key: cord-0702145-s63zgehf authors: Saadat, Mahsa; Manshadi, Mohammad K.D.; Mohammadi, Mehdi; Zare, Mohammad Javad; Zarei, Mohammad; Kamali, Reza; Sanati-Nezhad, Amir title: Magnetic particle targeting for diagnosis and therapy of lung cancers date: 2020-09-11 journal: J Control Release DOI: 10.1016/j.jconrel.2020.09.017 sha: 30d165b8bd3af3222b4ffeb4ff005c6309093730 doc_id: 702145 cord_uid: s63zgehf Over the past decade, the growing interest in targeted lung cancer therapy has guided researchers toward the cutting edge of controlled drug delivery, particularly magnetic particle targeting. Targeting of tissues by magnetic particles has tackled several limitations of traditional drug delivery methods for both cancer detection (e.g., using magnetic resonance imaging) and therapy. Delivery of magnetic particles offers the key advantage of high efficiency in the local deposition of drugs in the target tissue with the least harmful effect on other healthy tissues. This review first overviews clinical aspects of lung morphology and pathogenesis as well as clinical features of lung cancer. It is followed by reviewing the advances in using magnetic particles for diagnosis and therapy of lung cancers: (i) a combination of magnetic particle targeting with MRI imaging for diagnosis and screening of lung cancers, (ii) magnetic drug targeting (MDT) through either intravenous injection and pulmonary delivery for lung cancer therapy, and (iii) computational simulations that models new and effective approaches for magnetic particle drug delivery to the lung, all supporting improved lung cancer treatment. The review further discusses future opportunities to improve the clinical performance of MDT for diagnosis and treatment of lung cancer and highlights clinical therapy application of the MDT as a new horizon to cure with minimal side effects a wide variety of lung diseases and possibly other acute respiratory syndromes (COVID-19, MERS, and SARS). combination of chemotherapy with chest radiotherapy (RT) given its high responsiveness, which may, with high probability, stop cancer retrieving, cure or shrink the tumor, and suppress the symptoms of cancer [9] . On the other hand, NSCLC is widely encompassed, accounting for almost 85% of all lung cancers. The most common type of NSCLC is adenocarcinomas that spread to lymph nodes and multiple sites in the lungs like alveolar walls [10] . Squamous cell carcinomas, on the other hand, arise in the central chest area of bronchi and grow large and forming a cavity [11] . The least common type of this category is large cell carcinomas, spreading to the lymph nodes and distant sites [12] . However, several subtypes of NSCLC are much less common, e.g., adenoid cystic carcinomas, lymphomas, and sarcomas. These subtypes originate from salivary glands, white blood cells (lymphocytes), and mesenchymal (connective) tissue, spreading to the lungs through the bloodstream or lymphatic system [13] . Three factors of tumor size (T), spreading of a tumor to adjacent nodes (N), and metastasis to nearby tissues (M) determine the progression of lung cancers [14] . Imaging methods such as magnetic field X-rays [15, 16] , sound waves [17] , and radioactive substances [18] are known to be used before and after the diagnosis of lung cancer to determine where cancer cells spread and what would be the most efficient treatment approach. Among various imaging techniques, magnetic resonance imaging (MRI) generates the most detailed structural images of the tumor J o u r n a l P r e -p r o o f Journal Pre-proof [19, 20] . Upon determining the stage of the tumor, the extent of cancer, and the overall health and function of the lungs, a proper therapeutic procedure needs to be selected. Different stages of the NSCLC and corresponding types of treatments are summarized in Table 1 [14, [21] [22] [23] . The surgery is the primary treatment advice for stage 0 lung cancer to remove the tumor. The higher the number of cancer cells, the more chance of spreading cancer, necessitates combining chemotherapy and radiation besides the surgery [24] . Table 1 . Stages of non-small cell lung carcinoma (NSCLC) and corresponding treatment methods Definition of NSCLC's stage Treatments of NSCLC The tumor size is too small to be distinguished by imaging tests and bronchoscopy. There is no node (N0) and no metastasis (M0); therefore there is no tumor found in the lung while there exist cancer cells in sputum. The tumor known as carcinoma in situ is found at the lining layer of the lung airways. Cancer cells have not yet spread into the lungs tissue (M0, N0) Surgery-stereotactic body radiation therapy (SBRT)-radiofrequency ablation (RFA) This stage is divided into two subdivisions: The tumor invaded across the lung tissue but in less than ½ cm, N0 (no nodes)-M0 (no metastasis) Surgery to remove part of the lung (a lobectomy) or all the lung (pneumonectomy) The tumor is about 1 cm, N0 (no nodes) -M0 (no metastasis). It is invaded across the lung membrane without any effect on the bronchi or branches. Radiotherapy and radiofrequency ablation are alternative treatments for patients with serious physical problems. The tumor is larger than 3 cm-M0 (no metastasis)-it spreads through the carina (causes clogging the airway) or into the chest wall Surgery and chemotherapy are recommended to reduce the chance of cancer return. The tumor is larger than 5 cm in size and spreads into blood vessels, trachea and esophagus-M0 Surgery to remove all the tumor, then chemotherapy, along with radiotherapy. Any size of tumor spreading to nearby nodes as well as other organs like bones, brains and liver. The survival rate of stage IV is 1%, owing to the extent of tumor growth and invasion [25] . Based on the tumor location, individual or combination of the following methods are utilized -Surgery -Chemotherapy -Targeted therapy -Radiotherapy -Immunotherapy -Photodynamic therapy (PDT) of drugs has been considered as a promising method to reduce the harmful effect on healthy tissues [31] . Moreover, the carriers of drugs can produce image contrast and therefore provide brighter images from the tissues needed for screening purposes [32] . Nanoparticles, as the carriers of drug administration, have provided an excellent opportunity to practice optimal targeting strategies in the lung for both diagnosis and treatment purposes. Several review articles have overviewed the efficacy of nanoparticle carriers for cancer therapy. For example, the performance of pH-sensitive nanoparticle carriers in targeted cancer therapy was reviewed by Kanamala et al. [33] . Nano-liposomes loaded with ligands or antibodies have been reviewed for their performance in the therapy of lung cancers. Najeeb Ullah et al. [34] provided in-depth insight into the site-directed application of nano-liposomes to release their encapsulated drugs to tumor areas. On the other hand, the appropriate design of the drug-carrier complex is key for successful drug delivery. Rizvi and Saleh [35] in 2018 reviewed the design and application of nanoparticles-drugs to target tumors with the least side toxicity and less frequent dosing. Sun et al. [36] overviewed the utility of magnetic nanoparticles in MR imaging for cancer diagnosis. They proposed new strategies to improve the imaging contrast by incorporating surface coatings (gold, silica, and biocompatible polymers) or employing higher strength magnetic core (e.g. doped iron oxide nanocrystals, nanocomposites and metallic/alloy nanoparticles). Targeted cancer treatment using nanomedicine has been performed by the release of particles in the blood circulation or respiratory system [37, 38] . The main dispute though, is to entrap particles in the desired location. The targeted delivery methods are divided into two main groups: passive methods without using any external forces, and active methods that utilize an external energy source to navigate nanoparticles to the location of interest. In the passive targeting, drugs are usually coated with substances like polyethylene glycol (PEG) [39] , polyglutamic acid (PGA) [40] , polylactic-co-glycolic (PLGA) [41] , and polysaccharides such as cyclodextrin [20] to bind with oxygen to extend the time of stay in the bloodstream and boosting the efficiency of treating the diseased tissue [42] . In active methods, an external force such as a magnetic field [43] or ultrasound is employed [44] to steer drugs toward the desired tissue. Alternatively, a responsive material [45] or a cell-specific ligand [46] is exploited to improve the affinity of drugs to target cells. Among various active methods, MDT has demonstrated to be a J o u r n a l P r e -p r o o f Journal Pre-proof promising approach for high efficacy drug delivery due to its fewer side-effects, quick response, and low cost [47, 48] . The MDT methods have been extensively investigated by researchers through different in vivo, in vitro, and numerical simulation studies [43, [49] [50] [51] . Also, it has been used for lung cancer diagnosis and therapy [52] , inhalable drug delivery [53, 54] , intracellular drug delivery [55] . In this method, drug is loaded on magnetizable porous micro/nano particles. These drug-conjugated particles can be manipulated throughout their journey in the body by a magnetic field, captured in the target location, and released in the desired tissue to perform treatment on the organs such as lung [56, 57] It is noted that the real-time and sensitive measurement of the distribution of nanoparticles in small animals is challenging and very expensive [36, 58, 59] . Computational fluid dynamic (CFD) methods have instead supported the prediction of MNPs fates in various human tissues [60] [61] [62] [63] [64] . Numerical simulations have also enabled to investigate complex drug delivery scenarios that are difficult to implement in-vivo and in-vitro, therefore they offer valuable insights for the transport and deposition of drugs into target tissues [64, 65] . This review discusses clinical features of the lungs, experimental techniques and numerical methods developed for MDT studies, and advances in new technologies utilized to implement MDT in the lungs with the focus on lung cancer diagnosis and treatment. It further highlights the challenges and future perspectives of developing efficient MDT strategies based on the clinical features of the lungs. Lung carcinoma accounts for a vast majority of primary lung tumors, while a smaller portion is related to other categories such as carcinoids, mesenchymal malignancies, lymphomas, and a small number of benign lesions. Patients within 50-70 years old constitute the largest group of lung carcinoma patients [66] . More than half of these patients already have distant metastases when detected with lung carcinoma, and about 25% of them have the illness in the regional lymph nodes [67] . J o u r n a l P r e -p r o o f Compared to other types of lung cancer, adenocarcinomas grow at a slow pace and generates smaller masses. However, it is able to metastasize extensively in the initial stages of the disease [68] . Currently, adenocarcinoma is the most widespread type of lung cancer, being accounted for about 50% of lung cancers diagnosed [66] . Typical adenomatous hyperplasia (AAH) is supposed to presage adenocarcinoma [69] , which follows a stepwise process to adenocarcinoma in situ, minimally invasive adenocarcinoma (with a diameter smaller than 3 cm and an invasive component of smaller than 5 mm), and invasive adenocarcinoma (various-sized tumors with an area of invasion larger than 5 mm). Adenocarcinoma in situ (AIS) usually includes peripheral portions of the lungs as the nodules [70, 71] . A majority of squamous cell carcinomas (between 60% to 80%) emerge in the proximal parts of the tracheobronchial tree following a series of squamous metaplasia-dysplasia-carcinoma in situ. However, it is growingly emerging as peripheral lesions [72, 73] . Central necrosis with consequent cavitation might be displayed by central and peripheral squamous cell carcinomas [74, 75] . A small group of central, well-differentiated squamous cell carcinomas appears as exophytic, endobronchial, papillary lesions. Patients who experience this unique form of squamous cell carcinoma often show permanent cough, repeated hemoptysis, or relapsing pulmonary infections resulting from airway blockage. A majority of patients with exophytic endobronchial squamous cell carcinoma have been detected with low-grade disease and a suitable prognosis, which could lead to a greater than 60% five-year survival rate [76] . Finally, the small neoplasm comes to asymptomatic phase, when a distinguished tumor mass starts blocking the lumen of the main bronchus, usually leading to distal atelectasis and infection [75] . Undifferentiated malignant epithelial tumors in which no glandular or squamous differentiation could be observed are categorized as large cell carcinomas. LCC is often a sizeable peripheral mass with notable necrosis [68] . The SCLCs usually emerge as pale gray masses, position centrally, and expand into the lung parenchyma [77, 78] . Most of these tumors have already metastasized to hilar and mediastinal lymph nodes when they are detectable. SCLCs generally tend to grow faster, more central and mediastinal localization and have quicker metastasis to extrathoracic sites with shorter total survival periods [79, 80] . Normally, a simplified system of clinical finite or clinical broad disease manages small cell carcinoma. The main duty of tumor/node/metastasis (TNM) staging Overall, squamous cell carcinoma and adenocarcinoma present a more favorable prognosis than SCLC, and if they are diagnosed prior to metastasis or local spread, they may be cured by lobectomy or pneumonectomy [68, 90] . Specific inhibitors could have significant effects on unresectable adenocarcinomas related to targetable mutations in tyrosine kinases such as Epidermal Growth Factor Receptor (EGFR) [91] . On the other hand, SCLCs are already extended when they are diagnosed, even if the primary tumor seems to be tiny and localized, therefore, surgical resection could not be considered as a feasible solution. Even with therapy, the median survival does not exceed one year, and only 5% of patients survive for 10 years [92, 93] . The genetic instability in human cancers appears to exist at two levels: at the chromosomal level, that includes large scale losses and gains, and at the nucleotide level, including single or several base changes [94] . Like other cancers, lung carcinomas arise by the accumulation of driver mutations resulting in the transformation of benign progenitor cells in the lung into neoplastic cells presenting many cancer hallmarks [68, 95] . Lung cancers harbor many numeric including DNA mismatch repair genes, although an alteration in simple repeat sequences has been observed [96] . The primary molecular alterations in lung cancers are summarized in Table 2 . J o u r n a l P r e -p r o o f [97, 98] . Mutations in KRAS promotes growth and prevents apoptosis Rare [68, 99] Observed in approximately 20-25% of lung adenocarcinomas in the United States; Generally associated with smoking [100] ALK rearrangements Fusions involving one of three tropomyosin receptor kinases (TRK); The TRK family contains three members, TRKA, TRKB, and TRKC [106] . Present approximately in 1% of NSCLC [106] . HER2 mutation HER2 (ERBB2) is an EGFR family receptor tyrosine kinase [107, 108] . Present approximately in 1 to 3 percent of NSCLC tumors [107, 108] MET is a tyrosine kinase receptor for a hepatocyte growth factor (HGF). c-MET mutation present [109] MET abnormalities (drug MET exon 14 skipping mutations) are present in 3% of lung adenocarcinomas; MET and EGFR co-mutations are present in 5 to 20 percent of EGFR-mutated tumors which are resistance to EGFR inhibitors [110] [111] [112] . Inactivation of the putative tumor suppressor genes [113] located on the short arm of chromosome 3 (3p) is a very common early event [68] . more than 90% of SCLCs [68] The retinoblastoma gene is mutated in several types of human cancers [114] . A very common tumor suppressor gene abnormality in SCLCs [99] ; Present in about 90% of SCLCs [68] Present in about 20% of NSCLCs [68] TP3 mutations TP53 is a tumor suppressor gene which is most commonly affected by point mutations in cancers; occurs relatively late [115] . A very common tumor suppressor gene abnormality in SCLCs [99] ; Present in more than 90% of SCLCs [68] Present in more than 50% of SCLCs [68] Nanoparticles have been used in various imaging methods such as computed tomography (CT) [116] , magnetic resonance imaging (MRI) [117] , and near-infrared (NIR) imaging [118] for detection of lung cancers. Chest X-rays and low dose CT-scans provide pictures to show size, shape, and position of cancer cells in lymph nodes [15] . CT-scan has disadvantages like causing severe artifacts in images by internal organ motion and tattoos along with low sensitivity (55-65%) and low specificity (65-75%) [119, 120] . The CT-scan and X-rays are unable to provide detailed images of soft tissues like inside the lungs, cartilages, joints, or muscles. More importantly, the amount of radiation exposed to patients due to CT or X-rays imaging may increase the risk of cancer, along with the occurrence of false-negative results when no lung cancer is found consequently [121, 122] . Positron emission tomography (PET) has challenges with differentiating metastatic or non-metastatic nodes [120, 123] . While the combination of CTscan and PET showed a better outcome in lung cancer imaging, but they still have restrictions in detecting non-resectable lung cancers [124] . On the other hand, the MRI has been utilized extensively for lung cancer diagnosis due to its decent non-invasiveness and effectiveness. Also, utilizing magnetic MNPs in MRI provides a high contrast for generating the most detailed imaging. For instance, magnetic iron oxide (Fe 3 O 4 ) nanoparticles have been used for MR imaging of the lungs because of their excellent biocompatibility and magnetization as well as their proper drug uptake and release [125] [126] [127] . Water-dispersible PEI-coated Fe 3 O 4 NPs have been used for MRI-based tumor imaging [126] . More importantly, tracking of drug-loaded superparamagnetic iron oxide nanoparticles (SPIONs) in the lungs has shown to be feasible for imaging via an external magnetic field. The endothelial progenitor cells (EPCs) stabilized with supermagnetic iron oxide (SPIO) were used for cancer ablation and repair of vascular injury, meantime they facilitate MRI imaging of lung cancers by providing the patterns of EPCsin tumor J o u r n a l P r e -p r o o f cells [128] . Also, the non-toxic and stable drugs folate-conjugated polyethylene glycol (FA-PEG) SPIONs were prepared as an efficient imaging agent for active targeting in the in-vivo models of lung cancers [129] . Cell-mediated delivery of nanogels loaded with Fe 3 O 4 is another effective and novel targeted nanoplatform for increasing the MR contrast of images from lung tumors [130] . In addition, Dextran-Benzoporphyrin Derivative (BPD) loaded in SPIONs is another novel nanomedicine drug for treating lung cancers while applicable for lung cancer imaging, where they enhance the MRI contrast [131] . Guthi et al. [132] encapsulated superparamagnetic iron oxide (SPIO) with doxorubicin in micelle cores as the MRI contrast agent. Moreover, the size and surface chemistry of MNPs are elemental characteristics of these particles, determining their route of delivery [133] . Different nano-carries such as liposomes, dendrimers, polymeric micelles, and inorganic magnetic particles have been used for active targeting in lung cancer imaging [53] . For instance, the optimal size of NPs is known to be 10-100 nm to ensure that they are not sequestered by the spleen or removed through the kidney [134] . MNPs with improper size may also accumulate in the spleen, brain, and liver, therefore the overall size of MNPs with their coating should not exceed 100 nm [135] . The utilization of MNP contrast agents in MRI imaging of the lungs has enabled the detection of solid pulmonary nodules (SPNs), characterization of SPNs, staging of lung cancers, and prediction of tumor treatment response [136] . MR imaging has also been combined with other imaging techniques to improve the diagnosis of lung cancers. Chang et al. [137] used new iron oxide NPs with dual optical and magnetic properties to enable combined MRI and diffusion-weighted imaging (DWI) in order to monitor the early response of lung cancers to chemoradiation. Such combinatory imaging technique has not been clinically practiced due to the low apparent diffusion coefficient of MNPs [138] . Yoon et al. [139] further used combined PET/MRI with appropriate MNP contrast agents for lung cancer detection. The work was successful to identify tumor necrosis, hypoxia, and heterogeneity of the tumor microenvironment. Although the ultrasonic nebulization system was employed for respiratory drug delivery [140] , the first SPIO nano-platform was utilized for lung cancer imaging in-vivo to enhance imaging sensitivity with the magnetic resonance-guided focused ultrasound surgery (MRgFUS) [44] . MRgFUS is a thermal treatment method used for various types of cancers in soft tissues like prostate, kidney, and liver [44] . The key challenge of MRgFUS for in vivo applications is related to its high ultrasound power, which may result in J o u r n a l P r e -p r o o f skin burns, edema, perforation of intestines, and injury of peripheral nerve surrounding the tumor. This challenge has been addressed by the SPIO nanoplatform with a demonstrated MRI effectiveness and tumor-ablative efficacy for lung cancer treatment [44] . Also, the potential of a combined MDT MRgFUS and MDT methods was further demonstrated for brain cancer treatment [141] . Moeier-Schroers et al. [142] compared MRI and low-dose CT (LDCT) for lung cancer detection, where they showed that the MRI has excellent sensitivity and specificity for the primary screening of lung cancer patients with the capability in prediction of nodules. The effectiveness of different MRI methods and their combination with other imaging techniques utilized for lung cancer detection are presented in Table 3 . [136] , [124, 143] , [144] , [145] , [146] Sensitivity: 96%-100% Specificity: 61% -Excellent image quality -No artifacts in images -High accuracy -Long examination time -Difficult access [147] , [148] , [149] MRI/DWI Sensitivity: 87% Specificity: 88% Beneficial for diagnosis of malignancy and benignity in the lungs -30 min test time [150] , [124] , [138] Table 4 Overview of the major types of MNPs and their compositions, advantages, and drawbacks. The second column of Table 4 summarizes the clinical utility of the MNPs as carriers for drug delivery to lung tumors and the corresponding clinical outcomes. Colloidal iron oxide nanoparticles (SPIO and USPIO) typically composed of nanocrystalline magnetite (Fe3O4) or maghemite (γFe2O3) protected with coating [151] . Advantages excellent biocompatibility and biodegradability SPIONs were used for magnetic hyperthermia. A single magnetic hyperthermia regimen reduced the tumor growth [49] . Superparamagnetic iron oxide NPs (SPIONPs) with an average size of 10±2 J o u r n a l P r e -p r o o f nanoparticles ease of synthesis Disadvantages variable magnetization vastly among synthesis methods even within particles of similar size due to incorporation of impurities disrupting the crystal structure toxicity due to ROS production non-specific targeting [152, 153] nm were coated with doxorubicin (Dox)conjugated heparin (DH-SPIO) and used for targeted anticancer drug delivery. DH-SPIO NPs displayed a higher efficacy than Dox in inhibiting tumor growth and therapy of A549 human lung carcinoma [154] . Composition made from iron, gold, cobalt, or nickel, often overlooked for biological applications due to their chemical instability. Iron nanoparticles: Advantage Iron nanoparticles possess high magnetization and are able to maintain super-paramagnetism at larger particle sizes compared to other oxide counterparts [155] Disadvantages 1-complex synthesis process 2-are typically protected by coatings, such as gold or silica to form a core-shell structure [156] Gold coatings: Advantage better biocompatibility and bioavailability, accumulate at tumor site & enhance x-ray effect Disadvantage stability related issue during aqueous formation [157] . silver magnetic nanoparticles: Advantage induced apoptosis in the targeted area, accumulation at the tumor site, and enhanced x-ray effect Disadvantage toxicity due to ROS production [158] Papain-encapsulated and fluorouracil bioconjugated gold NPs were synthesized while using papain as an anti-cancer. The efficacy of 5F-PpGNPs against human lung cancer A549 cell line improved significantly over that of pure 5-drug [159] A controlled synthesis of methotrexate (MTX) AgNPs using borohydride and citrate were utilized as reduction and reduction/capping agents, respectively. A significant performance against lung cancer cells (A-549) was reported [160] . Dual-functional nanoparticles made from hydroxyapatite with iron and platinum ions incorporation (Pt-Fe-HAP) Applicable for chemo-hyperthermia Pt-Fe-HAP was shown to be highly toxic to A549 cells after magnetic field treatment under hyperthermia but no damage to fibroblast cells was observed J o u r n a l P r e -p r o o f These MNPs exhibit super-paramagnetic properties. stable in biologically relevant media such as PBS the ability these MNPs to bind DNAs and proteins [161] . Recent advances in the synthesis of FePt nanoparticles have made these MNPs an option of choice for biomedical applications. The nteraction between the two chemical species in these NPs leads to a greater chemical stability in comparison with other high moment metallic nanoparticles [162] . Composition coating of MNPs with polymers is the most common way to solve the stability issue of nanoparticles against oxidation [163, 164] . Disadvantages non-specific targeting [165] drug delivery via chitosan coated Fe 2 O 3 MNPs in vitro could be improved if the drugs were modified with antibodies, proteins, or ligands [166] . EGRF-PLGA MNPs were used for drug delivery system where drug-loaded MNPs reduced the number of viable A549 cells significantly [167] . Silibinin-loaded PLGA-PEG-Fe3O4 nanoparticles was used where an enhanced inhibitory effect on the growth of A549 lung cancer cell line and hTERT gene expression was detected in compared to pure Silibinin [168] . mesoporous silica nanoparticles (MSNs) was conjugated to polymer matrix acting as drug container to enhance the drug encapsulation efficacy. Methotrexate (MTX) used as a model drug was successfully loaded in MNCs (M-MNCs) with promising dose-dependent anticancer efficacy against A548 cell [169] . dextran-coated magnetite seed particles increased the capturing efficiency of magnetic drug carrier particles in capillary tissues [170] . nanoparticles coated with Polyethylene Glycol (PEG) promoted water solubility, reduced toxicity, decreased enzymatic degradation and increased the in vivo half-lives of small molecule drugs during their magnetic drug delivery [171] [172] . are trapped in the region of interest under the magnetic field exerted from a stent, core, or a permanent magnet [127, 176] . The advances in MDT modeling of intravenous drug delivery to the lungs are discussed below and classified in Table 5 . The MNPs are injected throughout the blood and steered to the desired tissues under the influence of the magnetic field. The low dose of anticancer drugs can be employed in the presence of a magnetic field to avoid the aggregation of magnetic nanoparticles in the blood [177] . Various MDT methods have been used to employ smaller dosages of drugs and to reduce the toxicity of chemotherapeutic agents in the untargeted tissues [178] . Mykhaylyk et al. [179] conducted and 87% for DOX-loaded MNPs under the magnetic field, DOX-loaded MNPs with no magnet, and control (drug-free), respectively [183] . It is noted that the maximum threshold of the applied magnetic field should not exceed 0.4 T to prevent any harm to human tissues [184] . investigate the retention of drugs with the artery walls. Different parameters such as magnet size, particle size, drug/cargo size, and relative magnetic permeability were studied to optimize MDT through the artery wall. Cherry et al. [190] studied the effectiveness of permanent magnet for trapping magnetic particles flowing in the laminar blood flow in different arteries. The results showed that trapping the MNPs under the influence of Maxwell coil was more difficult in large arteries than in small ones. Moreover, the effect of parameters, such as blood flow velocity, drug particle size, and magnetic field strength, was assessed on the efficacy of MDT. In another study, controlling the swarm of magnetic particles was shown to increase the drug concentration and decrease the travel time of the particles in the target tissue [191] . Kumar et al. [192] further presented a physical-based model of MDT for drug delivery to an artery to optimize the path of a swarm of particles in the presence of a permanent magnet with 2 T magnetic field strength. Utilizing a magnetic field increased the number of particles with an increased scale of 6.4, demonstrating a promising outcome in the localization of particles inside tissues. Another model utilized a numerical simulation to characterize the response of magnetic nanoparticles in the aorta to a tree bar magnet (magnetization of each was =1.195 T). They estimated particle trajectories and retention of particles considering the key parameters of flow velocity and retention rate [193] . Numerical modeling was also employed to optimize the process of MDT. Kenjeres [194] included a non-uniform magnetic field (1-4T) for different stenosis in a realistic model of rightcoronary human arteries in which non-uniform magnetic field caused changes in the secondary flow pattern (a streamwise velocity contours deformed to perpendicular). In another study, the effect of Brownian motion and the interaction of red blood cells and super-paramagnetic J o u r n a l P r e -p r o o f nanoparticles were modeled in a Poiseuill flow [195] . The optimized size of nanoparticles was successfully steered to tumors with the size of up to 2 mm in diameter under the influence of an external magnetic field. The Brownian motion was shown to play a pivotal role in the trajectory of particles given its importance in modeling the diffusion of particles and their collisions with red blood cells. Numerical simulation has also been used to design appropriate magnetic particles to guide drugs to a targeted zone [196] . Agiotis et al. [197] designed a magnetic carrier using Fe 3 O 4 core for loading anticancer drugs to deliver the drugs to tumor cells. The effect of shape of electromagnet on magnetic drug targeting was studied and the results were in good agreement with the experimental data. Tip-top design, one side of the core, adopts a tip design in between the two face-to-face permanent magnet and provides the highest magnetic field strength for particle manipulation and field gradients for controling the orientation of particles. More importantly, magnetization optimization has gained much interest to control the trajectory of particles by an individual or arrayed magnets [198, 199] . Barnsley et al. [200] developed a numerical simulation and an in-vitro model to optimize the attraction of magnetic nanoparticles against a constant flow using a two-layer magnet array. This permanent magnet eases the disadvantages of other systems like Halbach arrays [201] to provide and modify magnetization without changing its physical dimension. Given a practical challenge of employing a permanent magnet in some part of the body due to its large distance to the target site (5-10 cm), implanting an intravascular catheter would be a promising approach to deliver magnetic particles in the bloodstream [202] . Iacovacci et al. [203] developed an axisymmetric model of the bloodstream by considering the physical effects of fluidic drag force because of the blood flow, magnetic attraction due to the external magnet, and particle motion under the effect of the fluidic force and the magnetic field. This magnetic catheter consisting of 27 permanent magnets succeeded in both deployment and retrieving unused 500 nm and 250 nm SPIONs from the bloodstream. In a more advanced simulation, the interaction of paramagnetic nanoparticles with each other due to an external magnetic field in the realistic model of the central blood distribution system was modeled using the Lattice-Boltzmann method in a three-dimensional vascular system [ 402 ] . The study focused on assessing the density of the particles in a targeted site in the Willis vascular system. Different parameters were J o u r n a l P r e -p r o o f optimized, such as the effect of coating thickness, impact of gravity, and magnetic properties of the particles. For instance, no difference is observed due to the coating or gravity for large particle size. Also, the size and crystallinity of supermagnetic particles were determined for particles with radius larger than 65 nm to achieve the maximal magnetic susceptibility. Despite many numerical studies on MDT in the bloodstream focusing MDT in the brain and heart, there is no report of theoretical modeling of MDT in the lung cancers, where drugs are intravenously delivered to the body. The in vivo, in vitro, and numerical models developed for intravenous magnetic drug targeting of the lungs are summarized in Table 5 . In addition to the intravenous injection of drugs and their delivery to the lungs, researchers and clinicians have demonstrated lung disease therapy using inhalational nanomedicine particles. The MDT, through the respiratory system, is one of the promising approaches to enhance local drug concentration for the treatment of lung diseases [205] . Here, we classified these studies in three subsections of in vivo and in vitro experiments as well as numerical simulations ( Table 6 ). Monitoring the deposition of aerosol particles in an animal's lungs have provided scientists with insights on lung diseases [206] [207] [208] [209] [210] . This delivery route has also been used for MNP-based anticancer drug delivery to the lungs under stimulation of external magnetic fields. Dames et al. In vitro MDT experiments have also been utilized for targeted delivery of aerosol particles carrying chemotherapeutic agents [218] . Given the easy exhale of MNPs from lungs due to their small size, MNPs were loaded into magnetic particles while D-mental was used for hyperthermia therapy. Also, preparation of these drugs with aqueous co-precipitation further increased the deposition of particles in the lungs. Xie et al. [220] used numerical simulations to predict particle deposition of a previously studied in vitro MDT model by employing the wedge-shaped permanent magnet (The magnet placed at a distance of 2 mm). The numerical model was used to study effect of different parameters such as flow rate, tube diameter, and particle size on the efficacy of particle deposition. The larger the diameter of particles, the higher the efficacy of deposition fraction. In addition, increasing the flow rate and tube diameter enhanced the deposition fraction. The experimental results were found to be in good agreement with the CFD simulation data. In another study, Martinez et al. simulated a deep respiratory region in which the effect of a permanent magnet, magnet position, and inhalation flow rate on particle deposition was studied. For the magnetic field strengths of below 1.5 T, the deposition efficiency was enhanced by increasing the particle size. However, for magnetic field strengths of above 1.5 T, the deposition efficiency decreased by increasing the particle size. The premier study of Kraficik et al. [227] investigated the effect of a quadrupole magnetic field on the steering of aerosolized magnetic nanoparticles into the alveolar region. In another research, Ostrovski et al. [228] simulated the deposition of SPION in a deep site of acinus under the effect of a permanent magnet. Placing the magnet closer to the acinar region enhanced the magnetic field strength and therefore improved the deposition efficiency from 40% to 100%. Kenjeres et al. [229] developed a CFD model to simulate a real human lung from mouth to the eighth generation of a bronchial branch under the delivery of iron oxide-maghemite core. The magnetic stimulation of these particles increased the deposition efficiency for about 85%, demonstrating the applicability of MDT approaches for the treatment of respiratory diseases. In another study, therapeutic performance of magnetic nano-drug targeting using a rectangular coil as an external magnet was studied on a realistic model of the trachea [230] . As a result, the deposition of aerosol particles reduced from 50% to 47% by imposing a magnetization field. The study design was not therefore effective to improve drug delivery, highlighting the needs to selection of appropriate design parameters. Another CFD model of respiratory airway tree was simulated to investigate targeted drug delivery of angle of the magnetic source on particle deposition. The results showed about 75% deposition efficacy of 8 μm magnetic particle size at 5 L/min airflow rate. Also, the optimal angel of the magnetic source was estimated to be 0° when the patient lie on his/her back (Fig. 2B) . Respiratory magnetic drug delivery in lung cancers [38] . A) Magnetic drug targeting of aerosol particles via the respiratory system [38] . B) Particle trapping under the influence of different magnetic J o u r n a l P r e -p r o o f fields for oral and oronasal breathing [232] . C) Mechanism of magnetic aerosol drug targeting (MADT) in lung cancer [233] . A few CFD studies have been conducted specifically to simulate MDT performance in lung tumors. Sabz et al. [205] investigated the MDT in lung cancer in the upper airways by using a coil to produce a magnetic field. In the following study, we simulated the lung cancer model in the airways (G0-G3) and used a permanent magnet to steer magnetic drug particles toward tumors [233] (Fig. 2B) . The effect of parameters such as permeability, magnet size, magnet position, and magnetic field strength on drug delivery was studied. The results show that implementing a permanent magnet near the G0 resulted in 49% trapping of 7 μm particles. Moreover, increasing the magnet size (H=4 cm, D=2 cm) contributed to 75.8% particle deposition fraction. Furthermore, an increase in magnetic field strength from 0.25 T to 1.25 T enhanced the delivery from 5.7% to 34% for 7 μm MNPs (Fig. 2C) . The summary of these numerical studies is detailed in Table 6 . *polymer poly (lactic-co-glycolic acid) -N.A.: not available The field of magnetic particle delivery has demonstrated considerable advances in clinical practices. Magnetic particle targeting is prone to be the most significant technological advances owing to its less invasive treatment and highly efficient targeted drug delivery. However, several challenges still need to be addressed to facilitate its diagnostic and treatment utility for lung J o u r n a l P r e -p r o o f cancers. Also, researchers need to further evaluate its therapeutic efficiency and identify clinical risks. Utilizing proper imaging techniques like PET and DWI creates detailed images applicable for better lung cancer detection. Also, a combination of these imaging techniques with MRI facilitates diagnosis of lung cancers due to much higher sensitivity and specificity in detecting metastatic nodes [234, 235] . MRI plays a leading role in the diagnosis of NSCLC's stages. Magnetic particle targeting approaches in lung cancers involves intravascular injection and pulmonary system, employed so far in the lungs, liver, and spleen in vivo and in vitro models. The permanent magnet is the most effective method to steer drugs to particular tissues without being aggregated in healthy tissue. However, in most of these studies, steering drugs in non- More importantly, one of the global concerns these days is the severe acute respiratory syndrome coronavirus 2 (COVID- 19) , which has no specific medication recommended hitherto [237] . Although a few drug candidates were recently considered by FDA for COVID-19 treatment, there is a certain need to facilitate finding effective therapeutic agents to inhibit the production of virus particles, block the receptors, and/or develop vaccine [237, 238] . In this context, an excellent drug delivery technique like MDT might be a promising alternative to overcome passive transfer of candidate drugs and therefore elevate cellular uptake, enhance J o u r n a l P r e -p r o o f permeability and efficacy, decrease expenses, and reduce the complexity of pathology to address the needs of pandemics. The respiratory system is the main entrance for nanoparticles due to the large surface area in contact with the outside environment (about 143 ±12 m 2 alveolar surface area with about 2.2 µm structural barrier between the air and the blood). This huge gateway is exposed to different environmental materials through inhalation and systemic administration, which results in activation of various defense mechanisms (e.g., dendritic cells, surfactant, secretory immunoglobulins, alveolar macrophages, and mucociliary escalator) in the lung [239] . Vulnerable lung tissues are also affected by different disease conditions like cancer. Lung cancer is the third cause of death worldwide and needs new diagnostic and treatment strategies to cure. are detected by the signature of fibrotic stripes [240] . Magnetic drug delivery systems have been offered to deliver therapeutic agents to the inflamed lung tissue more efficiently and with fewer side effects. Magnetic nanoparticle-coated drugs can be administered as either spray or injection, where the magnet can be placed next to the lesion. This strategy can lead to a more efficient treatment and clinical prognosis. Also, computational fluid dynamics could be utilized to determine appropriate particle size, location of magnet, spray velocity, and dosing, for effective therapies for pulmonary viral infectious diseases like COVID-19 [241] . Although MNPs have a large number of potential therapeutic use in various diseases, there are still limitations in implementing magnetic particle delivery systems. The primary challenge is related to the toxicity of MNPs, which needs detailed evaluation for any new particle or even formulation. This matter has been meticulously studied by researchers in this field though only for specific types of MNPs (e.g., MNP accumulation, inflammatory reactions, oxidative stress, increases in microvascular permeability, and chronic iron toxicity [242] ) in the lung [27] [28] [29] [30] 35] . The other limitation of using MNPs is relevant to the high strength of the external magnetic field applied to manipulate MNPs and capture the NPs in the location of interest. The geometry and the distance of the magnet source is crucial to regulate their capability to manipulate NPs. To address this issue, employing of a permeant magnet inside or outside the body has been computationally suggested [56, 185, 201, 233, 242] . Further in vivo studies need to be implemented to identify the potential utility of a permanent magnet for effective magnetic drug delivery. In addition, the size and particle material are also important and these two characteristics of particles need to be adjusted to avoid magnetic agglomeration wherever the magnetic field is removed [64, 243, 244] . Besides, most of investigations in this field have been so far applied on animals. However, challenges may arise once these methods are examined in human due to the physiological differences [245, 246] . Last but not the least, the MDT methods have been shown a level of success in well-defined tumors. Further investigation is needed to examine their utility for metastatic neoplasms and small tumors in the early stages. Further advances in developing new magnetic particle drug delivery methods could not only contribute significantly to the diagnosis and treatment of lung cancers but also other lung infectious diseases and acute respiratory syndromes, including COVID-19, MERS, and SARS. J o u r n a l P r e -p r o o f Table 1 . Stages of non-small cell lung carcinoma (NSCLC) and corresponding treatment methods The tumor size is too small to be distinguished by imaging tests and bronchoscopy. There is no node (N0) and no metastasis (M0), therefore there is no tumor found in the lung while there exist cancer cells in sputum. The tumor known as carcinoma in situ is found at the lining layer of the lung airways. Cancer cells have not yet spread into the lungs tissue (M0, N0) Surgery-stereotactic body radiation therapy (SBRT)-radiofrequency ablation (RFA) This stage is divided into two subdivisions: The tumor invaded across the lung tissue but in less than ½ cm, N0 (no nodes)-M0 (no metastasis) Surgery to remove part of the lung (a lobectomy) or all the lung (pneumonectomy) The tumor is about 1 cm, N0 (no nodes) -M0 (no metastasis). It is invaded across the lung membrane without any effect on the bronchi or branches. Radiotherapy and radiofrequency ablation are alternative treatments for patients with serious physical problems. The tumor is larger than 3 cm-M0 (no metastasis)-it spreads through the carina (causes clogging the airway) or into the chest wall Surgery and chemotherapy are recommended to reduce the chance of cancer return. The tumor is larger than 5 cm in size and spreads into blood vessels, trachea and esophagus-M0 Surgery to remove all the tumor, then chemotherapy along with radiotherapy. Any size of tumor spreading to nearby nodes as well as other organs like bones, brains and liver. The survival rate of stage IV is 1%, owing to the extent of tumor growth and invasion [24] . [93, 94] . Mutations in KRAS promotes growth and prevents apoptosis Rare [66, 95] Observed in approximately 20-25% of lung adenocarcinomas in the United States; Generally associated with smoking [96] ALK rearrangements Fusions involving one of three tropomyosin receptor kinases (TRK); The TRK family contains three members, TRKA, TRKB, and TRKC [102] . Present approximately in 1% of NSCLC [102] . HER2 mutation HER2 (ERBB2) is an EGFR family receptor tyrosine kinase [103, 104] . Present approximately in 1 to 3 percent of NSCLC tumors [103, 104] MET abnormalities MET is a tyrosine kinase receptor for a hepatocyte growth factor (HGF). c-MET mutation present [105] MET abnormalities (drug MET exon 14 skipping mutations) are present in 3% of lung adenocarcinomas; MET and EGFR co-mutations are present in 5 to 20 percent of EGFR-mutated tumors which are resistance to EGFR J o u r n a l P r e -p r o o f Inactivation of the putative tumor suppressor genes [109] located on the short arm of chromosome 3 (3p) is a very common early event [66] . A very common tumor suppressor gene abnormality in SCLCs [95] ; Present in more than 90% of SCLCs [66] Present in more than 80% of NSCLCs [66] The retinoblastoma gene is mutated in several types of human cancers [110] . A very common tumor suppressor gene abnormality in SCLCs [95] ; Present in about 90% of SCLCs [66] Present in about 20% of NSCLCs [66] TP3 mutations TP53 is a tumor suppressor gene which is most commonly affected by point mutations in cancers; occurs relatively late [111] . A very common tumor suppressor gene abnormality in SCLCs [95] ; Present in more than 90% of SCLCs [66] Present in more than 50% of SCLCs [66] J o u r n a l P r e -p r o o f [154] , [142, 161] , [162] , [163] , [164] [168] , [142] , [156] J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f Journal Pre-proof Medical nanoparticles for next generation drug delivery to the lungs GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries Non-small-cell lung cancer Seminars in respiratory and critical care medicine Feasibility study of chemoradiotherapy followed by amrubicin and cisplatin for limited-disease small cell lung cancer Staging and clinical prognostic factors for small-cell lung cancer Treatment of extensive-stage small cell lung carcinoma: current status and future prospects The development and progression of adenocarcinoma of the lung Mucoepidermoid carcinoma of the lung: highresolution CT and histopathologic findings in five cases Principles of Pulmonary Medicine E-Book The pivotal role of pathology in the management of lung cancer An ontology-based system for cancer diseases knowledge management The usefulness of FDG positron emission tomography for the detection of mediastinal lymph node metastases in patients with non-small cell lung cancer: a comparative study with X-ray computed tomography Mesenchymal stem cell therapy for ischemic tissues Evaluation of lung flute in sputum samples for molecular analysis of lung cancer Nuclear medicine: radioactivity for diagnosis and therapy How does it work?: Magnetic resonance imaging Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship Concurrent chemoradiotherapy in non-small cell lung cancer Radiofrequency ablation for the treatment of non-small cell lung cancer in marginal surgical candidates Non-small cell lung cancer: current treatment and future advances Society, Non-small cell lung cancer survival rates Targeted cancer therapy: the next generation of cancer treatment Chemotherapy related toxicity in locally advanced non-small cell lung cancer Effects of chemotherapy on quality of life for patients with lung cancer Quality-of-life outcomes for adjuvant chemotherapy in early-stage Non-small-cell lung cancer: results from a randomized trial Predictors of toxicity of weekly docetaxel in chemotherapy-treated non-small cell lung cancers Innovative strategy for treatment of lung cancer: targeted nanotechnology-based inhalation co-delivery of anticancer drugs and siRNA Magnetic resonance imaging for lung cancer Mechanisms and biomaterials in pHresponsive tumour targeted drug delivery: a review Liposome as nanocarrier: Site targeted delivery in lung cancer Applications of nanoparticle systems in drug delivery technology Magnetic nanoparticles in MR imaging and drug delivery Passive and active drug targeting: drug delivery to tumors as an example Drug-targeting methodologies with applications: A review Poly (ethylene glycol)-modified nanocarriers for tumor-targeted and intracellular delivery Methoxypoly (ethylene glycol)-block-Poly (L-glutamic acid)-loaded cisplatin and a combination with iRGD for the treatment of non-small-cell lung cancers Comparative studies on chitosan and polylactic-co-glycolic acid incorporated nanoparticles of low molecular weight heparin Extracellularly activated nanocarriers: a new paradigm of tumor targeted drug delivery Targeted delivery of magnetic aerosol droplets to the lung Active targeting theranostic iron oxide nanoparticles for MRI and magnetic resonance-guided focused ultrasound ablation of lung cancer Nanoscaled poly (L-glutamic acid)/doxorubicin-amphiphile complex as pH-responsive drug delivery system for effective treatment of nonsmall cell lung cancer A novel peptide enhances therapeutic efficacy of liposomal anti-cancer drugs in mice models of human lung cancer Magnetic drug delivery with FePd nanowires Applications of magnetic nanoparticles in biomedicine Inhalable magnetic nanoparticles for targeted hyperthermia in lung cancer therapy Magnetic targeting of aerosol particles for cancer therapy Magnetic drug targeting to lung tracheal region Applications of nanoparticle systems in drug delivery technology Inhalable particulate drug delivery systems for lung cancer therapy: nanoparticles, microparticles, nanocomposites and nanoaggregates The potential to treat lung cancer via inhalation of repurposed drugs Intracellular drug delivery: Potential usefulness of engineered Shiga toxin subunit B for targeted cancer therapy Delivery of magnetic micro/nanoparticles and magnetic-based drug/cargo into arterial flow for targeted therapy Controlled release of magnetic particles for drug delivery in the human lung Functional magnetic particles for medical application Thermotherapy of prostate cancer using magnetic nanoparticles: feasibility, imaging, and three-dimensional temperature distribution Application of magnetic techniques in the field of drug discovery and biomedicine Numerical simulation of magnetic nanoparticles targeting in a bifurcation vessel Magnetic nanoparticles and blood flow behavior in non-Newtonian pulsating flow within the carotid artery in drug delivery application Simulations of magnetic capturing of drug carriers in the brain vascular system Magnetically assisted intraperitoneal drug delivery for cancer chemotherapy Pulmonary drug delivery strategies: A concise, systematic review Lung cancer statistics, Lung cancer and personalized medicine Metastatic sites and survival in lung cancer Robbins basic pathology e-book Stepwise progression of pulmonary adenocarcinoma-clinical and molecular implications Prognostic significance of adenocarcinoma in situ, minimally invasive adenocarcinoma, and nonmucinous lepidic predominant invasive adenocarcinoma of the lung in patients with stage I disease Quantitative CT analysis of pulmonary ground-glass opacity nodules for the distinction of invasive adenocarcinoma from pre-invasive or minimally invasive adenocarcinoma Clinicopathologic characteristics of peripheral squamous cell carcinoma of the lung Squamous-cell carcinoma of the lungs: is it really so different? Morphological computed tomography features of surgically resectable pulmonary squamous cell carcinomas: Impact on prognosis and comparison with adenocarcinomas Exophytic endobronchial epidermoid carcinoma Diagnostic difficulties with the diagnosis of small cell carcinoma of the lung Pancreatic metastasis in a case of small cell lung carcinoma: Diagnostic role of fine-needle aspiration cytology and immunocytochemistry Clinical manifestation and radiological features of small cell lung cancer (SCLC), Wiadomosci lekarskie Filter-based isolation, enrichment, and characterization of circulating tumor cells Detection of rib metastases in patients with lung cancer: a comparative study of MRI Methods for staging non-small cell lung cancer: diagnosis and management of lung J o u r n a l P r e -p r o o f cancer: American College of Chest Physicians evidence-based clinical practice guidelines Metastatic tumours of the adrenal glands: a 30-year experience in a teaching hospital Prevalence of adrenal incidentaloma in a contemporary computerized tomography series Liver metastasis at the time of initial diagnosis of lung cancer Historical perspectives: the evolution of the thymic epithelial tumors staging system Prognostic impact of malignant pleural effusion at presentation in patients with metastatic non-small-cell lung cancer Etiology of pleural effusions: analysis of more than 3,000 consecutive thoracenteses Squamous cell carcinoma of the lung: molecular subtypes and therapeutic opportunities Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer Small-cell lung cancer (SCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Genetic instabilities in human cancers Translational models of tumor angiogenesis: A nexus of in silico and in vitro models Molecular pathogenesis of lung cancer Prospective analysis of oncogenic driver mutations and environmental factors: Japan Molecular Epidemiology for Lung Cancer Study American Society of Clinical Oncology provisional clinical opinion: epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy The molecular pathogenesis of small cell lung cancer Molecular biomarkers in non-small-cell lung cancer: a retrospective analysis of data from the phase 3 FLEX study Screening of anaplastic lymphoma kinase rearrangement by immunohistochemistry in non-small lung cancer: correlation with fluorescence in situ hybridization Analysis of receptor tyrosine kinase ROS1-positive tumors in non-small cell lung cancer: identification of a FIG-ROS1 fusion Immunohistochemical detection of ROS1 is useful for identifying ROS1 rearrangements in lung cancers Clinicopathological features of nonsmall cell lung carcinomas with BRAF mutations Genotyping and genomic profiling of non-small-cell lung cancer: implications for current and future therapies Durable clinical response to entrectinib in NTRK1-rearranged non-small cell lung cancer Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas Callis, AZD8931, an equipotent, reversible inhibitor of signaling by epidermal growth factor receptor, ERBB2 (HER2), and ERBB3: a unique agent for simultaneous ERBB receptor blockade in cancer Salgia, c-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions MET gene amplification or EGFR mutation activate MET in lung cancers untreated with EGFR tyrosine kinase inhibitors Met gene copy number predicts the prognosis for completely resected non-small cell lung cancer Next-generation sequencing of pulmonary sarcomatoid carcinoma reveals high frequency of actionable MET gene mutations Detection of aberrant promoter hypermethylation of tumor suppressor genes in serum DNA from non-small cell lung cancer patients Effects of an Rb mutation in the mouse PTEN mutations and relationship to EGFR, ERBB2, KRAS, and TP53 mutations in nonsmall cell lung cancers Folic acid-modified dendrimer-entrapped gold nanoparticles as nanoprobes for targeted CT imaging of human lung adencarcinoma Computer-Aided Diagnosis of Lung Cancer in Magnetic XXVI Brazilian Congress on Biomedical Engineering Near-infrared intraoperative imaging for minimally invasive pulmonary metastasectomy for sarcomas Respiratory motion in positron emission tomography/computed tomography: a review Elective nodal irradiation (ENI) vs. involved field radiotherapy (IFRT) for locally advanced non-small cell lung cancer (NSCLC): a comparative analysis of toxicities and clinical outcomes Limitations of screening for lung cancer with low-dose spiral computed tomography Benefits and harms of CT screening for lung cancer: a systematic review Preoperative intrathoracic lymph node staging in patients with non-small-cell lung cancer: accuracy of integrated positron emission tomography and computed tomography Use of magnetic resonance imaging for N-staging in patients with non-small cell lung cancer. A systematic review Magnetic iron oxide nanoparticles: synthesis, stabilization, vectorization, physicochemical characterizations, and biological applications Conjugation of iron oxide nanoparticles with RGD-modified dendrimers for targeted tumor MR imaging A perspective on magnetic core-shell carriers for responsive and targeted drug delivery systems Magnetic resonance tracking of endothelial progenitor cells labeled with alkyl-polyethylenimine 2 kDa/superparamagnetic iron oxide in a mouse lung carcinoma xenograft model Folate-PEG-superparamagnetic iron oxide nanoparticles for lung cancer imaging Stem cell-mediated delivery of nanogels loaded with ultrasmall iron oxide nanoparticles for enhanced tumor MR imaging Dextran-Benzoporphyrin derivative (BPD) coated superparamagnetic iron oxide nanoparticle (SPION) micelles for T2-weighted magnetic resonance imaging and photodynamic therapy MRI-visible micellar nanomedicine for targeted drug delivery to lung cancer Cells Nanoparticles: pharmacological and toxicological significance Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications Magnetic nanoparticles for theragnostics Magnetic resonance imaging for lung cancer Diffusion-weighted magnetic resonance imaging of lung cancer at 3.0 T: a preliminary study on monitoring diffusion changes during chemoradiation therapy FDG-PET/CT and diffusion-weighted imaging for resected lung cancer: correlation of maximum standardized uptake value and apparent diffusion coefficient value with prognostic factors Positron emission tomography/magnetic resonance imaging evaluation of lung cancer: current status and future prospects Ultrasonic nebulization system for respiratory drug delivery, Pharmaceutical development and technology Chemotherapy sensitization of glioblastoma by focused ultrasound-mediated delivery of therapeutic liposomes Lung cancer screening with MRI: results of the first screening round MR imaging of pulmonary nodules: detection rate and accuracy of size estimation in comparison to computed tomography Diffusionweighted magnetic resonance imaging can be used in place of positron emission tomography for N staging of non-small cell lung cancer with fewer false-positive results Diagnostic performance of diffusion-weighted imaging for multiple hilar and mediastinal lymph nodes with FDG accumulation Artifacts in magnetic resonance imaging 18 F-FDG PET/MRI in patients suffering from lymphoma: how much MRI information is really needed?, European journal of nuclear medicine and molecular imaging Assessment of sequential PET/MRI in comparison with PET/CT of pediatric lymphoma: a prospective study Clinical applications of PET/MRI: current status and future perspectives Economic benefits and diagnostic quality of diffusion-weighted magnetic resonance imaging for primary lung cancer Superparamagnetic iron oxide: pharmacokinetics and toxicity Magnetic properties and antitumor effect of nanocomplexes of iron oxide and doxorubicin Toxic effects of the Fe2O3 nanoparticles on the liver and lung tissue Doxorubicin-conjugated heparin-coated superparamagnetic iron oxide nanoparticles for combined anticancer drug delivery and magnetic resonance imaging Synthesis, properties, and applications of iron nanoparticles Synthesis and characterization of FePt/Au core-shell nanoparticles Advantages and limitations of nanoparticle labeling for early diagnosis of infection Magnetic nanoparticles: From design and synthesis to real world applications Papain bioinspired gold nanoparticles augmented the anticancer potency of 5-FU against lung cancer Synthesis of controlled-size silver nanoparticles for the administration of methotrexate drug and its activity in colon and lung cancer cells Development of a dualfunctional Pt-Fe-HAP magnetic nanoparticles application for chemo-hyperthermia treatment of cancer Recent advances in chemical synthesis, self-assembly, and applications of FePt nanoparticles Nanoparticles in cellular drug delivery Nanoparticle-based targeted drug delivery Synthesis and in vitro study of cisplatin-loaded Fe3O4 nanoparticles modified with PLGA-PEG6000 copolymers in treatment of lung cancer Multifunctional magnetic nanoparticles for targeted delivery Magnetic core-shell nanoparticles for drug delivery by nebulization Silibinin-loaded magnetic nanoparticles inhibit hTERT gene expression and J o u r n a l P r e -p r o o f proliferation of lung cancer cells pH-and thermosensitive MTX-loaded magnetic nanocomposites: synthesis, characterization, and in vitro studies on A549 lung cancer cell and MR imaging In vitro study of magnetic particle seeding for implant assisted-magnetic drug targeting Surface modified Fe3O4 nanoparticles as a protein delivery vehicle Substantiating in vivo magnetic brain tumor targeting of cationic iron oxide nanocarriers via adsorptive surface masking Biodegradable metals for cardiovascular stent application: interests and new opportunities Tracheobronchial stents: indications and applications, Lung Cancer Theranostic uspio-loaded microbubbles for mediating and monitoring blood-brain barrier permeation Computational modeling of magnetic nanoparticle targeting to stent surface under high gradient field Targeting cancer cells: magnetic nanoparticles as drug carriers Magnetic drug targeting: biodistribution and dependency on magnetic field strength Materials, Doxorubicin magnetic conjugate targeting upon intravenous injection into mice: High gradient magnetic field inhibits the clearance of nanoparticles from the blood Effects of external magnetic field on biodistribution of nanoparticles: A histological study Doxorubicin loaded magnetic gold nanoparticles for in vivo targeted drug delivery Magnetic and acoustically active lipospheres for magnetically targeted nucleic acid delivery Coencapsulation of magnetic Fe3O4 nanoparticles and doxorubicin into biodegradable PLGA nanocarriers for intratumoral drug delivery Guidelines on limits of exposure to static magnetic fields In vitro study of magnetic particle seeding for implantassisted-magnetic drug targeting: Seed and magnetic drug carrier particle capture A study on magnetically targeted drug delivery system using superconducting magnet Drug accumulation by means of noninvasive magnetic drug delivery system Airflow structures and nano-particle deposition in a human upper airway model Numerical simulation of magnetic nano drug targeting in patientspecific lower respiratory tract Particle size, magnetic field, and blood velocity effects on particle retention in magnetic drug targeting A genetic algorithm-based area coverage approach for controlled drug delivery using microrobots Optimized targeting of magnetic nano particles for drug delivery system Analysis of trajectories for targeting of magnetic nanoparticles in blood vessels Numerical analysis of blood flow in realistic arteries subjected to strong nonuniform magnetic fields Modeling superparamagnetic particles in blood flow for applications in magnetic drug targeting Open challenges in magnetic drug targeting Magnetic manipulation of superparamagnetic nanoparticles in a microfluidic system for drug delivery applications Optimal Halbach permanent magnet designs for maximally pulling and pushing nanoparticles Design of halbach magnet array based on optimization techniques Halbach arrays consisting of cubic elements optimised for high field gradients in magnetic drug targeting applications Design of permanent multipole magnets with oriented rare earth cobalt material Exact solution to the inverse Womersley problem for pulsatile flows in cylindrical vessels, with application to magnetic particle targeting An intravascular magnetic catheter enables the retrieval of nanoagents from the bloodstream Modelling patient-specific magnetic drug targeting within the intracranial vasculature Numerical simulation of magnetic drug targeting to a tumor in the simplified model of the human lung Magnetic nanoparticles and nanocomposites for remote controlled therapies Intratracheal delivery of nano-and microparticles and hyperpolarized gases: a promising strategy for imaging and treatment of respiratory disease Visualizing treatment delivery and deposition in mouse lungs using in vivo x-ray imaging Engineering of nebulized metal-phenolic capsules for controlled pulmonary deposition Lungs deposition and pharmacokinetic study of submicron budesonide particles in Wistar rats intended for immediate effect in asthma Targeted delivery of magnetic aerosol droplets to the lung Inhalable magnetic nanoparticles for targeted hyperthermia in lung cancer therapy In vivo pulmonary delivery and magnetictargeting of dry powder nano-in-microparticles Magnetic core-shell nanoparticles for drug delivery by nebulization Magnetized aerosols comprising superparamagnetic iron oxide nanoparticles improve targeted drug and gene delivery to the lung Respiration triggered magnetic drug targeting in the lungs In vitro and in vivo lung deposition of coated magnetic aerosol particles Magnetic targeting of aerosol particles for cancer therapy Enhanced deposition of high aspect ratio aerosols in small airway bifurcations using magnetic field alignment Magnetic deposition of aerosols composed of aggregated superparamagnetic nanoparticles Magnetised thermo responsive lipid vehicles for targeted and controlled lung drug delivery Superparamagnetic iron oxide nanoparticles (SPIONs)-loaded Trojan microparticles for targeted aerosol delivery to the lung Formulation and characterization of inhalable magnetic nanocomposite microparticles (MnMs) for targeted pulmonary delivery via spray drying Simulation of enhanced deposition due to magnetic field alignment of ellipsoidal particles in a lung bifurcation Simulation of magnetic drug targeting through tracheobronchial airways in the presence of an external non-uniform magnetic magnetic particle tracking Magnetic drug targeting through a realistic model of human tracheobronchial airways using computational fluid and particle dynamics Computational analysis of magnetic field induced deposition of magnetic particles in lung alveolus in comparison to deposition produced with viscous drag and gravitational force Augmenting regional and targeted delivery in the pulmonary acinus using magnetic particles Numerical simulations of targeted delivery of magnetic drug aerosols in the human upper and central respiratory system: a validation study Numerical simulation of magnetic nano drug targeting in patientspecific lower respiratory tract CFPD simulation of magnetic drug delivery to a human lung using an SAW nebulizer Enhancing drug delivery to human trachea through oral airway using magnetophoretic steering of microsphere carriers composed of aggregated superparamagnetic nanoparticles and nanomedicine: A numerical study Magnetic aerosol drug targeting in lung cancer therapy using permanent magnet Diffusion-weighted magnetic resonance imaging for the detection of metastatic lymph nodes in patients with lung cancer: A meta-analysis Diffusionweighted MRI in solitary pulmonary lesions: associations between apparent diffusion coefficient and multiple histopathological parameters Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review Remdesivir for the Treatment of Covid-19 -Preliminary Report Magnetic nanoparticles: an update of application for drug delivery and possible toxic effects Clinical and computed tomographic imaging features of novel coronavirus pneumonia caused by SARS-CoV-2 Intranasal Antiviral Drug Delivery and Coronavirus Disease 2019 (COVID-19): A State of the Art Review 3 H dendrimer nanoparticle organ/tumor distribution Applications of magnetic nanoparticles in biomedicine Magnetic targeting and ultrasound mediated drug delivery: benefits, limitations and combination Clinical applications of magnetic drug targeting Physiological aspects in magnetic drugtargeting typically composed of nanocrystalline magnetite (Fe3O4) or maghemite (γFe2O3) protected with coating [112] .Advantages: 1-excellent biocompatibility and biodegradability 2-ease of synthesis Disadvantages: 1-variable magnetization vastly among synthesis methods even within particles of similar size due to incorporation of impurities disrupting the crystal structure 2-cause toxicity due to ROS production 3-non specific targeting [113, 114] .1-SPIONs were used for magnetic hyperthermia, A single magnetic hyperthermia regimen reduced the tumor growth [48] . Superparamagnetic iron oxide (SPIONPs) with an average size of 10±2 nm were coated with doxorubicin (Dox)conjugated heparin (DH-SPIO) and were used for targeted anticancer drug delivery.Outcome: DHSPIO NPs displayed a higher efficacy than Dox in inhibiting tumor growth and therapy of A549 human lung carcinoma [115] . Composition: made from iron, cobalt, or nickel, which are often overlooked for biological applications due to their chemical instability. Advantage: Iron nanoparticles possess high magnetization and are able to maintain superparamagnetism at larger particle sizes compared to other oxide counterparts [116] .Disadvantage: complex synthesis process.These metallic NPs are typically protected by coatings, such as gold or silica to form a coreshell structure like the following cases [117] : Advantage: better biocompatibility and bioavailability, accumulate at tumor site & enhance x-ray effect Disadvantage: stability related issue during aqueous formation [118] . silver magnetic nanoparticles:Advantages: induced apoptosis in the targeted area, accumulation at the tumor site & enhance x-ray effect 1-papain-encapsulated and 5-Fluorouracil bio-conjugated gold NPs were synthesized using papain. Papain is anti-cancer by nature; hence, it rendered this anti-cancer property to the PpGNPs as well.Outcome: The efficacy of 5F-PpGNPs against human lung cancer A549 cell line improved significantly over that of pure 5-FU [120] .2-A controlled synthesis of methotrexate (MTX) silver nanoparticles (AgNPs-MTX) using borohydride and citrate as reduction and reduction/capping agents, respectively, was performed.Outcome: significant for a lung cancer cell line (A-549) [121] .J o u r n a l P r e -p r o o f Disadvantage: cause toxicity due to ROS production [119] Bimetallic (or metal alloy) nanoparticles Advantage: these MNPs exhibit superparamagnetic properties -Recent advances in the synthesis of FePt nanoparticles have made these MNPs an option of choice for biomedical applications.Interactions between the two chemical species lead to greater chemical stability in comparison to other high moment metallic nanoparticles [122] .Advantages: 1-stable in biologically relevant media such as PBS 2-The ability to bind DNA and protein to the surface of these MNPs Dual-functional nanoparticles made from hydroxyapatite with iron and platinum ions incorporation (Pt-Fe-HAP) were developed for chemo-hyperthermia application.Outcome: Pt-Fe-HAP was highly toxic to A549 cells after magnetic field treatment under hyperthermia but no damage to fibroblast cells was observed [123] . Composition: coating of MNPs with polymers is the most common way to solve the stability of nanoparticles against oxidation [124, 125] . Disadvantages: non-specific targeting [126] . Fe2O3 MNPs constituting a powerful tool for drug therapy in vivo. Furthermore, drug delivery in vitro could be improved if the drugs were modified with antibodies, proteins, or ligands [127] .B-Dextran was also used in the study of Alvis et al. [128] , whose prepared dextran-coated magnetite seed particles system as implant to increase the capture of magnetic drug carrier particles in capillary tissue C-Xu et al. [129] synthesized Fe3O4 nanoparticles coated with Polyethylene Glycol (PEG). The attachment of PEG promotes water solubility, reduces toxicity, decreases enzymatic degradation and increases the in vivo half-lives of small molecule drugs [130] .1-EGRF-PLGA MNPs used for drug delivery system.Outcome: drug-loaded MNPs reduced the number of viable A549 cells significantly [131] .2-Silibinin-loaded PLGA-PEG-Fe3O4 nanoparticles was used.Outcome: an inhibitory effect on the growth of A549 lung cancer cell line and hTERT gene expression in comparison to pure Silibinin [132] . N,Ndimethylaminoethyl methacrylate (DMAEMA) and Nisopropyl acrylamide (NIPAAm). In addition, mesoporous silica nanoparticles (MSNs) was conjugated to polymer matrix acting as drug container to enhance the drug encapsulation efficacy. Methotrexate (MTX) as a model drug was successfully loaded in MNCs (M-MNCs).Outcome: promising dose-dependent anticancer efficacy against A548 cell [133] .