Academic Editor: Stella Giulia Maria
Introduction: Local treatment of the airways and lung parenchyma has been used in clinical practice for several years for a variety of diseases. Methods: A variety of endoscopic tools for local treatment exist, especially for treating malignancies. Using these endoscopic tools, one can administer drugs specifically designed for the airways. Discussion: This article presents all locally administered treatment options and provides useful insights for future local endoscopically applied treatments.
Local endoscopic treatments have been in use for several years. A variety of endoscopic tools for local treatment exist such as argon plasma coagulation (APC), laser, cryoprobes and electrocatheters. One can use these tools through an endoscope in order to open a channel through a tumor or granulomatous tissue. Such invasive procedures are usually followed by a stent placement (silicon/metallic) with a balloon dilation system .
Specifically designed needles, used for applying glue in post-operative fistulas within the airways, exist. Moreover, specially designed catheters which produce spray for applying interferon and anti-vascular endothelial factor (VEGF) in the case of endobronchial HPV infections can also be found [2, 3]. Other types of catheters can spray biopolymer powder used for hemostasis with the help of a portable air-compressor. The same air-compressor can be used in order to generate aerosol formulations of different drugs such as interferon and anti-VEGF.
Stents have been used as a mechanical means of ensuring patency of the airways [4, 5, 6, 7, 8]. In the case of benign diseases, such as tracheomalacia, silicon stents have been used for some time, and recently drug eluting silicon stents containing everolimus, sirolimus and zotarolimus have been used for the prevention of granulomatous tissue formation. In the case of malignancies, metallic auto-expandable stents coated with paclitaxel or cisplatin have been used.
There is extensive research activity going on towards creating and introducing tissue friendly biogradable stents. Polymers and co-polymers are currently considered the best available option .
Efforts for improving stents include the use of electrospinning as a method to cover all types of stents. The main issue with drug eluting stents has been the time limitations in drug release. By using electrospinning, one can place large drug doses on the relatively small surface of stents.
The various interactions between the surface of stents and the mucosa have also been of interest in the recent years. Nowadays, stents can be custom made because it is feasible to use the information acquired from a CT of the thorax to create suitable stents using a 3D printer .
In the past year physicians have also had the opportunity to use a local
ablation microwave system developed by Bronchus
The future success of local treatments using endoscopic tools depends on the technological advancements, particularly in molecular biology and radiology techniques. Positron emission tomography (PET-CT) can identify active lesions and it can be used for treatment re-evaluation. Rapid on-site evaluation systems such as the Cellvisio® can be used to identify local disease and treatment efficiency. Other novel radiology techniques such as the Cios-Spin can assist in the navigation and application of local interventional treatments . This article aims to present the existing knowledge supporting choosing local treatments applied through the use of endoscopic tools for treating lung diseases.
Aerosol particles are deposited in the airways are removed by mucociliary
clearance mechanisms. The airway surface consists of epithelial goblet cells and
submucosal glands secreting mucus. These two cell types produce a two-layer mucus
blanket over the ciliated epithelium: (a) the low-viscosity sol layer and (b) a
high-viscosity gel layer. All insoluble particles are trapped in the gel layer
and with the help of the beating cilia are moved towards the pharynx or the
gastrointestinal tract or even removed through coughing. The activity of the
mucus varies depending on the airway area and the clearance is also
synergistically determined by the number of ciliated cells and their beat
frequency which differs in different parts of the airways. For normal mucociliary
clearance there must be no underlying lung disease. Furthermore, the chemical
composition of the sol layer should be optimal along with the rheology of the
mucus. Mucociliary clearance is dysfunctional in lung diseases such as immotile
cilia syndrome, chronic obstructive pulmonary disease (COPD), cystic fibrosis,
bronchiectasis, and asthma . It has been observed that lipophilic molecules
pass easily through the airway epithelium via passive transport, while the
hydrophilic molecules cross via extracellular pathways and exocytosis .
Particles deposited on the bronchial epithelium are absorbed into the systemic
bronchial circulation and then into the lymphatic system. Aerosol particles that
are deposited in the alveolar region may either be phagocytosed and cleared by
alveolar macrophages, or they are absorbed into the pulmonary circulation.
Alveolar macrophages situated in the alveoli are phagocytic cells and they are
the first defense layer against inhaled microorganisms and particles .
Macrophages phagocytose insoluble particles that are deposited in the alveoli,
and are either cleared by the lymphatic system or moved with the help of beating
cilia covered in alveolar fluid in the upper airways to the gastrointestinal
tract . However; depending on the particle’s chemical structure, this process
can take weeks to months to complete . There are cases where particles can be
enzymatically degraded intracellularly with the help of local enzymes . The
bacterial biofilm of the mucus also plays a crucial role in the rate of drug
absorption of the bronchial epithelium and alveoli . An extensive
investigation of these factors has been done in cystic fibrosis patients and
therefore all factors have been more or less elucidated . Pre-treatment with
aerosolized corticosteroids or saline in other cases provides enhanced local drug
absorption, in dosages of 1 mg/2 mL
The lungs receive the largest part of the cardiac output through the pulmonary arteries and are considered to be the highest perfused organs in the body. The alveoli are the parts of the lungs that are the most highly supplied. Only 1% of the cardiac output circulates to the trachea and bronchi. In bronchiectasis the bronchial blood flow is augmented from 1% to as much as 30% of the cardiac output . It has been observed that inhaled drugs that are deposited in tracheobronchial regions can be locally absorbed by the local vessels .
It has been observed in previous studies that tumor size affects the distribution and deposition of an inhaled compound and therefore the maximum diameter of the tumors had to be up to 5 cm upon diagnosis, otherwise patients were excluded from trials [24, 25, 26, 27, 28, 29]. Anticancer drugs have been observed to penetrate normal tissues by both diffusion and convection and finally reabsorption into the lymphatic circulation. However; a major issue is the unstructured neo-angiogenesis and lack of functional lymphatics in several tumors [30, 31]. This tumor microenvironment increases the levels of interstitial fluid pressure in tumors [32, 33, 34], reduces convection and inhibits distribution of macromolecules [35, 36]. The penetration of a drug particle depends on its: (a) charge, (b) shape, (c) molecular weight, and (d) aqueous solubility. Water-soluble drugs are distributed in the extracellular matrix and diffuse efficiently around and between the cells. Lipid-soluble drugs, on the other hand, penetrate lipid membranes, and so can be transported through cells. One can use 22G, 21G and 19G needles for local drug administration. Indeed, 19G needles can deliver larger quantities, however; depending on the stiffness of the tissue, the drug penetration will differ. Needles with pores on their sides exist to facilitate absorption of more cells during biopsy. Such needles can also be used to deliver more drug in different parts of a lesion when they are used for drug delivery [12, 37].
The most important physical properties that have to be considered when creating an aerosolized drug are: (a) viscosity ionic strength, (b) pH and (c) osmolarity. It has been observed that if pH and osmolarity are not in the normal range, then bronchoconstriction and coughing will occur due to mucosal irritation [38, 39].
It has been observed when studying aerosolized drugs that lung disease plays a crucial role in local drug absorption. This knowledge comes from studies of large patient populations with diabetes and aerosolized insulin administration, either as liquid or powder form . However; all these drugs are deposited to a large percentage of the surface of the airway epithelium. In the case of local intratumoral administration only the extracellular matrix (ECM) and the parameters contained in this environment play a key role. However, one should keep in mind that chronic obstructive pulmonary disease (COPD) or heart failure might be contraindications to performing an endoscopy for the administration of intratumoral therapy. In cases of underlying disease exacerbation, one should increase the dosage and administrations. Additional issues such as the oxygenation of a patient need to be resolved and aerosol pretreatment as previously described must be increased up to double. In the worst case scenario, one should switch to intravenous administration until the exacerbation is adequately managed. All this information can be found in a previously published article by Zarogoulidis et al. .
Liposomes are drug carriers that help secure sustained release, reduced toxicity and reduced irritation to the lung parenchyma. They can be easily manipulated and have stability . The dose of the drug carried by the liposomes, its release rate and the deposition in the alveoli depends on: (a) lipid composition, (b) particle size, (c) charge, (d) drug/lipid ratio, and (e) method of delivery [41, 42, 43]. Liposomes are produced from phospholipids, and they may or may not be electrically charged [44, 45]. Their structure consists of an aqueous part, which is entrapped by a synthetic lipid single layer or bilayer, with or without the addition of cholesterol. They can encapsulate either hydrophilic or lipophilic chemical entities . However, drugs with intermediate solubility are poorly retained by liposomes, so they have to be manipulated to achieve a higher degree of retention . Liposomes are prepared for inhalation either in liquid or dry powder form . Unfortunately, it has been observed that during nebulization, an amount of the formulation is lost and hence the operating conditions need to be optimized in order to minimize loss [49, 50, 51, 52]. The dry powder liposome formulations are produced by lyophilization, usually followed by milling or by spray-drying [53, 54]. The sustained release capability of liposomes has been observed in examples of aerosolized treatments for lung diseases in several studies [24, 55, 56]. In order to enhance the sustained-release properties of liposomes, a polymer surface coating called polyethylene glycol (PEG) has been developed recently. PEG coating provides a “stealth” shield to the molecule to bypass the body’s defense mechanisms [47, 57, 58].
Microparticles are produced from naturally occurring or synthetic polymers.
Their size ranges between 0.1 and 500
Further development of this molecules led to the development of “Trojan” particles , these have the ability to escape both phagocytic and mucociliary clearance of the respiratory system. They are prepared from nanoparticles, of low density (0.1 mg/mL). These particles can be aerosolized from dry powder . A single cancer cell can ingest one or multiple microparticles and these particles can be arranged in such a way so as to reduce the space occupied inside the cell [71, 72].
There are currently three carbohydrates used as used drug carriers: (a) lactose
(a-lactose monohydrate), (b) glucose, and (c) mannitol. These carriers act also
as stability enhancers. In the last decade several carriers were assessed and it
was observed that mannitol is the best candidate for dry powder inhaler
formulations . Current techniques that are used to produce a inhalable
formulation are: (a) supercritical fluid technology, (b) lyophilizing followed by
milling/jet milling or spray-drying, (c) freeze-drying, and (d) spray-freeze
drying [74, 75, 76, 77, 78]. Lactose enhances the uptake of poly-D-lysine into airway cells,
increasing intracellular localization of proteins and peptides . Lactose can
be mixed with fine lactose particles (about 5
Cyclodextrins (cyclic oligosaccharides), have also been proven to be useful
excipients in the respiratory distribution of small molecules . In a recent
study, the use of dimethyl-
Polyethylene glycol (PEG) added to proteins enables a sustained release at the site of deposition, due to a “stealth” effect, by bypassing the defense mechanisms of the respiratory tract (macrophages), and by decreasing degradation of the formulation in the lungs [47, 82]. PEG has been shown to be a safe carrier for inhalable agents .
Polylactic acid has properties that favor sustained release, but it is not suitable for lung delivery due to its prolonged biological half-life. However, an oligomer of lactic acid, with a shorter half-life (6–8 days), can be used instead for drug delivery. Hydroxypropyl cellulose, is another option absorbed over approximately 24 hours that bypasses mucociliary clearance. However, not enough data exist about its the toxicity profile [45, 84].
Bioadhesives have been used to prolong the attachment of the carrier-drug complex to the bronchial cells of the airways [85, 86]. Several multivalent binding agents have been incorporated in drug-carrier systems, such as; lectins, heparin, octa-arginine, peptides, heparin sulfate, and antibodies [87, 88].
Cell targeting has been used in recent years as the best method to improve local absorption. Gene therapy is considered the best method for cell-selective targeting . Additionally alveolar macrophages have been investigated as a vehicle by which to deliver a chemotherapeutic agent to the lymph nodes through the lymphatic circulation. It has been observed that liposomes and microspheres are engulfed by alveolar macrophages. Several receptors which are overexpressed in tumors, such as epidermal growth factor, have been exploited to target specific cells in cancer therapy [90, 91]. Low-density lipoprotein has been previously used for receptor assimilation .
Intracellular targeting is an additional strategy enabling a drug to reach the proper surface area [93, 94]. Most chemotherapy regimens interact within the reproductive cell cycle, so this delivery strategy should be further pursued . Three are the most important parameters concerning the cell microenvironment and drug-formulation interactions: (a) endosomal release, (b) intracellular trafficking, and (c) nuclear localization.
ABC transporters are a large family (50 members) of transmembrane proteins, consisting of seven subfamilies. ABC transporters act as a defense mechanism in lung epithelial tissue . P-glycoprotein, also known as multidrug resistant proteins, has been shown to play a role in multidrug resistance, especially in chemotherapy resistance . P-glycoprotein and its properties have been extensively studied in the lung. It has been observed that its presence decreases oral drug absorption, prevents drug entry in the central nervous system, and it is responsible for many drug to drug interactions . The transporter is found on the apical membrane of the bronchial and bronchiolar epithelium [99, 100, 101, 102], in the endothelial cells of the bronchial capillaries , and in alveolar macrophages [100, 101]. Unfortunately the expression of P-glycoprotein in smokers with lung disease versus people with normal lungs has not been adequately investigated. It has been observed that P-glycoprotein and immunohistochemical multidrug-resistant protein analyses can predict a patient’s response to chemotherapy . However; in one study, the mRNA levels in the lung tissue of smokers, non-smokers, and ex-smokers were not found to be significantly different . Several studies have previously demonstrated a direct or indirect connection between the P-glycoprotein transporter expression and underlying lung disease. In cystic fibrosis, for example, due to changes induced by the disease, it has been shown that the P-glycoprotein transporter is upregulated [105, 106]. Furthermore, it has been observed in another study that toxins released from microorganisms infecting patients with cystic fibrosis also inhibit P-glycoprotein . On the other hand, there are no significant data indicating modification of P-glycoprotein expression between different disease stages in chronic obstructive pulmonary disease patients [108, 109] and no relevant data exist for asthma patients. It has been observed that corticosteroids administered by inhalation, oral, and intraperitoneal routes upregulate the P-glycoprotein transporter [110, 111]. In a previous study, inhibition of P-glycoprotein was observed by lipid nanocapsules, which is a crucial mechanism of resistance for paclitaxel . Nine multidrug resistance proteins (MRPs) exist. In normal lung tissue, MRP 1 and MRP 5 have been found to be highly expressed, MRP 6 and MRP 7 are moderately expressed, and MRPs 2, 3, 4, 8, and 9 are either low or undetectable [113, 114]. MRP-1 and MRP-2 are found in the bronchial and bronchiolar epithelium [100, 115, 116]. MRP-1 is also found in alveolar macrophages [100, 115]. MRP-1 expression levels are altered in patients with chronic obstructive pulmonary disease [108, 115]. It has been shown that smoking downregulates these transporters, and these transporters play a protective role against cell damage [108, 117]. Ipratropium, N-acetylcysteine, and budesonide stimulate MRP-1 efflux and activity . Formoterol on its own does not have an effect on the transporter, however, the co-administration of inhaled corticosteroids reduces the transporter expressions . In a previous study on the use of inhaled doxorubicin, MRP-1 and MRP-2 were overexpressed . This information is important to keep in mind, because most lung cancer patients are also diagnosed with chronic obstructive disease and because most are or have been smokers, the transporter expression has been found to be increased after doxorubicin use.
Organic cation transporters comprise of five types of carriers: (a) electrogenic OCT 1-3, (b) electroneutral OCT N1 and (c) OCT N2. OCT 1–3 can be found in the trachea, smooth muscles of the airway, and ciliated bronchial cells. OCT N1 is expressed in the tracheal epithelium and alveolar macrophages. OCT N2 is expressed in the alveolar epithelium and airway epithelium [120, 121, 122, 123]. Previously published data from animal and in vitro cell lines studies implicate upregulation or downregulation of OCT transporters upon induced inflammation or drug interactions related to asthma and/or chronic obstructive pulmonary disease. Nevertheless, these data have not been clearly demonstrated in humans [122, 123, 124, 125].
Peptide transporters belong to the proton-coupled oligopeptide transporter group. PEPT 1 and PEPT 2 are the two main transporters, which contribute to the high bioavailability of peptide-like molecules. These two peptides can affect the absorption and distribution of inhaled antibiotics and antiviral drugs . PEPT 2 and PEPT 1 have been detected in the airway epithelium and bronchial epithelium [127, 128]. PEPT 1 and PEPT 2 have been found in animal tissues and various cell lines [129, 130]. Their mechanism of action, however, has not been fully investigated .
There are six members identified: (a) OAT 1–4, (b) URAT 1, and (c) OAT 5, mostly found in the kidneys . Gene microarrays have confirmed their absence in human and murine lungs, but OAT 2 is highly expressed at these sites . Moreover; OAT 4 mRNA was highly expressed in the bronchial cell lines Calu-3 and 16HBE14o- .
There are 11 human organic anion transporting polypeptides (OATPs), which are divided into six families . Their actual tissue distribution has not been fully investigated . OATP 2B1, OATP 3A1, OATP 4C1, and OATP 4A1 expression has been observed in: (a) cell lines, (b) human lungs, and (c) animals [120, 129, 134].
Several studies have been performed, both in humans and in animals, with inhaled
platinum analogs and instillation day 1 and cisplatin (50 mg/m
5-FU was the first chemotherapy drug to be used as local chemotherapy treatment
almost 30 years ago . A high-efficiency particulate arrestance filter and a
plexi-glass chamber were used for the administration. Safety and efficacy were
evaluated via blood samples, high performance liquid chromatography and imaging
techniques [142, 143, 144, 145]. The drug was administered intrabronchially and regression
of the tumor was observed with endoscopy in all their treatment sessions. The
drug has not been delivered intratumorally as in other studies 100 mg/m
Taxanes (paclitaxel and docetaxel) have been administered locally in the
respiratory system alone or in combination with other drugs [148, 149]. In one of
the first published studies cyclosporin A was co-administered as a method to
augment the efficiency of aerosolized taxanes paclitaxel (175 mg/m
This chemotherapy drug has been administered as local treatment. Safety and
efficacy assessments were performed with respiratory capacity tests (spirometry,
diffusion capacity and 6 minute walking test), high performance liquid
chromatography, V/Q display, imaging techniques, pathology findings,
blood samples, confocal laser scanning microscopy and colorimetric assay for cell
proliferation. Adverse effects observed included (a) acute chest pain, (b)
wheezing, alveolar hemorrhage, (c) weight loss, (d) cardiac toxicity, (e) hypoxia
Gemcitabine has less severe systemic side effects when administered
intravenously . In previous studies gemcitabine was administered as aerosol
in specially designed chambers and cages 2362 mg/m
9-NC has been previously investigated in animals and humans as aerosol and via
instillation. The safety and efficiency profile has been investigated with blood
and urine samples, imaging techniques, Ki-67 proliferation, pathology samples,
platelet-endothelial cell adhesion and performance liquid chromatography. The
only adverse effects observed included; (a) cough, (b) pharyngitis and (c)
bronchitis and these were dose-dependent. The 9-NC has been administered only as
a liposome form in doses of 26.6
Bevacisumab has not been administered as a local treatment for NSCLC, however, it is a strong anti-neovascularization drug used to treat NSCLC . It has been used for hereditary hemorrhagic telangiectasia-associated epistaxis as anasal spray and submucosal injections [159, 160]. It has also been used as local instillation treatment in bronchial HPV patients . The concept for its usage in general is to block the local anarchic proliferation of the vessels. The adverse effects observed were mainly ageusia, anosmia, headache, hemorrhage, hypertension, septal perforation and nasal obstruction (15 mg/kg on day 1Assessment of safety and efficacy was performed via blood samples, epistaxis severity score and phone administered custom-made questionnaires.
In a recently published multicenter study immunotherapy was administered locally
with the help of 19G needles under the guidance of endobronchial ultrasound with
a convex probe. The patients were stage four NSCLC and the safety and efficiency
of their treatment was evaluated with positron emission tomography (PET-CT) and
next generation sequencing (NGS) . Indeed, the combination of intratumoral
chemotherapy and immunotherapy improved survival rates in patients with
Local drug application can be achieved through instillation with a simple or spraying catheter . There are different catheters that one can use for the instillation of a liquid drug in a specific area via bronchoscopic guidance, Small compressors exist that can be used to produce compressed air and with the use of a catheter with specially designed tips one can either instill a drug or spray it with the help of the compressor (Fig. 1).
Left is the spraying catheter that produces aerosol with the help of positive pressure from a 60cc needle. Right the procedure using iodine solution on a piece of paper to present the spraying effect. An air compressor can be used if available.
Through a simple catheter one can spray a drug in powder form (Fig. 2).
Left an air compressor (yellow arrow), middle the drug in powder form, right green arrow sprayed powder inside a bronchus.
21G Olympus needle that can be used to apply drug solutions intratumorally.
22G Mediglobe Sonotip needle with a “CORONA” tip for enhanced cut-through effect and local drug application.
22G Mediglobe simple needle that can be used to apply intratumorally drug solutions.
19G Olympus needle that can be used to apply intratumorally drug solutions.
Another needle design exists that facilitates the combination of two drugs at the tip of the needle and the final combination can be applied in the designated exact location with the help of the bronchoscope (Fig. 7).
Needle with two separate channels in order to mix drugs at the tip. It can be used for the application of coagulation drugs that need mixing.
The “Blue fish balloon needle” is also available where a balloon catheter is expanded and at 12 o’clock a 34G needle is coming out to puncture the walls of a bronchus . This needle is usually used to apply drugs through stents as local treatment for granulomatous tissue formation or lung cancer tissue (Figs. 8, 9).
34G “Blow Fish” needle that can apply drug in the bronchial epithelium through a silicon stent.
34G “Blow Fish” needle in the trachea form the record of Professor Lutz Freitag, Department of Pulmonology, University Hospital Zurich, Rämistrasse 100, 8091, Zurich Switzerland.
Several locally administered drugs have been used for the treatment of non-small cell lung cancer, delivered through inhalation, instillation or intratumoral administration. All these different forms of local administration come with different issues to resolve. In the case of aerosolized drugs administered through inhalation, underlying airway disease is an issue as previously demonstrated with inhaled insulin . Another issue of course is the equipment that is used to produce small aerodynamic particles for inhalation. Upgrading the currently available equipment or coming up with novel equipment and techniques is necessary. In the case of central tumor obstruction, local ablation systems should be used prior to drug administration in order to secure airway patency. Various catheters can be used for different clinical situations, depending on the method of drug administration and drug chemical characteristics. Issues like spilling of possibly toxic to the surrounding tissues drugs need to be taken into consideration, because such occurrences might induce adverse effects such as pulmonary edema.
There is clearly need to use suitable equipment for targeted local administration and to create formulations that diffuse easily through the matrix of a lesion, to enhance fast, localized absorption. Autologous blood transplantation is another method of local treatment and can be used in a variety of medical conditions [165, 166]. The pros and cons of local application for each drug has been reported in the above sections. Local treatment has the major advantage of efficiency with less adverse effects. However; in order to achieve this we have to choose the optimal delivery system and the optimal drug for each environment. The treating physician has to choose according to a case by case scenario and choose the appropriate method. Another issue is the mode of ventilation and sedation for each patient. Again, this has to be chosen based on the underlying disease and method of application. The best combination of all these factors will have the best result (Table 1).
|-Benign tracheal stenosis|
Local drug treatment of lung diseases is feasible, and suitable for managing many diseases because it reduces systemic adverse effects and increases local drug efficiency. It should be an option depending on the patients’ current medical condition and history. However, novel delivery systems are needed and therefore clinicians should work closely with the pharmaceutical industry to produce the much-needed solutions.
PZ, CK, KS, WHS, DM, KT, AL, CB, HH, CA, AI, CS wrote the manuscript and collected the data.
The authors thank Dr. Lutz Freitag Professor of Pulmonary Medicine, “Ruhrland“ Clinic, Essen, Germany for his useful insights.
This research received no external funding.
The authors declare no conflict of interest.