Abstract
Lung cancer is the second most prevalent and the deadliest among all cancer types. Chemotherapy is recommended for lung cancers to control tumor growth and to prolong patient survival. Systemic chemotherapy typically has very limited efficacy as well as severe systemic adverse effects, which are often attributed to the distribution of anticancer drugs to non-targeted sites. In contrast, inhalation routes permit the delivery of drugs directly to the lungs providing high local concentrations that may enhance the anti-tumor effect while alleviating systemic adverse effects. Preliminary studies in animals and humans have suggested that most inhaled chemotherapies are tolerable with manageable pulmonary adverse effects, including cough and bronchospasm. Promoting the deposition of anticancer drugs in tumorous cells and minimizing access to healthy lung cells can further augment the efficacy and reduce the risk of local toxicities caused by inhaled chemotherapy. Sustained release and tumor localization characteristics make nanoparticle formulations a promising candidate for the inhaled delivery of chemotherapeutic agents against lung cancers. However, the physiology of respiratory tracts and lung clearance mechanisms present key barriers for the effective deposition and retention of inhaled nanoparticle formulations in the lungs. Recent research has focused on the development of novel formulations to maximize lung deposition and to minimize pulmonary clearance of inhaled nanoparticles. This article systematically reviews the challenges and opportunities for the pulmonary delivery of nanoparticle formulations for the treatment of lung cancers.
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Introduction
Lung cancer is the second most common cancer worldwide, representing ∼14% of newly reported cases. The majority (85%) of lung cancer cases is classified as non-small cell lung cancer (NSCLC), with the remaining classified as small cell lung cancer (SCLS)1. The American Cancer Society estimates that there were more than 200 000 new cases of lung cancer and approximately 150 000 deaths in 2017 in the United States alone, making it the deadliest among all types of cancer2.
Unfortunately, an early diagnosis of lung cancer is challenging, and at the time a diagnosis most lung cancers are in advanced metastatic stage. The metastatic spread of cancer to distant organs is the dominant reason for the dismal survival rate of advanced-stage lung cancer patients, with a 5-year survival rate of only 10%3,4,5,6,7,8,9. The most common metastatic locations for lung cancer are typically the nervous system, bone, liver, respiratory system, and adrenal glands10.
Surgical removal/resection is the main treatment for non-metastatic lung cancers. However, this technique can only be used in 10%–20% of patients with NSCLC and is limited by the number and the site of the lesions and the patient's respiratory and/or general status11,12. Lung cancers for which surgery is not a feasible option generally require chemotherapy to prolong survival, control symptoms and improve the quality of life of patients13,14,15,16.
Anticancer drugs must penetrate cancer tissues to attain a concentration necessary to exert effective tumor killing; indeed, suboptimal drug concentrations typically exhibit weak anti-tumor activity and additional concerns regarding drug resistance17,18. Intravenous administration inevitably causes a considerable proportion of chemotherapeutics to be widely distributed in various organs, leading to substantially low drug concentrations at tumorous sites. This necessitates the administration of high doses to attain therapeutically effective drug concentrations at the diseased sites. Such high doses can cause severe adverse effects, especially at the sites of rapidly dividing cells such as hair, skin, spleen and liver, among others18,19,20. These toxicity concerns compromise the efficacy and compliance of systemic chemotherapy against lung cancer21,22,23,24. Furthermore, lung cancer sub-types may also be genetically diverse, making treatment even more difficult. Thus, there is an urgent need for new treatments with improved safety and efficacy.
Inhaled chemotherapy
Localized chemotherapy refers to the delivery of anticancer drugs directly to the affected organs, which can ensure higher concentrations in tumors compared to other non-target sites. Localized chemotherapy has been confirmed to be effective against various types of cancers, including ovarian and colorectal cancers25,26,27,28,29,30. Inhaled drug delivery facilitates the localized delivery of drugs directly to the lungs via the oral or nasal inhalation route. Inhalation is a non-invasive route of administration, and some inhaled dosage forms are easy to carry and use, making it a promising alternative to the parenteral routes of drug delivery for treating respiratory diseases. Inhalation therapies have been shown to be effective and are well accepted for the treatment of respiratory tract diseases such as asthma, chronic obstructive pulmonary disease (COPD) and respiratory tract infections.
Inhaled chemotherapy has been shown to be promising against lung cancers (Table 1)31,32,33,34,35,36. Inhalation can alter the bio-distribution of drugs and promote the accumulation of a larger fraction in the lungs compared to parenteral administration37,38,39,40,41. Furthermore, inhalation limits the systemic distribution of anticancer drugs and thus the associated toxicity35,36. Most adverse effects associated with inhaled chemotherapy were shown to be localized, including cough and glottitis, which are common and treatable. In some cases, respiration-related complications, such as a drop in forced expiratory volume and hypoxia, have been reported. Most local adverse effects following inhaled chemotherapy have also been shown to be drug-, dose- and time-dependent31,32,33,34,35,36,42,43,44. However, it is not clear whether these adverse events were associated with disease progression or inhaled chemotherapy34,35.
A high proportion of inhaled drug has commonly been detected in the lymph nodes32. Inhaled drugs can also be deposited in the lymphatic tissue via the lymphatic circulation32. Thus, inhaled chemotherapy may also be beneficial for the treatment of lung cancer that has metastasized to the lymph nodes32. Moreover, drugs that are absorbed into the lymphatic circulation can redistribute in peripheral airways, allowing access to otherwise poorly accessible areas of the lungs42,45. Thus, inhaled chemotherapy may be extremely beneficial in cases of cancer that has metastasized to the lung, which are usually located away from the major airways but receive blood from the pulmonary arteries and veins46,47,48. Aerosolized delivery of liposomal interleukin-2 (IL-2) in dogs has been shown to be effective against pulmonary metastases from osteosarcoma49. A combination of intravenously injected human natural killer cells and inhaled interleukin-2 had a synergic effect and increased the survival of mice with osteosarcoma lung metastases50. Inhaled chemotherapy has also been used as an adjuvant with systemic chemotherapy; however, no improvement in tumor efficacy was observed compared to systemic chemotherapy alone33.
Most lung cancers are in the metastatic stage at the time of diagnosis, and the treatment of lung cancer that has metastasized to other organs may further improve the efficacy of chemotherapy. There has been increasing interest in exploring the inhalation route for systemic drug delivery, such as insulin for diabetes or gene therapy51,52. Thus, it is possible that delivery via inhalation may be used to deliver chemotherapeutic agents systemically and target lung cancer metastasis to other organs. However, the effect of inhaled chemotherapy on metastasized lung cancer has not been investigated.
Although inhaled delivery has a clear pharmacokinetic advantage over systemic delivery, ensuring the deposition of the drug in the resident tumor is key to achieving efficient anti-tumor activity. However, the efficacy of inhaled chemotherapy depends on multiple factors, including tumor size, disease stage, drug penetration at the tumor site, physico-chemical properties of drugs, local adverse effects, and patient condition. These factors play a dominant role in determining whether inhaled delivery is indeed a feasible and/or effective option for lung cancer therapy.
Respiratory tract obstruction due to lung cancer and other obstructive respiratory conditions such as cystic fibrosis and bronchiectasis can affect the deposition and distribution patterns of aerosols in the lungs. For example, a lung tumor can physically occlude the respiratory tract by reducing the cross-sectional area of the lung, which can divert the airflow to non-occluded areas and reduce the deposition of inhaled drugs to the tumor. The effects of tumors in terms of size and location on airflow, particle transport, and deposition patterns have been modeled53. It was shown that the particle deposition at tumor sites increases until the tumor blocks approximately half of the airway lumen and then decreases with further obstruction. It has also been proposed that the majority of the inhaled drug is deposited on the frontal surface of the tumor53.
Despite the direct access to the lung tumor via inhalation, enhancing drug penetration to the lung tumor is also critical for achieving efficient anti-tumor activity. The depth of tumor penetration following topical deposition is usually limited and also depends on the physico-chemical properties of drugs, including the molecular weight, solubility, and apoptotic activity17,42,54,55,56,57,58. Furthermore, penetration of the drug to the tumor depends on the nature of the tumor, including the size, cellularity of the tumor and density of the interstitium59. It has been demonstrated that small nodules respond better to inhaled chemotherapy than larger nodules40. Thus, limited penetration and an inability to achieve an adequate drug concentration in the tumor tissue may limit the effectiveness of inhaled chemotherapy.
The uptake and direct toxicity of inhaled chemotherapy to healthy lung cells are relatively unknown. The deposition of high concentrations of anticancer drugs in healthy lung cells may increase the risk of undesirable local toxicities. Overall, the effectiveness of inhaled chemotherapy against lung cancers is established, but there is considerable uncertainty regarding the toxicities of inhaled chemotherapy to healthy lung cells, making their safety a subject of constant debate. Hence, promoting uptake in cancer cells and minimizing accumulation in healthy cells may be a more effective approach to ensure the safety and efficacy of inhaled chemotherapy.
Nano-carriers for inhaled drug delivery
The delivery of anticancer drugs via nanoparticles has been shown to be efficacious and safe in a variety of cancers60,61,62. Nanoparticles can encapsulate toxic anticancer drugs by biocompatible and biodegradable excipients and facilitate targeted and/or controlled delivery63,64,65,66,67. Anticancer drugs can also be formulated into drug nanocrystals with high drug loading and minimal use of excipients68,69,70. Thus, pulmonary administration of nanoparticles could also reduce the systemic toxicity of chemotherapeutic agents compared with free drugs. For example, Roa et al showed that inhaled doxorubicin nanoparticles exhibited lower cardiac toxicity compared with the same dose of free doxorubicin after intratracheal administration71. Zou et al showed that paclitaxel-polyglutamic acid conjugate was well tolerated by mice following intratracheal administration72. Furthermore, the sustained release characteristics of nanoparticles may further aid the effectiveness of inhaled chemotherapy by maintaining drug concentrations at tumor sites for longer durations73,74,75.
Due to their small size, nanoparticles inherently tend to penetrate and accumulate within the leaky tumor vasculature when a drug is delivered via systemic administration, which is termed the enhanced permeation and retention (EPR) effect76,77,78,79,80. The EPR effect may not play a role in tumor deposition when nanoparticles are administered via inhalation. However, delivery of the drug directly into the lungs enables passive targeting to the lung tumor. Furthermore, nano-carriers are taken up into the cancer cell via endocytosis, which typically does not occur in the case of solubilized drug81,82. Thus, nanoparticles can increase penetration and accumulation of inhaled drugs in tumor tissues and cells, leading to improved anti-tumor activity compared with the free drug42,83,84,85.
A large fraction of nanoparticles are taken up by the reticuloendothelial system (RES), such as the liver, kidney and spleen, following intravenous administration85,86,87, whereas the primary site of distribution of inhaled particles is the lungs. Thus, a relatively large fraction of nanoparticles is deposited in the lungs following inhalation compared to systemic delivery73,74,83,84,85,88,89. However, the accumulation efficiency of nanoparticles in lung tumors following inhaled and systemic administration have not been thoroughly compared. Interestingly, inhaled doxorubicin-conjugated dendrimer showed better anticancer activity compared to systemic administration, indicating that there is a limited EPR effect in some lung tumors90.
Moreover, cellular uptake of particles is a particle size-dependent phenomenon and has been shown to increase with a decreasing particle size91,92. Hence, the selection of nanoparticles for inhaled delivery is inherently advantageous in terms of penetration-enhancing ability, as compared with microparticles. Roa et al showed that nanoparticles embedded in an effervescent carrier matrix facilitated the rapid release of primary nanoparticles and enhanced anti-tumor activity compared with those embedded in a non-effervescent carrier matrix following inhaled delivery71.
The ability of nanoparticles to release a chemotherapeutic agent in close proximity to the tumor is imperative to achieve selective and efficient tumor killing. However, premature release of encapsulated drug from nanoparticles may lead to non-specific toxicity to normal lung parenchyma. To circumvent this limitation, nanoparticles with site-specific and triggered release characteristics have been explored. Low extracellular and intracellular pH of tumor tissue/cells have been exploited to enable triggered release through the design of pH-sensitive fusogenic lipid nano-vesicles. These nano-vesicles fuse with the cell plasma membrane and lysosomal membrane at low pH, thus providing site-specific and triggered delivery of anticancer drugs to cancer cells93,94,95. It has been demonstrated that pulmonary surfactant mimetic pH-sensitive nanoparticles are cytotoxic to lung tumor cells while being compatible with healthy lung cells, indicating a selective toxicity of the developed formulation to lung cancer cells96.
Nanoparticles can also be actively targeted to tumor cells by attaching tumor-specific ligands, which are thought to guide drug-loaded nanoparticles and facilitate specific interactions with lung cancer cells. Such targeting can inhibit the non-specific interaction between drug-loaded nanoparticles and healthy lung cells and reduce local toxicity90. Lung cancer cells overexpress several receptors, such as epidermal growth factor receptor (EGF receptor), folate receptor, and luteinizing hormone-releasing hormone (LHRH receptors97,98,99,100,101,102,103,104. Tseng et al showed that EGF receptor-targeted biotinylated gelatin nanoparticles deposited more selectively into cancer cells owing to receptor-mediated uptake and caused no injury to the lungs105,106. EGF receptor-targeted inhalable magnetic nanoparticles demonstrated increased uptake in cancer cells compared with non-targeted particles and exhibited greater anti-tumor activities107. EGF receptor-targeted cisplatin-loaded gelatin nanoparticles demonstrated greater lung deposition and retention, resulting in enhanced anti-tumor efficacy compared with free cisplatin or non-targeted nanoparticles108. Taratula et al developed LHRH peptide-coated mesoporous silica nanoparticles (MSNs) to deliver anticancer drugs (doxorubicin and cisplatin) and antisense oligonucleotides targeted to MRP1 and BCL-2 against resistant lung cancer. Inhalation allowed the deposition of higher drug/siRNA concentrations in the lungs compared to intravenous administration. The targeted nanoparticles were effectively internalized into human lung cancer cells and demonstrated an enhanced anticancer activity75. Taratula et al also showed that lipid nanoparticle targeted to LHRH receptors can facilitate the selective deposition of doxorubicin and siRNA in lung tumor cells and minimize deposition in healthy lung tissues109.
Solid tumors are characterized by increased extracellular matrix deposition and tumor fibrosis110,111. This matrix is mainly composed of collagen networks and leads to the compartmentalization of tumors, which enhances tumor cell survival and proliferation111,112,113. Such a dense collagen network can inhibit nanoparticle penetration and distribution into the tumor110,114,115,116,117. Anti-fibrotic agents have been reported to decrease tumor interstitial fibrosis and promote the intra-tumoral distribution of nanoparticles115,118. Inhaled anti-fibrotic agents, ie, losartan and telmisartan, have also been shown to improve the uptake and accumulation of nanoparticles in lung cancer models119.
Overall, nanoparticles can improve the anti-tumor activity of loaded chemotherapeutics120,121,122,123. Nanoparticle-mediated inhaled chemotherapy has been shown to be safe and effective against lung cancer in pre-clinical and clinical studies (Table 2).
Drug resistance is another factor that can substantially compromise the therapeutic efficacy of chemotherapeutic agents against cancers. Lung cancers with acquired, ie, “pump” or “non-pump” resistance are less responsive to anticancer drugs128. Pump resistance is typically associated with the expression of proteins such as multidrug resistance-associated protein (MRP) and P-glycoprotein, which can actively pump anticancer drugs out of cancer cells, reducing their intracellular concentration and consequently effectiveness129. Non-pump resistance is caused by the activation of anti-apoptotic cellular defense due to the upregulation of B-cell lymphoma-2 (BCL-2) protein, which prevents the release of cytochrome c and hence the execution of caspase-mediated cell apoptosis130, 131. Suppression of drug resistance-associated proteins such as BCL-2 protein and MRP could reduce the efflux of anticancer drug and promote apoptosis sensitivity against anti-tumor drugs. Nanoparticles can co-deliver anticancer drugs with genes and other adjuvants to effectively suppress these resistance mechanisms and increase the sensitivity of such resistant cancer cells against chemotherapies75. Garbuzenko et al developed inhaled nanoparticles containing doxorubicin in combination with antisense oligonucleotides targeted to MRP1 mRNA as a suppressor of pump resistance and BCL-2 mRNA (as a suppressor of non-pump resistance) for lung cancer. This formulation has been shown to enhance the sensitivity of lung cancer to anticancer drugs, increasing the efficacy upon inhalation132.
Physiological barriers to inhaled drug delivery
For inhaled chemotherapy, drugs should be deposited and retained in the lungs at therapeutically effective concentrations to elicit an efficient anti-tumor effect. However, the architecture of the respiratory tract and clearance mechanisms of the lungs pose a key challenge to the deposition and retention of inhaled nanoparticles in the lungs. To effectively address these issues, it is important to understand the barriers to deposition and retention of inhaled nanoparticles. The current understanding of the deposition and clearance behaviors of inhaled nanoparticle is largely derived from studies investigating the clearance of environmental nanoparticle pollutants, which can be extrapolated to drug nanoparticles to a certain extent134.
Deposition of inhaled particles
The lungs are composed of a series of branching airways, which can be classified into the conducting zone and the respiratory zone. The conductive zone or upper airway consists of the trachea, which divides into two bronchi and further subdivides into bronchioles, whereas the respiratory zone, or the deep lung, includes the respiratory bronchioles, the alveolar ducts and the alveolar sacs.
Inhaled particles are carried with tidal air through the respiratory tracts. Particulate properties such as geometric size, shape and density determine the inertia acting on particles during their travel through the airway and thereby determine their deposition along the respiratory tract136,137,138. This aerodynamic behavior is often characterized by the aerodynamic diameter, which represents the diameter of a sphere of unit density. Particles of the same aerodynamic diameter reach the same velocity in the air stream as the particle of interest of arbitrary density. Particle measurement techniques, such as light scattering, laser diffraction or image analysis, provide geometric diameters, which can be converted to the aerodynamic diameter using a widely accepted model that describes the relationship between the geometric diameter, density and aerodynamic diameter139:
Where Da is the aerodynamic diameter, Dg is the geometric diameter, ρ0 is the unit particle density, ρ is the particle density, and χ is the dynamic shape factor of the particle.
Based on the aerodynamic diameter, inhaled particles are believed to distribute along the airways via three main mechanisms: inertial impaction, gravitational sedimentation and diffusion140,141. Particles with an aerodynamic diameter >5 μm lack the ability to change their trajectories with the tidal air, leading to impaction and deposition in the upper airways. The main mechanism of deposition is thus inertial impaction142,143,144. Particles with an aerodynamic diameter between 1 and 5 μm are believed to deposit mostly in the lower airways (bronchioles and alveoli) via the mechanism of gravitational sedimentation145. Particles with an aerodynamic diameter smaller than 1 μm remain suspended in the airstream and are likely exhaled after inhalation without being deposited in the airway. The main deposition mechanism for these particles is diffusion145,146. Interestingly, as the particle size decreases to less than approximately 500 nm, lung deposition may increase147,148,149.
For medications targeting the lower airways (ie, the deep lung), particles with an aerodynamic diameter of 1–5 μm are highly desirable. The performance of inhaled formulations is often described in terms of the fraction or dose of particles in the size range of 1-5 μm, which is termed as the fine particle fraction (FPF) or fine particle dose (FPD). Alternatively, the mass median aerodynamic diameter (MMDA), which is defined as the aerodynamic diameter at which 50% of the particles are smaller, can also be used as an indicator of the aerosol property of inhaled formulations138.
Clearance of particles in the respiratory tract
Depending on the regional distribution and particle properties, inhaled particles are cleared primarily via three mechanisms: muco-ciliary clearance, phagocytosis, and systemic uptake150.
Muco-ciliary clearance is the dominant clearance mechanism in the upper airway151. The ciliated columnar epithelium secretes mucus, which traps the particles deposited in the upper airways. These entrapped particles are propelled by the action of beating cilia in a proximal direction, causing them to be coughed out or swallowed. The majority of insoluble particles with a size >5 μm deposited in upper airways and are eliminated via muco-ciliary clearance152. Smaller particles are deposited in the deep lungs where muco-ciliary clearance is less functional and thus are retained longer than larger insoluble particles135,152,153,154. Macrophages are also present in the upper airway, but phagocytosis is less dominant in this region134,155.
The clearance mechanisms in the deep lungs are relatively complex and depend on particle properties such as dissolution kinetics. Slowly dissolving or insoluble particles may interact with epithelial and immune cells in the lungs and be removed by muco-ciliary clearance, phagocytosis via alveolar macrophages, and endocytosis156,157,158. Phagocytosis by alveolar macrophages is believed to be the dominant clearance mechanism in the deep lungs159,160. This process involves particle internalization by macrophages, followed by lysosomal digestion or removal of particle-loaded macrophages into the lymph or via muco-ciliary clearance161,162,163,164,165,166. Phagocytosis by macrophages is mainly responsible for clearance of particles between 1 and 5 μm in size167,168,169,170. Particles with a size <200 nm are not recognized by macrophages due to their small size153,171 and/or rapid uptake by epithelial cells172. The role of protein/receptor-mediated uptake has been highlighted in the translocation of a small fraction of inhaled nanoparticles to the systemic circulation152,153,161,173. Intact nanoparticles may also enter the systemic circulation by endocytosis via alveolar caveolae158.
Nanoparticles that undergo quick dissolution after deposition in the deep lungs may rapidly release drug, which can be absorbed into the systemic circulation162,163,174. The rate of absorption of a drug molecule is closely associated with its lipophilicity and molecular weight, whereby low-molecular-weight lipophilic drugs are the most rapidly absorbed.
Improving lung deposition
Particulate properties such as particle size, density, and surface composition play a vital role in developing effective inhalable medicines by determining the site of deposition. Thus, developing formulations with appropriate particulate properties is key to the effectiveness of inhaled medicines. Individual nanoparticles with sizes <500 nm tend to agglomerate due to strong cohesive forces, resulting in aggregates of uncontrolled sizes175,176,177. These aggregates are difficult to disperse into individual nanoparticles after inhalation, leading to inconsistent, unpredictable and often poor aerosolization84,178. Hence, nanoparticles are often administered as particles/droplets with 1–5 μm aerodynamic diameters. Nebulizer devices can convert nanoparticle suspensions into highly inhalable droplets. Alternatively, particle engineering can convert nanoparticles into uniformly sized inhalable particles.
Nanoparticles as inhalable droplets
Typically, nanoparticle suspensions are aerosolized into droplets with appropriate aerodynamic diameters using currently available inhalation devices. Nebulizers and pressurized Metered Dose Inhalers (pMDI) are employed to assist nanoparticle inhalation.
Nebulizers
The nebulizer is the most commonly used device for inhaled delivery of nanoparticle suspensions179. In general, nebulizers utilize compressed air to convert a suspension of nanoparticles into inhalable droplets180. For example, aerosolization of telmisartan and losartan bearing a solid lipid nanoparticle suspension using a jet nebulizer resulted in a FPF >70% and was deposited into the lungs in separate in vivo inhalation experiments119. Aerosols of nanoparticle suspensions exhibit a higher FPF than drug solutions after nebulization, indicating the suitability of nanoparticles for inhalation delivery96,125. There have been concerns about the negative effects of nebulization on the structure of delivery vehicles, especially lipid-based particles as well as susceptible drugs and genes181. Mainelis et al demonstrated that the one-jet collision nebulizer facilitated the deposition of liposomes containing doxorubicin and siRNA into the deep lungs without compromising liposome integrity and the biological activity of susceptible antisense oligonucleotide182. The bulky traditional jet nebulizers are not convenient to use; more portable and efficient nebulizers, such as vibrating mesh nebulizers, have recently been developed180,183,184,185,186. The mesh nebulizer was used to aerosolize a paclitaxel lipid nanocapsule suspension and showed an FPF >80% without altering the primary properties of the lipid nanocapsules181.
Pressurized metered dose inhaler (pMDI)
The pressurized metered dose inhaler (pMDI) creates small inhalable droplets of drug suspended in compressed propellant (ie, hydrofluoroalkane [HFA]). The small size of pMDI devices thus offer greater portability and can be used for inhaled delivery of the nanoparticle suspension. Conti et al showed that pMDI can convert a dendrimer–siRNA complex suspension into highly respirable droplets, leading to an FPF of 77%. The integrity and biological activity of siRNA in dendriplexes formulated for pMDIs remained intact after long-term exposure to the propellant HFA187. However, the application of pMDI technology is limited due to the typically low efficiency, with only approximately 10% of the aerosol emitted from pMDIs being deposited in the deep lungs188. Usage error by patients who lack hand-mouth coordination may also lead to low delivered doses189,190,191. Furthermore, pMDIs are unable to deliver high-dose medications180.
Nanoparticles as inhalable particles
Delivery of nanoparticles as a suspension often requires the nanoparticles to be stored in a liquid medium. Long-term storage as a liquid suspension may lead to physico-chemical instabilities such as aggregation, hydrolysis of polymer and drug leakage/degradation192,193. Formulating nanoparticles as a dry powder offers greater long-term stability than as a suspension192,193. Additionally, the majority of DPIs are breath actuated, avoiding the problem of coordinated inspiration and actuation. Controlling the size of nanoparticles is central for their formulation into reliable and efficient inhalable dry powders. Nanoparticles can be dried with/without excipients via spray-drying, freeze-drying and spray freeze-drying to generate stable and uniformly sized inhalable particles. A number of strategies have been explored to engineer nanoparticles into inhalable particles, which are discussed below.
Blending with carrier particles
Small particles with sizes <10 μm are highly cohesive and exhibit poor flow and inhalation performance194,195. Such cohesive particles are often formulated as “interactive mixtures” to improve their flow and dispersibility196. Interactive mixtures represent powders in which small particles are adhered to the surfaces of large carrier particles197,198,199. Kalantarian et al showed that mixing of 5-FU nanoparticles with lactose particles (Pharmatose® 80) led to a low FPF of ∼20%178. Such a low efficiency of interactive mixtures is often attributed to inefficient de-agglomeration and poor detachment of drug particles from carrier particles upon inhalation200.
Enlargement by co-drying with carrier/excipient
Nanoparticle aggregates
Co-drying nanoparticles with excipients lead to the formation of inhalable nanoparticle aggregates in an excipient matrix201,202,203. Azarmi et al used spray-freeze-dried doxorubicin nanoparticles with lactose to produce particles with an aerodynamic diameter of ∼3 μm204. FPF of the PLGA nanoparticle containing 6-3-hydroxyl-7H-indeno[2,1-c]quinolin-7-one dihydrochloride (TAS-103) improved from <1% to >10% after spray-drying with trehalose84, although it still displayed low aerosol performance. Upon inhalation, TAS-103-loaded PLGA nanoparticles provided 300 times higher drug concentration in the lungs of rats than those in plasma. The drug lung concentrations in rats were also 13-fold higher with TAS-103-loaded PLGA nanoparticles compared with the free drug administered via the intravenous route84. Some studies have shown that the carrier excipients dissolve and release primary nanoparticles upon deposition and thus achieve the aerosolization properties of microparticles while maintaining the release benefit of nanoparticles84,204,205. L-leucine is a commonly used force-control agent that is known to reduce inter-particle cohesion and improve the dispersibility of small particles206,207. El-Gendy et al showed that the particle sizes of paclitaxel-cisplatin nanoparticles and L-leucine freeze-dried nano-aggregates were ∼1–5 μm, which demonstrated an excellent FPF of >70%. Furthermore, L-leucine showed no cytotoxic effect up to 5 mg/mL in A549 cells208. Varshosaz et al spray-dried doxorubicin-loaded bovine serum albumin nanoparticles with trehalose, mannitol and L-leucine in which mannitol enabled a higher FPF than trehalose; L-leucine was abandoned in this study due to the formation of irregularly shaped particles209.
Effervescent particles
Ely et al introduced the effervescent technology, which involves spray-drying nanoparticles with effervescent excipients to enhance aerosolization and provide an effervescent effect for the quick release of nanoparticles upon dissolution of the excipients in aqueous media210. The effervescent effect is typically achieved by the combination of sodium bicarbonate and citric acid with ammonia. The pH of the feed solution is kept low to retard effervescing during the particle formation or drying process210. The effervescent technology has also been explored to facilitate inhaled delivery of nanoparticles against lung cancer. Azarmi et al showed that nanoparticles spray-dried with effervescent excipients achieved an MMAD of ∼5 μm, and animals (BALB/c nude mice) receiving effervescent particles showed no change in body weight or morbidity, indicating the safety and tolerability of the inhaled carrier system211. It has been shown that an effervescent carrier containing doxorubicin-loaded NP nanoparticles distributed throughout the lungs and released primary nanoparticles in the lungs212. Mice receiving doxorubicin-loaded n-butylcyanoacrylate nanoparticles that were spray-freeze-dried with effervescent excipients survived longer compared with those receiving intravenous doxorubicin solution or inhaled free doxorubicin71. Jyoti et al demonstrated that effervescent carriers improved the aerosolization and also increased the release of anticancer agent (9-bromo-noscapine) from the nanoparticles, leading to greater anticancer activity compared with non-effervescent carriers73.
Improving tumor targeting
Lung cancer cells are often located at specific sites in the lungs (ie, only in one lobe). However, inhaled chemotherapeutic agents may distribute uniformly throughout the lungs. Targeting inhaled nanoparticles specifically to the tumor cells is another approach to improve the safety and efficacy of inhaled chemotherapy.
Magnetic targeting
Drugs co-formulated with magnetically active particles can be guided to a specific location in the body using a strong external magnet213,214,215,216. As this process involves physical force to facilitate drug targeting, this concept of drug delivery is termed physical targeting. A range of pure metals and alloys can be used for this purpose, including iron oxide, cobalt, nickel, platinum and magnesium217. Magnetic nanoparticles have been shown to facilitate drug deposition in specific lung regions of mice with the help of a permanent magnet218,219,220,221. McBride et al spray-dried superparamagnetic iron oxide nanoparticles (SPIONs) with lactose and doxorubicin to form particles with an aerodynamic diameter of 3.27±1.69 μm. Such formulations showed more than twice the spatial deposition and retention in the regions under the influence of a strong magnetic gradient compared to a liquid suspension in an in vitro tracheal mimic study222. Verma et al showed that inhaled quercetin-loaded PLGA-coated magnetic (Fe3O4) nanoparticles showed marked in vitro anticancer activity and were well tolerated in mice with no signs of lung toxicity223.
Reducing phagocytic clearance
Particle engineering provides efficient control over particle size to generate inhalable nanoparticles and minimize muco-ciliary clearance in the upper airways. Nevertheless, particles deposited in the deep lungs are still subjected to clearance by phagocytosis, which can reduce the efficacy of inhaled chemotherapy. Alveolar macrophages can engulf particles <5 μm, depending on their physico-chemical properties such as size and surface chemistry224,225,226. Thus, an ideal pulmonary delivery system should circumvent the clearance of drug from the lungs. Unfortunately, only a few investigations have studied the effect of phagocytosis on the anti-tumor efficacy of inhaled nanoparticulate chemotherapeutics.
Large porous particles
Edward et al introduced the concept of large porous particles, which possess large geometric sizes ∼10 μm but exhibit aerodynamic diameters <5 μm due to their low density227,228,229. The large sizes of these porous particles enable them to overcome inter-particle forces, facilitating good aerosol performance and improving deposition in the deep lungs. Moreover, such large particles may escape phagocytosis by alveolar macrophages227,228,230. Spray-drying emulsions containing phospholipids and propellants have been developed to produce low-density hollow particles227,228,230,231,232.
Recent studies have shown the feasibility of using porous particles to improve the inhalation of nanoparticles. Tsapsis et al reported that nanoparticles can form large porous/hollow 'Trojan' particles under specific spray-drying conditions with or without excipients, which can disintegrate into individual nanoparticles upon reconstitution225. It was proposed that spray drying conditions that generated high Péclet numbers could form large porous particles225. The Péclet number is dimensionless and describes the mass transport of solutes in drying droplets. It is defined by the following equation225:
where Pe is the Péclet number, R is the radius of the droplet, D is the diffusion coefficient of the nanoparticle, and Td is the time required for the droplet to dry.
When Pe≪1, nanoparticles diffuse towards the center of the receding droplet by diffusion, yielding relatively dense dried particles. However, when Pe≫1, nanoparticles do not have enough time to redistribute to the center of the receding droplet, leading to their accumulation at the air-water interface. Further drying leads nanoparticles to be held together by physical forces (eg, van der Waals forces) or embedded in an excipient matrix forming a shell earlier in the drying phase. The increased vapor pressure ruptures the cell, and water vapors escape in the final phase of drying leading to formation of porous particles225. The physical properties, including the porosity and morphology of such large porous particles, were shown to depend on the nanoparticle size, chemical nature, excipients used, and nanoparticle concentration in the resultant particles224, 225,233. Hadinoto et al investigated the effect of phospholipids on the formation of such large porous particles. The phospholipid concentration was shown to govern the degree of hollowness of the resultant particles224. Furthermore, the release of drugs was shown to depend on the degree of hollowness233. However, to date, no studies have employed the porous particle platform for the inhaled delivery of anticancer drugs, which could be potentially useful for inhaled chemotherapy.
Swellable hydrogel particles
El-Sherbiny et al developed swellable hydrogel particles as carriers to prevent macrophage uptake of nanoparticles234. PEG-g-NPHCs self-assembled nanoparticles of a model protein, bovine serum albumin (BSA), were prepared and encapsulated in sodium alginate via spray-drying followed by ionotropic gelation using Ca2+ ions. The coated particles had aerodynamic diameters of ∼3 μm and a relatively low FPF of ∼30%. The microspheres showed swelling that was followed by enzymatic degradation235. The coated hydrogel particles demonstrated significantly delayed phagocytosis234. Such swellable hydrogel inhalable particle may be attractive for inhaled delivery of nanoparticulate chemotherapy against lung cancers.
Surface-modified particles
Surface coating and conjugation of actives with polyethylene glycol (PEG) have been shown to reduce clearance from the lungs. This phenomenon was attributed to the ability of PEG to facilitate muco-penetration and reduce uptake by alveolar macrophages226,236,237,238,239. Luo et al demonstrated that the conjugation of paclitaxel with PEG not only improved its lung residence time but also enhanced the anticancer activity in a mouse model of lung cancer240. Paclitaxel conjugated with higher-molecular-weight PEG demonstrated greater in vivo anti-tumor activity compared with lower-molecular-weight PEG240. PEGylation was also shown to reduce the lung inflammation and enable a higher tolerable dose than using free paclitaxel alone240.
Surface coating of particles with a lung surfactant (1,2-dipalmitoylphosphatidylcholine [DPPC]) has also been shown to reduce phagocytosis241, 242. In the presence of phospholipids, the adsorption of opsonic proteins on inhaled particles is inhibited, which allows inhaled particles to escape phagocytosis241, 242. Meenach et al generated inhalable lung surfactant-mimic phospholipid and PEGylated lipopolymer nanoparticles using advanced organic spray-drying process243. Spray-drying at optimal temperatures facilitates the formation of more inhalable particles243. Inhalable lung surfactant (DPPC/DPPG)-based carrier particles loaded with paclitaxel demonstrated an excellent FPF of >70% and enhanced anti-tumor activity compared with free paclitaxel244. However, in vivo studies investigating the efficacy of such inhalable surfactant modified nanoparticles against lung cancer are scarce.
Conclusion
Chemotherapy through pulmonary delivery is believed to achieve much higher drug concentrations in the lungs and reduce systemic drug exposure. This technology could offer a promising alternative to the oral and parenteral delivery of chemotherapies for the treatment of lung cancers. Nevertheless, effect of high concentrations of inhaled anticancer drugs in the lungs centers on local toxicity remain largely unknown. Moreover, the distributions of most inhaled free anticancer drugs in the lungs are not tumor-specific. Nanoparticle formulations are promising for the inhaled delivery of chemotherapeutics against lung cancer. Nanoparticles may encapsulate toxic drugs and release them in a more site-specific and controlled manner. Additionally, nanoparticles can carry multiple drugs, DNAs and RNAs, as well as imaging agents.
Recent research efforts have focused on enhancing the lung tumor deposition of inhaled drug delivery systems as well as minimizing their clearance from the lungs to maximize the efficacy and control the side effects. There are a few challenges for the pulmonary delivery of nanoparticles, largely stemming from their extremely low mass and cohesive nature.
Only the fraction of drug liberated from nanoparticles is able to exert anticancer activity. Due to analytical limitations, it is difficult to quantify the fraction of drug liberated from the nanoparticles rather than the total bound and unbound fraction of drug, making it difficult to assess the true potential of nanoparticles for improving drug penetration/uptake. Furthermore, the drug is typically quantified in the whole lung rather than the lung tumor, which may further add to the uncertainty about the true targeting potential and hence the anti-tumor efficacy of nanoparticles. Moreover, physicians typically prefer systemic routes over the inhaled route due to greater predictability and reliability (drug deposition may vary due to different lung functions of the patients). Thus, further improvement of aerosolization technology to enhance control over the dose, reliability and predictability of the inhaled drug fraction is desirable.
It is possible to utilize particle engineering and ensure consistent and highly efficient delivery of nanoparticles to the lungs through nano-aggregates, large porous particles, and other formulation techniques. Furthermore, physical targeting by magnetic nanoparticles and active targeting by ligand anchoring have shown the potential to enhance tumor targeting and improve the efficacy of inhaled anticancer drugs. Nanoparticles have also been shown to facilitate the co-delivery of anticancer drug with anti-sense oligonucleotides, making them an attractive candidate against drug-resistant lung cancers. Particle size enlargement and surface modification (eg, with PEG and surfactants) have been suggested to be effective for reducing the phagocytic clearance of nanoparticle formulations. In conclusion, inhaled nano-particulate chemotherapy bears great potential for the treatment of lung cancer. Efforts are needed to further investigate the safety and efficacy of this technology in clinical settings.
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Mangal, S., Gao, W., Li, T. et al. Pulmonary delivery of nanoparticle chemotherapy for the treatment of lung cancers: challenges and opportunities. Acta Pharmacol Sin 38, 782–797 (2017). https://doi.org/10.1038/aps.2017.34
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DOI: https://doi.org/10.1038/aps.2017.34
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