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Intratracheal Delivery of Nano- and Microparticles and Hyperpolarized Gases
Journal Pre-proof Intratracheal delivery of nano- and microparticles and hyperpolarized gases: a promising strategy for imaging and treatment of respiratory disease Hongbin Wang, MD, Lina Wu, PhD, Xilin Sun, MD, PhD PII:
S0012-3692(19)34448-4
DOI:
https://doi.org/10.1016/j.chest.2019.11.036
Reference:
CHEST 2782
To appear in:
CHEST
Received Date: 29 July 2019 Revised Date:
21 November 2019
Accepted Date: 29 November 2019
Please cite this article as: Wang H, Wu L, Sun X, Intratracheal delivery of nano- and microparticles and hyperpolarized gases: a promising strategy for imaging and treatment of respiratory disease, CHEST (2020), doi: https://doi.org/10.1016/j.chest.2019.11.036. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Copyright © 2019 Published by Elsevier Inc under license from the American College of Chest Physicians.
Word Counts: 149 for abstract, 3209 for text. Intratracheal delivery of nano- and microparticles and hyperpolarized gases: a promising strategy for imaging and treatment of respiratory disease Running head: Novel theranostic strategy for respiratory disease Hongbin Wang1,2, MD; Lina Wu1,2*, PhD; Xilin Sun1,2,3*, MD, PhD Address: 1. NHC and CAMS Key Laboratory of Molecular Probe and Targeted Theranostics, Harbin Medical University, Heilongjiang, PR China 2.Molecular Imaging Research Center (MIRC), Harbin Medical University, Harbin, Heilongjiang, PR China 3.TOF-PET/CT/MR Center, The Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang, PR China *
Correspondence: Prof. Xilin Sun, E-mail: [email protected] Prof. Lina Wu, E-mail: [email protected] Molecular Imaging Research Center, Harbin Medical University, 766 Xiangan N street, Harbin, Heilongjiang, China, 150028. Conflict of interest: None
Abbreviations
Abbreviation ALIS CF COPD CT EGFR MAC MRI PET/CT PFC SPIONs V/Q
Full definition Amikacin liposome inhalation suspension Cystic fibrosis Chronic obstructive pulmonary disease Computed tomography Epidermal growth factor receptor Mycobacterium avium complex Magnetic resonance imaging Positron emission tomography/CT Perfluorocarbon Superparamagnetic iron oxide nanoparticles Ventilation/perfusion
Abstract Accurate diagnosis is crucial for improving treatment and prognosis of respiratory disease, especially lung cancer. Tumors and lesions located deep in the lung are directly accessible via dendritic tracheal bronchus, thereby opening a new way to tackle respiratory disease. Intratracheal delivery is an innovative noninvasive approach for imaging and treating respiratory disease efficiently, when compared to other delivery methods. Intratracheal delivery of nano- and microparticles and hyperpolarized gases offers valuable clinical advantages, such as assessing lung function, monitoring ventilation and perfusion, controlling disease progression and inhibiting tumor growth. Especially, versatile nano-sized particles have enormous potential to benefit precision imaging and therapy at molecular level. Here we discuss the recent advances in intratracheal delivery of nano- and microparticle approaches and hyperpolarized gases for respiratory disease imaging and treatment, with an emphasis on intratracheal nanoparticles delivery of pulmonary imaging, which has extremely valuable clinical applications in precise theranostic for respiratory disease.
Key words: Respiratory disease; Pulmonary imaging; Intratracheal delivery; Inhalation; Nanoparticles 1 Introduction Respiratory diseases are prevalent and have increasing incidence globally, especially lung cancer, which remains the leading cause of cancer mortality.1 Traditional imaging diagnostic methods, such as CT (computed tomography), provide imaging with higher resolution and finer slice thickness (<1 mm) enabling discovery of 50 mm3 noncalcified nodules.2 However, insufficient molecular information about respiratory diseases limits precise diagnosis and subsequent treatment. Current treatment strategies for respiratory disease are mostly based on the systemic administration of antibiotics or anti-tumor drugs by oral or intravenous delivery, with low concentrations at the target site and high level of systemic drug, risking in toxicity and adverse effects. Thus, exploring innovative and noninvasive approaches for precisely diagnose and treat respiratory disease at a molecular level is of great significance. The unique anatomical structure and microenvironment of lung present particular challenges for molecular diagnosis and treatment. Most of the respiratory diseases are located deep in the gas rich lung tissue and are easily affected by breathing motions, which limit the resolution and efficacy of current imaging techniques. Furthermore, lung tissue has a powerful clearance mechanism and physiological barriers, compounded in lung cancer by a complex tumor microenvironment and blood supply by the bronchial arteries. These physiological features determine local concentration of drugs and imaging agents in the lung. Efficient, precise, and innovative theranostic strategies are urgently needed. Yet, the unique anatomical location of respiratory diseases also affords opportunities. The lung contacts the environment directly via tracheal and bronchial dendritic ramifications rich in blood vessels. In part tumors and lesions located in deep lung can be directly accessed via dendritic tracheal
bronchus. In addition, the epithelium covering the trachea and bronchi varies in composition according to cellular functions. The alveolar epithelium consists of cuboidal type II and tabular type I alveolar epithelial cells, with the latter covering over 95 % of the alveolar surface. This provides a thin air-blood barrier (about 0.1 - 0.2 µm) and large epithelial surface area (about 70-140 m2),3 thereby allowing homogeneous distribution, rapid absorption and uptake with high bioavailability after intratracheal delivery of imaging agents and therapeutic drugs. Intratracheal delivery, or inhalation, has been made great progress since it was employed for delivering medications to the lungs more than two thousand years ago.4A number of nanoand microparticle formulations and hyperpolarized gases have been designed for intratracheal delivery as contrast agents or delivery carriers including dry powder, aerosol, and spray. In the wake of delivery strategy innovation, intratracheal delivery devices have also made tremendous progress, for instance, pressurized metered dose inhalers, dry powder inhalers, nebulizers, soft mist inhalers, among others.5 Therefore, promising and exciting progress on intratracheal delivery for imaging and treatment of respiratory diseases, including lung cancer has been reported. Among those delivery formulations, nanoparticle is an extraordinary actor in delivery systems. Nanoparticles with a size range from 1-1000 nm, enabling unique medical effects,6 have been successfully employed for biomedical applications in the past several decades.7 To achieve specific imaging and therapeutic effects, nanoparticles can enter human body via ocular penetration,8 intravenous injection,9 oral administration,10 and subcutaneous route.11 However, factors such as hepatic first-pass metabolism, rapid blood clearance, and high dosage exposure in off-target tissues limit the efficacy of these conventional delivery methods, especially for respiratory disease. Intratracheal nanoparticle delivery is a promising noninvasive strategy for respiratory disease. By controlling the size of nanoparticles, they can reach the alveolar region in deep lung enabling homogeneous distribution, improved deposition and increased delivery efficacy. Tailorable nano-sized particles offer additional advantages, as versatile surface modification and high surface area–to–volume ratios favor drug binding and loading, thereby improving efficacy and residence time. Multifunctional nanoparticles loaded targeting ligands, imaging agents, and therapeutic drugs enable the synthesis of multimodal compounds that provide highly sensitive imaging and treatment at molecular and cellular levels.12 These properties enable inhaled nanoparticles to reach specific targeted sites and bind biomarkers in the deep lung, amplifying signals of molecular information, enhancing local drug concentrations and protecting secondary organs from systematic exposure. Thus, nanoparticles are very attractive candidates for the intratracheal delivery imaging and treatment strategy of respiratory disease.13 Figure 1 is a typical depiction of intratracheal delivery strategy.14-16 This promising and fascinating intratracheal delivery technique, combined with the advantages of nanotechnology, paves a new avenue for respiratory disease theranostics. This review summarizes essential developments and recent advances in intratracheal delivery of nano- and microparticles and hyperpolarized gases, particularly for delivered nanoparticles imaging respiratory disease. This is a valuable resource with systematized information on intratracheal particle delivery systems and their advantages and prospects for clinical applications in precise imaging and treatment of respiratory disease.
2 Intratracheal delivery of nano- and microparticles and their deposition characteristics Significant research efforts have been devoted to the understanding and improvement of nano- and microparticles deposition in the lung. Key factors including respiratory anatomy and particle size influence delivered particles deposition, as summarized in Figure 1. Given their greater gravitation and inertia, microparticles with diameters larger than 5 µm are transported to the upper airways and nasopharynx, and subsequently swallowed into gastrointestinal tract and coughed in sputum.17 Whereas microparticles sized between 1 and 5 µm are prone to deposition in bronchi and bronchioles by inertial impaction and sedimentation.18 Nanoparticles with a diameter ≤ 1000 nm deposit in the alveolar region due to sedimentation and Brownian diffusion, and could be optimized for intratracheal delivery. 19 A large number of nanoparticles remaining in the lung are removed by slow clearance mechanisms, including alveolar macrophages and epithelial transcytosis, and these processes may last between days to several months.20 Intratracheal delivered nanoparticles (< 6 nm) translocate to the lung capillaries and lymph nodes, and may reach other body regions following bloodstream, crossing the air-blood barrier and entering the circulation. 21,22 Nanoparticles deposited within lungs have a greater chance of escaping from lung clearance mechanisms and reaching epithelium directly, when compared to microparticles. The most commonly used nanoparticles measure between 50 and 500 nm, which is an optimal size for efficient endocytosis.23 However, the lung mucus and surfactant barriers present a major obstacle to the translocation and deposition of intratracheal-delivered nanoparticles. The modification of surface coating enables to minimize nanoparticles adhesion to mucus and protein, such as polyethylene glycol (PEG).24 Mucus-penetrating particles as large as 300 nm exhibited uniform distribution and markedly enhanced retention in lungs after inhalation.25 Nanoparticle, indeed, with its versatile size scale and properties, provides tunable options for imaging and treating respiratory disease. 3 Applications of intratracheal delivery strategy 3.1 Intratracheal delivery pulmonary-imaging 3.1.1 PET/CT imaging PET/CT (Positron emission tomography computed tomography) imaging is a comprehensive detection mothed depends on the uptake radiotracers with incremental value due to its higher sensitivity and accuracy, and superior quantification of lung function. Indeed, a large number of studies have used radioaerosol PET/CT imaging to assess lung function and physiology in respiratory diseases. Inhaled ultrasonically nebulized 99mTc-albumin colloid (diameter 3.4 µm) is a non-invasive and easy-performed method to test mucociliary function of the airways.26 Le Roux et al 27 presented an automated threshold-based approach to quantify pulmonary function using 68Ga-V/Q (ventilation/perfusion) PET/CT. More recently, they demonstrated the feasibility and accuracy of 68Ga-V/Q PET/CT in cancer patients with suspected pulmonary embolism, compared to CT pulmonary angiography (CTPA).28
Radiation-induced regional lung functional deficits of lung cancer patients can be estimated by simple linear models with 4D 68Ga-V/Q PET/CT imaging (Figure 2).14 Besides, high-resolution PET/CT imaging of 13N-NH3 labeled isotonic saline (inhalable aerosol, 4.9 µm) was shown to accurately detect aerosol distribution pattern in asthmatics patients.29 Cossío et al 30 reported three different pulmonary administration methods of aerosol labeled with 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG, diameter in the range 0.9-5.25 µm) for PET imaging and compared their regional distribution in rat lungs, providing paramount information for optimization aerosol delivery systems. By providing anatomical information and accurate estimation of diseased lung function, PET imaging of inhalable radioaerosols can benefit clinical practice, but motion artifacts, radiation exposure and cost are persistent issues. 3.1.2 MR imaging With advances in MRI (magnetic resonance imaging) techniques and optimization of imaging sequences, good quality MR images of lung can be performed with administrated potent contrast agents. For example, inhalable hyperpolarized 3He and129Xe gases (atoms, size < 1 nm) have been regarded as a promising MRI agents for evaluating lung function because of their longer longitudinal relaxation times (T1) resulting from a nuclear spin quantum number of 1/2.31 As shown in Figure 3,32 hyperpolarized 3He lung functional MR imaging has been used to assess inhaled gas distribution and quantify lung function in healthy young and older never-smokers, and in patients with asthma, COPD (chronic obstructive pulmonary disease), CF (cystic fibrosis) and radiation-induced lung injury. Reproducibility, feasibility, tolerability, and safety of lung function quantitative evaluation by 129Xe gas MRI was also demonstrated in patients and animal models with a variety of respiratory diseases.33-35 Oxygen-enhanced MRI has also been used to evaluate regional lung function, as paramagnetic oxygen molecules can shorten T1 and T2* values in the lungs.36 Hyperpolarized gases MRI is a highly specific, noninvasive, time-saving, and easy to operate methodology providing systematic and comprehensive information on lung function. However, the sophisticated production of polarized gases limits its clinical applications. Given excellent advantages of 19F, such as 100% naturally abundant, high gyromagnetic ratio (~95% of 1H) and high sensitivity of 83%,9 it is opportune to develop 19F-MR imaging. In 1996, perfluorocarbon (PFC) partial liquid ventilation was shown to alleviate neonatal respiratory distress syndrome and improve pulmonary function due to its high oxygen-dissolving and releasing capability, low surface tension and excellent physical-chemical properties.37 The combination of these features makes PFC the best 19F-MR contrast agent candidate for pulmonary imaging by intratracheal delivery. For example, aerosol deposition and oxygenation patterns in rat lungs have been detected by 19F-MR imaging after inhalation PFC aerosol (1.2 µm) produced by pneumatic generator.38 In another study in rats, high resolution three-dimensional 19F-MR imaging was able to assess airway pressures and strains with liquid PFC instilled into the lung.39 19 F-MR with nano-sized PFC enable highly sensitive diagnostic imaging of lung cancer. PFC nanoparticles (approximately 150 nm in size) administered by intratracheal delivery were shown to diffuse and distribute densely and deeply into the lung tumors, producing
excellent fluorescence and 1H- and 19F-MR imaging signals that persisted for at least 72 hours.15 Furthermore, fluorine imaging, demonstrated for the first time in lung cancer, obviates the need for gadolinium and circumvents potential safety issues. Indeed, PFC nanoparticles are safe in vitro and in vivo and are constrained to the tumor. 9,15 As PFC has a long history of medical applications as artificial blood substitute, liquid ventilation and drug delivery vehicles,37,40 the logical extension of this work suggests PFC nanoparticles represent an important theranostic opportunity to address the formidable challenges in treating lung cancer. More importantly, active targeted PFC nanoparticles show great promise as quantitative biomarkers for lung cancer molecular imaging. Recent data demonstrated that intratracheal administration of αvβ3-targeted PFC nanoparticles (about 170 nm) produced significantly higher 19F-MR signal in the tumor and actively targeted tumor angiogenesis in orthotopic lung cancer models (Figure 4a).41 Of note, multimodal imaging methods, including optical, 1H-MR and 19F-MR imaging, have also contributed to intratracheal-delivered PFC-based pre-clinical and clinical tests in lung cancer imaging. In addition to PFC nanoparticles, iron oxide nanoparticles are suitable for intratracheal delivery pulmonary MR imaging. Intratracheal-delivered antibody-conjugated superparamagnetic iron oxide nanoparticles (SPIONs, about 100 nm) have been shown to actively target and detect M1 and M2 macrophage subpopulations in a COPD mice model with MRI, and to provide early diagnosis of pulmonary inflammatory diseases.42 Recently, SPIONs (about 130 nm) were nebulized and delivered to the rat lungs, enabling lung imaging with high sensitivity and efficacy via magnetic particle imaging (Figure 4b).43 Novel nano-sized MRI contrast agents developed by Gao et al, 44 chitosan/Fe3O4-enclosed bispecific antibodies, were shown to significantly enhance signal intensity for lung cancer after pulmonary inhalation, when compared to MRI alone. 3.1.3 Optical imaging Fluorescence and bioluminescence imaging experienced rapid development with the nanotechnology revolution and innovation in nanomedicine. In particular, intratracheal-delivered nano- and microparticles have shown tremendous value in pulmonary optical imaging. Mizuno et al 16 succeeded in visualizing pulmonary delivery and gene expression simultaneously in vivo by fluorescence and bioluminescence of administrated well-designed ICG-pDNA dry power (about 20 µm in diameter) (Figure 5). Fluorescence images of live xenografted mice after inhalation nebulized gelatin nanoparticles modified with biotinylated EGF (epidermal growth factor) sized in 0.4-2 µm revealed that the aerosol particles bound to EGFR (epidermal growth factor receptor) and targeted cancerous lung tissue, with lower accumulation in normal lungs.45 In another study, polystyrene nanoparticles loaded near-infrared fluorescence dye (100 nm) were demonstrated by fluorescence imaging to accumulate in alveolar M2 macrophages and alveolar areas after administration in allergic airway inflammation mice via intranasal tract. 46 Cy5.5-labeled dry siRNA/chitosan powder was shown to exhibit effective and specific gene silencing and excellent fluorescence imaging in vivo, thereby integrating diagnosis and treatment.47 3.2 Inhalation treatment for respiratory diseases
3.2.1 Chronic respiratory infections Chronic respiratory infections such as asthma, COPD, CF, tuberculosis and other infectious lung diseases, are usually treated by systemic administration (orally or intravenously) of high doses of antibiotics, which may cause several adverse effects and bacterial resistance, ultimately resulting in treatment failure. Intratracheal delivery is an attractive approach to overcome these issues as it improves bioavailability and stability of particles or drugs in targeted lung lesions. Thus, nano- and microparticles delivery via the intratracheal route is increasingly being used in the treatment of these infectious diseases. Treatment of mycobacterium avium complex (MAC) lung disease is a long battle that requires a multidrug antibacterial regimen to completely eliminate the infectious bacteria. Amikacin liposome inhalation suspension (ALIS, Arikayce®) is a liposomal formulation of amikacin (an aminoglycoside antibacterial drugs) designed for nebulization and inhalation into the lungs, thereby facilitating targeted and localized drug action against MAC lung disease. ALIS is approximately 300 nm in diameter 48 and exhibit more effective penetration ability and antimicrobial activity than free amikacin.49 In the CONVERT phase III clinical trial, addition of ALIS to standard guideline-based therapy (GBT) for treatment-refractory MAC lung disease achieved significantly greater culture conversion by month 6 than GBT alone, with comparable rates of serious adverse events.50 More importantly, ALIS is the first and only inhalable therapeutic liposome with FDA approval for the treatment of MAC lung disease in adult patients who have treatment-refractory disease and limited or no alternative treatment options.51 Previous studies indicate that inhaled corticosteroids significantly reduce exacerbation frequency, improve patient health status, and decrease mortality in the long term.52 Budesonide is one of the most extensively used inhaled corticosteroids, with excellent topical anti-inflammatory capability. Inhalable submicron particles of budesonide have been shown to reach deep into the lungs, with an increase in plasma concentration of 28.85%.53 Recently, large porous particles loaded with budesonide were shown to reduce macrophage phagocytosis and to prolong residence time by 4 hours in the lungs.54 Another study reports similar results for inhalable drug-loaded large porous particles in asthma treatment.55 Idiopathic pulmonary fibrosis is a severe lung disease typically treated with glucocorticoids, supportive oxygen therapy, or pulmonary transplantation. As these treatments present several disadvantages and limitations, inhalation nano- and microparticles provide attractive new opportunities to treat this serious disease. Garbuzenko et al 56 have shown that inhalation treatment using lipid-based nanoparticles loaded with prostaglandin E2 and targeted siRNAs (about 400 nm) prevented the development of severe pulmonary fibrosis in mice. Their subsequent study demonstrated that inhalable lipid-based nanoparticles (about 130 nm) loaded with lumacaftor and ivacaftor were highly effective in treating CF (Figure 6).57 Similarly, azithromycin and rapamycin-loaded microparticles (~1 µm in diameter) exhibited rapid mucus penetration and controlled drug release after spray drying, which could significantly improve the treatment of recurrent infection in patients with CF. 58 Currently, the standard method to treat tuberculosis is multi-antibiotic administration for long periods, which leads to drug resistance, patient non-compliance, higher costs, and
lower drug deposition in lungs. Intratracheal-administrated nano- and microparticles are candidate delivery systems to circumvent these problems. Indeed, anti-tubercular drug rifampicin was loaded in glycerosomes carriers (about 100 nm), that significantly improved drug deposition in the lungs following intratracheal administration.59 Inhalable spray-dried particles carrying anti-tubercular drugs exhibited lower cytotoxicity and higher lung uptake ratio, and continued to release up to 8 hours.60 Nebulized nanoparticles loaded with anti-tubercular drugs isoniazid or rifampicin (about 230 nm) displayed more chemotherapeutic efficacy than the free drugs.61 Inhalable nano- and microparticles loaded with anti-tubercular drugs improve drug deposition and reduce systemic adverse effects, and are therefore a promising strategy for the management of tuberculosis. 3.2.2 Lung cancer Lung cancer is the most common cancer worldwide and its incidence and mortality rates continue to rise. Conventional treatment strategies include surgery, chemotherapy, radiotherapy, among others. Although these treatments can benefit patients to some extent, they exhibit various limitations. Surgery is invasive and limited to small early stage tumors without distant metastases. Lung cancer originates in the bronchial epithelium and is mostly supplied by bronchial arteries,62 receiving approximately less than 1% of cardiac blood output.63 Consequently, systemic chemotherapy mostly based on intravenous delivery has limited efficacy, as low drug concentrations reaching tumors, severe adverse side effects, and acquired resistance. Radiotherapy for lung cancer can cause damage and toxicity to the normal tissue. Thus, a molecular-targeted treatment strategy with direct lung administration, such as intratracheal delivery of nano- and microparticles, is a promising noninvasive and efficient alternative for lung cancer treatment. Indeed, inhalable nano- and microparticles loaded anti-cancer drugs have achieved many outstanding and encouraging progresses. The efficacy of lipid-coated 5-fluorouracil aerosol inhalation in lung cancer treatment has been demonstrated in hamsters.64 Inhalable doxorubicin-loaded human serum albumin nanoparticles (~340 nm) were significantly improved anti-tumor efficacy in lung metastatic tumor models (Figure 7).65 The anti-tumor effects of inhalable nanoparticles loaded with other drugs, such as erlotinib,66 taxanes,67 and rapamycin68 have also been investigated in lung cancer animal models. Nanoparticles with actively targeted sensitive biomarkers of lung cancer can increase drug release and improve treatment efficiency. For example, EGFR is over-expressed in 40-80% of non-small cell lung cancer (NSCLC) patients.69 EGFR-targeted SPIONs (about 360 nm in diameter) tracheal-instilled in mouse orthotopic models of NSCLC showed prominent anti-tumor efficacy when compared to magnetic hyperthermia treatment.70 Additionally, inhaled nanoparticles carrying RNAs71 and DNAs 72 have been shown to have superior anti-cancer activity. Intratracheal instilled siRNA/RGD (Arg-Gly-Asp peptides) gold nanoparticles showed excellent suppression of lung tumor cell proliferation and tumor size reduction.71 Given the vast number of potential applications for nanotechnology and nanomaterials in the biomedical field, more research effort should be dedicated to the assessment of inhalable nano- and microparticles biosafety and toxicity in animal models and humans, promoting its clinical translation for lung cancer therapy.
4 Conclusion This review summarizes important advances of intratracheal delivery nano- and microparticles and hyperpolarized gases for imaging and therapy of respiratory disease, particularly for intratracheal delivery nanoparticles of pulmonary imaging. The unique anatomy of the lung provides an opportunity to noninvasively deliver particles directly to lungs, allowing enhanced pulmonary accumulation, optimal molecular-targeted imaging, and improved therapeutic efficacy. Nanoparticles, with a unique tunable size and properties, combine an intratracheal delivery strategy, with precise molecular theranostic efficacy. Indeed, intratracheal-delivered nano- and microparticles enable accurate multimodal molecular imaging and can mitigate disease progression in asthma, COPD, CF, tuberculosis, and even lung cancer. The opportunity is ripe for theranostic research devoted to intratracheal delivery of nano- and microparticles.
Acknowledgments This work was supported by the National Basic Research Program of China (2015CB931800), National Natural Science Foundation of China (81627901, 81471724,81771903), The Tou-Yan Innovation Team Program of the Heilongjiang Province (2019-15), Natural Science Foundation of Heilongjiang Province of China (LC2016034), Heilongjiang Postdoctoral Funds for Scientific Research Initiation (Number LBH-Q15090), the Fourth Hospital of Harbin Medical University Fund for Distinguished Young Scholars (HYDSYJQ201601), and the Key Laboratory of Molecular Imaging Foundation (College of Heilongjiang Province).
Authors' Contributions Manuscript writing: Hongbin Wang Approval of manuscript: all Prof. Xilin Sun and Prof. Lina Wu were the guarantors of the paper.
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Figure Legends Figure 1. A typical depiction of intratracheal delivery strategy. Intratracheal delivery various sized particles and their deposition in the lungs are distinguished by different colors. Multifunctional nanoparticles directly deposit in lungs after intratracheal administration allows for precise multimodal imaging (including PET, MR and optical imaging) and therapy of respiratory disease. The PET ventilation image (A) is reprinted with permission from Siva et al.14 The MR image (B) of lung cancer is reprinted with permission from Wu et al.15 The optical image (C) is reprinted with permission from Mizuno et al.16 PET = positron emission tomography; MR= magnetic resonance. Figure 2. Images of a representative case show changes in PET perfusion (left), ventilation (middle), and CT density (right) between scan time points relative to radiation therapy dose distributions. Reprinted with permission from Siva et al.14 PET = positron emission tomography; CT=computer tomography. Figure 3. Hyperpolarized 3He MRI coronal center slice images for healthy young and old never smokers and subjects with asthma, COPD, RILI and CF. Reprinted with permission from Washko et al.32 COPD=Chronic obstructive pulmonary disease; RILI=Radiation-induced lung injury; CF=Cystic fibrosis. Figure 4. a) Merged 1H (gray) and 19F (red) images of rabbit Vx2 orthotopic lung cancer models after intratracheal delivery avβ3-targeted PFC nanoparticles. Reprinted with permission from Xu et al.41 b) Representative MPI/CT images of the rat lung airspace after inhalation SPION-labeled aerosol and delivery efficiency assessment. Reprinted with permission from Tay et al.43 PFC=perfluorocarbon, MPI=magnetic particle imaging, CT=computer tomography, SPION= Superparamagnetic iron oxide nanoparticle. Figure 5. Dual imaging of the pulmonary delivery and gene expression. (A) The fluorescence was detected in the whole body 20 min after administration ICG-pDNA dry powder. (B) The luciferase activity was measured 9 h post-administration. In mice in which fluorescence had been strongly detected, bioluminescence was detected more strongly. (C) The fluorescence that had been measured 20 min after administration of the dry powder remarkably correlated to the bioluminescence after 9 h (r2=0.994, the scale is in photon/s/cm2/sr). ICG=Indocyanine green, pDNA= plasmid DNA. Reprinted with permission from Mizuno et al.16 Figure 6. Representative MR images (a) and CT images (b) mice with CF before and after lumacaftor and ivacaftor-loaded nanoparticles inhalation treatment. Reprinted with permission from Garbuzenko et al.57 MR= magnetic resonance, CT=computer tomography, CF= Cystic fibrosis. Figure 7. (A) The lung deposition of TRAIL/Dox HSA nanoparticles in ICR mice using RGB spectra for Cy5.5 and doxorubicin over 3 days after administration. (B)Representative photographs of the lungs of BALB/c nu/nu mice at 8 weeks after H226 cell implantation and of the lungs of an age-matched normal mouse. Photographs of the lungs(C) and lung weights (D) of BALB/c nu/nu mice after H226 cell implantation with or without pulmonary TRAIL/Dox HSA-NP administration. The results represent the lungs of three or four individual mice and are presented as means ± SDs. *P < 0.07 vs. TRAIL/Dox HSA-NP; **P < 0.004 vs. Dox HSA-NP; and ***P < 0.01 vs. non-treated controls. TRAIL=tumor necrosis
factor (TNF)-related apoptosis- inducing ligand; HAS=human serum Dox=doxorubicin, NP=nanoparticles. Reprinted with permission from Choi et al.65
albumin;
S0012-3692(19)34448-4
DOI:
https://doi.org/10.1016/j.chest.2019.11.036
Reference:
CHEST 2782
To appear in:
CHEST
Received Date: 29 July 2019 Revised Date:
21 November 2019
Accepted Date: 29 November 2019
Please cite this article as: Wang H, Wu L, Sun X, Intratracheal delivery of nano- and microparticles and hyperpolarized gases: a promising strategy for imaging and treatment of respiratory disease, CHEST (2020), doi: https://doi.org/10.1016/j.chest.2019.11.036. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Copyright © 2019 Published by Elsevier Inc under license from the American College of Chest Physicians.
Word Counts: 149 for abstract, 3209 for text. Intratracheal delivery of nano- and microparticles and hyperpolarized gases: a promising strategy for imaging and treatment of respiratory disease Running head: Novel theranostic strategy for respiratory disease Hongbin Wang1,2, MD; Lina Wu1,2*, PhD; Xilin Sun1,2,3*, MD, PhD Address: 1. NHC and CAMS Key Laboratory of Molecular Probe and Targeted Theranostics, Harbin Medical University, Heilongjiang, PR China 2.Molecular Imaging Research Center (MIRC), Harbin Medical University, Harbin, Heilongjiang, PR China 3.TOF-PET/CT/MR Center, The Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang, PR China *
Correspondence: Prof. Xilin Sun, E-mail: [email protected] Prof. Lina Wu, E-mail: [email protected] Molecular Imaging Research Center, Harbin Medical University, 766 Xiangan N street, Harbin, Heilongjiang, China, 150028. Conflict of interest: None
Abbreviations
Abbreviation ALIS CF COPD CT EGFR MAC MRI PET/CT PFC SPIONs V/Q
Full definition Amikacin liposome inhalation suspension Cystic fibrosis Chronic obstructive pulmonary disease Computed tomography Epidermal growth factor receptor Mycobacterium avium complex Magnetic resonance imaging Positron emission tomography/CT Perfluorocarbon Superparamagnetic iron oxide nanoparticles Ventilation/perfusion
Abstract Accurate diagnosis is crucial for improving treatment and prognosis of respiratory disease, especially lung cancer. Tumors and lesions located deep in the lung are directly accessible via dendritic tracheal bronchus, thereby opening a new way to tackle respiratory disease. Intratracheal delivery is an innovative noninvasive approach for imaging and treating respiratory disease efficiently, when compared to other delivery methods. Intratracheal delivery of nano- and microparticles and hyperpolarized gases offers valuable clinical advantages, such as assessing lung function, monitoring ventilation and perfusion, controlling disease progression and inhibiting tumor growth. Especially, versatile nano-sized particles have enormous potential to benefit precision imaging and therapy at molecular level. Here we discuss the recent advances in intratracheal delivery of nano- and microparticle approaches and hyperpolarized gases for respiratory disease imaging and treatment, with an emphasis on intratracheal nanoparticles delivery of pulmonary imaging, which has extremely valuable clinical applications in precise theranostic for respiratory disease.
Key words: Respiratory disease; Pulmonary imaging; Intratracheal delivery; Inhalation; Nanoparticles 1 Introduction Respiratory diseases are prevalent and have increasing incidence globally, especially lung cancer, which remains the leading cause of cancer mortality.1 Traditional imaging diagnostic methods, such as CT (computed tomography), provide imaging with higher resolution and finer slice thickness (<1 mm) enabling discovery of 50 mm3 noncalcified nodules.2 However, insufficient molecular information about respiratory diseases limits precise diagnosis and subsequent treatment. Current treatment strategies for respiratory disease are mostly based on the systemic administration of antibiotics or anti-tumor drugs by oral or intravenous delivery, with low concentrations at the target site and high level of systemic drug, risking in toxicity and adverse effects. Thus, exploring innovative and noninvasive approaches for precisely diagnose and treat respiratory disease at a molecular level is of great significance. The unique anatomical structure and microenvironment of lung present particular challenges for molecular diagnosis and treatment. Most of the respiratory diseases are located deep in the gas rich lung tissue and are easily affected by breathing motions, which limit the resolution and efficacy of current imaging techniques. Furthermore, lung tissue has a powerful clearance mechanism and physiological barriers, compounded in lung cancer by a complex tumor microenvironment and blood supply by the bronchial arteries. These physiological features determine local concentration of drugs and imaging agents in the lung. Efficient, precise, and innovative theranostic strategies are urgently needed. Yet, the unique anatomical location of respiratory diseases also affords opportunities. The lung contacts the environment directly via tracheal and bronchial dendritic ramifications rich in blood vessels. In part tumors and lesions located in deep lung can be directly accessed via dendritic tracheal
bronchus. In addition, the epithelium covering the trachea and bronchi varies in composition according to cellular functions. The alveolar epithelium consists of cuboidal type II and tabular type I alveolar epithelial cells, with the latter covering over 95 % of the alveolar surface. This provides a thin air-blood barrier (about 0.1 - 0.2 µm) and large epithelial surface area (about 70-140 m2),3 thereby allowing homogeneous distribution, rapid absorption and uptake with high bioavailability after intratracheal delivery of imaging agents and therapeutic drugs. Intratracheal delivery, or inhalation, has been made great progress since it was employed for delivering medications to the lungs more than two thousand years ago.4A number of nanoand microparticle formulations and hyperpolarized gases have been designed for intratracheal delivery as contrast agents or delivery carriers including dry powder, aerosol, and spray. In the wake of delivery strategy innovation, intratracheal delivery devices have also made tremendous progress, for instance, pressurized metered dose inhalers, dry powder inhalers, nebulizers, soft mist inhalers, among others.5 Therefore, promising and exciting progress on intratracheal delivery for imaging and treatment of respiratory diseases, including lung cancer has been reported. Among those delivery formulations, nanoparticle is an extraordinary actor in delivery systems. Nanoparticles with a size range from 1-1000 nm, enabling unique medical effects,6 have been successfully employed for biomedical applications in the past several decades.7 To achieve specific imaging and therapeutic effects, nanoparticles can enter human body via ocular penetration,8 intravenous injection,9 oral administration,10 and subcutaneous route.11 However, factors such as hepatic first-pass metabolism, rapid blood clearance, and high dosage exposure in off-target tissues limit the efficacy of these conventional delivery methods, especially for respiratory disease. Intratracheal nanoparticle delivery is a promising noninvasive strategy for respiratory disease. By controlling the size of nanoparticles, they can reach the alveolar region in deep lung enabling homogeneous distribution, improved deposition and increased delivery efficacy. Tailorable nano-sized particles offer additional advantages, as versatile surface modification and high surface area–to–volume ratios favor drug binding and loading, thereby improving efficacy and residence time. Multifunctional nanoparticles loaded targeting ligands, imaging agents, and therapeutic drugs enable the synthesis of multimodal compounds that provide highly sensitive imaging and treatment at molecular and cellular levels.12 These properties enable inhaled nanoparticles to reach specific targeted sites and bind biomarkers in the deep lung, amplifying signals of molecular information, enhancing local drug concentrations and protecting secondary organs from systematic exposure. Thus, nanoparticles are very attractive candidates for the intratracheal delivery imaging and treatment strategy of respiratory disease.13 Figure 1 is a typical depiction of intratracheal delivery strategy.14-16 This promising and fascinating intratracheal delivery technique, combined with the advantages of nanotechnology, paves a new avenue for respiratory disease theranostics. This review summarizes essential developments and recent advances in intratracheal delivery of nano- and microparticles and hyperpolarized gases, particularly for delivered nanoparticles imaging respiratory disease. This is a valuable resource with systematized information on intratracheal particle delivery systems and their advantages and prospects for clinical applications in precise imaging and treatment of respiratory disease.
2 Intratracheal delivery of nano- and microparticles and their deposition characteristics Significant research efforts have been devoted to the understanding and improvement of nano- and microparticles deposition in the lung. Key factors including respiratory anatomy and particle size influence delivered particles deposition, as summarized in Figure 1. Given their greater gravitation and inertia, microparticles with diameters larger than 5 µm are transported to the upper airways and nasopharynx, and subsequently swallowed into gastrointestinal tract and coughed in sputum.17 Whereas microparticles sized between 1 and 5 µm are prone to deposition in bronchi and bronchioles by inertial impaction and sedimentation.18 Nanoparticles with a diameter ≤ 1000 nm deposit in the alveolar region due to sedimentation and Brownian diffusion, and could be optimized for intratracheal delivery. 19 A large number of nanoparticles remaining in the lung are removed by slow clearance mechanisms, including alveolar macrophages and epithelial transcytosis, and these processes may last between days to several months.20 Intratracheal delivered nanoparticles (< 6 nm) translocate to the lung capillaries and lymph nodes, and may reach other body regions following bloodstream, crossing the air-blood barrier and entering the circulation. 21,22 Nanoparticles deposited within lungs have a greater chance of escaping from lung clearance mechanisms and reaching epithelium directly, when compared to microparticles. The most commonly used nanoparticles measure between 50 and 500 nm, which is an optimal size for efficient endocytosis.23 However, the lung mucus and surfactant barriers present a major obstacle to the translocation and deposition of intratracheal-delivered nanoparticles. The modification of surface coating enables to minimize nanoparticles adhesion to mucus and protein, such as polyethylene glycol (PEG).24 Mucus-penetrating particles as large as 300 nm exhibited uniform distribution and markedly enhanced retention in lungs after inhalation.25 Nanoparticle, indeed, with its versatile size scale and properties, provides tunable options for imaging and treating respiratory disease. 3 Applications of intratracheal delivery strategy 3.1 Intratracheal delivery pulmonary-imaging 3.1.1 PET/CT imaging PET/CT (Positron emission tomography computed tomography) imaging is a comprehensive detection mothed depends on the uptake radiotracers with incremental value due to its higher sensitivity and accuracy, and superior quantification of lung function. Indeed, a large number of studies have used radioaerosol PET/CT imaging to assess lung function and physiology in respiratory diseases. Inhaled ultrasonically nebulized 99mTc-albumin colloid (diameter 3.4 µm) is a non-invasive and easy-performed method to test mucociliary function of the airways.26 Le Roux et al 27 presented an automated threshold-based approach to quantify pulmonary function using 68Ga-V/Q (ventilation/perfusion) PET/CT. More recently, they demonstrated the feasibility and accuracy of 68Ga-V/Q PET/CT in cancer patients with suspected pulmonary embolism, compared to CT pulmonary angiography (CTPA).28
Radiation-induced regional lung functional deficits of lung cancer patients can be estimated by simple linear models with 4D 68Ga-V/Q PET/CT imaging (Figure 2).14 Besides, high-resolution PET/CT imaging of 13N-NH3 labeled isotonic saline (inhalable aerosol, 4.9 µm) was shown to accurately detect aerosol distribution pattern in asthmatics patients.29 Cossío et al 30 reported three different pulmonary administration methods of aerosol labeled with 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG, diameter in the range 0.9-5.25 µm) for PET imaging and compared their regional distribution in rat lungs, providing paramount information for optimization aerosol delivery systems. By providing anatomical information and accurate estimation of diseased lung function, PET imaging of inhalable radioaerosols can benefit clinical practice, but motion artifacts, radiation exposure and cost are persistent issues. 3.1.2 MR imaging With advances in MRI (magnetic resonance imaging) techniques and optimization of imaging sequences, good quality MR images of lung can be performed with administrated potent contrast agents. For example, inhalable hyperpolarized 3He and129Xe gases (atoms, size < 1 nm) have been regarded as a promising MRI agents for evaluating lung function because of their longer longitudinal relaxation times (T1) resulting from a nuclear spin quantum number of 1/2.31 As shown in Figure 3,32 hyperpolarized 3He lung functional MR imaging has been used to assess inhaled gas distribution and quantify lung function in healthy young and older never-smokers, and in patients with asthma, COPD (chronic obstructive pulmonary disease), CF (cystic fibrosis) and radiation-induced lung injury. Reproducibility, feasibility, tolerability, and safety of lung function quantitative evaluation by 129Xe gas MRI was also demonstrated in patients and animal models with a variety of respiratory diseases.33-35 Oxygen-enhanced MRI has also been used to evaluate regional lung function, as paramagnetic oxygen molecules can shorten T1 and T2* values in the lungs.36 Hyperpolarized gases MRI is a highly specific, noninvasive, time-saving, and easy to operate methodology providing systematic and comprehensive information on lung function. However, the sophisticated production of polarized gases limits its clinical applications. Given excellent advantages of 19F, such as 100% naturally abundant, high gyromagnetic ratio (~95% of 1H) and high sensitivity of 83%,9 it is opportune to develop 19F-MR imaging. In 1996, perfluorocarbon (PFC) partial liquid ventilation was shown to alleviate neonatal respiratory distress syndrome and improve pulmonary function due to its high oxygen-dissolving and releasing capability, low surface tension and excellent physical-chemical properties.37 The combination of these features makes PFC the best 19F-MR contrast agent candidate for pulmonary imaging by intratracheal delivery. For example, aerosol deposition and oxygenation patterns in rat lungs have been detected by 19F-MR imaging after inhalation PFC aerosol (1.2 µm) produced by pneumatic generator.38 In another study in rats, high resolution three-dimensional 19F-MR imaging was able to assess airway pressures and strains with liquid PFC instilled into the lung.39 19 F-MR with nano-sized PFC enable highly sensitive diagnostic imaging of lung cancer. PFC nanoparticles (approximately 150 nm in size) administered by intratracheal delivery were shown to diffuse and distribute densely and deeply into the lung tumors, producing
excellent fluorescence and 1H- and 19F-MR imaging signals that persisted for at least 72 hours.15 Furthermore, fluorine imaging, demonstrated for the first time in lung cancer, obviates the need for gadolinium and circumvents potential safety issues. Indeed, PFC nanoparticles are safe in vitro and in vivo and are constrained to the tumor. 9,15 As PFC has a long history of medical applications as artificial blood substitute, liquid ventilation and drug delivery vehicles,37,40 the logical extension of this work suggests PFC nanoparticles represent an important theranostic opportunity to address the formidable challenges in treating lung cancer. More importantly, active targeted PFC nanoparticles show great promise as quantitative biomarkers for lung cancer molecular imaging. Recent data demonstrated that intratracheal administration of αvβ3-targeted PFC nanoparticles (about 170 nm) produced significantly higher 19F-MR signal in the tumor and actively targeted tumor angiogenesis in orthotopic lung cancer models (Figure 4a).41 Of note, multimodal imaging methods, including optical, 1H-MR and 19F-MR imaging, have also contributed to intratracheal-delivered PFC-based pre-clinical and clinical tests in lung cancer imaging. In addition to PFC nanoparticles, iron oxide nanoparticles are suitable for intratracheal delivery pulmonary MR imaging. Intratracheal-delivered antibody-conjugated superparamagnetic iron oxide nanoparticles (SPIONs, about 100 nm) have been shown to actively target and detect M1 and M2 macrophage subpopulations in a COPD mice model with MRI, and to provide early diagnosis of pulmonary inflammatory diseases.42 Recently, SPIONs (about 130 nm) were nebulized and delivered to the rat lungs, enabling lung imaging with high sensitivity and efficacy via magnetic particle imaging (Figure 4b).43 Novel nano-sized MRI contrast agents developed by Gao et al, 44 chitosan/Fe3O4-enclosed bispecific antibodies, were shown to significantly enhance signal intensity for lung cancer after pulmonary inhalation, when compared to MRI alone. 3.1.3 Optical imaging Fluorescence and bioluminescence imaging experienced rapid development with the nanotechnology revolution and innovation in nanomedicine. In particular, intratracheal-delivered nano- and microparticles have shown tremendous value in pulmonary optical imaging. Mizuno et al 16 succeeded in visualizing pulmonary delivery and gene expression simultaneously in vivo by fluorescence and bioluminescence of administrated well-designed ICG-pDNA dry power (about 20 µm in diameter) (Figure 5). Fluorescence images of live xenografted mice after inhalation nebulized gelatin nanoparticles modified with biotinylated EGF (epidermal growth factor) sized in 0.4-2 µm revealed that the aerosol particles bound to EGFR (epidermal growth factor receptor) and targeted cancerous lung tissue, with lower accumulation in normal lungs.45 In another study, polystyrene nanoparticles loaded near-infrared fluorescence dye (100 nm) were demonstrated by fluorescence imaging to accumulate in alveolar M2 macrophages and alveolar areas after administration in allergic airway inflammation mice via intranasal tract. 46 Cy5.5-labeled dry siRNA/chitosan powder was shown to exhibit effective and specific gene silencing and excellent fluorescence imaging in vivo, thereby integrating diagnosis and treatment.47 3.2 Inhalation treatment for respiratory diseases
3.2.1 Chronic respiratory infections Chronic respiratory infections such as asthma, COPD, CF, tuberculosis and other infectious lung diseases, are usually treated by systemic administration (orally or intravenously) of high doses of antibiotics, which may cause several adverse effects and bacterial resistance, ultimately resulting in treatment failure. Intratracheal delivery is an attractive approach to overcome these issues as it improves bioavailability and stability of particles or drugs in targeted lung lesions. Thus, nano- and microparticles delivery via the intratracheal route is increasingly being used in the treatment of these infectious diseases. Treatment of mycobacterium avium complex (MAC) lung disease is a long battle that requires a multidrug antibacterial regimen to completely eliminate the infectious bacteria. Amikacin liposome inhalation suspension (ALIS, Arikayce®) is a liposomal formulation of amikacin (an aminoglycoside antibacterial drugs) designed for nebulization and inhalation into the lungs, thereby facilitating targeted and localized drug action against MAC lung disease. ALIS is approximately 300 nm in diameter 48 and exhibit more effective penetration ability and antimicrobial activity than free amikacin.49 In the CONVERT phase III clinical trial, addition of ALIS to standard guideline-based therapy (GBT) for treatment-refractory MAC lung disease achieved significantly greater culture conversion by month 6 than GBT alone, with comparable rates of serious adverse events.50 More importantly, ALIS is the first and only inhalable therapeutic liposome with FDA approval for the treatment of MAC lung disease in adult patients who have treatment-refractory disease and limited or no alternative treatment options.51 Previous studies indicate that inhaled corticosteroids significantly reduce exacerbation frequency, improve patient health status, and decrease mortality in the long term.52 Budesonide is one of the most extensively used inhaled corticosteroids, with excellent topical anti-inflammatory capability. Inhalable submicron particles of budesonide have been shown to reach deep into the lungs, with an increase in plasma concentration of 28.85%.53 Recently, large porous particles loaded with budesonide were shown to reduce macrophage phagocytosis and to prolong residence time by 4 hours in the lungs.54 Another study reports similar results for inhalable drug-loaded large porous particles in asthma treatment.55 Idiopathic pulmonary fibrosis is a severe lung disease typically treated with glucocorticoids, supportive oxygen therapy, or pulmonary transplantation. As these treatments present several disadvantages and limitations, inhalation nano- and microparticles provide attractive new opportunities to treat this serious disease. Garbuzenko et al 56 have shown that inhalation treatment using lipid-based nanoparticles loaded with prostaglandin E2 and targeted siRNAs (about 400 nm) prevented the development of severe pulmonary fibrosis in mice. Their subsequent study demonstrated that inhalable lipid-based nanoparticles (about 130 nm) loaded with lumacaftor and ivacaftor were highly effective in treating CF (Figure 6).57 Similarly, azithromycin and rapamycin-loaded microparticles (~1 µm in diameter) exhibited rapid mucus penetration and controlled drug release after spray drying, which could significantly improve the treatment of recurrent infection in patients with CF. 58 Currently, the standard method to treat tuberculosis is multi-antibiotic administration for long periods, which leads to drug resistance, patient non-compliance, higher costs, and
lower drug deposition in lungs. Intratracheal-administrated nano- and microparticles are candidate delivery systems to circumvent these problems. Indeed, anti-tubercular drug rifampicin was loaded in glycerosomes carriers (about 100 nm), that significantly improved drug deposition in the lungs following intratracheal administration.59 Inhalable spray-dried particles carrying anti-tubercular drugs exhibited lower cytotoxicity and higher lung uptake ratio, and continued to release up to 8 hours.60 Nebulized nanoparticles loaded with anti-tubercular drugs isoniazid or rifampicin (about 230 nm) displayed more chemotherapeutic efficacy than the free drugs.61 Inhalable nano- and microparticles loaded with anti-tubercular drugs improve drug deposition and reduce systemic adverse effects, and are therefore a promising strategy for the management of tuberculosis. 3.2.2 Lung cancer Lung cancer is the most common cancer worldwide and its incidence and mortality rates continue to rise. Conventional treatment strategies include surgery, chemotherapy, radiotherapy, among others. Although these treatments can benefit patients to some extent, they exhibit various limitations. Surgery is invasive and limited to small early stage tumors without distant metastases. Lung cancer originates in the bronchial epithelium and is mostly supplied by bronchial arteries,62 receiving approximately less than 1% of cardiac blood output.63 Consequently, systemic chemotherapy mostly based on intravenous delivery has limited efficacy, as low drug concentrations reaching tumors, severe adverse side effects, and acquired resistance. Radiotherapy for lung cancer can cause damage and toxicity to the normal tissue. Thus, a molecular-targeted treatment strategy with direct lung administration, such as intratracheal delivery of nano- and microparticles, is a promising noninvasive and efficient alternative for lung cancer treatment. Indeed, inhalable nano- and microparticles loaded anti-cancer drugs have achieved many outstanding and encouraging progresses. The efficacy of lipid-coated 5-fluorouracil aerosol inhalation in lung cancer treatment has been demonstrated in hamsters.64 Inhalable doxorubicin-loaded human serum albumin nanoparticles (~340 nm) were significantly improved anti-tumor efficacy in lung metastatic tumor models (Figure 7).65 The anti-tumor effects of inhalable nanoparticles loaded with other drugs, such as erlotinib,66 taxanes,67 and rapamycin68 have also been investigated in lung cancer animal models. Nanoparticles with actively targeted sensitive biomarkers of lung cancer can increase drug release and improve treatment efficiency. For example, EGFR is over-expressed in 40-80% of non-small cell lung cancer (NSCLC) patients.69 EGFR-targeted SPIONs (about 360 nm in diameter) tracheal-instilled in mouse orthotopic models of NSCLC showed prominent anti-tumor efficacy when compared to magnetic hyperthermia treatment.70 Additionally, inhaled nanoparticles carrying RNAs71 and DNAs 72 have been shown to have superior anti-cancer activity. Intratracheal instilled siRNA/RGD (Arg-Gly-Asp peptides) gold nanoparticles showed excellent suppression of lung tumor cell proliferation and tumor size reduction.71 Given the vast number of potential applications for nanotechnology and nanomaterials in the biomedical field, more research effort should be dedicated to the assessment of inhalable nano- and microparticles biosafety and toxicity in animal models and humans, promoting its clinical translation for lung cancer therapy.
4 Conclusion This review summarizes important advances of intratracheal delivery nano- and microparticles and hyperpolarized gases for imaging and therapy of respiratory disease, particularly for intratracheal delivery nanoparticles of pulmonary imaging. The unique anatomy of the lung provides an opportunity to noninvasively deliver particles directly to lungs, allowing enhanced pulmonary accumulation, optimal molecular-targeted imaging, and improved therapeutic efficacy. Nanoparticles, with a unique tunable size and properties, combine an intratracheal delivery strategy, with precise molecular theranostic efficacy. Indeed, intratracheal-delivered nano- and microparticles enable accurate multimodal molecular imaging and can mitigate disease progression in asthma, COPD, CF, tuberculosis, and even lung cancer. The opportunity is ripe for theranostic research devoted to intratracheal delivery of nano- and microparticles.
Acknowledgments This work was supported by the National Basic Research Program of China (2015CB931800), National Natural Science Foundation of China (81627901, 81471724,81771903), The Tou-Yan Innovation Team Program of the Heilongjiang Province (2019-15), Natural Science Foundation of Heilongjiang Province of China (LC2016034), Heilongjiang Postdoctoral Funds for Scientific Research Initiation (Number LBH-Q15090), the Fourth Hospital of Harbin Medical University Fund for Distinguished Young Scholars (HYDSYJQ201601), and the Key Laboratory of Molecular Imaging Foundation (College of Heilongjiang Province).
Authors' Contributions Manuscript writing: Hongbin Wang Approval of manuscript: all Prof. Xilin Sun and Prof. Lina Wu were the guarantors of the paper.
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Figure Legends Figure 1. A typical depiction of intratracheal delivery strategy. Intratracheal delivery various sized particles and their deposition in the lungs are distinguished by different colors. Multifunctional nanoparticles directly deposit in lungs after intratracheal administration allows for precise multimodal imaging (including PET, MR and optical imaging) and therapy of respiratory disease. The PET ventilation image (A) is reprinted with permission from Siva et al.14 The MR image (B) of lung cancer is reprinted with permission from Wu et al.15 The optical image (C) is reprinted with permission from Mizuno et al.16 PET = positron emission tomography; MR= magnetic resonance. Figure 2. Images of a representative case show changes in PET perfusion (left), ventilation (middle), and CT density (right) between scan time points relative to radiation therapy dose distributions. Reprinted with permission from Siva et al.14 PET = positron emission tomography; CT=computer tomography. Figure 3. Hyperpolarized 3He MRI coronal center slice images for healthy young and old never smokers and subjects with asthma, COPD, RILI and CF. Reprinted with permission from Washko et al.32 COPD=Chronic obstructive pulmonary disease; RILI=Radiation-induced lung injury; CF=Cystic fibrosis. Figure 4. a) Merged 1H (gray) and 19F (red) images of rabbit Vx2 orthotopic lung cancer models after intratracheal delivery avβ3-targeted PFC nanoparticles. Reprinted with permission from Xu et al.41 b) Representative MPI/CT images of the rat lung airspace after inhalation SPION-labeled aerosol and delivery efficiency assessment. Reprinted with permission from Tay et al.43 PFC=perfluorocarbon, MPI=magnetic particle imaging, CT=computer tomography, SPION= Superparamagnetic iron oxide nanoparticle. Figure 5. Dual imaging of the pulmonary delivery and gene expression. (A) The fluorescence was detected in the whole body 20 min after administration ICG-pDNA dry powder. (B) The luciferase activity was measured 9 h post-administration. In mice in which fluorescence had been strongly detected, bioluminescence was detected more strongly. (C) The fluorescence that had been measured 20 min after administration of the dry powder remarkably correlated to the bioluminescence after 9 h (r2=0.994, the scale is in photon/s/cm2/sr). ICG=Indocyanine green, pDNA= plasmid DNA. Reprinted with permission from Mizuno et al.16 Figure 6. Representative MR images (a) and CT images (b) mice with CF before and after lumacaftor and ivacaftor-loaded nanoparticles inhalation treatment. Reprinted with permission from Garbuzenko et al.57 MR= magnetic resonance, CT=computer tomography, CF= Cystic fibrosis. Figure 7. (A) The lung deposition of TRAIL/Dox HSA nanoparticles in ICR mice using RGB spectra for Cy5.5 and doxorubicin over 3 days after administration. (B)Representative photographs of the lungs of BALB/c nu/nu mice at 8 weeks after H226 cell implantation and of the lungs of an age-matched normal mouse. Photographs of the lungs(C) and lung weights (D) of BALB/c nu/nu mice after H226 cell implantation with or without pulmonary TRAIL/Dox HSA-NP administration. The results represent the lungs of three or four individual mice and are presented as means ± SDs. *P < 0.07 vs. TRAIL/Dox HSA-NP; **P < 0.004 vs. Dox HSA-NP; and ***P < 0.01 vs. non-treated controls. TRAIL=tumor necrosis
factor (TNF)-related apoptosis- inducing ligand; HAS=human serum Dox=doxorubicin, NP=nanoparticles. Reprinted with permission from Choi et al.65
albumin;