Therapeutic Liposomal Dry Powder Inhalation Aerosols for Targeted Lung Delivery
Therapeutic liposomal powders (i.e., lipospheres and proliposomes) for dry powder inhalation aerosol delivery, formulated with phospholipids similar to endogenous lung surfactant, offer unique opportunities in pulmonary nanomedicine while offering controlled release and enhanced stability. Many pulmonary diseases such as lung cancer, tuberculosis (TB), cystic fibrosis (CF), bacterial and fungal lung infections, asthma, and chronic obstructive pulmonary disease (COPD) could greatly benefit from this type of pulmonary nanomedicine approach that can be delivered in a targeted manner by dry powder inhalers (DPIs). These delivery systems may require smaller doses for efficacy, exhibit reduced toxicity, fewer side effects, controlled drug release over a prolonged time period, and increased formulation stability as inhaled powders. This state-of-the-art review presents these novel aspects in depth.
KeywordsPulmonary nanomedicine Asthma Chronic obstructive pulmonary disease Cystic fibrosis Tuberculosis Lung cancer
Currently, there are three main delivery devices used for pulmonary delivery of drugs: nebulizers, pressurized metered-dose inhalers, and dry powder inhalers (DPIs) [1, 2, 3, 4, 5]. Each device has the ability to deliver different drug formulations; nebulizers and pressurized metered-dose inhalers can deliver solutions and suspensions while DPIs deliver dry particles. Tailoring the surface chemistry of particles through inclusion of certain types of phospholipids (e.g., dipalmitoylphosphatidylcholine, DPPC) so that the particle surface is less foreign to alveolar macrophages (i.e., more biocompatible) has been demonstrated to be a very promising and effective biocompatible strategy for evading alveolar macrophage uptake . Nanoparticles, as defined by the plethora of existing scientific literature, are less than 1,000 nm in diameter [1, 7, 8, 9]. However, nanoparticles tend to agglomerate. DPI formulations of nanoparticles are designed to reduce interparticle attractive forces and to improve the DPI performance, which can be achieved by blending with larger carrier materials . Nanocarrier systems in pulmonary drug delivery offer many advantages , including (1) the potential to achieve relatively uniform distribution of drug dose among the alveoli, (2) an achievement of enhanced solubility of the drug other than its own aqueous solubility, (3) the sustained release of the drug that consequently reduces the dosing frequency, (4) suitability for delivery of macromolecules, (5) decreased incidence of side effects, (6) improved patient compliance, (7) increased stability, and (8) the potential of drug internalization by cells [1, 11, 12, 13, 14].
Nanoparticles can also be used to enhance the bioavailability of insoluble hydrophobic drugs . Because nanocarrier systems may be administered to the airways easily and there are a variety of subtypes, a number of respiratory diseases may be approached using nanoparticles, e.g., lung cancer, obstructive lung diseases, including chronic obstructive pulmonary disease (COPD), asthma, and cystic fibrosis (CF); and infectious diseases, including tuberculosis and pneumonia [16, 17].
The potential pulmonary toxicity of nanoparticles is not fully known as it is the subject of considerable current research in the context of both size/composition and translocation out of the lung to other tissues compared with alveolar macrophage uptake or evasion . Dailey et al.  describe research in the field of environmental toxicology and acute pulmonary inflammation. Research was conducted exploring the varying degrees of pulmonary inflammation, measured by the amount of lactate dehydrogenase release, after pulmonary administration of biodegradable and nonbiodegradable drug carriers. Results from the work of Dailey et al.  found less pulmonary inflammation with the use of poly(lactic-co-glycolic acid) (PGLA) compared to nonbiodegradable drug carriers. Evora et al.  concluded that DPPC decreased alveolar macrophage uptake of nanoparticles formulated with PGLA. Therefore, although more research is needed to better understand pulmonary toxicity related to nanoparticle administration, the use of materials endogenous to pulmonary surfactant, such as DPPC, can significantly decrease toxicities such as acute pulmonary inflammation. Several current lung surfactant replacement pharmaceutical products contain DPPC liposomes  for pulmonary administration.
Inhaled Therapeutic Liposomal Aerosols as Dry Powders
Inhaled therapeutic liposomal dry powder aerosol formulations of drugs, oligonucleotides, peptides, and proteins have been successfully produced [11, 14, 24, 25, 26, 27]. Drug encapsulation in liposomes has been shown to improve the therapeutic effect and index of pharmaceutical drugs. In addition, lyophilization of liposomes increases the stability of the formulation, and the freeze-dried particles can be used for a variety of purposes [2, 5, 28, 29]. Spray-drying offers many advantages in designing and producing particles for DPIs, including increasing the stability of liposomes [5, 30, 31, 32] compared to liposomal solutions which are used for nebulizer delivery. Dry powder systems avoid the stability issues seen with nebulized solutions.
Liposome-encapsulated drugs seem to be a feasible system for targeting the lung, and liposomes have been shown to be well tolerated and are nonimmunogenic in humans [33, 34, 35, 36]. Liposomes can be phagocytosed by immune cells (e.g., macrophages) and therefore can provide a means to target antimicrobials and other drug agents to these immune cells [37, 38]. The versatility of the liposomal surface, interacting with other molecules, can assist in evading phagocytosis by surface coverage at defined concentrations with polyethylene glycol (PEG). Liposomal aerosol particles, with an aerodynamic size <5 μm, can be deposited in the deep lung . For a drug to have efficient and increased deposition in the lower airways, the aerodynamic size should be <3 μm .
Liposomes are an appropriate delivery system for lung administration of drugs because they can be prepared using compounds endogenous to the lungs, such as the major component of lung surfactant dipalmitoylphosphatidylcholine (DPPC), which comprises 70–80% of the pulmonary surfactant composition [1, 9, 33, 41, 42, 43]. Liposomal dry powder formulations have been described as being very promising in the delivery of various types of pulmonary drugs and are shown to decrease adverse effects without compromising efficacy of encapsulated drug compounds [1, 44].
Types of Drugs for Inhaled Dry Powder Therapeutic Liposomal Aerosols
Drugs that have been or may be good candidates for liposomal DPI formulation
β agonists and anti-inflammatories
Approved DPI pharmaceutical products and indications
Active therapeutic agent
1. Fluticasone propionate
2. Salmeterol xinafoate
2. Long acting bronchodilator
Identifying bronchial hyperresponsiveness to assist in the diagnosis of asthma
Treatment of CF, bronchiectasis, chronic bronchitis
Asthma, COPD, exercise-induced bronchospasm
Flexhaler® (Turbuhaler® discontinued)
Asthma, COPD, exercise-induced bronchospasm
Tiotropium bromide monohydrate
Influenza A and B prophylaxis and treatment
Chemical structuresa of some pulmonary drugs delivered as approved DPIs
Formoterol fumarate dihydrate
Tiotropium bromide monohydrate
Budesonide is a potent corticosteroid with prolonged tissue retention due to its hydrophobicity which inhibits inflammatory symptoms like edema and vascular permeability seen in asthma and COPD by decreasing airway hyperresponsiveness and reducing the number of inflammatory cells present in the airways [45, 46]. Liposomal encapsulation of budesonide was shown to control the drug release rate and allows therapeutic concentrations to be maintained in the lungs for longer periods while reducing systemic toxicity .
Formoterol is a highly potent, long-acting, β2-selective receptor agonist used for asthma and COPD bronchoconstriction relief with rapid onset and long duration of action [48, 49]. Saari et al. [36, 48, 50] formulated liposomes containing beclomethasone and formoterol and showed that beclomethasone maintained its long-lasting effect while formoterol enhanced lung function and peripheral lung deposition without a significant effect on mucociliary escalator. The short-acting β-blocker salbutamol sulfate has been successfully formulated into a sustained-release DPI liposomal delivery system .
Ketotifen fumarate is a mast cell stabilizer used for prophylaxis and treatment of asthma and helps control the inflammatory response seen in this chronic disease . Joshi and Misra [52, 53] showed that liposomes loaded with ketotifen fumarate can be effectively delivered as a DPI to the desired sites in the lung.
Targeted pulmonary delivery of antimicrobials (i.e., antibacterials and antifungals) by inhalation aerosols  is the subject of much recent interest in research and development, including several clinical trials. Liposomal dry powders can be an appropriate means of delivering antibacterial and antifungal agents to the lungs. Liposomes are among the most widely studied carriers for macrophage-specific antimicrobial drug delivery [55, 56, 57, 58, 59].
Amphotericin B (AmB) is a macrolide antifungal that is first-line therapy for the prophylaxis or treatment of fungal infections such as pulmonary aspergillosis, commonly seen in CF patients and lung transplant patients [39, 60]. AmBisome® (Astellas Pharma US Inc., Deerfield, IL) is AmB formulated into liposomes suitable for pulmonary aerosol delivery by nebulization. It shows fewer side effects than administration of liposome-free AmB, has been reported as effective in animal models of pulmonary aspergillosis, is well tolerated in immunocompromised patients, and liposomal formulation shows increased pulmonary deposition and retention [61, 62, 63, 64, 65]. Takazono et al.  combined AmB and micafungin in a liposome for the treatment of invasive pulmonary aspergillosis and found there to be increased concentrations of drug in murine lungs, thus contributing to the efficacy of the two antifungal agents together. A dry powder liposomal DPI formulation of AmB has been reported using a mixture of various hydrogenated soy phospholipids .
Cystic fibrosis (CF) is a genetically inherited disease caused by a gene mutation that affects almost every organ system in the body; primarily, the pulmonary epithelia are greatly affected by dehydration of the pulmonary secretions and decreased mucociliary clearance in the lungs [68, 69, 70]. The pulmonary manifestations in CF result from an exaggerated inflammatory response, defective bactericidal activity, and altered mucous clearance [68, 71]. Pulmonary liposomal aerosol delivery of antimicrobials can effectively fight infections, [54, 55, 72, 73] such as pneumonia, that commonly plague CF lungs due to the inability to clear mucus, bacteria, and/or fungi. Pseudomonas aeruginosa has been found in approximately 27% of CF patients 2–5 years old and approximately 80% of CF patients 25–34 years old . Inhaled aminoglycosides have become the treatment of choice for chronic P. aeruginosa infections in CF patients; however, currently marketed antibiotic inhalation products are limited to inhaled nebulized solutions for chronic use. Recently, DPI formulations for CF treatment have been designed that combine an antibiotic with a mucolytic agent .
Amiloride is a potassium-sparing diuretic that is used off-label for treatment of CF patients . Due to its short duration of action, the nebulized formulation needs to be administered four times daily, which can be a burden to patients and lead to decreased compliance . The ability to make an amiloride dry powder formulation would decrease patient burden and possibly, if delivered with a Turbohaler®, could be as effective or more effective than most jet nebulizers . A nanoliposomal amiloride hydrochloride DPI formulation was shown to exhibit more lung deposition with in vitro aerosol performance studies than particles not in nano-size range . It was also demonstrated that nanoliposomes had a prolonged residence time in rat lungs in vivo for up to 12 h .
The unique antimicrobial drug that exhibits anti-inflammatory and immunomodulating activity, dapsone, has been successfully delivered as a nanoliposomal DPI  in the treatment of Pneumocystis carinii pneumonia, an opportunistic pulmonary infection. DPPC and cholesterol were incorporated into the liposome and spray-dried to form the inhalable dry powder .
Tacrolimus and cyclosporine A are immunosuppressants that are frequently used to decrease rejection of transplanted organs such as lungs in the case of pulmonary drug delivery [76, 80]. Tacrolimus is effective, potent, safe, and superior to cyclosporine A, and shows promising results in reducing the risk of acute organ rejection . The clinical utility of tacrolimus is somewhat limited by its dose-related efficacy and toxicity, narrow therapeutic index, potential drug interactions, and large inter-/intrapatient variability in the pharmacokinetics of oral or parenteral formulations . Using liposomes for aerosol delivery is one way to overcome these constraints and has the potential advantage to suitably carry most lipophilic drugs . There are currently no tacrolimus liposomal DPI products on the market; however, a study done by Chougule et al.  found promising in vitro aerosol performance for tacrolimus-loaded nanoliposome DPIs, suggesting high deep-lung deposition as well as prolonged drug release of up to 18 h in vitro. The data from in vivo studies show drug residence within the lungs of up to 24 h and slow systemic dilution of tacrolimus, which when combined with the high deep-lung deposition, is expected to provide prolonged local action and necessitate less frequent administration and/or lower doses of tacrolimus as well as decreased systemic toxicities .
Cyclosporine A is a neutral, lipophilic, potent, immunosuppressive agent used to prevent allograft rejection . Systemic cyclosporine A use has been limited due to the high incidence of side effects . Behr et al.  formulated unilamellar liposomes of cyclosporine A to be delivered via nebulized solution. Inhaled liposomal cyclosporine A may be a promising approach to optimize immunosuppression and improve long-term outcomes while reducing systemic side effects, as liposomes demonstrate a large capacity as aerosol drug carriers [84, 85]. There are considerable advantages in formulating this lipophilic drug into DPI liposomal formulations, which would also impart controlled-release properties so that dosing frequency could be reduced for this chronically administered drug. Cyclosporine A is an agent that is not only important in helping prevent allograft rejection but has also been shown to reverse resistance that develops to potent first-line anticancer drugs such as paclitaxel [64, 80, 86, 87, 88].
Doxorubicin  is used clinically for the treatment of lung cancer, among other cancers, while the camptothecin derivative 9-nitrocamptothecin (9-NC) has been used in animal studies [94, 101, 102] and clinical trials  for treatment of metastatic lung cancer. The use of liposomal 9-NC formulations for aerosol delivery is being explored as a delivery method, providing increased efficacy with decreased toxicity [102, 104, 105]. Some limiting factors for the clinical efficacy of 9-NC are its poor oral bioavailability , its poor solubility in aqueous solutions [104, 105], its virtual insolubility in most physiologically compatible and pharmaceutically acceptable solvents , and the dose-limiting toxicity of chemical pharyngitis in humans, when delivered via nebulized liposome . Studies have shown that concentrations lower than those traditionally used in mice treated with 9-NC via other routes can be administered in liposomes to decrease toxicity while still seeing beneficial effects in lung cancer patients [102, 105]. In addition, Verschraegen et al.  formulated liposomes with 9-NC and dilauroylphosphatidylcholine (DLPC) and noted that inhaled 9-NC is rapidly absorbed into systemic circulation, reaching concentrations similar to those achieved with oral dosing. While this may lead to increased side effects, they will presumably still be less than the side effects from parenteral administration of 9-NC.
Recent phase I studies have demonstrated the ability to successfully deliver aerosolized doxorubicin and liposomal formulations of 9-NC and cisplatin in patients with primary and metastatic lung cancer [94, 99, 103, 106]. Otterson et al.  conducted a phase I study of inhaled doxorubicin in patients with advanced pulmonary tumors, primary or metastatic, which revealed no drug-related systemic toxicity at the doses given in the study; however, doxorubicin showed dose-limiting toxicity due to the direct effects of the inhaled drug on the upper and lower respiratory tract. A study by Azarmi et al.  showed that doxorubicin-loaded nanoparticles via dry powder delivery were internalized more readily by lung cancer cells compared to a passive diffusion mechanism and showed a concentration-related increase in cytotoxicity in vitro.
Paclitaxel is a water-insoluble drug used as a first-line agent for non-small-cell lung cancer treatment; therefore, the need for an alternate delivery form, such as pulmonary liposomes, is evident . Latimer et al.  explored in a murine model the effects of pulmonary delivery of paclitaxel liposomes on metastases of breast cancer to the lungs; their results showed a substantial decrease in the incidence of pulmonary metastases and tumor burden when the paclitaxel liposomes were administered sequentially with 2,5,7,8-tetramethyl-2R-(4R, 8R-12-trimethyltridecyl) chroman-6-yloxyacetic acid (a vitamin E analog) aerosolized liposomes.
Tuberculosis (TB) is a contagious disease, largely manifested in pulmonary tissue, among other body systems, caused by Mycobacterium tuberculosis. It is treated with first-line agents such as isoniazid (INH), pyrazinamide (PZA), rifampicin (or rifampin), and ethambutol [1, 28]. There are 8.8 million cases of TB annually leading to 1.1 million deaths . Considering that TB manifests mainly in the lungs by proliferating in lung macrophages  and that oral therapy is associated with decreased bioavailability, unfavorable tissue distribution, and adverse effects , the use of inhaled controlled-release liposomes to directly target the bacterial infection is of interest . Mycobacteria are 2–5 μm in diameter, which makes them the ideal size to enter the lower parts of the lung . Using traditional oral therapy makes it difficult to maintain adequate blood concentrations to completely eradicate the bacteria . The fact that mycobacterium proliferate in lung macrophages means that administration of a drug via liposomal DPI will be most favorable to allow concentration of the drug in the alveolar macrophages .
INH was combined in a 1:1 w/w ratio with DPPC in research done by Chimote and Banerjee . The INH–DPPC liposomes exhibited the ability to maintain patency of a narrow glass capillary tube, which mimics terminal airways in humans . The benefit of liposomal DPIs for the treatment of TB is that these INH–DPPC particles were proven to open atelectatic alveoli, which allows the drug to penetrate the deep, inaccessible parts of the lungs .
PZA is an important component in the TB treatment regimen and can significantly shorten the treatment duration from 9–12 months to 6 months . PZA was incorporated into the lipophilic and hydrophilic phases of liposomes which showed significant enhancement of drug entrapment . Relatively large multilamellar vesicles (MLVs) were produced, which was important for sustained-release drug delivery in pulmonary TB treatment . It was found that liposomal PZA in two-fifths the dose of free PZA was superior for the management of TB infection in vivo .
Recently, rifampin was formulated in a liposomal DPI delivery system [24, 41]. Liposomes using DPPC combined with rifampin and INH were shown to have good in vitro alveolar deposition and sustained-release characteristics . Rifampin is prone to degradation in the acidic pH of the stomach; hence, the ability to slow the release rate by using a liposomal formulation would be beneficial . Vyas et al.  formulated rifampin liposomes affixed with macrophage-specific ligands to help target the infected alveolar macrophages and found the preliminary results to be promising. Due to the superior surface activity of the dry particles formulated with INH, rifampin, or ethambutol, in DPPC liposomes, atelectatic alveoli can effectively open in vivo allowing the drug to penetrate the deep lung where TB infections often reside . Not only does antitubercular liposomal delivery to the lungs help TB patients, but the surfactant properties of DPPC, which is the greatest component of normal lung surfactant, can alleviate compromised lung compliance .
In conclusion, liposomal powders (i.e., lipospheres and proliposomes) for dry powder inhalation aerosol delivery that are formulated with phospholipids similar to endogenous lung surfactant offer unique opportunities in pulmonary nanomedicine while offering controlled release and enhanced stability. Many pulmonary diseases such as lung cancer, TB, CF, bacterial lung infections, fungal lung infections, asthma, and COPD could greatly benefit from this type of pulmonary nanomedicine approach using pharmacologic agents that can be delivered in a targeted manner by DPIs. These delivery systems may require smaller doses for efficacy, exhibit reduced toxicity, fewer side effects, controlled drug release over a prolonged time period, and increased formulation stability as inhaled powders.
Conflict of interest
The authors have no conflicts of interest or financial ties to disclose.
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