins to release the nanoparticles (Porsio et al., 2018; Emami et al., 2019) . In any case, bulking or microencapsulation, care must be taken to avoid the modification of the J o u r n a l P r e -p r o o f original properties of nanoparticles while are submitted to the increase of size process, and any extra material used must be biocompatible, non-toxic, and should allow a rapid release of nanoparticles once the lung deposition is done (Keil et al., 2019) .

As mentioned in Chapter 3, the reticuloendothelial system represents another challenge to take into account when designing nanostructures. The presence of pulmonary macrophages can reduce the effectiveness of DDS therapeutics (Mejías & Roy, 2019) . When DDS are administered into the respiratory system, usually the objective is to reach the lung epithelium tissue either to deliver the drug into epithelial cells or to reach the circulatory system for systemic delivery, however, the macrophage uptake can result in an important decrease of bioavailability (Belchamber & Donnelly, 2020) . In this sense, the modification of DDS must be done to avoid macrophages and other defense cells to enhance the effectiveness of drugs.

Also, the presence of mucus in the respiratory tract has an important role in lung drug delivery. Nanoparticles with a size greater than 200 nm will be trapped by the glycoprotein network that conforms to the mucus ). In addition to particle size, the surface charge of the DDS will define if the particles interact with the mucus barrier, in this sense, it has been shown that neutral DDS has better diffusion into the mucus layer (Alp & Aydogan, 2020).

In both cases, reduction of macrophage uptake and mucus permeation, the use of polyethylene glycol (PEG), also known as polyethylene oxide (PEO), for coating of DDS is the most common method to avoid (or reduce) the macrophage uptake in nanoparticles. Polyethylene glycol (PEG) is a linear polyether with the molecular formula HO-(CH2-CH2-O)n-H, one of the most interesting characteristics of this polymer is the hydrophilicity that gives it the capability to have reduced protein binding, and therefore, increased bioavailability, biocompatibility, and slow clearance rate in the organism (Verhoef et al., 2014) . Due to the previously mentioned properties of the PEG, this polymer has been used to coat different pharmaceutical agents such as proteins, enzymes, bioactive molecules, and DDS, in order to increase its biocompatibility and reduce their clearance rate; this process is known as PEGylation and has gained a lot of interest since the 1970s to the date. Multiple studies have focused on the understanding of immunogenic response to PEGylated DDS, in general terms, factors associated with the PEG characteristics are: the length (molecular weight), the terminal group (that can be hydroxy, amino, methoxy, butoxy, tert-butoxy), the density of the PEG coating; nevertheless, factors associated with the DDS such as the size, hydrophilicity, and immunogenicity (of the DDS, and the loaded drug itself) that can trigger different immunogenic responses (Kozma et al., 2020; Hoang Thi et al., 2020) . In summary, despite the knowledge about the PEGylated immunogenic response, it is not appropriate to fully discard the use of PEG as a coating for DDS, or to provide optimal configuration for PEG to successfully coat specific DDS. More studies will be required to give a final conclusion to this issue. Hence, continuous attempts have been made to find a coat that can provide DDS enhanced circulation times and satisfactory bioavailability. 

Respiratory diseases are a major burden in terms of morbidity and mortality throughout the world. Undeniably, nanotechnology-enabled drug delivery systems in clinical practice represent a critical tool to improve patient survival and quality of life.

Nanotechnology has gained great interest in the past decades for drug delivery, the potential benefits of the use of nanostructures are the possibility of developing targeted therapies for certain diseases. Nanostructures exhibit multiple advantages such as biocompatibility, low toxicity, sustained and controlled release, capacity for targeting, multifunctionality, and high aqueous solubility. The present review discusses the most representative work in the field of drug delivery nanostructures for respiratory diseases treatment. We outline strategies for engineering nanoparticles to improve several crucial properties to make them more efficient to treat respiratory diseases. Additionally, it was pointed out the importance of finding new materials to make nanostructures less toxic, to show sustained and controlled release in the respiratory tract, and to improve capacity for targeting and sorting biological/physical barriers.

To date, there are some DDS commercially available, most of them correspond to liposome nanostructures, probably because of the reduced toxicity and enhanced bioavailability of this type of nanostructures when compared with others. Therefore, the development of new materials or finding new formulations from known materials that potentially overcome the challenges of the DDS is still significant in this field of research. However, it also requires more effort in understanding the interaction between complex biological systems with nanoscale systems giving the tools for proper design of new DDS platforms which can reach the clinical application that ultimately will benefit patients.

Deaths: leading causes for

Chronic respiratory diseases global mortality trends, treatment guidelines, life style modifications, and air pollution: preliminary analysis

Scope and limitations on aerosol drug delivery for the treatment of infectious respiratory diseases

Global epidemiology of tuberculosis and progress toward achieving global targets-2017

Latent tuberculosis infection: Opportunities and challenges

Silver nanoparticle functionalized CS-g-(CA-MA-PZA) carrier for sustainable anti-tuberculosis drug delivery

Dual delivery of tuberculosis drugs via cyclodextrin conjugated curdlan nanoparticles to infected macrophages

Green synthesis of quaternized chitosan/silver nanocomposites for targeting mycobacterium tuberculosis and lung carcinoma cells (A-549)

Inhalable solid lipid nanoparticles for intracellular tuberculosis infection therapy: Macrophage-targeting and pH-sensitive properties

Comparison and discussion of the treatment guidelines for small cell lung cancer

Lung cancer worldwide

Middle East respiratory syndrome coronavirus (MERS-CoV): A review

The risk factors associated with MERS-CoV patient fatality: A global survey. Diagnostic microbiology and infectious disease

Narrative review of Middle East respiratoryARDS syndrome coronavirus (MERS-CoV) infection: updates and implications for practice

The COVID-19 epidemic

Epidemiology and pathobiology of SARS-CoV-2 (COVID-19) in comparison with SARS, MERS: An updated overview of current knowledge and future perspectives

Challenges in ensuring global access to COVID-19 vaccines: production, affordability, allocation, and deployment

MERS-CoV as an emerging respiratory illness: a review of prevention methods. Travel medicine and infectious disease

Modern world applications for nano-bio materials: Tissue engineering and COVID-19

Delivering drugs to the lungs: The history of repurposing in the treatment of respiratory diseases

Emerging frontiers in drug delivery

Nano based drug delivery systems: recent developments and future prospects

The optimal choice of medication administration route regarding intravenous, intramuscular, and subcutaneous injection

Pharmacokinetics and toxicokinetics

Inhalation therapy devices for the treatment of obstructive lung diseases: the history of inhalers towards the ideal inhaler

Nanotechnology and pulmonary delivery to overcome resistance in infectious diseases

Challenges and future prospects for the delivery of biologics: oral mucosal, pulmonary, and transdermal routes

Methods to identify drug deposition in the lungs following inhalation

Inhaled therapy in respiratory disease: the complex interplay of pulmonary kinetic processes

Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aerosolized medications

Nanoparticles in the lung

Rapid translocation of nanoparticles from the lung airspaces to the body

Elimination pathways of nanoparticles

Nanoparticle-liver interactions: cellular uptake and hepatobiliary elimination

Nanomedicine, nanotechnology in medicine

Impact of nanotechnology on drug delivery

Nanostructured materials in drug and gene delivery: a review of the state of the art

Polymer-based nanocapsules for drug delivery

Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles

Erythrocyte membranecamouflaged polymeric nanoparticles as a biomimetic delivery platform

Degradable controlled-release polymers and polymeric nanoparticles: mechanisms of controlling drug release

Polymeric nanoparticles: the future of nanomedicine

Cationic surface modification of PLG nanoparticles offers sustained gene delivery to pulmonary epithelial cells

Polymeric nanoparticles for pulmonary protein and DNA delivery

Antimicrobial efficacy of tobramycin polymeric nanoparticles for Pseudomonas aeruginosa infections in cystic fibrosis: formulation, characterization and functionalization with dornase alfa (DNase)

Tailored nanocarriers for the pulmonary delivery of levofloxacin against Pseudomonas aeruginosa: a comparative study

Antioxidant polymeric nanoparticles as novel therapeutics for airway inflammatory diseases

Pulmonary targeting with biodegradable salbutamol-loaded nanoparticles

Biodegradable Janus nanoparticles for local pulmonary delivery of hydrophilic and hydrophobic molecules to the lungs

Rapid lymph accumulation of polystyrene nanoparticles following pulmonary administration

Biophysical inhibition of pulmonary surfactant function by polymeric nanoparticles: Role of surfactant protein B and C

Characterization of novel spray-dried polymeric particles for controlled pulmonary drug delivery

Polymeric nanoparticles in gene therapy: New avenues of design and optimization for delivery applications

A comparative pulmonary pharmacokinetic study of budesonide using polymeric nanoparticles targeted to the lungs in treatment of asthma

Comparative study of mucoadhesive and mucus-penetrative nanoparticles based on phospholipid complex to overcome the mucus barrier for inhaled delivery of baicalein

Encapsulation of Docetaxel into Diblock Polymeric Polymersome as a Nanodrug

The emergence of SARS, MERS and novel SARS-2 coronaviruses in the 21st century

Nanomaterials and nanotechnology-associated innovations against viral infections with a focus on coronaviruses

Viromimetic STING agonist-loaded hollow polymeric nanoparticles for safe and effective vaccination against Middle East respiratory syndrome coronavirus

Inhalable linezolid loaded PLGA nanoparticles for treatment of tuberculosis: design, development and in vitro evaluation

Alginate modified-PLGA nanoparticles entrapping amikacin and moxifloxacin as a novel host-directed therapy for multidrug-resistant tuberculosis

Polymeric nanoparticles for the delivery of miRNA to treat chronic obstructive pulmonary disease (COPD)

Inflammation-targeting polymeric nanoparticles deliver sparfloxacin and tacrolimus for combating acute lung sepsis

Platinum complexes of curcumin delivered by dual-responsive polymeric nanoparticles improve chemotherapeutic efficacy based on the enhanced anti-metastasis activity and reduce side effects

Inhalable resveratrol-cyclodextrin complex loaded biodegradable nanoparticles for enhanced efficacy against non-small cell lung cancer

Development and characterization of PLA nanoparticles for pulmonary drug delivery: Co-encapsulation of theophylline and budesonide, a hydrophilic and lipophilic drug

Anti-tumor effect of PEG-coated PLGA nanoparticles of febuxostat on A549 non-small cell lung cancer cells

Improving payload capacity and anti-tumor efficacy of mesenchymal stem cells using TAT peptide functionalized polymeric nanoparticles

Inhalable functional mixed-polymer microspheres to enhance doxorubicin release behavior for lung cancer treatment

Lung carcinoma therapy using epidermal growth factor receptor-targeted lipid polymeric nanoparticles co-loaded with cisplatin and doxorubicin

Evaluation of the Physicochemical Properties, Pharmacokinetics, and In Vitro Anticancer Effects of Docetaxel and Osthol Encapsulated in Methoxy Poly (ethylene glycol)-b-Poly (caprolactone) Polymeric Micelles

Physicochemical, pharmacokinetic, and toxicity evaluation of methoxy poly (ethylene glycol)-b-poly (d, l-Lactide) polymeric micelles encapsulating alpinumisoflavone extracted from unripe Cudrania tricuspidata fruit

Advances in polymeric micelles for drug delivery and tumor targeting

Polymeric micelles for nano-scale drug delivery

Fabrication of micellar nanoparticles for drug delivery through the self-assembly of block copolymers

The potential of Pluronic polymeric micelles encapsulated with paclitaxel for the treatment of melanoma using subcutaneous and pulmonary metastatic mice models

Preparation and evaluation of folate-modified cationic pluronic micelles for poorly soluble anticancer drug

Improving anti-tumor activity with polymeric micelles entrapping paclitaxel in pulmonary carcinoma

PEG-detachable polymeric micelles self-assembled from amphiphilic copolymers for tumor-acidity-triggered drug delivery and controlled release

Anti-tumor efficacy of c (RGDfK)-decorated polypeptide-based micelles co-loaded with docetaxel and cisplatin

Preparation and evaluation of inhalable itraconazole chitosan based polymeric micelles

Peptide-Micelle Hybrids Containing Fasudil for Targeted Delivery to the Pulmonary Arteries and Arterioles to Treat Pulmonary Arterial Hypertension

Self-assembled polymeric micelles for combined delivery of anti-inflammatory gene and drug to the lungs by inhalation

Pulmonary delivered polymeric micelles-pharmacokinetic evaluation and biodistribution studies

In vitro uptake and transport studies of PEG-PLGA polymeric micelles in respiratory epithelial cells

Advances in Nanocarriers for Effective Delivery of Docetaxel in the Treatment of Lung Cancer: An Overview

Drug combination synergy in worm-like polymeric micelles improves treatment outcome for small cell and non-small cell lung cancer

α-Conotoxin ImImodified polymeric micelles as potential nanocarriers for targeted docetaxel delivery to α7-nAChR overexpressed non-small cell lung cancer. Drug delivery

Cholesterol-grafted chitosan micelles as a nanocarrier system for drug-siRNA co-delivery to the lung cancer cells

Preparation and optimization of biodegradable self-assembled PCL-PEG-PCL nano-sized micelles for drug delivery systems

Drug delivery of rifampicin by natural micelles based on inulin: Physicochemical properties, antibacterial activity and human macrophages uptake

Development of extended-voyaging antioxidant linked amphiphilic polymeric nanomicelles for anti-tuberculosis drug delivery

Preparation and characterization of spray-dried inhalable powders containing polymeric micelles for pulmonary delivery of paclitaxel in lung cancer

Pulmonary delivery of rifampicin-loaded soluplus micelles against Mycobacterium tuberculosis

In vitro/in vivo investigation on the potential of Pluronic® mixed micelles for pulmonary drug delivery

Pulmonary-affinity paclitaxel polymer micelles in response to biological functions of ambroxol enhance therapeutic effect on lung cancer

Preparation and antitumor evaluation of hinokiflavone hybrid micelles with mitochondria targeted for lung adenocarcinoma treatment

Self-assembled polymeric micelles for combined delivery of anti-inflammatory gene and drug to the lungs by inhalation

pH-sensitive liposomes for drug delivery in cancer treatment

Liposomes as drug delivery systems for the treatment of TB

Liposomes: targeted and controlled delivery system

A comprehensive review on recent preparation techniques of liposomes

Giant liposome formation toward the synthesis of well-defined artificial cells

encapsulation of isoniazid-conjugated phthalocyanine-incyclodextrin-in-Liposomes Using Heating Method

Lipids, curvature, and nano-medicine

Recent advances on thermosensitive and pH-sensitive liposomes employed in controlled release

Formation of ciprofloxacin nanocrystals within liposomes by spray drying for controlled release via inhalation

Endothelial targeting of liposomes encapsulating SOD/catalase mimetic EUK-134 alleviates acute pulmonary inflammation

In-vitro and in-vivo evaluation of ciprofloxacin liposomes for pulmonary administration

Development and characterization of ligand-appended liposomes for multiple drug therapy for pulmonary tuberculosis. Artificial cells, nanomedicine, and biotechnology

Efficient drug delivery to lung epithelial lining fluid by aerosolization of ciprofloxacin incorporated into PEGylated liposomes for treatment of respiratory infections

The potential efficacy of R8-modified paclitaxel-loaded liposomes on pulmonary arterial hypertension

Starch-coated magnetic liposomes as an inhalable carrier for accumulation of fasudil in the pulmonary vasculature

Real-time in vivo imaging of surface-modified liposomes to evaluate their behavior after pulmonary administration

Pulmonary delivery of elcatonin using surface-modified liposomes to improve systemic absorption: polyvinyl alcohol with a hydrophobic anchor and chitosan oligosaccharide as effective surface modifiers

Liposomes coated with chitosan-xanthan gum (chitosomes) as potential carriers for pulmonary delivery of rifampicin

Systematic development and optimization of inhalable pirfenidone liposomes for non-small cell lung cancer treatment

Preparation of drug-loaded small unilamellar liposomes and evaluation of their potential for the treatment of chronic respiratory diseases

pH-sensitive multi-drug liposomes targeting folate receptor β for efficient treatment of non-small cell lung cancer

iRGD conjugated nimbolide liposomes protect against endotoxin induced acute respiratory distress syndrome

A Strategy to Treat COVID-19 Disease With Targeted Delivery of Inhalable Liposomal Hydroxychloroquine: A Preclinical Pharmacokinetic Study

Liposomal Lactoferrin Effect in Preventing SARS-CoV-2 Binding in HACAT Keratinocytes

Inhalation treatment of primary lung cancer using liposomal curcumin dry powder inhalers

Amikacin liposome inhalation suspension for treatment-refractory lung disease caused by Mycobacterium avium complex (CONVERT). A prospective, open-label, randomized study. American journal of respiratory and critical care medicine

Inhalable dry powder prepared from folic acid-conjugated docetaxel liposomes alters pharmacodynamic and pharmacokinetic properties relevant to lung cancer chemotherapy

Lipidbased vaccine nanoparticles for induction of humoral immune responses against HIV-1 and SARS-CoV-2

SLN and NLC for topical, dermal, and transdermal drug delivery

Mechanisms of drug release from advanced drug formulations such as polymeric-based drug-delivery systems and lipid nanoparticles

Lipid nanoparticles (SLN, NLC): Overcoming the anatomical and physiological barriers of the eye-Part II-Ocular drug-loaded lipid nanoparticles

Nanostructured lipid carriers for site-specific drug delivery

Inhalation treatment of cystic fibrosis with lumacaftor and ivacaftor co-delivered by nanostructured lipid carriers

Rifampicin loaded mannosylated cationic nanostructured lipid carriers for alveolar macrophage-specific delivery

Safety and effectiveness of sodium colistimethate-loaded nanostructured lipid carriers (SCM-NLC) against P. aeruginosa: In vitro and in vivo studies following pulmonary and intramuscular administration

Synthesis and investigations of ciprofloxacin loaded engineered selenium lipid nanocarriers for effective drug delivery system for preventing lung infections of interstitial lung disease

Nanostructured lipid carriers versus solid lipid nanoparticles for the potential treatment of pulmonary hypertension via nebulization

Nanostructured lipid carriers as novel drug delivery system for lung cancer gene therapy

Aerosolizable siRNA-encapsulated solid lipid nanoparticles prepared by thin-film freeze-drying for potential pulmonary delivery

Formulation Development of Itraconazole PEGylated Nano-Lipid Carriers for Pulmonary Aspergillosis using Hot-Melt Extrusion Technology

In vivo synergistic anti-tumor effect of lumefantrine combined with pH responsive behavior of nano calcium phosphate based lipid nanoparticles on lung cancer

Solid lipid nanoparticles for the delivery of anti-microbial oligonucleotides

Inhalable solid lipid nanoparticles for intracellular tuberculosis infection therapy: macrophage-targeting and pH-sensitive properties

Dendrimer as nanocarrier for drug delivery

Dendrimer-mediated drug delivery to the skin

Dendrimers in drug delivery and targeting: Drug-dendrimer interactions and toxicity issues

A convergent approach to sulfonimide-based dendrimers and dendrons

Pulmonary administration of PEGylated polylysine dendrimers: absorption from the lung versus retention within the lung is highly size-dependent

Dendrimer nanocarriers for transport modulation across models of the pulmonary epithelium

Poly (amidoamine) dendrimer as a respiratory nanocarrier: Insights from experiments and molecular dynamics simulations

PAMAM dendrimers as aerosol drug nanocarriers for pulmonary delivery via nebulization

Polyamidoamine dendrimers can improve the pulmonary absorption of insulin and calcitonin in rats

TPPdendrimer nanocarriers for siRNA delivery to the pulmonary epithelium and their dry powder and metered-dose inhaler formulations

A pilot study of the antiviral activity of anionic and cationic polyamidoamine dendrimers against the Middle East respiratory syndrome coronavirus

Structure activity relationship of dendrimer microbicides with dual action antiviral activity

Astodrimer sodium, dendrimer antiviral, inhibits replication of SARS-CoV-2 in vitro

Treatment of acute lung inflammation by pulmonary delivery of anti-TNF-α siRNA with PAMAM dendrimers in a murine model

Conjugation to poly (amidoamine) dendrimers and pulmonary delivery reduce cardiac accumulation and enhance antitumor activity of doxorubicin in lung metastasis

Chemo-biologic combinatorial drug delivery using folate receptor-targeted dendrimer nanoparticles for lung cancer treatment

Nano-in-Micro Sildenafil Dry Powder Formulations for the Treatment of Pulmonary

Arterial Hypertension Disorders: The Synergic Effect of POxylated Polyurea Dendrimers, PLGA, and Cholesterol. Particle & Particle Systems Characterization

Antiinflammatory effect of anti-TNF-α SiRNA cationic phosphorus dendrimer nanocomplexes administered intranasally in a murine acute lung injury model

Zwitterionic gadolinium (III)-complexed dendrimer-entrapped gold nanoparticles for enhanced computed tomography/magnetic resonance imaging of lung cancer metastasis

Extracellular vesicles as drug delivery systems: Why and how

Recent advancements in the use of exosomes as drug delivery systems

Extracellular vesicles for drug delivery

Engineering exosomes as refined biological nanoplatforms for drug delivery

Using exosomes, naturally-equipped nanocarriers, for drug delivery

Exosomes from cell culture-conditioned medium: Isolation by ultracentrifugation and characterization

Rapid and Efficient Isolation of Exosomes by Clustering and Scattering

A costeffective polyethylene glycol-based method for the isolation of functional edible nanoparticles from ginger rhizomes

Nanosomes carrying doxorubicin exhibit potent anticancer activity against human lung cancer cells

Engineered targeting tLyp-1 exosomes as gene therapy vectors for efficient delivery of siRNA into lung cancer cells

Edible plant-derived exosomal microRNAs: Exploiting a cross-kingdom regulatory mechanism for targeting SARS-CoV-2

Exosomal formulation enhances therapeutic response of celastrol against lung cancer

Adipose mesenchymal stem cell-derived antioxidative extracellular vesicles exhibit anti-oxidative stress and immunomodulatory effects under PM2. 5 exposure

Nanoparticles and its biomedical applications in health and diseases: special focus on drug delivery

Drug Delivery Systems Based on Nanoparticles and Related Nanostructures

Factors affecting the morphology of some organic and inorganic nanostructures for drug delivery: characterization, modifications, and toxicological perspectives

Nanoparticle toxicology

Molecular and immunological toxic effects of nanoparticles

Factors relating to the biodistribution & clearance of nanoparticles & their effects on in vivo application

Mesenchymal stem cellderived exosomes and other extracellular vesicles as new remedies in the therapy of inflammatory diseases

Potential therapeutic application of mesenchymal stem cell-derived exosomes in SARS-CoV-2 pneumonia

COVID-19 vaccine frontrunners and their nanotechnology design

Surface functionalization of polymeric nanoparticles for tumor drug delivery: approaches and challenges

Polymeric nanoparticles for controlled drug delivery

Polymeric nanoparticles for drug delivery: Recent developments and future prospects

Liposomes for drug delivery in stroke

Exosomes as drug delivery systems: A brief overview and progress update

Toxicity and biocompatibility aspects of dendrimers

Cancer statistics

Immunological mechanisms of human resistance to persistent Mycobacterium tuberculosis infection

Micro/nanoparticles fabricated with triblock PLLA-based copolymers containing PEG-like subunit for controlled drug release: Effect of chemical structure and molecular architecture on drug release profile

Recent developments in functionalized polymer nanoparticles for efficient drug delivery system

Nanotechnology approaches to pulmonary drug delivery: Targeted delivery of small molecule and gene-based therapeutics to the lung

Influence of particle size on regional lung deposition-what evidence is there?

Characterization of spray dried powders with nucleic acid-containing PEI nanoparticles

Mucus and cellpenetrating nanoparticles embedded in nano-into-micro formulations for pulmonary delivery of ivacaftor in patients with cystic fibrosis

Poly (lactic acid)/poly (lactic-co-glycolic acid) particulate carriers for pulmonary drug delivery

In-vitro and in-vivo characterization of a multi-stage enzyme-responsive nanoparticle-in-microgel pulmonary drug delivery system

Targeting defective pulmonary innate immunity-A new therapeutic option?

Enhancing nanoparticle penetration through airway mucus to improve drug delivery efficacy in the lung

Lipid-based mucus penetrating nanoparticles and their biophysical interactions with pulmonary mucus layer

Potential induction of anti-PEG antibodies and complement activation toward PEGylated therapeutics

PEGylated liposomes: immunological responses

Anti-PEG antibodies: Properties, formation and role in adverse immune reactions to PEGylated nano-biopharmaceuticals

The importance of poly (ethylene glycol) alternatives for overcoming PEG immunogenicity in drug delivery and bioconjugation

Antibodies against polyethylene glycol in healthy subjects and in patients treated with PEG-conjugated agents

Beyond PEGylation: alternative surface-modification of nanoparticles with mucus-inert biomaterials

Leading Key Players, Demand Forecast and Revenue Analysis with Top Countries Data

This research was supported by Consejo Nacional de Ciencia y Tecnología 

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 

o This manuscript has not been submitted to, nor is under review at, another journal or other publishing venue.o The authors have no affiliation with any organization with a direct or indirect financial interest in the subject matter discussed in the manuscript.

Corresponding author