The respiratory system, as well as the skin, are organs in direct contact with the environment and it they represent possible doors for the entrance of therapeutic agents into the body. Because of the increasing incidence of pulmonary diseases with high mortality and morbidity, pulmonary drug delivery is emerging as a non-invasive and attractive approach for the treatment of several pathologies. It must be pointed out that the development of drug delivery systems for pulmonary application requires a detailed knowledge of the lung, both in its healthy and disease state. Among the various drug delivery systems considered for pulmonary application, nanocarriers show several advantages over other conventional approaches for the treatment of respiratory diseases, for example prolonged drug release and cell-specific targeted drug delivery. Nano-size drug carriers can incorporate various therapeutics (e.g., poorly water soluble drugs, macromolecules) and show interesting features as drug delivery systems to the lung, such as: controlled release, protection from metabolism and degradation, decreased drug toxicity and targeting capabilities. Since gene therapy (e.g. small interfering RNA, siRNA) is currently being developed for a wide range of acute and chronic lung diseases, including CF, cancer and asthma, the use of nanocarriers for lung release/targeting represents a promising application of such nano-sized structures. Despite the many promising proof of concepts of various delivery technologies reported in this review, further efforts are needed to ensure the safety of long-term in vivo applications and the development of scale up from laboratory to industry in order to reach, together with safety, large - scale production at affordable costs of innovative lung delivery technologies.
KeywordsPulmonary DeliveryNanovectors
W. Yang, J. I. Peters and R. O. Williams III, “Inhaled Nanoparticles—A Current Review,” International Journal of Pharmaceutics, Vol. 356, No. 1-2, 2008, pp. 239- 247. doi:10.1016/j.ijpharm.2008.02.011
J. S. Patton and P. R. Byron, “Inhaling Medicines: Delivering Drugs to the Body through the Lungs,” Nature Reviews Drug Discovery, Vol. 6, No. 1, 2007, pp. 67-74. doi:10.1038/nrd2153
E. Marttin, J. C. Verhoef, S. G. Romeijin and F. W. H. M. Merkus, “Effects of Absorption Enhancers on Rat Nasal Epithelium in Vivo: Release of Marker Compounds in the Nasal Cavity,” Pharmaceutical Research, Vol. 12, No. 8, 1995, pp. 1151-1157. doi:10.1023/A:1016207809199
F W. H. M. Merkus, N. G. M. Schiepper, W. A. J. J. Hermens, V. S. G. Romeijin and J. C. Verhoef, “Absorption Enhancers in Nasal Drug Delivery: Efficacy and Safety,” Journal of Controlled Release, Vol. 24, No. 1-3, 1993, pp. 201-208. doi:10.1016/0168-3659(93)90179-9
W. T. Cefalu, “Concept, Strategies, and Feasibility of Noninvasive Insulin Delivery,” Diabetes Care, Vol. 27, No. 1, 2004, pp. 239-246. doi:10.2337/diacare.27.1.239
L. Illum, “Nasal Drug Delivery: New Developments and Strategies,” Drug Discovery Today, Vol. 7, No. 23, 2002, pp. 1184-1189. doi:10.1016/S1359-6446(02)02529-1
J. J. Neumiller and R. K Campbell, “Technosphere Insulin: An Inhaled Prandial Insulin Product,” BioDrugs, Vol. 24, No. 3, 2010, pp. 165-172. doi:10.2165/11536700-000000000-00000
A. Rossiter, C. P. Howard., N. Amin, D. J. Costello and A. H. Boss, “Technosphere? Insulin: Safety in Type 2 Diabetes Mellitus,” ADA Scientific Sessions, Orlando Florida, June 2010.
T. Gessler, W. Seeger and T. Schmehl, “Inhaled Prostanoids in the Therapy of Pulmonary Hypertension,” Journal of Aerosol Medicine, Vol. 21, No. 1, pp. 1-12, 2008. doi:10.1089/jamp.2007.0657
J. D. Crapo, B. E. Barry, P. Gehr, M. Bachofen and E. R. Weibel, “Cell Number and Cell Characteristics of the Normal Human Lung,” American Review of Respiratory Disease, Vol. 126, No. 3, 1982, pp. 332-337.
R. R. Mercer, M. L. Russell, V. L. Roggli and J. D. Crapo, “Cell Number and Distribution in Human and Rat Airways,” American Journal of Respiriratory Cell and Molecular Biology, Vol. 10, No. 6, 1994, pp. 613-624.
H. M. Courrier, N. Butz and T. F. Vandamme, “Pulmonary Drug Delivery Systems: Recent Developments and Prospects,” Critical Reviews in Therapeutic Drug Carrier Systems, Vol. 19, No. 4-5, 2002, pp. 425-498. doi:10.1615/CritRevTherDrugCarrierSyst.v19.i45.40
C. P. Van der Schans, “Bronchial Mucus Transport,” Respiratory Care, Vol. 52, No. 9, 2007, pp. 1150-1158.
M. T. Clunes and R. C. Boucher, “Cystic Fibrosis: The Mechanisms of Pathogenesis of an Inherited Lung Disorder,” Drug Discovery Today Disease Mechanism, Vol. 4, No. 2, 2007, pp. 63-72. doi:10.1016/j.ddmec.2007.09.001
S. K. Lai, Y. Y. Wang and J. Hanes, “Mucus-Penetrating Nanoparticles for Drug and Gene Delivery to Mucosal Tissues,” Advanced Drug Delivery Reviews, Vol. 61, No. 2, 2009, pp. 158-171. doi:10.1016/j.addr.2008.11.002
R. Bansil and B. S. Turner, “Mucin Structure, Aggregation, Physiological Functions and Biomedical Applications,” Current Opinion in Colloid & Interface Science, Vol. 11, No. 2-3, 2006, pp. 164-170. doi: 10.1016/j.cocis.2005.11.001.
W. Bernhard, P. L. Haslam and J. Floros, “From Birds to Humans: New Concepts on Airways Relative to Alveolar Surfactant,” American Journal of Respiriratory Cell and Molecular Biology, Vol. 30, No. 1, 2004, pp. 6-11 doi:10.1165/rcmb.2003-0158TR
J. Perez-Gil, “Structure of Pulmonary Surfactant Membranes and Films: The Role of Proteins and Lipid-Protein Interactions,” Biochimica et Biophysica Acta (BBA)— Biomembranes, Vol. 1778, No. 7-8, 2008, pp. 1676-1695. doi:10.1016/j.bbamem.2008.05.003
M. Geiser, “Update on Macrophage Clearance of Inhaled Micro- and Nanoparticles,” Journal of Aerosol Medicine and Pulmonary Drug Delivery, Vol. 23, No. 4, 2010, pp. 207-217. doi:10.1089/jamp.2009.0797
P. G. Holt, D. H. Strickland, M. E. Wikstrom and F. L. Jahnsen, “Regulation of Immunological Homeostasis in the Respiratory Tract,” Nature Reviews Immunology, Vol. 8, 2008, pp. 142-152. doi:10.1038/nri2236
V. van der Velden and A. R. Hulsmann, “Peptidases: Structure, Function and Modulation of Peptide-Mediated Effects in the Human Lung,” Clinical & Experimental Allergy, Vol. 29, No. 4, 1999, pp. 445-456. doi:10.1046/j.1365-2222.1999.00462.x
F. Buhling, D. Groneberg and T. Welte, “Proteases and Their Role in Chronic Inflammatory Lung Diseases,” Current Drug Targets, Vol. 7, No. 6, 2006, pp. 751-759. doi:10.2174/138945006777435362 T. D. Tetley, “Macrophages and the Pathogenesis of COPD,” Chest, Vol. 121, No. 5 Suppl., pp. 156S-159S. doi:10.1378/chest.121.5_suppl.156S
S. El-Chemaly, G. Pacheco-Rodriguez, Y. Ikeda, D. Malide and J. Moss, “Lymphatics in Idiopathic Pulmonary Fibrosis: New Insights into an Old Disease,” Lymphatic Research and Biology, Vol. 7, No. 4, 2009, pp. 197-203. doi:10.1089/lrb.2009.0014
J. D. Brain, “Inhalation, Deposition, and Fate of Insulin and Other Therapeutic Proteins,” Diabetes Technology & Therapeutics, Vol. 9, Suppl. 1, 2007, p. S-4-15. doi:10.1089/dia.2007.0228
W. C. Hinds, “Uniform Particle Motion,” In: W. C. Hinds, Ed., Aerosol Technology: Properties, Behavior and Measurement of Airborne Particles, Second Edition, Wiley, New York, 1999, pp. 53-55.
J. Heyder, J. Gebhart, G. Rudolf, C. F. Schiller and W. Stahlhofen, “Deposition of Particles in the Human Respiratory Tract in the Size Range 0.005 - 15 μm,” Journal of Aerosol Science, Vol. 17, No. 5, 1985, pp. 811-625. doi:10.1016/0021-8502(86)90035-2
S. R. Schmidt, “Fusion-Proteins as Biopharmaceuticals- Applications and Challenges,” Current Opinion in Drug Discovery & Development, Vol. 12, No. 2, 2009, pp. 284-295.
F. M. Veronese and G. Pasut, “PEGylation, Successful Approach to Drug Delivery,” Drug Discov Today, Vol. 10, No. 21, 2005, pp.1451-1458. doi:10.1016/S1359-6446(05)03575-0
O. C. Farokhzad and R. Langer, “Impact of Nanotechnology on Drug Delivery,” Acs Nano, Vol. 3, No. 1, 2009, pp. 16-20. doi:10.1021/nn900002m
N. Nimje, A. Agarwal, G. K Saraogi, N. Lariya, G. Rai, H. Agrawal and G. P. Agrawai, “Mannosylated Nano-particulate Carriers of Rifabutin for Alveolar Targeting,” Journal of Drug Targeting, Vol. 17, No. 10, 2009, pp. 777-787. doi:10.3109/10611860903115308
J. Todoroff and R. Vanbever, “Fate of Nanomedicines in the Lungs,” Current Opinion in Colloid & Interface Science, Vol. 16, 2011, pp. 246-254. doi:10.1016/j.cocis.2011.03.001
B. Haley and E. Frenkel, “Nanoparticles for Drug Delivery in Cancer Treatment,” Urologic Oncology: Seminars and Original Investigations, Vol. 26, No. 1, 2008, pp. 57-64. doi:10.1016/j.urolonc.2007.03.015
R. Singh and N. H. Singh “Medical Applications of Nanoparticles in Biological Imaging, Cell Labeling, Anti-microbial Agents, and Anticancer Nanodrugs,” Journal of Biomedical Nanotechnology, Vol. 7, No. 4, 2011, pp. 489-503. doi:10.1166/jbn.2011.1324
K. M. Al-Hallak, S. Azarmi, A. Anwar-Mohamed , W. H. Roa and R. L?benberg, “Secondary Cytotoxicity Mediated by Alveolar Macrophages: A Contribution to the Total Efficacy of Nanoparticles in Lung Cancer Therapy?” European Journal of Pharmaceutics and Biopharmaceutics, Vol. 76. No 1, 2010, pp. 112-119. doi:10.1016/j.ejpb.2010.05.002
W. H. Roa, S. Azarmi, M. H. D. K Al-Hallak, W. H. Finlay, A. M. Magliocco and R. L?benberg, “Inhalable Nanoparticles, a Non-Invasive Approach to Treat Lung Cancer in a Mouse Model,” Journal of Controlled Release, Vol. 150, No. 1, 2011, pp. 49-55. doi:10.1016/j.jconrel.2010.10.035
H. M. Mansour, Y. S. Rhee and X. Wu, “Nanomedicine in Pulmonary Delivery,” International Journal of Nano- medicine, Vol. 4, 2009, pp. 299-319. doi:10.2147/IJN.S4937
J. Weers, B. Metzheiser, G. Taylor, S. Warren, P. Meers and W. R. Perkins, “A Gamma Scintigraphy Study to Investigate Lung Deposition and Clearance of Inhaled Amikacin-Loaded Liposomes in Healthy Male Volunteers,” Journal of Aerosol Medicine and Pulmonary Drug Delivery, Vol. 22, No. 2, 2009, pp. 131-138, doi:10.1089/jamp.2008.0693
P. Bruinenberg, D. Serisier, D. Cipolla and J. Blanchard, “Safety, Tolerability and Pharmacokinetics of Novel Liposomal Ciprofloxacin Formulations for Inhalation in Healthy Volunteers and Non-Cystic Bronchiectasis Patients,” American Journal of Respiratory and Critical Care Medicine, B49 Meeting Abstract “American Thoracic Society 2010 International Conference, Vol. 181, Orleans, May 2010, p. A3192.
O. O. Okusanya, S. M. Bhavnani, J. Hammel, P. Minic, L. J. Dupont, A. Forrest, G. J. Mulder, C. Mackinson, P. G. Ambroseand and R. Gupta, “Pharmacokinetic and Pharmacodynamic Evaluation of Liposomal Amikacin for Inhalation in Cystic Fibrosis Patients with Chronic Pseudomonal Infection,” Antimicrobial Agents and Chemotherapy, Vol. 53, No. 9, 2009, pp. 3847-3854 doi:10.1128/AAC.00872-08
P. Meers, M. Neville, V. Malinin, A. W. Scotto, G. Sardaryan, R. Kurumunda, C. Mackinson, G. James, S. Fisher and W. R. Perkins, “Biofilm Penetration, Triggered Release and in Vivo Activity of Inhaled Liposomal Amikacin in Chronic Pseudomonas Aeruginosa Lung Infections,” Journal of Antimicrobial Chemotherapy, Vol. 61, No. 4, 2008, pp. 859-868. doi:10.1093/jac/dkn059
P. Mitsopoulos and Z. E Suntres, “Protective Effects of Liposomal N-Acetylcysteine against Paraquat-Induced Cytotoxicity and Gene Expression,” Journal of Toxicology, Vol. 2011, 2011, Article ID 808967 (14 Pages). doi:10.1155/2011/808967
W. H. Huang, Z. J. Yang , H. Wu , Y. F. Wong , Z. Z. Zhao and L. Liu, “Development of Liposomal Salbutamol Sulfate Dry Powder Inhaler Formulation,” Biological & Pharmaceutical Bulletin, Vol. 33, No. 3, 2010, pp. 512- 517. doi:10.1248/bpb.33.512
A. Misra, K. Jinturkar, D. Patel, J. Lalani and M. Chougule, “Recent Advances in Liposomal Dry Powder Formulations: Preparation and Evaluation,” Expert Opinion on Drug Delivery, Vol. 6, No. 1, 2009, pp. 71-89. doi:10.1517/17425240802652309.
A. Abd-Elbary, H. M. El-laithy , M. I. Tadros, “Sucrose Stearate-Based Proniosome-Derived Niosomes for the Nebulisable Delivery of Cromolyn Sodium,” International Journal of Pharmaceutics, Vol. 357, No. 1-2, 2008, pp. 189-198. doi:10.1016/j.ijpharm.2008.01.056
K. M. Surinder, N. Jindal and G. Kaur, “Quantitative Investigation, Stability and in Vitro Release Studies of Anti-TB Drugs in Triton Niosomes,” Colloids and Surfaces B: Biointerfaces, Vol. 87, No. 1, 2011, pp. 173-179. doi:10.1016/j.colsurfb.2011.05.018
V. S. Jatav, S. K Singh, P. Khatri, A. K. Sharma and R. Singh, “Formulation and In-Vitro Evaluation of Rifampicin-Loaded Niosomes,” Journal of Chemical and Pharmaceutical Research, Vol. 3, No. 2, 2011, pp. 199- 203.
C. Terzano, L. Allegra, F. Alhaique, C. Marianecci and M. Carafa, “Non-Phospholipid Vesicles for Pulmonary Glucocorticoid Delivery,” European Journal of Pharmaceutics and Biopharmaceutics, Vol. 59, No. 1, 2005, pp. 57-62. doi:10.1016/j.ejpb.2004.06.010
C. Marianecci, D. Paolino, C. Celia, M. Fresta, M. Carafa and F. Alhaique, “Non-Ionic Surfactant Vesicles in Pulmonary Glucocorticoid Delivery: Characterization and Interaction with Human Lung Fibroblasts,” Journal of Controlled Release, Vol. 147, No. 1, 2010, 127-135. doi:10.1016/j.jconrel.2010.06.022
Z. Zhong1, X. Wei, B. Qi, W. Xiao, L. Yang, Y. Wei and L. Chen, “A Novel Liposomal Vaccine Improves Humoral Immunity and Prevents Tumor Pulmonary Metastasis in Mice,” International Journal of Pharmaceutics, Vol. 399, No. 1-2, 2010, pp 156-162. doi:10.1016/j.ijpharm.2010.07.053
J. K. Lam, W. Liang and H. K. Chan, “Pulmonary Delivery of Therapeutic siRNA,” Advanced Drug Delivery Reviews, 2011, Article in Press. doi:10.1016/j.addr.2011.02.006
U. Griesenbach and E. W. Alton, “Gene Transfer to the Lung: Lessons Learned from More Than 2 Decades of CF Gene Therapy,” Advanced Drug Delivery Reviews, Vol. 61, No. 2, 2009, pp. 128-139. doi:10.1016/j.addr.2008.09.010
J. Nguyen, R. Reul, T. Betz, E. Dayyoub, T. Schmehl, T. Gessler, U. Bakowsky, W. Seeger and T. Kissel, “Nanocomposites of Lung Surfactant and Biodegradable Cationic Nanoparticles Improve Transfection Efficiency to Lung Cells,” Journal of Controlled Release, Vol. 140, No. 1, 2009, pp. 47-54. doi:10.1016/j.jconrel.2009.07.017.
X. Yuan, S. Naguib, and Z. Wu, “Recent Advances of siRNA Delivery by Nanoparticles,” Expert Opinion on Drug Delivery, Vol. 8, No. 4, 2011, pp. 521-536. doi:10.1517/17425247.2011.559223
P. Li, D. Liu, X. Sun, C. Liu, Y. Liu and N. Zhang, “A Novel Cationic Liposome Formulation for Efficient Gene Delivery via a Pulmonary Route,” Nanotechnology, Vol. 22, No. 24, 2011, Article ID 245104. doi:10.1088/0957-4484/22/24/245104
T. Ishitsuka, H. Akita and H. Harashima, “Functional Improvement of an IRQ-PEG-MEND for Delivering Genes to the Lung,” Journal of Controlled Release, Vol. 154, No. 1, pp. 77-83. doi:10.1016/j.jconrel.2011.05.012
M. R. Gwinn and V. Vallyathan, “Nanoparticles: Health Effects—Pros and Cons,” Environmental Health Perspectives, Vol. 114. No. 12, 2006, pp. 1818-1825. doi: 10.1289/ehp.8871
J. D. Byrne and J. A. Baugh, “The Significance of Nanoparticles in Particle-Induced Pulmonary Fibrosis,” McGill Journal of Medicine, Vol. 11, No. 1, 2008, pp. 43-50.
O. Lkhasuren, K. Takahashi and L. Dash-Onolt, “Occupational lung Diseases and the Mining Industry in Mongolia,” International Journal of Occupational and Environmental Health, Vol. 13, No. 2, 2007, pp. 195-201.
T. Xia, N. Li and A. E. Nel, “Potential Health Impact of Nanoparticles,” Annual Review of Public Health, Vol. 30, 2009, pp. 137-150. doi:10.1146/annurev.publhealth.031308.100155
C. C. Huang, R. S. Aronstam, D. R. Chen and Y. W. Huang, “Oxidative Stress, Calcium Homeostasis, and Altered Gene Expression in Human Lung Epithelial Cells Exposed to ZnO Nanoparticles,” Toxicology in Vitro, Vol. 24, No. 1, 2010, pp. 45-55. doi:10.1016/j.tiv.2009.09.007
S. J. Klaine, P. J. J. Alvarez, G. E. Batley, T. F. Fernandes and R. D. Handy, “Nanomaterials in the Environment: Behavior, Fate, Bioavailability, and Effects,” Environmental Toxicology and Chemistry, Vol. 27, No. 9, 2008, pp. 1825-1851. doi:10.1897/08-090.1
M. Beck-Broichsitter, C. Ruppert, T. Schmehl, A. Guenther, T. Betz, U. Bakowsky, W. Seeger, T. Kissel and T. Gessler, “Biophysical Investigation of Pulmonary Surfactant Surface Properties upon Contact with Polymeric Nanoparticles in Vitro,” Nanomedicine: Nanotechnology, Biology and Medicine, Vol. 7, No. 3, 2011, pp. 341-350. doi:10.1016/j.nano.2010.10.007
S. Azarmi, W. H. Roa and R. L?benberg, “Targeted Delivery of Nanoparticles for the Treatment of lung Diseases,” Advanced Drug Delivery Reviews, Vol. 60, No. 8, 2008, pp. 863-875. doi:10.1016/j.addr.2007.11.006
G. Taylor and I. Kellaway, “Pulmonary Drug Delivery,” In: A. Hillery, A. Lloyd and J. Swarbrick, Eds., Drug Delivery and Targeting, Taylor & Francis, New York, 2001, pp. 269-300.