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WIREs Nanomed Nanobiotechnol
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Inhalable nanotherapeutics to improve treatment efficacy for common lung diseases

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Abstract Respiratory illnesses are prevalent around the world, and inhalation‐based therapies provide an attractive, noninvasive means of directly delivering therapeutic agents to their site of action to improve treatment efficacy and limit adverse systemic side effects. Recent trends in medicine and nanoscience have prompted the development of inhalable nanomedicines to further enhance effectiveness, patient compliance, and quality of life for people suffering from lung cancer, chronic pulmonary diseases, and tuberculosis. Herein, we discuss recent advancements in the development of inhalable nanomaterial‐based drug delivery systems and analyze several representative systems to illustrate their key design principles that can translate to improved therapeutic efficacy for prevalent respiratory diseases. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Respiratory Disease
A wide variety of nanomaterial systems have been employed to develop inhalable nanomedicine systems (depicted here are liposomes, micelles, polymeric nanoparticles, dendrimers, and magnetic nanoparticles as examples of designs explored for this application). After administration with various aerosolization devices (jet nebulizer represented here), these systems are noninvasively delivered directly to lung tissues to passively target diseased cells. For a variety of respiratory diseases, this is advantageous as it enhances therapeutic efficacy and mitigates systemic toxicity, which can be further improved by decorating nanomaterials with targeting moieties for a particular lung disease
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Asymmetric liposomes for the inhalable treatment of tuberculosis (TB). (a) Image of L‐α‐phosphatidic acid (PA) liposomes via fluorescence confocal microscopy characterized with fluorescent phosphatidic acid to show asymmetric distribution of phospholipids (scale bar = 16.3 μm). (b) In vitro uptake of apoptotic body‐like (ABL) liposomes into different cell types, showing that ABL liposomes are more efficiently internalized into macrophages as compared to alveolar epithelial cells. (c) The effect of ABL liposomes on different cytokine secretion in dTHP‐1 cells indicating that ABL liposomes reduce TB‐infected cell inflammatory response. (d) The effect of different liposomal formulations on Mycobacterium tuberculosis (MTB)‐infected dTHP‐1 cells where the greatest colony forming units (CFU) reduction was observed with the ABL/PA formulation. (e) In vivo study with MTB‐infected BALB/c mice treated with intranasally delivered ABL/PA, with or without isoniazid (INH) incorporated in drinking water, to see effects on CFUs in lung, spleen, and liver. In all organs, reduction of CFUs was observed with combined ABL/PA and INH therapy (in comparison to MTB‐infect control mice: *p < 0.001, **p < 0.05, #p = not significant). (Reprinted with permission from Greco et al. (). Copyright 2012 National Academy of Sciences)
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Nanoembedded microparticles for the delivery of rifampicin (RIF) and isoniazid (INH) via pulmonary route for the treatment of tuberculosis (TB) (a) Scanning electron microscopy images of chitosan and guar gum chitosan nanoembedded microparticles, where the nanoembedded microparticles are either blank, loaded with RIF, or loaded with INH. (b) in vitro release study in PBS of different nanoembedded microparticle formulations loaded with either RIF or INH, where RIF‐loaded formulations released drug at a slower rate than INH‐loaded formulations. (c) In vitro cellular uptake of different formulations into J‐774 macrophage over time. Chitosan formulations displayed delayed cellular uptake, while mannan formulations and both guar gum formulations performed comparably, likely due to mannose moieties that allowing for targeting of mannan receptors on macrophages. (d) In vitro cell viability study in J‐774 macrophages, showing reduced toxicity of nanoembedded microparticles as compared to free drug. (e) In vivo study to investigate drug distribution in the lungs of BALB/c mice over time of different formulations, where the various nanoembedded microparticles resulted in greater retention of drug as compared to free drug, with guar gum chitosan formulations exhibiting the longest retention time. (Reprinted with permission from Goyal et al. (). Copyright 2015 American Chemical Society)
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Design, inflammatory cell response, cytokine release, and immunohistological imaging of an anti‐IL4Rα‐NP system. (a) An illustration representing the design of the anti‐IL4Rα NPs. (b) BALF levels of pro‐inflammatory cytokines in mice treated with or without the anti‐IL4Rα‐NPs, where cytokine levels decreased in mice treated with anti‐IL4Rα‐NPs. (c) i) CD4 and ii) CD8 T cells isolated from the lungs of ovalbumin (OVA)‐challenged mice treated with or without the anti‐IL4Rα‐NPs, highlighting attenuated inflammatory marker expression from anti‐IL4Rα‐NP treatment. (d) Effect of the anti‐IL4Rα‐NPs on the BALF inflammatory cells in the treated OVA‐challenged mice showing observed decrease in lymphocyte frequency. (e) frequencies of neutrophils and eosinophils isolated from the lungs of OVA‐challenged mice treated with or without anti‐IL4Rα‐NPs, showing decreased levels of both cell types from the anti‐interleukin‐4 receptor α (IL4Rα)‐NPs (for control vs OVA: *p < 0.05, **p < 0.01, ***p < 0.001; for OVA vs anti‐IL4α‐NPs: #p < 0.05, ##p < 0.01). (Reprinted with permission from Halwani et al. (). Copyright 2016 Springer Nature)
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Synthesis and antiangiogenic effects of Sn2 lipase‐liable prodrug micelles for the treatment of asthma. (a) Synthesis of fumagillin PAzPC prodrug and through saponification and esterification alongside structure of αVβ3‐peptidomimetic‐PEG2000‐PE. (b) Synthesis of docetaxel prodrug. (c) i) 19F/1H magneitc resonance (MR) tomographic molecular imaging following antiangiogenesis treatment in HDM rats with αVβ3‐Dxtl‐PD micelles (right) revealed markedly reduced airway neovascular MR signal when compared to the control asthmatic animals receiving αVβ3‐empty micelles (left). ii) Normalized lung signal quantification of 19F/1H MR tomographic molecular imaging (*p < 0.01). (d) Histogram of 19F/1H MR tomographic molecular imaging results showing equivalent reduction in neovascularity with anti‐angiogenesis micelles. (e) Pulmonary functional changes in HDM rats receiving αVβ3‐Dxtl‐PD, αVβ3‐Fum‐PD, or αVβ3‐no‐drug micelles. i) Respiratory system resistance (Rrs) was measured after increasing methacholine (MCh) concentrations showing attenuated reactivity among rats treated with αVβ3‐Dxtl‐PD or αVβ3‐Fum‐PD micelles(***p < 0.001). ii) Respiratory system compliance (Crs) in HDM rats following the MCh challenge showing greater compliance after the treatment with drug‐loaded micelles (***p < 0.001). (f) Bronchoalveolar (BAL) cell profiles showing a lower percentage of eosinophils (EOS) in HDM rats receiving αVβ3‐Dxtl‐PD and αVβ3‐Fum‐PD micelles (left) and flow cytometry of BAL fluid (right) revealing that αVβ3‐Fum‐PD and αVβ3‐Dxtl‐PD micelles decreased αVβ3+ macrophage/monocyte numbers versus empty micelles(*p < 0.05, ***p < 0.001). (Reprinted with permission from Lanza et al. (). Copyright 2017 Ivyspring International Publisher)
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Thymulin gene therapy in allergic asthma provided via DNA‐nanoparticles (NPs) that mitigate airway remodeling and inflammation after pulmonary delivery. (a) Transmission electron micrograph of the CK30PEG‐MSTF NPs where scalebar represents 200 nm. Inflammatory cytokine concentrations, (b) interleukin 13 (IL‐13), (c) Eotaxin, and (d) interferon‐γ (IFN‐γ) in lung tissues of healthy control or ovalbumin‐challenged mice, highlighting anti‐inflammatory effect of the DNA NPs. (e) Total number of cells counted in bronchoalveolar lavage fluid of healthy or ovalbumin‐challenged mice, showing reduction of cell numbers representative of an inflammatory response after treatment with DNA NPs. Lung function of mice as represented by (f) lung static elastance and (g) airway hyper‐responsiveness, highlighting reduction in elastance and resistance after treatment with DNA NPs. C, control mice challenged with saline; ovalbumin (OVA), mice challenged with ovalbumin; SAL, mice treated with saline; THY‐NANO, mice treated with DNA NPs; THY‐pDNA, mice treated with naked plasmid DNA. Statistically significant (p < .05) results from C‐SAL (*), C‐THY‐NANO (†), C‐THY‐pDNA (‡), OVA‐SAL (**), or OVA‐THY‐NANO (#). (Reprinted with permission from da Silva et al. (). Copyright 2014 Elsevier)
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Gadolinium‐based ultra‐small rigid platform nanoparticles (USRPs) as a theranostic agent for the imaging and treatment of lung cancer administered via nebulization. (a) Schematic representation of the USRP system and its components, which allow for ultrashort echo time magnetic resonance and fluorescence imaging alongside radiotherapy. (b) Localization of USRPs after pulmonary delivery in orthotopic H358‐Luc tumor mouse model. (i) Fluorescence tomography imaging of mice 1, 5, or 24 hr after pulmonary administration or IV injection of USRPs (top), with bioluminescence and fluorescence imaging performed on isolated lungs showcasing colocalization of tumor cells with the USRPs at the same time points (bottom). ii) Biodistribution of USRPs in mice 24 hr after pulmonary administration or IV injection, showing enhanced accumulation in lung and tissue tumors followed by kidneys with little retention comparatively in the liver. iii) Before (top) and after (bottom) pulmonary administration of USRPs allows for detection of lung cancer tumors via magnetic resonance imaging (MRI) imaging. (c) Survival curve of H358 tumor‐bearing mice without treatment (n = 6), after one irradiation (n = 11), or after USRP administration followed by one irradiation 24 hr later (n = 11), showing longer mean survival time for mice treated with USRPs and irradiation. (Reprinted with permission from Morlieras et al. () and Dufort et al. (). Copyright 2013 American Chemical Society and Copyright 2015 John Wiley and Sons)
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Nanostructured lipid carrier (NLC) system for the pulmonary codelivery of paclitaxel (TAX) and siRNAs for resistance suppression to treat lung cancer. (a) Illustration of the NLC system, showing drugs loaded in the core (TAX), siRNAs complexed to cationic heads groups of the lipid particle (DOTAP), and lung cancer targeting moiety, luteinizing hormone‐release hormone (LHRH) conjugated to DSPE‐PEG on the surface. (b) Cell viability of A549 human lung adenocarcinoma cells after 48 hr incubation with blank NLC and PEGylated NLC, showing great biocompatibility of the carrier with increased safety after surface decoration with PEG. (c) in vitro cytotoxicity of the TAX‐loaded NLCs and free TAX against A549 cells; the NLC systems showed enhanced cytotoxicity (lower IC50 value) compared to free TAX, where the addition of resistance suppressing siRNAs on the surface even further enhanced cytotoxic activity. (d) in vivo distribution of fluorescently‐labeled (Cy5.5 dye) NLCs in mice after IV injection (left) and inhalation (right), showing increased accumulation and retention in lungs from pulmonary delivery. (e) Distribution of fluorescently‐labeled NLCs in mice lungs bearing A549 tumors, highlighting improved targeting to tumor tissues by LHRH. (f) Bright‐field and fluorescence microscope images of tumor tissues of mice treated with Cy5.5‐loaded LHRH‐NLCs, showing improved tumor targeting and retention with minimal accumulation in healthy lung tissues. (g) Tumor volume changes in mice after the beginning of treatment with repeated treatments every 3–5 days (x‐axis), emphasizing the enhanced antitumor efficacy of LHRH‐NLC‐TAX‐siRNAs system (1, untreated mice; 2, inhaled LHRH‐NLC; 3, IV injected TAX; 4, inhaled LHRH‐NLC‐TAX; 5, inhaled LHRH‐NLC‐TAX‐siRNAs). (Reprinted with permission from Taratula et al. (). Copyright 2013 Elsevier)
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Copolymer nanoparticle (NP) system for the pulmonary codelivery of doxorubicin (DOX) and cisplatin (CDDP). (a) Schematic representation of the copolymer NP showing the incorporation of DOX through electrostatic interactions and CDDP through chelate interactions to create Co‐NPs. The Co‐NPs are aerosolized to be administered to mice bearing lung tumors, where within the Co‐NPs penetrate and enter tumor cells and begin to rapidly release their contents to induce cytotoxicity. (b) The encapsulated drug release of DOX (left) and CDDP (right) from the Co‐NPs in PBS, showing faster release at lower pH. (c) Cytotoxicity assay results against B16F10 melanoma cells in relation to DOX concentration (left) and CDDP concentration (right), indicating the enhanced cancer cell toxicity of the codelivery system compared to either drug alone. (d) The in vivo biodistribution of DOX in main organs of mice after either systemic delivery (SD) or pulmonary delivery (PD) of free DOX or Co‐NPs (H, heart; L1, liver; S, spleen; L2, lung; K, kidney) at different time points over 72 hr, showing increased retention from Co‐NPs in PD. (e) in vivo antitumor efficacy in a B16F10 metastatic lung cancer mice model with the treatment timeline (top). Surgically removed lungs (left) and their average weight (right) for each treatment group (I, healthy mice control; II, PBS; III, free CDDP; IV, free DOX; V, CDDP‐NPs; VI, DOX‐NPs; VII, Co‐NPs) after pulmonary delivery. (Reprinted with permission from Xu et al. (). Copyright 2019 Elsevier)
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