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Nanomedicines via the pulmonary route: a promising strategy to reach the target?

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Abstract

Over the past decades, research on nanomedicines as innovative tools in combating complex pathologies has increased tenfold, spanning fields from infectiology and ophthalmology to oncology. This process has further accelerated since the introduction of SARS-CoV-2 vaccines. When it comes to human health, nano-objects are designed to protect, transport, and improve the solubility of compounds to allow the delivery of active ingredients on their targets. Nanomedicines can be administered by different routes, such as intravenous, oral, intramuscular, or pulmonary routes. In the latter route, nanomedicines can be aerosolized or nebulized to reach the deep lung. This review summarizes existing nanomedicines proposed for inhalation administration, from their synthesis to their potential clinical use. It also outlines the respiratory organs, their structure, and particularities, with a specific emphasis on how these factors impact the administration of nanomedicines. Furthermore, the review addresses the organs accessible through pulmonary administration, along with various pathologies such as infections, genetic diseases, or cancer that can be addressed through inhaled nanotherapeutics. Finally, it examines the existing devices suitable for the aerosolization of nanomedicines and the range of nanomedicines in clinical development.

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References

  1. International Organisation for Standardisation, ISO/TR 18401:2017. Geneva, Switzerland, 2017. https://www.iso.org/standard/62384.html.

  2. Khan I, Saeed K, Khan I. Nanoparticles: Properties, applications and toxicities. Arab J Chem. 2019;12:908–31.

    Article  CAS  Google Scholar 

  3. Anderson PJ. History of aerosol therapy: liquid nebulization to MDIs to DPIs. Respir CARE. 2005;50:1139–50.

    PubMed  Google Scholar 

  4. Jeevanandam J, Barhoum A, Chan YS, Dufresne A, Danquah MK. Review on nanoparticles and nanostructured materials: history, sources, toxicity and regulations. Beilstein J Nanotechnol. 2018;9:1050–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Rahman MT, Rebrov EV. Microreactors for gold nanoparticles synthesis: from faraday to flow. Processes. 2014;2:466–93.

    Article  Google Scholar 

  6. Faraday MX. The Bakerian Lecture. —Experimental relations of gold (and other metals) to light. Philos Trans R Soc Lond. 1997;147:145–81.

    Google Scholar 

  7. Wilcoxon J. Optical absorption properties of dispersed gold and silver alloy nanoparticles. J Phys Chem B. 2009;113:2647–56.

    Article  CAS  PubMed  Google Scholar 

  8. Lu H, Tang S-Y, Yun G, Li H, Zhang Y, Qiao R, et al. Modular and integrated systems for nanoparticle and microparticle synthesis—a review. Biosensors. 2020;10:165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Iravani S. Green synthesis of metal nanoparticles using plants. Green Chem. 2011;13:2638–50.

    Article  CAS  Google Scholar 

  10. Krukemeyer MG, Kreen V, Huebner F. History and possible uses of nanomedicine based on nanoparticles and nanotechnological progress. J Nanomedicine Nanotechnol. 2015;06:1000336.

    Google Scholar 

  11. Astruc D. Introduction to nanomedicine. Molecules. 2016;21:4.

    Article  Google Scholar 

  12. Lee D-E, Koo H, Sun I-C, Ryu JH, Kim K, Kwon IC. Multifunctional nanoparticles for multimodal imaging and theragnosis. Chem Soc Rev. 2012;41:2656–72.

    Article  CAS  PubMed  Google Scholar 

  13. Thapa RK, Kim JO. Nanomedicine-based commercial formulations: current developments and future prospects. J Pharm Investig. 2023;53:19–33.

    Article  CAS  PubMed  Google Scholar 

  14. Wang L, Hu C, Shao L. The antimicrobial activity of nanoparticles: present situation and prospects for the future. Int J Nanomedicine. 2017;12:1227–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Verma NK, Crosbie-Staunton K, Satti A, Gallagher S, Ryan KB, Doody T, et al. Magnetic core-shell nanoparticles for drug delivery by nebulization. J Nanobiotechnology. 2013;11:1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. De Jong WH, Borm PJ. Drug delivery and nanoparticles: Applications and hazards. Int J Nanomedicine. 2008;3:133–49.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Johnstone TC, Suntharalingam K, Lippard SJ. The next generation of platinum drugs: targeted Pt(II) Agents, nanoparticle delivery, and Pt(IV) prodrugs. Chem Rev. 2016;116:3436–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wang S, McGuirk CM, d’Aquino A, Mason JA, Mirkin CA. Metal-organic framework nanoparticles. Adv Mater. 2018;30:1800202.

    Article  Google Scholar 

  19. Zhang D, Zhang M, Pang Y, Li M, Ma W. Folic acid-modified long-circulating liposomes loaded with sulfasalazine for targeted induction of ferroptosis in melanoma. ACS Biomater Sci Eng. 2024;10:588–98.

    Article  CAS  PubMed  Google Scholar 

  20. Rahmani A, Salmanipour S, Nami Y, Mousavi HZ, Salehi R. pH-responsive star-shaped poly (ε-carprolactone)-co-poly maleic anhydride micelles for synergistic breast cancer combination chemotherapy. React Funct Polym. 2023;193: 105773.

    Article  CAS  Google Scholar 

  21. Zhu H, Peng N, Liang X, Yang S, Cai S, Chen Z, et al. Synthesis, properties and mechanism of carbon dots-based nano-antibacterial materials. Biomed Mater. 2023;18: 062002.

    Article  Google Scholar 

  22. Alheshibri M, Elsayed KA, Khan FA, Haladu SA, Ercan F, Çevik E, et al. Tuning the morphology of Au/ZnO nanocomposite using pulsed laser ablation for anticancer applications. Arab J Sci Eng. 2024;49:1063–74.

    Article  CAS  Google Scholar 

  23. Ding H, Xia Q, Shen J, Zhu C, Zhang Y, Feng N. Advances and prospects of tumor immunotherapy mediated by immune cell-derived biomimetic metal-organic frameworks. Colloids Surf B Biointerfaces. 2023;232: 113607.

    Article  CAS  Google Scholar 

  24. Wu J. The enhanced permeability and retention (EPR) Effect: The significance of the concept and methods to enhance its application. J Pers Med. 2021;11:771.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Ramadon D, McCrudden MTC, Courtenay AJ, Donnelly RF. Enhancement strategies for transdermal drug delivery systems: current trends and applications. Drug Deliv Transl Res. 2022;12:758–91.

    Article  PubMed  Google Scholar 

  26. Jeong S-H, Jang J-H, Lee Y-B. Pharmacokinetic comparison of three different administration routes for topotecan hydrochloride in rats. Pharmaceuticals. 2020;13:231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sun R, Xiang J, Zhou Q, Piao Y, Tang J, Shao S, et al. The tumor EPR effect for cancer drug delivery: Current status, limitations, and alternatives. Adv Drug Deliv Rev. 2022;191: 114614.

    Article  CAS  PubMed  Google Scholar 

  28. Jeon S, Jun E, Chang H, Yhee JY, Koh E-Y, Kim Y, et al. Prediction the clinical EPR effect of nanoparticles in patient-derived xenograft models. J Controlled Release. 2022;351:37–49.

    Article  CAS  Google Scholar 

  29. Liu Q, Zou J, Chen Z, He W, Wu W. Current research trends of nanomedicines. Acta Pharm Sin B. 2023;13:4391–416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ensign LM, Cone R, Hanes J. Oral drug delivery with polymeric nanoparticles: The gastrointestinal mucus barriers. Adv Drug Deliv Rev. 2012;64:557–70.

    Article  CAS  PubMed  Google Scholar 

  31. Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med. 2021;384:403–16.

    Article  CAS  PubMed  Google Scholar 

  32. Tenchov R, Bird R, Curtze AE, Zhou Q. Lipid nanoparticles─from liposomes to mRNA vaccine delivery, a landscape of research diversity and advancement. ACS Nano. 2021;15:16982–7015.

    Article  CAS  PubMed  Google Scholar 

  33. Barenholz YC. Doxil® — The first FDA-approved nano-drug: lessons learned. J Controlled Release. 2012;160:117–34.

    Article  CAS  Google Scholar 

  34. Tiwari G, Tiwari R, Sriwastawa B, Bhati L, Pandey S, Pandey P, et al. Drug delivery systems: an updated review. Int J Pharm Investig. 2012;2:2–11.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Patlolla RR, Chougule M, Patel AR, Jackson T, Tata PNV, Singh M. Formulation, characterization and pulmonary deposition of nebulized celecoxib encapsulated nanostructured lipid carriers. J Control Release Off J Control Release Soc. 2010;144:233–41.

    Article  CAS  Google Scholar 

  36. Kreyling WG, Hirn S, Schleh C. Nanoparticles in the lung. Nat Biotechnol. 2010;28:1275–6.

    Article  CAS  PubMed  Google Scholar 

  37. Stein SW, Thiel CG. The history of therapeutic aerosols: a chronological review. J Aerosol Med Pulm Drug Deliv. 2017;30:20–41.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Chang RYK, Chan H-K. Advancements in particle engineering for inhalation delivery of small molecules and biotherapeutics. Pharm Res. 2022;39:3047–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Paranjpe M, Müller-Goymann CC. Nanoparticle-mediated pulmonary drug delivery: a review. Int J Mol Sci. 2014;15:5852–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Dorrello NV, Vunjak-Novakovic G. Bioengineering of pulmonary epithelium with preservation of the vascular niche. Front Bioeng Biotechnol. 2020;8:269.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Praphawatvet T, Peters JI, Williams RO. Inhaled nanoparticles–An updated review. Int J Pharm. 2020;587: 119671.

    Article  CAS  PubMed  Google Scholar 

  42. Geiser M, Rothen-Rutishauser B, Kapp N, Schürch S, Kreyling W, Schulz H, et al. Ultrafine particles cross cellular membranes by nonphagocytic mechanisms in lungs and in cultured cells. Environ Health Perspect. 2005;113:1555–60.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Patton JS, Byron PR. Inhaling medicines: delivering drugs to the body through the lungs. Nat Rev Drug Discov. 2007;6:67–74.

    Article  CAS  PubMed  Google Scholar 

  44. Pilcer G, Amighi K. Formulation strategy and use of excipients in pulmonary drug delivery. Int J Pharm. 2010;392:1–19.

    Article  CAS  PubMed  Google Scholar 

  45. He Y, Liang Y, Han R, Lu W-L, Mak JCW, Zheng Y. Rational particle design to overcome pulmonary barriers for obstructive lung diseases therapy. J Controlled Release. 2019;314:48–61.

    Article  CAS  Google Scholar 

  46. Neupane AS, Willson M, Chojnacki AK, Vargas E, Silva Castanheira F, Morehouse C, Carestia A, et al. Patrolling alveolar macrophages conceal bacteria from the immune system to maintain homeostasis. Cell. 2020;183:110-125.e11.

    Article  CAS  PubMed  Google Scholar 

  47. Bain CC, MacDonald AS. The impact of the lung environment on macrophage development, activation and function: diversity in the face of adversity. Mucosal Immunol. 2022;15:223–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Mansour HM, Rhee Y-S, Wu X. Nanomedicine in pulmonary delivery. Int J Nanomedicine. 2009;4:299–319.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Choi HS, Ashitate Y, Lee JH, Kim SH, Matsui A, Insin N, et al. Rapid translocation of nanoparticles from the lung airspaces to the body. Nat Biotechnol. 2010;28:1300–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Geiser M, Casaulta M, Kupferschmid B, Schulz H, Semmler-Behnke M, Kreyling W. The role of macrophages in the clearance of inhaled ultrafine titanium dioxide particles. Am J Respir Cell Mol Biol. 2008;38:371–6.

    Article  CAS  PubMed  Google Scholar 

  51. Cai D, Gao W, Li Z, Zhang Y, Xiao L, Xiao Y. Current development of nano-drug delivery to target macrophages. Biomedicines. 2022;10:1203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Yao X, Qi C, Sun C, Huo F, Jiang X. Poly(ethylene glycol) alternatives in biomedical applications. Nano Today. 2023;48: 101738.

    Article  CAS  Google Scholar 

  53. Geiser M, Kreyling W. Deposition and biokinetics of inhaled nanoparticles. Part Fibre Toxicol. 2010;7:2.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Wright JR. Immunoregulatory functions of surfactant proteins. Nat Rev Immunol. 2005;5:58–68.

    Article  CAS  PubMed  Google Scholar 

  55. Han S, Mallampalli RK. The role of surfactant in lung disease and host defense against pulmonary infections. Ann Am Thorac Soc. 2015;12:765–74.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Radiom M, Sarkis M, Brookes O, Oikonomou EK, Baeza-Squiban A, Berret J-F. Pulmonary surfactant inhibition of nanoparticle uptake by alveolar epithelial cells. Sci Rep. 2020;10:19436.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Lai SK, Wang Y-Y, Hanes J. Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues. Adv Drug Deliv Rev. 2009;61:158–71.

    Article  CAS  PubMed  Google Scholar 

  58. Cahn D, Amosu M, Maisel K, Duncan GA. Biomaterials for intranasal and inhaled vaccine delivery. Nat Rev Bioeng. 2023;1:83–4.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Velino C, Carella F, Adamiano A, Sanguinetti M, Vitali A, Catalucci D, et al. Nanomedicine approaches for the pulmonary treatment of cystic fibrosis. Front Bioeng Biotechnol. 2019;7:406.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Chen D, Liu J, Wu J, Suk JS. Enhancing nanoparticle penetration through airway mucus to improve drug delivery efficacy in the lung. Expert Opin Drug Deliv. 2021;18:595–606.

    Article  PubMed  Google Scholar 

  61. Siekmeier R, Scheuch G. Treatment of systemic diseases by inhalation of biomolecule aerosols. J Physiol Pharmacol Off J Pol Physiol Soc. 2009;60(Suppl 5):15–26.

    Google Scholar 

  62. Labiris NR, Dolovich MB. Pulmonary drug delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol. 2003;56:588–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Pleasants RA, Hess DR. Aerosol delivery devices for obstructive lung diseases. Respir Care. 2018;63:708–33.

    Article  PubMed  Google Scholar 

  64. Omlor AJ, Nguyen J, Bals R, Dinh QT. Nanotechnology in respiratory medicine. Respir Res. 2015;16:64.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Simionescu D, Simionescu M. Differentiated distribution of the cell surface charge on the alveolar-capillary unit: characteristic paucity of anionic sites on the air-blood barrier. Microvasc Res. 1983;25:85–100.

    Article  CAS  PubMed  Google Scholar 

  66. Mandal RS, Saha S, Das S. Metagenomic surveys of gut microbiota. GPB. 2015;13:148–58.

    PubMed  PubMed Central  Google Scholar 

  67. Sommariva M, Le Noci V, Bianchi F, Camelliti S, Balsari A, Tagliabue E, et al. The lung microbiota: role in maintaining pulmonary immune homeostasis and its implications in cancer development and therapy. Cell Mol Life Sci CMLS. 2020;77:2739–49.

    Article  CAS  PubMed  Google Scholar 

  68. Dickson RP, Huffnagle GB. The lung microbiome: new principles for respiratory bacteriology in health and disease. PLOS Pathog. 2015;11: e1004923.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Natalini JG, Singh S, Segal LN. The dynamic lung microbiome in health and disease. Nat Rev Microbiol. 2023;21:222–35.

    Article  CAS  PubMed  Google Scholar 

  70. Man WH, de Steenhuijsen Piters WAA, Bogaert D. The microbiota of the respiratory tract: gatekeeper to respiratory health. Nat Rev Microbiol. 2017;15:259–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Zhang T, Yin X, Yang X, Man J, He Q, Wu Q, et al. Research trends on the relationship between microbiota and gastric cancer: a bibliometric analysis from 2000 to 2019. J Cancer. 2020;11:4823–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Fernández MF, Reina-Pérez I, Astorga JM, Rodríguez-Carrillo A, Plaza-Díaz J, Fontana L. Breast cancer and its relationship with the microbiota. Int J Environ Res Public Health. 2018;15:1747.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Perez-Chanona E, Trinchieri G. The role of microbiota in cancer therapy. Curr Opin Immunol. 2016;39:75–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Elkrief A, Derosa L, Zitvogel L, Kroemer G, Routy B. The intimate relationship between gut microbiota and cancer immunotherapy. Gut Microbes. 2019;10:424–8.

    Article  CAS  PubMed  Google Scholar 

  75. Westman EL, Canova MJ, Radhi IJ, Koteva K, Kireeva I, Waglechner N, et al. Bacterial inactivation of the anticancer drug doxorubicin. Chem Biol. 2012;19:1255–64.

    Article  CAS  PubMed  Google Scholar 

  76. Lehouritis P, Cummins J, Stanton M, Murphy CT, McCarthy FO, Reid G, et al. Local bacteria affect the efficacy of chemotherapeutic drugs. Sci Rep. 2015;5:14554.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Barcik W, Boutin RCT, Sokolowska M, Finlay BB. The Role of Lung and Gut Microbiota in the Pathology of Asthma. Immunity. 2020;52:241–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Thornton CS, Acosta N, Surette MG, Parkins MD. Exploring the cystic fibrosis lung microbiome: making the most of a sticky situation. J Pediatr Infect Dis Soc. 2022;11:S13-22.

    Article  Google Scholar 

  79. Zheng L, Sun R, Zhu Y, Li Z, She X, Jian X, et al. Lung microbiome alterations in NSCLC patients. Sci Rep. 2021;11:11736.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Cipolla D, Gonda I, Chan H-K. Liposomal formulations for inhalation Ther Deliv. 2013;4:1047–72.

    CAS  PubMed  Google Scholar 

  81. Timsina MP, Martin GP, Marriott C, Ganderton D, Yianneskis M. Drug delivery to the respiratory tract using dry powder inhalers. Int J Pharm. 1994;101:1–13.

    Article  CAS  Google Scholar 

  82. Magramane S, Pápay Z, Turbucz B, Antal I. Formulation and characterization of pulmonary drug delivery systems. Acta Pharm Hung. 2019;89:63–83.

    Google Scholar 

  83. Wachtel H, Kattenbeck S, Dunne S, Disse B. The respimat® development story: patient-centered innovation. Pulm Ther. 2017;3:19–30.

    Article  Google Scholar 

  84. Labiris NR, Dolovich MB. Pulmonary drug delivery. Part II: the role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol. 2003;56:600–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Respaud R, Vecellio L, Diot P, Heuzé-Vourc’h N. Nebulization as a delivery method for mAbs in respiratory diseases. Expert Opin Drug Deliv. 2015;12:1027–39.

    Article  CAS  PubMed  Google Scholar 

  86. Neary MT, Mulder LM, Kowalski PS, MacLoughlin R, Crean AM, Ryan KB. Nebulised delivery of RNA formulations to the lungs: From aerosol to cytosol. J Controlled Release. 2024;366:812–33.

    Article  CAS  Google Scholar 

  87. Lee H-Y, Mohammed KA, Goldberg EP, Kaye F, Nasreen N. Cisplatin loaded albumin mesospheres for lung cancer treatment. Am J Cancer Res. 2015;5:603–15.

    PubMed  PubMed Central  Google Scholar 

  88. Lokugamage MP, Vanover D, Beyersdorf J, Hatit MZC, Rotolo L, Echeverri ES, et al. Optimization of lipid nanoparticles for the delivery of nebulized therapeutic mRNA to the lungs. Nat Biomed Eng. 2021;5:1059–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Braet H, Andretto V, Mariën R, Yücesan B, van der Vegte S, Haegebaert R, et al. The effect of electrostatic high pressure nebulization on the stability, activity and ex vivo distribution of ionic self-assembled nanomedicines. Acta Biomater. 2023;170:318–29.

    Article  CAS  PubMed  Google Scholar 

  90. Klein DM, Poortinga A, Verhoeven FM, Bonn D, Bonnet S, van Rijn CJM. Degradation of lipid based drug delivery formulations during nebulization. Chem Phys. 2021;547: 111192.

    Article  CAS  Google Scholar 

  91. Khan I, Apostolou M, Bnyan R, Houacine C, Elhissi A, Yousaf SS. Paclitaxel-loaded micro or nano transfersome formulation into novel tablets for pulmonary drug delivery via nebulization. Int J Pharm. 2020;575: 118919.

    Article  CAS  PubMed  Google Scholar 

  92. Kesavan J, Schepers DR, Bottiger JR, King MD, McFarland AR. Aerosolization of bacterial spores with pressurized metered dose inhalers. Aerosol Sci Technol. 2013;47:1108–17.

    Article  CAS  Google Scholar 

  93. Robertson J, Valder CE. Process for the precipitation of inhalable pharmaceutical agents the propellant. WO 2011/023734 A1. 2011.

  94. Parker J. Barriers to green inhaler prescribing: ethical issues in environmentally sustainable clinical practice. J Med Ethics. 2023;49:92–8.

    Article  PubMed  Google Scholar 

  95. Melani AS, Bonavia M, Cilenti V, Cinti C, Lodi M, Martucci P, et al. Inhaler mishandling remains common in real life and is associated with reduced disease control. Respir Med. 2011;105:930–8.

    Article  PubMed  Google Scholar 

  96. Djupesland PG. Nasal drug delivery devices: characteristics and performance in a clinical perspective-a review. Drug Deliv Transl Res. 2013;3:42–62.

    Article  CAS  PubMed  Google Scholar 

  97. Kumar R, Mehta P, Shankar KR, Rajora MAK, Mishra YK, Mostafavi E, et al. Nanotechnology-assisted metered-dose inhalers (MDIs) for high-performance pulmonary drug delivery applications. Pharm Res. 2022;39:2831–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Elkins MR, Anderson SD, Perry CP, Daviskas E, Charlton B. Inspiratory flows and volumes in subjects with non-cf bronchiectasis using a new dry powder inhaler device. Open Respir Med J. 2014;8:8–13.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Rabbani NR, Seville PC. The influence of formulation components on the aerosolisation properties of spray-dried powders. J Controlled Release. 2005;110:130–40.

    Article  CAS  Google Scholar 

  100. Kole E, Jadhav K, Shirsath N, Dudhe P, Verma RK, Chatterjee A, et al. Nanotherapeutics for pulmonary drug delivery: an emerging approach to overcome respiratory diseases. J Drug Deliv Sci Technol. 2023;81: 104261.

    Article  CAS  Google Scholar 

  101. Arpagaus C, John P, Collenberg A, Rütti D. 10 - Nanocapsules formation by nano spray drying. Nanoencapsulation Technologies for the Food and Nutraceutical Industries; 2017. p. 346–401.

    Google Scholar 

  102. Faheem A, Haggag Y. Evaluation of nano spray drying as a method for drying and formulation of therapeutic peptides and proteins. Front Pharmacol. 2015;6:140.

    PubMed  PubMed Central  Google Scholar 

  103. Pardeshi SR, Kole EB, Kapare HS, Chandankar SM, Shinde PJ, Boisa GS, et al. Progress on thin film freezing technology for dry powder inhalation formulations. Pharmaceutics. 2022;14:2632.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Beck-Broichsitter M, Schweiger C, Schmehl T, Gessler T, Seeger W, Kissel T. Characterization of novel spray-dried polymeric particles for controlled pulmonary drug delivery. J Control Release Off J Control Release Soc. 2012;158:329–35.

    Article  CAS  Google Scholar 

  105. Wauthoz N, Rosière R, Amighi K. Inhaled cytotoxic chemotherapy: clinical challenges, recent developments, and future prospects. Expert Opin Drug Deliv. 2021;18:333–54.

    Article  CAS  PubMed  Google Scholar 

  106. Dalby R, Spallek M, Voshaar T. A review of the development of Respimat Soft Mist Inhaler. Int J Pharm. 2004;283:1–9.

    Article  CAS  PubMed  Google Scholar 

  107. Iwanaga T, Tohda Y, Nakamura S, Suga Y. The respimat® soft mist inhaler: implications of drug delivery characteristics for patients. Clin Drug Investig. 2019;39:1021–30.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Chaurasiya B, Zhao Y-Y. Dry powder for pulmonary delivery: a comprehensive review. Pharmaceutics. 2021;13:31.

    Article  CAS  Google Scholar 

  109. Dailey LA, Schmehl T, Gessler T, Wittmar M, Grimminger F, Seeger W, et al. Nebulization of biodegradable nanoparticles: impact of nebulizer technology and nanoparticle characteristics on aerosol features. J Controlled Release. 2003;86:131–44.

    Article  CAS  Google Scholar 

  110. Crompton G. A brief history of inhaled asthma therapy over the last fifty years. Prim Care Respir J. 2006;15:326–31.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Holgate ST, Wenzel S, Postma DS, Weiss ST, Renz H, Sly PD. Asthma Nat Rev Dis Primer. 2015;1:1–22.

    Google Scholar 

  112. Hou S, Wu J, Li X, Shu H. Practical, regulatory and clinical considerations for development of inhalation drug products. Asian J Pharm Sci. 2015;10:490–500.

    Article  Google Scholar 

  113. Ahrens RC, Smith GD. Albuterol: an adrenergic agent for use in the treatment of asthma pharmacology, pharmacokinetics and clinical use. Pharmacotherapy. 1984;4:105–21.

    Article  CAS  PubMed  Google Scholar 

  114. Kerem E, Levison H, Schuh S, O’Brodovich H, Reisman J, Bentur L, et al. Efficacy of albuterol administered by nebulizer versus spacer device in children with acute asthma. J Pediatr. 1993;123:313–7.

    Article  CAS  PubMed  Google Scholar 

  115. Lara-Reyna S, Holbrook J, Jarosz-Griffiths HH, Peckham D, McDermott MF. Dysregulated signalling pathways in innate immune cells with cystic fibrosis mutations. Cell Mol Life Sci. 2020;77:4485–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Ribeiro CMP, Higgs MG, Muhlebach MS, Wolfgang MC, Borgatti M, Lampronti I, et al. Revisiting host-pathogen interactions in cystic fibrosis lungs in the era of CFTR modulators. Int J Mol Sci. 2023;24:5010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Quon BS, Goss CH, Ramsey BW. Inhaled antibiotics for lower airway infections. Ann Am Thorac Soc. 2014;11:425–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Zhong W, Zhang X, Zeng Y, Lin D, Wu J. Recent applications and strategies in nanotechnology for lung diseases. Nano Res. 2021;14:2067–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Doroudian M, MacLoughlin R, Poynton F, Prina-Mello A, Donnelly SC. Nanotechnology based therapeutics for lung disease. Thorax. 2019;74:965–76.

    Article  PubMed  Google Scholar 

  120. Barjaktarevic IZ, Milstone AP. Nebulized Therapies in COPD: Past, Present, and the Future. Int J Chron Obstruct Pulmon Dis. 2020;15:1665–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Miragoli M, Ceriotti P, Iafisco M, Vacchiano M, Salvarani N, Alogna A, et al. Inhalation of peptide-loaded nanoparticles improves heart failure. Sci Transl Med. 2018;10:eaan6205.

    Article  PubMed  Google Scholar 

  122. Liu C, Chen L, Ma Y, Hu K, Wu P, Pan L, et al. Pulmonary circulation-mediated heart targeting for the prevention of heart failure by inhalation of intrinsically bioactive nanoparticles. Theranostics. 2021;11:8550–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Sonvico F, Clementino A, Buttini F, Colombo G, Pescina S, Stanisçuaski Guterres S, et al. Surface-modified nanocarriers for nose-to-brain delivery: from bioadhesion to targeting. Pharmaceutics. 2018;10:34.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Ye Y, Ma Y, Zhu J. The future of dry powder inhaled therapy: Promising or discouraging for systemic disorders? Int J Pharm. 2022;614: 121457.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Hauser RA, LeWitt PA, Waters CH, Grosset DG, Blank B. The clinical development of levodopa inhalation powder. Clin Neuropharmacol. 2023;46:66–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Jani R, Triplitt C, Reasner C, Defronzo RA. First approved inhaled insulin therapy for diabetes mellitus. Expert Opin Drug Deliv. 2007;4:63–76.

    Article  CAS  PubMed  Google Scholar 

  127. Forest V, Pourchez J. Nano-delivery to the lung - by inhalation or other routes and why nano when micro is largely sufficient? Adv Drug Deliv Rev. 2022;183: 114173.

    Article  CAS  PubMed  Google Scholar 

  128. Patton JS, Fishburn CS, Weers JG. The lungs as a portal of entry for systemic drug delivery. Proc Am Thorac Soc. 2004;1:338–44.

    Article  CAS  PubMed  Google Scholar 

  129. Tang J, Cai L, Xu C, Sun S, Liu Y, Rosenecker J, et al. Nanotechnologies in delivery of DNA and mRNA vaccines to the nasal and pulmonary mucosa. Nanomaterials. 2022;12:226.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Kim J, Jozic A, Lin Y, Eygeris Y, Bloom E, Tan X, et al. Engineering lipid nanoparticles for enhanced intracellular delivery of mRNA through inhalation. ACS Nano. 2022;16:14792–806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Kunde SS, Ghosh R, Wairkar S. Emerging trends in pulmonary delivery of biopharmaceuticals. Drug Discov Today. 2022;27:1474–82.

    Article  CAS  PubMed  Google Scholar 

  132. Shirley M. Amikacin liposome inhalation suspension: a review in mycobacterium avium complex lung Disease. Drugs. 2019;79:555–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Meers P, Neville M, Malinin V, Scotto AW, Sardaryan G, Kurumunda R, et al. Biofilm penetration, triggered release and in vivo activity of inhaled liposomal amikacin in chronic Pseudomonas aeruginosa lung infections. J Antimicrob Chemother. 2008;61:859–68.

    Article  CAS  PubMed  Google Scholar 

  134. Leong EWX, Ge R. Lipid nanoparticles as delivery vehicles for inhaled therapeutics. Biomedicines. 2022;10:2179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Ray L. Chapter 4 - Polymeric nanoparticle-based drug/gene delivery for lung cancer. Nanotechnology-Based Targeted Drug Delivery Systems for Lung Cancer. Academic Press; 2019. p. 77–93.

    Book  Google Scholar 

  136. Nguyen LNM, Ngo W, Lin ZP, Sindhwani S, MacMillan P, Mladjenovic SM, et al. The mechanisms of nanoparticle delivery to solid tumours. Nat Rev Bioeng. 2024;2:201–13.

    Article  Google Scholar 

  137. Umscheid CA, Margolis DJ, Grossman CE. Key concepts of clinical trials: a narrative review. Postgrad Med. 2011;123:194–204.

    Article  PubMed  PubMed Central  Google Scholar 

  138. Osman G, Rodriguez J, Chan SY, Chisholm J, Duncan G, Kim N, et al. PEGylated enhanced cell penetrating peptide nanoparticles for lung gene therapy. J Control Release Off J Control Release Soc. 2018;285:35–45.

    Article  CAS  Google Scholar 

  139. Griesenbach U, Pytel KM, Alton EWFW. Cystic fibrosis gene therapy in the uk and elsewhere. Hum Gene Ther. 2015;26:266–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Xiao B, Jiang Y, Yuan S, Cai L, Xu T, Jia L. Silibinin, a potential fasting mimetic, inhibits hepatocellular carcinoma by triggering extrinsic apoptosis. MedComm. 2024;5: e457.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Mokhtari MJ, Motamed N, Shokrgozar MA. Evaluation of silibinin on the viability, migration and adhesion of the human prostate adenocarcinoma (PC-3) cell line. Cell Biol Int. 2008;32:888–92.

    Article  CAS  PubMed  Google Scholar 

  142. Sharma G, Singh RP, Chan DC, Agarwal R. Silibinin induces growth inhibition and apoptotic cell death in human lung carcinoma cells. Anticancer Res. 2003;23:2649–55.

    CAS  PubMed  Google Scholar 

  143. Khalid A, Naseem I. Increased therapeutic effect of nanotized silibinin against glycation and diabetes: An in vitro and in silico-based approach. Biochim Biophys Acta BBA - Gen Subj. 2023;1867: 130364.

    Article  CAS  Google Scholar 

  144. Patel P, Raval M, Manvar A, Airao V, Bhatt V, Shah P. Lung cancer targeting efficiency of silibinin loaded poly caprolactone /pluronic F68 inhalable nanoparticles: in vitro and in vivo study. PLoS ONE. 2022;17: e0267257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Singh E, Osmani RAM, Banerjee R, Abu Lila AS, Moin A, Almansour K, et al. Poly ε-Caprolactone nanoparticles for sustained intra-articular immune modulation in adjuvant-induced arthritis rodent model. Pharmaceutics. 2022;14:519.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Sanmugam A, Sellappan LK, Manoharan S, Rameshkumar A, Kumar RS, Almansour AI, et al. Development of chitosan-based cerium and titanium oxide loaded polycaprolactone for cutaneous wound healing and antibacterial applications. Int J Biol Macromol. 2024;256: 128458.

    Article  CAS  PubMed  Google Scholar 

  147. Tiburcio BV, de Menezes LR, Merat LC, da Rocha LVM, da Silva EO, Tavares MIB. Encapsulation of orange oil by colloidal carriers based on PCL/Pluronic F68 nanoparticles for controlled delivery. Polym Bull. 2024;81:2889–913.

    Article  CAS  Google Scholar 

  148. Kumar M, Hilles AR, Almurisi SH, Bhatia A, Mahmood S. Micro and nano-carriers-based pulmonary drug delivery system: their current updates, challenges, and limitations – A review. JCIS Open. 2023;12: 100095.

    Article  Google Scholar 

  149. Mu X, Hur S. Immunogenicity of in vitro-transcribed RNA. Acc Chem Res. 2021;54:4012–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Loughrey D, Dahlman JE. Non-liver mRNA Delivery. Acc Chem Res. 2022;55:13–23.

    Article  CAS  PubMed  Google Scholar 

  151. Patel AK, Kaczmarek JC, Bose S, Kauffman KJ, Mir F, Heartlein MW, et al. Inhaled nanoformulated mRNA polyplexes for protein production in lung epithelium. Adv Mater. 2019;31:1805116.

    Article  Google Scholar 

  152. Debus H, Baumhof P, Probst J, Kissel T. Delivery of messenger RNA using poly(ethylene imine)–poly(ethylene glycol)-copolymer blends for polyplex formation: biophysical characterization and in vitro transfection properties. J Controlled Release. 2010;148:334–43.

    Article  CAS  Google Scholar 

  153. Bhat B, Karve S, Anderson DG. mRNA therapeutics: beyond vaccine applications. Trends Mol Med. 2021;27:923–4.

    Article  CAS  PubMed  Google Scholar 

  154. Sarode A, Patel P, Vargas-Montoya N, Allawzi A, Zhilin-Roth A, Karmakar S, et al. Inhalable dry powder product (DPP) of mRNA lipid nanoparticles (LNPs) for pulmonary delivery. Drug Deliv Transl Res. 2024;14:360–72.

    Article  CAS  PubMed  Google Scholar 

  155. Zhou T, Munson EJ. Advances in solid formulation of pharmaceutical biologics. Adv Drug Deliv Rev. 2021;175.

    Article  CAS  Google Scholar 

  156. Mukherjee A, Macdonald K, Kim J, Henderson M, Eygeris Y, Sahay G. Engineered mutant α-ENaC subunit mRNA delivered by lipid nanoparticles reduces amiloride currents in cystic fibrosis–based cell and mice models. Sci Adv. 2020;6:eabc5911.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Al-Humiari MA, Yu L, Liu LP, Nouri M-Z, Tuna KM, Denslow ND, et al. Extracellular vesicles from BALF of pediatric cystic fibrosis and asthma patients increase epithelial sodium channel activity in small airway epithelial cells. Biochim Biophys Acta BBA - Biomembr. 2024;1866: 184219.

    Article  CAS  Google Scholar 

  158. Santin Y, Formoso K, Haidar F, Fuentes MDPO, Bourgailh F, Hifdi N, et al. Inhalation of acidic nanoparticles prevents doxorubicin cardiotoxicity through improvement of lysosomal function. Theranostics. 2023;13:5435–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Thorn CF, Oshiro C, Marsh S, Hernandez-Boussard T, McLeod H, Klein TE, et al. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genomics. 2011;21:440–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Chatterjee K, Zhang J, Honbo N, Karliner JS. Doxorubicin Cardiomyopathy. Cardiology. 2010;115:155–62.

    Article  CAS  PubMed  Google Scholar 

  161. Li DL, Wang ZV, Ding G, Tan W, Luo X, Criollo A, et al. Doxorubicin blocks cardiomyocyte autophagic flux by inhibiting lysosome acidification. Circulation. 2016;133:1668–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Zeng J, Martin A, Han X, Shirihai OS, Grinstaff MW. Biodegradable PLGA nanoparticles restore lysosomal acidity and protect neural PC-12 cells against mitochondrial toxicity. Ind Eng Chem Res. 2019;58:13910–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Di Mauro V, Iafisco M, Salvarani N, Vacchiano M, Carullo P, Ramírez-Rodríguez GB, et al. Bioinspired negatively charged calcium phosphate nanocarriers for cardiac delivery of MicroRNAs. Nanomed. 2016;11:891–906.

    Article  Google Scholar 

  164. Arina P, Sorge M, Gallo A, Di Mauro V, Vitale N, Cappello P, et al. Modulation of LTCC pathways by a melusin mimetic increases ventricular contractility during lps-induced cardiomyopathy. Shock. 2022;57:318.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank the University of Angers and the Angers Loire Metropole for the PhD founding.

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This work was supported by University of Angers, by Angers Loire Metropole and by the Institut Universitaire de France (IUF).

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The first draft of the manuscript was written by Mélina Guérin and Elise Lepeltier commented and corrected the different versions of the manuscript. All authors read and approved the final manuscript.

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Guérin, M., Lepeltier, E. Nanomedicines via the pulmonary route: a promising strategy to reach the target?. Drug Deliv. and Transl. Res. (2024). https://doi.org/10.1007/s13346-024-01590-1

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