Nano-Strategies for Improving the Bioavailability of Inhaled Pharmaceutical Formulations

Yue       Xing; Peng      Lu; Zhifeng       Xue; Chunxia       Liang; Bing       Zhang; Dereje       Kebebe; Hongfei       Liu; Zhidong       Liu
Abstract

Pulmonary pharmaceutical formulations are targeted for the treatment of respiratory diseases. However, their application is limited due to the physiological characteristics of the lungs, such as branching structure, mucociliary and macrophages, as well as certain properties of the drugs like particle size and solubility. Nano-formulations can ameliorate particle sizes and improve drug solubility to enhance bioavailability in the lungs. The nano-formulations for lungs reviewed in this article can be classified into nanocarriers, no-carrier-added nanosuspensions and polymer-drug conjugates. Compared with conventional inhalation preparations, these novel pulmonary pharmaceutical formulations have their own advantages, such as increasing drug solubility for better absorption and less inflammatory reaction caused by the aggregation of insoluble drugs; prolonging pulmonary retention time and reducing drug clearance; improving the patient compliance by avoiding multiple repeated administrations. This review will provide the reader with some background information for pulmonary drug delivery and give an overview of the existing literature about nano-formulations for pulmonary application to explore nano-strategies for improving the bioavailability of pulmonary pharmaceutical formulations.
Keywords: Nano-strategies, pulmonary pharmaceutical formulations, bioavailability, nanocarriers, no-carrier-added nanosuspensions, polymer-drug conjugates.
Graphical Abstract

[1] 
Conti, S.; Harari, S.; Caminati, A.; Zanobetti, A.; Schwartz, J.D.; Bertazzi, P.A.; Cesana, G.; Madotto, F. The association between air pollution and the incidence of idiopathic pulmonary fibrosis in Northern Italy. Eur. Respir. J.,  2018, 51(1) 1700397
[http://dx.doi.org/10.1183/13993003.00397-2017] [PMID: 29371377] 
[2] 
Shin, I.S.; Shin, N.R.; Park, J.W.; Jeon, C.M.; Hong, J.M.; Kwon, O.K.; Kim, J.S.; Lee, I.C.; Kim, J.C.; Oh, S.R.; Ahn, K.S. Melatonin attenuates neutrophil inflammation and mucus secretion in cigarette smoke-induced chronic obstructive pulmonary diseases via the suppression of Erk-Sp1 signaling. J. Pineal Res.,  2015, 58(1), 50-60.
[http://dx.doi.org/10.1111/jpi.12192] [PMID: 25388990] 
[3] 
Haktanir Abul, M.; Phipatanakul, W. Severe asthma in children: Evaluation and management. Allergol. Int.,  2019, 68(2), 150-157.
[http://dx.doi.org/10.1016/j.alit.2018.11.007] [PMID: 30648539] 
[4] 
Osuoha, C.A.; Callahan, K.E.; Ponce, C.P.; Pinheiro, P.S. Disparities in lung cancer survival and receipt of surgical treatment. Lung Cancer,  2018, 122, 54-59.
[http://dx.doi.org/10.1016/j.lungcan.2018.05.022] [PMID: 30032845] 
[5] 
Abdelaziz, H.M.; Gaber, M.; Abd-Elwakil, M.M.; Mabrouk, M.T.; Elgohary, M.M.; Kamel, N.M.; Kabary, D.M.; Freag, M.S.; Samaha, M.W.; Mortada, S.M.; Elkhodairy, K.A.; Fang, J.Y.; Elzoghby, A.O. Inhalable particulate drug delivery systems for lung cancer therapy: Nanoparticles, microparticles, nanocomposites and nanoaggregates. J. Control. Release,  2018, 269, 374-392.
[http://dx.doi.org/10.1016/j.jconrel.2017.11.036] [PMID: 29180168] 
[6] 
de Kruijf, W.; Ehrhardt, C. Inhalation delivery of complex drugs the next steps. Curr. Opin. Pharmacol.,  2017, 36, 52-57.
[http://dx.doi.org/10.1016/j.coph.2017.07.015] [PMID: 28846876] 
[7] 
Haque, S.; McLeod, V.M.; Jones, S.; Fung, S.; Whittaker, M.; McIntosh, M.; Pouton, C.; Owen, D.J.; Porter, C.J.H.; Kaminskas, L.M. Effect of increased surface hydrophobicity via drug conjugation on the clearance of inhaled PEGylated polylysine dendrimers. Eur. J. Pharm. Biopharm.,  2017, 119, 408-418.
[http://dx.doi.org/10.1016/j.ejpb.2017.07.005] [PMID: 28713018] 
[8] 
Haque, S.; Whittaker, M.R.; McIntosh, M.P.; Pouton, C.W.; Kaminskas, L.M. Disposition and safety of inhaled biodegradable nanomedicines: Opportunities and challenges. Nanomedicine (Lond.),  2016, 12(6), 1703-1724.
[http://dx.doi.org/10.1016/j.nano.2016.03.002] [PMID: 27033834] 
[9] 
Elsayed, M.M.A.; Shalash, A.O. Modeling the performance of carrier-based dry powder inhalation formulations: Where are we, and how to get there? J. Control. Release,  2018, 279, 251-261.
[http://dx.doi.org/10.1016/j.jconrel.2018.03.020] [PMID: 29574042] 
[10] 
Yang, M.Y.; Chan, J.G.Y.; Chan, H.K. Pulmonary drug delivery by powder aerosols. J. Control. Release,  2014, 193, 228-240.
[http://dx.doi.org/10.1016/j.jconrel.2014.04.055] [PMID: 24818765] 
[11] 
Ling, X.; Shen, Y.; Sun, C.M.; Tu, J.S. Current progress on pulmonary drug delivery. J. Pharm. Res.,  2014, 33, 711-714.
[12] 
Triolo, D.; Craparo, E.F.; Porsio, B.; Fiorica, C.; Giammona, G.; Cavallaro, G. Polymeric drug delivery micelle-like nanocarriers for pulmonary administration of beclomethasone dipropionate. Colloids Surf. B Biointerfaces,  2017, 151, 206-214.
[http://dx.doi.org/10.1016/j.colsurfb.2016.11.025] [PMID: 28013164] 
[13] 
Loira-Pastoriza, C.; Todoroff, J.; Vanbever, R. Delivery strategies for sustained drug release in the lungs. Adv. Drug Deliv. Rev.,  2014, 75, 81-91.
[http://dx.doi.org/10.1016/j.addr.2014.05.017] [PMID: 24915637] 
[14] 
Kukut Hatipoglu, M.; Hickey, A.J.; Garcia-Contreras, L. Pharmacokinetics and pharmacodynamics of high doses of inhaled dry powder drugs. Int. J. Pharm.,  2018, 549(1-2), 306-316.
[http://dx.doi.org/10.1016/j.ijpharm.2018.07.050] [PMID: 30077761] 
[15] 
Abdelrahim, M.E.; Assi, K.H.; Chrystyn, H. Relative bioavailability of terbutaline to the lung following inhalation, using urinary excretion. Br. J. Clin. Pharmacol.,  2011, 71(4), 608-610.
[http://dx.doi.org/10.1111/j.1365-2125.2010.03873.x] [PMID: 21395654] 
[16] 
Mashat, M.; Clark, B.J.; Assi, K.H.; Chrystyn, H. Assessment of recent nebulizer delivery systems using urinary pharmacokinetics method and aerodynamic characteristics of TOBI ® nebulized dose following inhalation. J. Drug Deliv. Sci. Technol.,  2017, 39, 428-434.
[http://dx.doi.org/10.1016/j.jddst.2017.04.007] 
[17] 
He, C.; Lin, W. Hybrid nanoparticles for cancer imaging and therapy. Cancer Treat. Res.,  2015, 166, 173-192.
[http://dx.doi.org/10.1007/978-3-319-16555-4_8] [PMID:  25895869] 
[18] 
Mottaghitalab, F.; Farokhi, M.; Fatahi, Y.; Atyabi, F.; Dinarvand, R. New insights into designing hybrid nanoparticles for lung cancer: Diagnosis and treatment. J. Control. Release,  2019, 295, 250-267.
[http://dx.doi.org/10.1016/j.jconrel.2019.01.009] [PMID: 30639691] 
[19] 
Brannon-Peppas, L.; Blanchette, J.O. Nanoparticle and targeted systems for cancer therapy. Adv. Drug Deliv. Rev.,  2012, 64, 206-212.
[http://dx.doi.org/10.1016/j.addr.2012.09.033] [PMID: 15350294] 
[20] 
Sharma, G.; Kumar, A.; Sharma, S.; Naushad, M.; Dwivedi, R.P. ALOthman, Z.A.; Mola, G.T. Novel development of nanoparticles to bimetallic nanoparticles and their composites: A review. J. King Saud Univ. Sci.,  2019, 31, 257-269.
[21] 
George, A.; Shah, P.A.; Shrivastav, P.S. Natural biodegradable polymers based nano-formulations for drug delivery: A review. Int. J. Pharm.,  2019, 561, 244-264.
[http://dx.doi.org/10.1016/j.ijpharm.2019.03.011] [PMID: 30851391] 
[22] 
Gupta, V.; Gupta, N.; Shaik, I.H.; Mehvar, R.; McMurtry, I.F.; Oka, M.; Nozik-Grayck, E.; Komatsu, M.; Ahsan, F. Liposomal fasudil, a rho-kinase inhibitor, for prolonged pulmonary preferential vasodilation in pulmonary arterial hypertension. J. Control. Release,  2013, 167(2), 189-199.
[http://dx.doi.org/10.1016/j.jconrel.2013.01.011] [PMID: 23353807] 
[23] 
Ji, P.; Yu, T.; Liu, Y.; Jiang, J.; Xu, J.; Zhao, Y.; Hao, Y.; Qiu, Y.; Zhao, W.; Wu, C. Naringenin-loaded solid lipid nanoparticles: Preparation, controlled delivery, cellular uptake, and pulmonary pharmacokinetics. Drug Des. Devel. Ther.,  2016, 10, 911-925.
[PMID:  27041995] 
[24] 
Weber, S.; Zimmer, A.; Pardeike, J. Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC) for pulmonary application: A review of the state of the art. Eur. J. Pharm. Biopharm.,  2014, 86(1), 7-22.
[http://dx.doi.org/10.1016/j.ejpb.2013.08.013] [PMID: 24007657] 
[25] 
Hu, X.; Yang, F.F.; Quan, L.H.; Liu, C.Y.; Liu, X.M.; Ehrhardt, C.; Liao, Y.H. Pulmonary delivered polymeric micelles--pharmacokinetic evaluation and biodistribution studies. Eur. J. Pharm. Biopharm.,  2014, 88(3), 1064-1075.
[http://dx.doi.org/10.1016/j.ejpb.2014.10.010] [PMID: 25460153] 
[26] 
Jeevanandam, J.; Chan, Y.S.; Danquah, M.K. Nano-formulations of drugs: Recent developments, impact and challenges. Biochimie,  2016, 128-129, 99-112.
[http://dx.doi.org/10.1016/j.biochi.2016.07.008] [PMID: 27436182] 
[27] 
Varma, J.N.; Kumar, T.S.; Prasanthi, B.; Ratna, J.V. Formulation and characterization of pyrazinamide polymeric nanoparticles for pulmonary tuberculosis: Efficiency for alveolar macrophage targeting. Indian J. Pharm. Sci.,  2015, 77(3), 258-266.
[http://dx.doi.org/10.4103/0250-474X.159602] [PMID: 26180270] 
[28] 
Rundfeldt, C.; Steckel, H.; Scherliess, H.; Wyska, E.; Wlaź, P. Inhalable highly concentrated itraconazole nanosuspension for the treatment of bronchopulmonary aspergillosis. Eur. J. Pharm. Biopharm.,  2013, 83(1), 44-53.
[http://dx.doi.org/10.1016/j.ejpb.2012.09.018] [PMID: 23064325] 
[29] 
Nasr, M.; Najlah, M.; D’Emanuele, A.; Elhissi, A. PAMAM dendrimers as aerosol drug nanocarriers for pulmonary delivery via nebulization. Int. J. Pharm.,  2014, 461(1-2), 242-250.
[http://dx.doi.org/10.1016/j.ijpharm.2013.11.023] [PMID: 24275446] 
[30] 
Freches, D.; Patil, H.P.; Machado Franco, M.; Uyttenhove, C.; Heywood, S.; Vanbever, R. PEGylation prolongs the pulmonary retention of an anti-IL-17A Fab’ antibody fragment after pulmonary delivery in three different species. Int. J. Pharm.,  2017, 521(1-2), 120-129.
[http://dx.doi.org/10.1016/j.ijpharm.2017.02.021] [PMID: 28192159] 
[31] 
Cryer, A.M.; Thorley, A.J. Nanotechnology in the diagnosis and treatment of lung cancer. Pharm. Ther, 2019. Available online 21
[32] 
Youngren-Ortiz, S.R.; Gandhi, N.S.; España-Serrano, L.; Chougule, M.B. Aerosol delivery of siRNA to the lungs. Part 1: Rationale for gene delivery systems. Kona,  2016, 33, 63-85.
[http://dx.doi.org/10.14356/kona.2016014] [PMID: 27081214] 
[33] 
Lam, J.K.; Liang, W.; Chan, H.K. Pulmonary delivery of therapeutic siRNA. Adv. Drug Deliv. Rev.,  2012, 64(1), 1-15.
[http://dx.doi.org/10.1016/j.addr.2011.02.006] [PMID: 21356260] 
[34] 
David, A.R.; Yin, W.; Frame, M.D. Biofluid Mechanics; Academic Press: New York, 2016. 
[35] 
Mpe, M.J. Indications for and benefits of long-term oxygen therapy in patients with COPD: More about pulmonary. Pneumonol. Pol.,  2009, 46, 863-868.
[36] 
Qureshi, S.M.; Mustafa, R. Measurement of respiratory function: Gas exchange and its clinical applications. Anaesth. Intensive Care,  2018, 19, 65-71.
[http://dx.doi.org/10.1016/j.mpaic.2017.11.006] 
[37] 
Rozycki, H.J. Potential contribution of type I alveolar epithelial cells to chronic neonatal lung disease. Front Pediatr.,  2014, 2, 45.
[http://dx.doi.org/10.3389/fped.2014.00045] [PMID: 24904906] 
[38] 
Jubrail, J.; Kurian, N.; Niedergang, F. Macrophage phagocytosis cracking the defect code in COPD. Biomed. J.,  2017, 40(6), 305-312.
[http://dx.doi.org/10.1016/j.bj.2017.09.004] [PMID: 29433833] 
[39] 
Byrne, A.J.; Maher, T.M.; Lloyd, C.M. Pulmonary macrophages: A new therapeutic pathway in fibrosing lung disease? Trends Mol. Med.,  2016, 22(4), 303-316.
[http://dx.doi.org/10.1016/j.molmed.2016.02.004] [PMID: 26979628] 
[40] 
Yue, H.; Wei, W.; Yue, Z.; Lv, P.; Wang, L.; Ma, G.; Su, Z. Particle size affects the cellular response in macrophages. Eur. J. Pharm. Sci.,  2010, 41(5), 650-657.
[http://dx.doi.org/10.1016/j.ejps.2010.09.006] [PMID: 20870022] 
[41] 
Sun, Y.; Qiu, X.; Wu, G.; Wang, J.; Li, J.; Tang, H.; Xia, Z. The effects of porcine pulmonary surfactant on smoke inhalation injury. J. Surg. Res.,  2015, 198(1), 200-207.
[http://dx.doi.org/10.1016/j.jss.2015.05.019] [PMID: 26073349] 
[42] 
Lemke, A.; Castillo-Sánchez, J.C.; Prodinger, F.; Ceranic, A.; Hennerbichler-Lugscheider, S.; Pérez-Gil, J.; Redl, H.; Wolbank, S. Human amniotic membrane as newly identified source of amniotic fluid pulmonary surfactant. Sci. Rep.,  2017, 7(1), 6406.
[http://dx.doi.org/10.1038/s41598-017-06402-w] [PMID: 28743969] 
[43] 
Iyer, R.; Hsia, C.C.; Nguyen, K.T. Nano-therapeutics for the lung: State-of-the-art and future perspectives. Curr. Pharm. Des.,  2015, 21(36), 5233-5244.
[http://dx.doi.org/10.2174/1381612821666150923095742 ] [PMID:  26412358] 
[44] 
Fishler, R.; Verhoeven, F.; de Kruijf, W.; Sznitman, J. Particle sizing of pharmaceutical aerosols via direct imaging of particle settling velocities. Eur. J. Pharm. Sci.,  2018, 113, 152-158.
[http://dx.doi.org/10.1016/j.ejps.2017.08.016] [PMID: 28821437] 
[45] 
Shweta, S.; Singh, H.S.; Singh, S.K.; Lalwani, G. Factors that Affect the Lung Deposition. Int. J. Mod. Phys.,  2013, 22, 729-732.
[46] 
Busatto, C.; Pesoa, J.; Helbling, I.; Luna, J.; Estenoz, D. Effect of particle size, polydispersity and polymer degradation on progesterone release from PLGA microparticles: Experimental and mathematical modeling. Int. J. Pharm.,  2018, 536(1), 360-369.
[http://dx.doi.org/10.1016/j.ijpharm.2017.12.006] [PMID: 29217474] 
[47] 
Musante, C.J.; Schroeter, J.D.; Rosati, J.A.; Crowder, T.M.; Hickey, A.J.; Martonen, T.B. Factors affecting the deposition of inhaled porous drug particles. J. Pharm. Sci.,  2002, 91(7), 1590-1600.
[http://dx.doi.org/10.1002/jps.10152] [PMID: 12115821] 
[48] 
Kurbatova, P.; Bessonov, N.; Volpert, V.; Tiddens, H.A.; Cornu, C.; Nony, P.; Caudri, D. Model of mucociliary clearance in cystic fibrosis lungs. J. Theor. Biol.,  2015, 372, 81-88.
[http://dx.doi.org/10.1016/j.jtbi.2015.02.023] [PMID: 25746843] 
[49] 
Carvalho, T.C.; Peters, J.I.; Williams, R.O., III Influence of particle size on regional lung deposition--what evidence is there? Int. J. Pharm.,  2011, 406(1-2), 1-10.
[http://dx.doi.org/10.1016/j.ijpharm.2010.12.040] [PMID: 21232585] 
[50] 
Edwards, D.A.; Hanes, J.; Caponetti, G.; Hrkach, J.; Ben-Jebria, A.; Eskew, M.L.; Mintzes, J.; Deaver, D.; Lotan, N.; Langer, R. Large porous particles for pulmonary drug delivery. Science,  1997, 276(5320), 1868-1871.
[http://dx.doi.org/10.1126/science.276.5320.1868] [PMID: 9188534] 
[51] 
Darquenne, C. Particles deposition in the lung. In: Encyclopedia of
	Respiratory Medicine, 2006, 4, pp. 300-304.
[52] 
Koullapis, P.G.; Kassinos, S.C.; Bivolarova, M.P.; Melikov, A.K. Particle deposition in a realistic geometry of the human conducting airways: Effects of inlet velocity profile, inhalation flowrate and electrostatic charge. J. Biomech.,  2016, 49(11), 2201-2212.
[http://dx.doi.org/10.1016/j.jbiomech.2015.11.029] [PMID: 26806688] 
[53] 
Desai, N. Challenges in development of nanoparticle-based therapeutics. AAPS J.,  2012, 14(2), 282-295.
[http://dx.doi.org/10.1208/s12248-012-9339-4] [PMID: 22407288] 
[54] 
Bustamante-Marin, X.M.; Ostrowski, L.E. Cilia and Mucociliary Clearance. Cold Spring Harb. Perspect. Biol,  2017, 9(4), a02824.1.
[http://dx.doi.org/10.1101/cshperspect.a028241] [PMID: 27864314] 
[55] 
Patton, J.S.; Brain, J.D.; Davies, L.A.; Fiegel, J.; Gumbleton, M.; Kim, K.J.; Sakagami, M.; Vanbever, R.; Ehrhardt, C. The particle has landed--characterizing the fate of inhaled pharmaceuticals. J. Aerosol Med. Pulm. Drug Deliv.,  2010, 23(Suppl. 2), S71-S87.
[http://dx.doi.org/10.1089/jamp.2010.0836] [PMID: 21133802] 
[56] 
Shah, R.M.; Rajasekaran, D.; Ludford-Menting, M.; Eldridge, D.S.; Palombo, E.A.; Harding, I.H. Transport of stearic acid-based solid lipid nanoparticles (SLNs) into human epithelial cells. Colloids Surf. B Biointerfaces,  2016, 140, 204-212.
[http://dx.doi.org/10.1016/j.colsurfb.2015.12.029] [PMID: 26764103] 
[57] 
Bo, O.; Bondesson, E.; Borgström, L.; Edsbäcker, S.; Eirefelt, S.; Gustavsson, L.; Hegelund-Myrbäck, T. Pulmonary Drug Metabolism, Clearance, and Absorption; Controlled Pulm; Deliv, 2011, pp. 25-51.
[58] 
Hidalgo, A.; Cruz, A.; Pérez-Gil, J. Barrier or carrier? Pulmonary surfactant and drug delivery. Eur. J. Pharm. Biopharm,  2015, 95(Pt A), 117-127.
[http://dx.doi.org/10.1016/j.ejpb.2015.02.014] [PMID: 25709061] 
[59] 
Pornpattananangkul, D. Antimicrobial Nanoparticle for the Treatment of Bacterial Infection; University of California: San Diego, 2012. 
[60] 
Gibbons, A.; McElvaney, N.G.; Cryan, S.A. A dry powder formulation of liposome-encapsulated recombinant secretory leukocyte protease inhibitor (rSLPI) for inhalation: Preparation and characterisation. AAPS PharmSciTech,  2010, 11(3), 1411-1421.
[http://dx.doi.org/10.1208/s12249-010-9500-2] [PMID: 20839079] 
[61] 
Tang, Y.; Zhang, H.; Lu, X.; Jiang, L.; Xi, X.; Liu, J.; Zhu, J. Development and evaluation of a dry powder formulation of liposome-encapsulated oseltamivir phosphate for inhalation. Drug Deliv.,  2015, 22(5), 608-618.
[http://dx.doi.org/10.3109/10717544.2013.863526] [PMID: 24299495] 
[62] 
Rudokas, M.; Najlah, M.; Alhnan, M.A.; Elhissi, A. Liposome delivery systems for inhalation: A critical review highlighting formulation issues and anticancer applications. Med. Princ. Pract.,  2016, 25(Suppl. 2), 60-72.
[http://dx.doi.org/10.1159/000445116] [PMID: 26938856] 
[63] 
Chennakesavulu, S.; Mishra, A.; Sudheer, A.; Sowmya, C.; Reddy, C.S.; Bhargav, E. Pulmonary delivery of liposomal dry powder inhaler formulation for effective treatment of idiopathic pulmonary fibrosis. AAPS Pharm.Sci.Tech,  2010, 3, 1413-1421.
[64] 
Manconi, M.; Manca, M.L.; Valenti, D.; Escribano, E.; Hillaireau, H.; Fadda, A.M.; Fattal, E. Chitosan and hyaluronan coated liposomes for pulmonary administration of curcumin. Int. J. Pharm.,  2017, 525(1), 203-210.
[http://dx.doi.org/10.1016/j.ijpharm.2017.04.044] [PMID: 28438698] 
[65] 
Galili, U. Inhalation of α-Gal/Sialic Acid Liposomes for Decreasing
  Influenza Virus Infection; The natural anti-gal antibody as foe
  turned friend in medicine; , 2018, pp. 277-285.
[http://dx.doi.org/10.1016/B978-0-12-813362-0.00016-6] 
[66] 
Nahar, K.; Absar, S.; Patel, B.; Ahsan, F. Starch-coated magnetic liposomes as an inhalable carrier for accumulation of fasudil in the pulmonary vasculature. Int. J. Pharm.,  2014, 464(1-2), 185-195.
[http://dx.doi.org/10.1016/j.ijpharm.2014.01.007] [PMID: 24463004] 
[67] 
Bai, S.; Gupta, V.; Ahsan, F. Cationic liposomes as carriers for aerosolized formulations of an anionic drug: Safety and efficacy study. Eur. J. Pharm. Sci.,  2009, 38(2), 165-171.
[http://dx.doi.org/10.1016/j.ejps.2009.07.002] [PMID: 19616095] 
[68] 
Hu, Y.Z.; Li, M.; Zhang, T.T.; Jin, Y.G. Preparation of liposomal artesunate dry powder inhalers and the effect on the acute lung injury of rats. Yao Xue Xue Bao,  2016, 51(12), 1906-1912.
[PMID:  29923696] 
[69] 
Allen, T.M.; Cullis, P.R. Liposomal drug delivery systems: From concept to clinical applications. Adv. Drug Deliv. Rev.,  2013, 65(1), 36-48.
[http://dx.doi.org/10.1016/j.addr.2012.09.037] [PMID: 23036225] 
[70] 
Winthrop, K. Liposomal Amikacin for Inhalation (LAI) in the
	Treatment of Mycobacterium Abscessus Lung Disease. http://www.clinicaltrials.gov/ct2/show/NTC03038178?term
[71] 
Pittsburgh, U.O. Pharmacokinetic profile of inhaled liposomal
	amphotericin b in lung transplant recipients – Ambisome study. https://www.clinicaltrials.gov/ct2/show/
[72] 
Center, E.M. Inhalation of Liposomal Amphotericin B to Prevent Invasive Aspergillosis, https://www.clinicaltrials.gov/ct2/show/NCT00263315?term=Inhalation+of+Liposomal+Amphotericin+B+to+Prevent+Invasive+Aspergillosis&rank=1
[73] 
Hospital, P.U. Evaluation of a Therapeutic Strategy Including
Nebulised Liposomal Amphotericin B (Ambisome®) in Maintenance
	Treatment of Allergic Bronchopulmonary Aspergillosis (Cystic Fibrosis Excluded). (NEBULAMB) https://www.clinicaltrials.gov/ct2/show/NCT02273661?term=inhalation+Liposomes&type=Intr&draw=4&rank=24
[74] 
University, C.M. Value of Amphotericin B Inhalation for Prophylaxis of Invasive Pulmonary Aspergillosis After Renal Transplantation., https://www.clinicaltrials.gov/ct2/show/NCT00986713 ?term= inhalation+Liposomes&type=Intr&draw=5&rank=31
[75] 
Center, M.S.K.C. Inhaled Doxorubicin in Treating Patients with Primary Lung Cancer or Lung Metastases., https://www.clinicaltrials.gov/ct2/show/NCT00004930?term=inhalation+
[76] 
(CC), N.I.o.H.C.C. Inhaled Doxorubicin in Treating Patients with
	Advanced Solid Tumors Affecting the Lungs https://www.clinicaltrials.gov/ct2/show/NCT00020124?term=2018
[77] 
 Zivena, Inhaled Doxorubicin Plus IV Docetaxel and Cisplatin in
	Patients with Non-Small-Cell Lung Carcinoma (NSCLC) https://www.clinicaltrials.gov/ct2/show/NCT00082472?term=
[78] 
Corporation, A. Corporation, A. Phase 3 Study with ciprofloxacin
	dispersion for inhalation in Non-CF Bronchiectasis (ORBIT-3). https://www.clinicaltrials.gov/ct2/show/NCT01515007?term=
[79] 
Incorporated, I.  multidose safety and tolerability study of dose
	escalation of liposomal amikacin for inhalation (ARIKAYCE™)., https://www.clinicaltrials.gov/ct2/show/
[80] 
Incorporated, I. A study to determine the safety and tolerability of
	arikace™ versus placebo in patients who have bronchiectasis. https://www.clinicaltrials.gov/ct2/show/NCT00775138? term=inhalation+Liposomes&type=Intr&draw=4
[81] 
Incorporated, I. Extension study of arikayce in cystic fibrosis (cf)
	patients with chronic pseudomonas aeruginosa infection. https://www.clinicaltrials.gov/ct2/show/NCT01316276? term=inhalation+Liposomes&type=Intr&rank=9
[82] 
Network, U.H. Safety and efficacy study of inhaled ambisome for prevention of aspergillus colonization in lung transplant recipients., https://www.clinicaltrials.gov/ct2/show/
[83] 
Gmb, H.P.P.  L-CsA in the Prevention of Bronchiolitis Obliterans
	Syndrome (BOS) in Lung Transplant (LT) patients https://www.clinicaltrials.gov/ct2/show/NCT01334892 ?term= inhalation+Liposomes&type=Intr&draw=2&rank=20
[84] 
München, T.U. LipoAerosol© Inhalation after tracheostomy. https://www.clinicaltrials.gov/ct2/show/NCT02157129?term=inhalation+Liposomes&type=Intr&draw=3&rank=21
[85] 
Maryland, U.o. Aerosol liposomal cyclosporine for chronic rejection in lung transplant recipients., https://www.clinicaltrials.gov/ct2/show/NCT01650545?term=inhalation+Liposomes&type=Intr&dra=4&rank=25
[86] 
Nassimi, M.; Schleh, C.; Lauenstein, H.D.; Hussein, R.; Hoymann, H.G.; Koch, W.; Pohlmann, G.; Krug, N.; Sewald, K.; Rittinghausen, S.; Braun, A.; Müller-Goymann, C. A toxicological evaluation of inhaled solid lipid nanoparticles used as a potential drug delivery system for the lung. Eur. J. Pharm. Biopharm.,  2010, 75(2), 107-116.
[http://dx.doi.org/10.1016/j.ejpb.2010.02.014] [PMID: 20206256] 
[87] 
Loureiro, J.A.; Andrade, S.; Duarte, A.; Neves, A.R.; Queiroz, J.F.; Nunes, C.; Sevin, E.; Fenart, L.; Gosselet, F.; Coelho, M.A.N.; Pereira, M.C. Resveratrol and grape extract-loaded solid lipid nanoparticles for the treatment of alzheimer’s disease. Molecules,  2017, 22(2), 277.
[http://dx.doi.org/10.3390/molecules22020277] [PMID: 28208831] 
[88] 
Wang, F.; Li, L.; Liu, B.; Chen, Z.; Li, C. Hyaluronic acid decorated pluronic P85 solid lipid nanoparticles as a potential carrier to overcome multidrug resistance in cervical and breast cancer. Biomed. Pharmacother.,  2017, 86, 595-604.
[http://dx.doi.org/10.1016/j.biopha.2016.12.041] [PMID: 28027535] 
[89] 
Nafee, N.; Husari, A.; Maurer, C.K.; Lu, C.; de Rossi, C.; Steinbach, A.; Hartmann, R.W.; Lehr, C.M.; Schneider, M. Antibiotic free nanotherapeutics: Ultra-small, mucus-penetrating solid lipid nanoparticles enhance the pulmonary delivery and anti-virulence efficacy of novel quorum sensing inhibitors. J. Control. Release,  2014, 192, 131-140.
[http://dx.doi.org/10.1016/j.jconrel.2014.06.055 ] [PMID:  24997276] 
[90] 
Rodenak-Kladniew, B.; Islan, G.A.; de Bravo, M.G.; Durán, N.; Castro, G.R. Design, characterization and in vitro evaluation of linalool-loaded solid lipid nanoparticles as potent tool in cancer therapy. Colloids Surf. B Biointerfaces,  2017, 154, 123-132.
[http://dx.doi.org/10.1016/j.colsurfb.2017.03.021] [PMID: 28334689] 
[91] 
Shah, R.M.; Eldridge, D.S.; Palombo, E.A.; Harding, I.H. Microwave-assisted formulation of solid lipid nanoparticles loaded with non-steroidal anti-inflammatory drugs. Int. J. Pharm.,  2016, 515(1-2), 543-554.
[http://dx.doi.org/10.1016/j.ijpharm.2016.10.054] [PMID: 27789371] 
[92] 
Ghaffari, S.; Varshosaz, J.; Saadat, A.; Atyabi, F. Stability and antimicrobial effect of amikacin-loaded solid lipid nanoparticles. Int. J. Nanomedicine,  2010, 6, 35-43.
[PMID:  21289980] 
[93] 
Baek, J.S.; Cho, C.W. Surface modification of solid lipid nanoparticles for oral delivery of curcumin: Improvement of bioavailability through enhanced cellular uptake, and lymphatic uptake. Eur. J. Pharm. Biopharm.,  2017, 117, 132-140.
[http://dx.doi.org/10.1016/j.ejpb.2017.04.013] [PMID: 28412471] 
[94] 
Makled, S.; Nafee, N.; Boraie, N. Nebulized solid lipid nanoparticles for the potential treatment of pulmonary hypertension via targeted delivery of phosphodiesterase-5-inhibitor. Int. J. Pharm.,  2017, 517(1-2), 312-321.
[http://dx.doi.org/10.1016/j.ijpharm.2016.12.026] [PMID: 27979766] 
[95] 
Soni, N.; Soni, N.; Pandey, H.; Maheshwari, R.; Kesharwani, P.; Tekade, R.K. Augmented delivery of gemcitabine in lung cancer cells exploring mannose anchored solid lipid nanoparticles. J. Colloid Interface Sci.,  2016, 481, 107-116.
[http://dx.doi.org/10.1016/j.jcis.2016.07.020] [PMID: 27459173] 
[96] 
Videira, M.; Almeida, A.J.; Fabra, A. Preclinical evaluation of a pulmonary delivered paclitaxel-loaded lipid nanocarrier antitumor effect. Nanomedicine (Lond.),  2012, 8(7), 1208-1215.
[http://dx.doi.org/10.1016/j.nano.2011.12.007] [PMID: 22206945] 
[97] 
Ji, P. Preparation of naringenin loaded solid lipid nanoparticles and its preliminary evaluation to improve lung absorption., 2016.
[98] 
Zhao, Y.; Chang, Y.X.; Hu, X.; Liu, C.Y.; Quan, L.H.; Liao, Y.H. Solid lipid nanoparticles for sustained pulmonary delivery of Yuxingcao essential oil: Preparation, characterization and in vivo evaluation. Int. J. Pharm.,  2017, 516(1-2), 364-371.
[http://dx.doi.org/10.1016/j.ijpharm.2016.11.046 ] [PMID:  27884712] 
[99] 
Vedanti, R. Salvi; Pravin Pawar. Nanostructured lipid carriers (NLC) system: A novel drug targeting carrier. J. Drug Deliv. Sci. Technol.,  2019, 51, 255-267.
[http://dx.doi.org/10.1016/j.jddst.2019.02.017] 
[100] 
Soleimanian, Y.; Goli, S.A.H.; Varshosaz, J.; Sahafi, S.M. Formulation and characterization of novel nanostructured lipid carriers made from beeswax, propolis wax and pomegranate seed oil. Food Chem.,  2018, 244, 83-92.
[http://dx.doi.org/10.1016/j.foodchem.2017.10.010 ] [PMID:  29120809] 
[101] 
Garcês, A.; Amaral, M.H.; Sousa, Lobo J.M.; Silva, A.C. Formulations based on solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) for cutaneous use: A review. Eur. J. Pharm. Sci.,  2018, 112, 159-167.
[http://dx.doi.org/10.1016/j.ejps.2017.11.023] [PMID: 29183800] 
[102] 
Pardeike, J.; Weber, S.; Zarfl, H.P.; Pagitz, M.; Zimmer, A. Itraconazole-loaded nanostructured lipid carriers (NLC) for pulmonary treatment of aspergillosis in falcons. Eur. J. Pharm. Biopharm.,  2016, 108, 269-276.
[http://dx.doi.org/10.1016/j.ejpb.2016.07.018] [PMID: 27449629] 
[103] 
Pastor; M.; Basas, J.; MSca, C.V.; Gainza, G.; Moreno-Sastre, M.; Gomis, X.; Fleischer, A.; Palomino, E.; Bachiller, D.; Gutiérrezf, F.B.; Aguirre, J.J.; Esquisabel, A.; Igartua, M.; Gainza, E.; Hernandez, R.M.; Gavaldà, J.; Pedraz, J.L. Safety and effectiveness of sodium colistimethate-loaded nanostructured lipid carriers (SCM-NLC) against P. aeruginosa: In vitro and in vivo studies following pulmonary and intramuscular administration. Nanomed-nanotechnol.,  2019, 18, 101-111.
[104] 
Pastor, M.; Moreno-Sastre, M.; Esquisabel, A.; Sans, E.; Viñas, M.; Bachiller, D.; Asensio, V.J.; Pozo, A.D.; Gainza, E.; Pedraz, J.L. Sodium colistimethate loaded lipid nanocarriers for the treatment of Pseudomonas aeruginosa infections associated with cystic fibrosis. Int. J. Pharm.,  2014, 477(1-2), 485-494.
[http://dx.doi.org/10.1016/j.ijpharm.2014.10.048] [PMID: 25445528] 
[105] 
Nafee, N.; Makled, S.; Boraie, N. Nanostructured lipid carriers versus solid lipid nanoparticles for the potential treatment of pulmonary hypertension via nebulization. Eur. J. Pharm. Sci.,  2018, 125, 151-162.
[http://dx.doi.org/10.1016/j.ejps.2018.10.003] [PMID: 30292750] 
[106] 
Patil-Gadhe, A.; Kyadarkunte, A.; Patole, M.; Pokharkar, V. Montelukast-loaded nanostructured lipid carriers: Part II pulmonary drug delivery and in vitro-in vivo aerosol performance. Eur. J. Pharm. Biopharm.,  2014, 88(1), 169-177.
[http://dx.doi.org/10.1016/j.ejpb.2014.07.007] [PMID: 25078860] 
[107] 
Patil-Gadhe, A.; Pokharkar, V. Pulmonary targeting potential of rosuvastatin loaded nanostructured lipid carrier: Optimization by factorial design. Int. J. Pharm.,  2016, 501(1-2), 199-210.
[http://dx.doi.org/10.1016/j.ijpharm.2016.01.080] [PMID: 26844785] 
[108] 
Moreno-Sastre, M.; Pastor, M.; Esquisabel, A.; Sans, E.; Viñas, M.; Fleischer, A.; Palomino, E.; Bachiller, D.; Pedraz, J.L. Pulmonary delivery of tobramycin-loaded nanostructured lipid carriers for Pseudomonas aeruginosa infections associated with cystic fibrosis. Int. J. Pharm.,  2016, 498(1-2), 263-273.
[http://dx.doi.org/10.1016/j.ijpharm.2015.12.028] [PMID: 26705155] 
[109] 
Patlolla, R.R.; Chougule, M.; Patel, A.R.; Jackson, T.; Tata, P.N.V.; Singh, M. Formulation, characterization and pulmonary deposition of nebulized celecoxib encapsulated nanostructured lipid carriers. J. Control. Release,  2010, 144(2), 233-241.
[http://dx.doi.org/10.1016/j.jconrel.2010.02.006] [PMID: 20153385] 
[110] 
Cagel, M.; Tesan, F.C.; Bernabeu, E.; Salgueiro, M.J.; Zubillaga, M.B.; Moretton, M.A.; Chiappetta, D.A. Polymeric mixed micelles as nanomedicines: Achievements and perspectives. Eur. J. Pharm. Biopharm.,  2017, 113, 211-228.
[http://dx.doi.org/10.1016/j.ejpb.2016.12.019] [PMID: 28087380] 
[111] 
Owen, S.C.; Chan, D.P.Y.; Shoichet, M.S. Polymeric micelle stability. Nano Today,  2012, 7, 53-65.
[http://dx.doi.org/10.1016/j.nantod.2012.01.002] 
[112] 
Wang, H.; Williams, G.R.; Wu, J.; Wu, J.; Niu, S.; Xie, X.; Li, S.; Zhu, L.M. Pluronic F127-based micelles for tumor-targeted bufalin delivery. Int. J. Pharm.,  2019, 559, 289-298.
[http://dx.doi.org/10.1016/j.ijpharm.2019.01.049] [PMID: 30707933] 
[113] 
Gao, D.; Lo, P.C. Polymeric micelles encapsulating pH-responsive doxorubicin prodrug and glutathione-activated zinc(II) phthalocyanine for combined chemotherapy and photodynamic therapy. J. Control. Release,  2018, 282, 46-61.
[http://dx.doi.org/10.1016/j.jconrel.2018.04.030] [PMID: 29673646] 
[114] 
Pellosi, D.S.; d’Angelo, I.; Maiolino, S.; Mitidieri, E.; d’Emmanuele di Villa Bianca, R.; Sorrentino, R.; Quaglia, F.; Ungaro, F. In vitro/in vivo investigation on the potential of Pluronic® mixed micelles for pulmonary drug delivery. Eur. J. Pharm. Biopharm.,  2018, 130, 30-38.
[http://dx.doi.org/10.1016/j.ejpb.2018.06.006] [PMID: 29890256] 
[115] 
Zhang, W.; Shi, Y.; Chen, Y.; Hao, J.; Sha, X.; Fang, X. The potential of Pluronic polymeric micelles encapsulated with paclitaxel for the treatment of melanoma using subcutaneous and pulmonary metastatic mice models. Biomaterials,  2011, 32(25), 5934-5944.
[http://dx.doi.org/10.1016/j.biomaterials.2011.04.075] [PMID: 21596432] 
[116] 
Craparo, E.F.; Teresi, G.; Bondi’, M.L.; Licciardi, M.; Cavallaro, G. Phospholipid-polyaspartamide micelles for pulmonary delivery of corticosteroids. Int. J. Pharm.,  2011, 406(1-2), 135-144.
[http://dx.doi.org/10.1016/j.ijpharm.2010.12.024] [PMID: 21185363] 
[117] 
Hu, X.; Yang, F.F.; Liu, C.Y.; Ehrhardt, C.; Liao, Y.H. In vitro uptake and transport studies of PEG-PLGA polymeric micelles in respiratory epithelial cells. Eur. J. Pharm. Biopharm.,  2017, 114, 29-37.
[http://dx.doi.org/10.1016/j.ejpb.2017.01.004] [PMID: 28093351] 
[118] 
Mahajan, H.S.; Mahajan, P.R. Development of grafted xyloglucan micelles for pulmonary delivery of curcumin: In vitro and in vivo studies. Int. J. Biol. Macromol.,  2016, 82, 621-627.
[http://dx.doi.org/10.1016/j.ijbiomac.2015.09.053] [PMID: 26432365] 
[119] 
Rosière, R.; Van Woensel, M.; Mathieu, V.; Langer, I.; Mathivet, T.; Vermeersch, M.; Amighi, K.; Wauthoz, N. Development and evaluation of well-tolerated and tumor-penetrating polymeric micelle-based dry powders for inhaled anti-cancer chemotherapy. Int. J. Pharm.,  2016, 501(1-2), 148-159.
[http://dx.doi.org/10.1016/j.ijpharm.2016.01.073] [PMID: 26850313] 
[120] 
El-Say, K.M.; El-Sawy, H.S. Polymeric nanoparticles: Promising platform for drug delivery. Int. J. Pharm.,  2017, 528(1-2), 675-691.
[http://dx.doi.org/10.1016/j.ijpharm.2017.06.052] [PMID: 28629982] 
[121] 
Su, W.P.; Cheng, F.Y.; Shieh, D.B.; Yeh, C.S.; Su, W.C. PLGA nanoparticles codeliver paclitaxel and Stat3 siRNA to overcome cellular resistance in lung cancer cells. Int. J. Nanomedicine,  2012, 7, 4269-4283.
[http://dx.doi.org/10.2147/IJN.S33666] [PMID: 22904633] 
[122] 
Maiolino, S.; Russo, A.; Pagliara, V.; Conte, C.; Ungaro, F.; Russo, G.; Quaglia, F. Biodegradable nanoparticles sequentially decorated with Polyethyleneimine and Hyaluronan for the targeted delivery of docetaxel to airway cancer cells. J. Nanobiotechnology,  2015, 13, 29.
[http://dx.doi.org/10.1186/s12951-015-0088-2] [PMID: 25888948] 
[123] 
DeMarino, C.; Schwab, A.; Pleet, M.; Mathiesen, A.; Friedman, J.; El-Hage, N.; Kashanchi, F. Biodegradable nanoparticles for delivery of therapeutics in CNS infection. J. Neuroimmune Pharmacol.,  2017, 12(1), 31-50.
[http://dx.doi.org/10.1007/s11481-016-9692-7] [PMID: 27372507] 
[124] 
Menon, J.U.; Ravikumar, P.; Pise, A.; Gyawali, D.; Hsia, C.C.; Nguyen, K.T. Polymeric nanoparticles for pulmonary protein and DNA delivery. Acta Biomater.,  2014, 10(6), 2643-2652.
[http://dx.doi.org/10.1016/j.actbio.2014.01.033] [PMID: 24512977] 
[125] 
Casamonti, M.; Risaliti, L.; Vanti, G.; Piazzini, V.; Bergonzi, M.C.; Bilia, A.R. Andrographolide loaded in micro- and nano-formulations: Improved bioavailability, target-tissue distribution, and efficacy of the “King of Bitters”. Engineering,  2019, 5, 69-75.
[http://dx.doi.org/10.1016/j.eng.2018.12.004] 
[126] 
Beck-Broichsitter, M. Compatibility of PEGylated polymer nanoparticles with the biophysical function of lung surfactant. Langmuir,  2018, 34(1), 540-545.
[http://dx.doi.org/10.1021/acs.langmuir.7b03818] [PMID: 29220196] 
[127] 
d’Angelo, I.; Costabile, G.; Durantie, E.; Brocca, P.; Rondelli, V.; Russo, A.; Russo, G.; Miro, A.; Quaglia, F.; Petri-Fink, A.; Rothen-Rutishauser, B.; Ungaro, F. Hybrid lipid/polymer nanoparticles for pulmonary delivery of siRNA: Development and fate upon in vitro deposition on the human epithelial airway barrier. J. Aerosol Med. Pulm. Drug Deliv.,  2018, 31(3), 170-181.
[http://dx.doi.org/10.1089/jamp.2017.1364] [PMID: 29035132] 
[128] 
Beck-Broichsitter, M.; Bohr, A.; Ruge, C.A. Poloxamer-Decorated polymer nanoparticles for lung surfactant compatibility. Mol. Pharm.,  2017, 14(10), 3464-3472.
[http://dx.doi.org/10.1021/acs.molpharmaceut.7b00477] [PMID: 28813610] 
[129] 
Chittasupho, C.; Xie, S.X.; Baoum, A.; Yakovleva, T.; Siahaan, T.J.; Berkland, C.J. ICAM-1 targeting of doxorubicin-loaded PLGA nanoparticles to lung epithelial cells. Eur. J. Pharm. Sci.,  2009, 37(2), 141-150.
[http://dx.doi.org/10.1016/j.ejps.2009.02.008] [PMID: 19429421] 
[130] 
Grabowski, N.; Hillaireau, H.; Vergnaud, J.; Santiago, L.A.; Kerdine-Romer, S.; Pallardy, M.; Tsapis, N.; Fattal, E. Toxicity of surface-modified PLGA nanoparticles toward lung alveolar epithelial cells. Int. J. Pharm.,  2013, 454(2), 686-694.
[http://dx.doi.org/10.1016/j.ijpharm.2013.05.025] [PMID: 23747506] 
[131] 
Masood, F. Polymeric nanoparticles for targeted drug delivery system for cancer therapy. Mater. Sci. Eng. C,  2016, 60, 569-578.
[http://dx.doi.org/10.1016/j.msec.2015.11.067] [PMID: 26706565] 
[132] 
Du, J.; Sun, Y.; Shi, Q.S.; Liu, P.F.; Zhu, M.J.; Wang, C.H.; Du, L.F.; Duan, Y.R. Biodegradable nanoparticles of mPEG-PLGA-PLL triblock copolymers as novel non-viral vectors for improving siRNA delivery and gene silencing. Int. J. Mol. Sci.,  2012, 13(1), 516-533.
[http://dx.doi.org/10.3390/ijms13010516] [PMID: 22312268] 
[133] 
Li, C.; Zhang, J.; Zu, Y.J.; Nie, S.F.; Cao, J.; Wang, Q.; Nie, S.P.; Deng, Z.Y.; Xie, M.Y.; Wang, S. Biocompatible and biodegradable nanoparticles for enhancement of anti-cancer activities of phytochemicals. Chin. J. Nat. Med.,  2015, 13(9), 641-652.
[http://dx.doi.org/10.1016/S1875-5364(15)30061-3] [PMID: 26412423] 
[134] 
Debnath, S.K.; Saisivam, S.; Omri, A. PLGA ethionamide nanoparticles for pulmonary delivery: Development and in vivo evaluation of dry powder inhaler. J. Pharm. Biomed. Anal.,  2017, 145, 854-859.
[http://dx.doi.org/10.1016/j.jpba.2017.07.051] [PMID: 28826144] 
[135] 
Pirooznia, N.; Hasannia, S.; Lotfi, A.S.; Ghanei, M. Encapsulation of alpha-1 antitrypsin in PLGA nanoparticles: In vitro characterization as an effective aerosol formulation in pulmonary diseases. J. Nanobiotechnology,  2012, 10, 20-35.
[http://dx.doi.org/10.1186/1477-3155-10-20] [PMID: 22607686] 
[136] 
Al-Nemrawi, N.K.; Alshraiedeh, N.H.; Zayed, A.L.; Altaani, B.M. Low molecular weight chitosan-coated PLGA nanoparticles for pulmonary delivery of tobramycin for cystic fibrosis. Pharmaceuticals (Basel),  2018, 11(1), 28.
[http://dx.doi.org/10.3390/ph11010028] [PMID: 29517998] 
[137] 
Pimple, S.; Manjappa, A.S.; Ukawala, M.; Murthy, R.S. PLGA nanoparticles loaded with etoposide and quercetin dihydrate individually: In vitro cell line study to ensure advantage of combination therapy. Cancer Nanotechnol.,  2012, 3(1-6), 25-36.
[http://dx.doi.org/10.1007/s12645-012-0027-y] [PMID: 26069494] 
[138] 
S.; Zhang, J.J.; Gao, Y.; Zhou, J.P. Recent progress in nanosuspension. Prog. Pharm. Sci.,  2007, 31, 9-14.
[139] 
Sattar, A.; Chen, D.; Jiang, L.; Pan, Y.; Tao, Y.; Huang, L.; Liu, Z.; Xie, S.; Yuan, Z. Preparation, characterization and pharmacokinetics of cyadox nanosuspension. Sci. Rep.,  2017, 7(1), 2289.
[http://dx.doi.org/10.1038/s41598-017-02523-4] [PMID: 28536446] 
[140] 
Wu, H.T.; Zhao, J.H.; Jia, D.C.; Cui, Q.C.; Liu, Y. Preparation of curcumenol nanosuspension and in vitro drug release study. J. Shenyang Pharm. Univ.,  2017, 34, 623-628.
[141] 
Wu, C.Q.; Li, X.F.; Mou, Q.Q.; Yan, M.J.; Liu, X.; Xie, L.; Liao, Y.M. Characterization of licorice total flavonoids nanosuspension lyophilized powder and investigation of its stability. Chinese. J. ETMF,  2018, 24, 34-38.
[142] 
Wang, L.L.; Liu, P.Z.; Zhang, J.Q. Research progress of nanosuspension drug delivery system. Chin. Pharm.,  2017, 28, 1415-1417.
[143] 
Sharma, P.; Zujovic, Z.D.; Bowmaker, G.A.; Marshall, A.J.; Denny, W.A.; Garg, S. Evaluation of a crystalline nanosuspension: Polymorphism, process induced transformation and in vivo studies. Int. J. Pharm.,  2011, 408(1-2), 138-151.
[http://dx.doi.org/10.1016/j.ijpharm.2011.01.032] [PMID: 21272627] 
[144] 
Raula, J.; Rahikkala, A.; Halkola, T.; Pessi, J.; Peltonen, L.; Hirvonen, J.; Järvinen, K.; Laaksonen, T.; Kauppinen, E.I. Coated particle assemblies for the concomitant pulmonary administration of budesonide and salbutamol sulphate. Int. J. Pharm.,  2013, 441(1-2), 248-254.
[http://dx.doi.org/10.1016/j.ijpharm.2012.11.036] [PMID: 23200957] 
[145] 
Rossi, I.; Sonvico, F.; McConville, J.T.; Rossi, F.; Fröhlich, E.; Zellnitz, S.; Rossi, A.; Del Favero, E.; Bettini, R.; Buttini, F. Nebulized coenzyme Q10 nanosuspensions: A versatile approach for pulmonary antioxidant therapy. Eur. J. Pharm. Sci.,  2018, 113, 159-170.
[http://dx.doi.org/10.1016/j.ejps.2017.10.024] [PMID: 29066385] 
[146] 
Tehrani, A.A.; Omranpoor, M.M.; Vatanara, A.; Seyedabadi, M.; Ramezani, V. Formation of nanosuspensions in bottom-up approach: Theories and optimization. Drug J. Pharm. Sci,  2019, 3, 1-23.
[147] 
Aleandri, S.; Schönenberger, M.; Niederquell, A.; Kuentz, M. Temperature-Induced surface effects on drug nanosuspensions. Pharm. Res.,  2018, 35(3), 69.
[http://dx.doi.org/10.1007/s11095-017-2300-6] [PMID: 29468420] 
[148] 
Ghaffari, M.; Dehghan, G.; Abedi-Gaballu, F.; Kashanian, S.; Baradaran, B.; Ezzati Nazhad Dolatabadi, J.; Losic, D. Surface functionalized dendrimers as controlled-release delivery nanosystems for tumor targeting. Eur. J. Pharm. Sci.,  2018, 122, 311-330.
[http://dx.doi.org/10.1016/j.ejps.2018.07.020] [PMID: 30003954] 
[149] 
Cheng, H.F.; Cheng, X.H. Research progress in functional dendrimers. Yunnan Chem. Technol.,  2017, 44, 6-11.
[150] 
Sun, W.Y.; Feng, S.Y. Dendrimers application in drug fields. Sci. Techol. Chem. Ind.,  2006, 14, 57-64.
[151] 
Zhong, Q.; Bielski, E.R.; Rodrigues, L.S.; Brown, M.R.; Reineke, J.J.; da Rocha, S.R. Conjugation to Poly(amidoamine) dendrimers and pulmonary delivery reduce cardiac accumulation and enhance antitumor activity of doxorubicin in lung metastasis. Mol. Pharm.,  2016, 13(7), 2363-2375.
[http://dx.doi.org/10.1021/acs.molpharmaceut.6b00126 ] [PMID:  27253493] 
[152] 
Zhong, Q.; Merkel, O.M.; Reineke, J.J.; da Rocha, S.R. Effect of the route of administration and PEGylation of Poly(amidoamine) dendrimers on their systemic and lung cellular Biodistribution. Mol. Pharm.,  2016, 13(6), 1866-1878.
[http://dx.doi.org/10.1021/acs.molpharmaceut.6b00036] [PMID: 27148629] 
[153] 
Inapagolla, R.; Guru, B.R.; Kurtoglu, Y.E.; Gao, X.; Lieh-Lai, M.; Bassett, D.J.P.; Kannan, R.M. In vivo efficacy of dendrimer-methylprednisolone conjugate formulation for the treatment of lung inflammation. Int. J. Pharm.,  2010, 399(1-2), 140-147.
[http://dx.doi.org/10.1016/j.ijpharm.2010.07.030] [PMID: 20667503] 
[154] 
Sikwal, D.R.; Kalhapure, R.S.; Govender, T. An emerging class of amphiphilic dendrimers for pharmaceutical and biomedical applications: Janus amphiphilic dendrimers. Eur. J. Pharm. Sci.,  2017, 97, 113-134.
[http://dx.doi.org/10.1016/j.ejps.2016.11.013] [PMID: 27864064] 
[155] 
Selin, M.; Peltonen, L.; Hirvonen, J.; Bimbo, L.M. Dendrimers and their supramolecular nanostructures for biomedical applications. J. Drug Deliv. Sci. Technol.,  2016, 34, 10-20.
[http://dx.doi.org/10.1016/j.jddst.2016.02.008] 
[156] 
Bielski, E.; Zhong, Q.; Mirza, H.; Brown, M.; Molla, A.; Carvajal, T.; da Rocha, S.R.P. TPP-dendrimer nanocarriers for siRNA delivery to the pulmonary epithelium and their dry powder and metered-dose inhaler formulations. Int. J. Pharm.,  2017, 527(1-2), 171-183.
[http://dx.doi.org/10.1016/j.ijpharm.2017.05.046] [PMID: 28549971] 
[157] 
Kaminskas, L.M.; McLeod, V.M.; Ryan, G.M.; Kelly, B.D.; Haynes, J.M.; Williamson, M.; Thienthong, N.; Owen, D.J.; Porter, C.J. Pulmonary administration of a doxorubicin-conjugated dendrimer enhances drug exposure to lung metastases and improves cancer therapy. J. Control. Release,  2014, 183, 18-26.
[http://dx.doi.org/10.1016/j.jconrel.2014.03.012] [PMID: 24637466] 
[158] 
Santiwarangkool, S.; Akita, H.; Nakatani, T.; Kusumoto, K.; Kimura, H.; Suzuki, M.; Nishimura, M.; Sato, Y.; Harashima, H. PEGylation of the GALA peptide enhances the lung-targeting activity of nanocarriers that contain encapsulated siRNA. J. Pharm. Sci.,  2017, 106(9), 2420-2427.
[http://dx.doi.org/10.1016/j.xphs.2017.04.075] [PMID: 28483420] 
[159] 
Li, S.; Wang, L.; Li, N.; Liu, Y.; Su, H. Combination lung cancer chemotherapy: Design of a pH-sensitive transferrin-PEG-Hz-lipid conjugate for the co-delivery of docetaxel and baicalin. Biomed. Pharmacother.,  2017, 95, 548-555.
[http://dx.doi.org/10.1016/j.biopha.2017.08.090] [PMID: 28869892] 
[160] 
Patil, T.S.; Deshpande, A.S. Nanostructured lipid carriers-based drug delivery for treating various lung diseases: A State-of-the-Art Review. Int. J. Pharm.,  2018, 547(1-2), 209-225.
[http://dx.doi.org/10.1016/j.ijpharm.2018.05.070] [PMID: 29859922] 
[161] 
Huang, X.; Huang, J.; Leng, D.; Yang, S.; Yao, Q.; Sun, J.; Hu, J. Gefitinib-loaded DSPE-PEG2000 nanomicelles with CD133 aptamers target lung cancer stem cells. World J. Surg. Oncol.,  2017, 15(1), 167.
[http://dx.doi.org/10.1186/s12957-017-1230-4] [PMID: 28854941] 
[162] 
Gill, K.K.; Kaddoumi, A.; Nazzal, S. Mixed micelles of PEG(2000)-DSPE and vitamin-E TPGS for concurrent delivery of paclitaxel and parthenolide: Enhanced chemosenstization and antitumor efficacy against non-small cell lung cancer (NSCLC) cell lines. Eur. J. Pharm. Sci.,  2012, 46(1-2), 64-71.
[http://dx.doi.org/10.1016/j.ejps.2012.02.010] [PMID: 22369858] 
[163] 
Mauri, E.; Cappella, F.; Masi, M.; Rossi, F. PEGylation influences drug delivery from nanogels. J. Drug Deliv. Sci. Technol.,  2018, 46, 87-92.
[http://dx.doi.org/10.1016/j.jddst.2018.05.003] 
[164] 
Turecek, P.L.; Bossard, M.J.; Schoetens, F.; Ivens, I.A. PEGylation of biopharmaceuticals: A review of chemistry and nonclinical Safety Information of approved drugs. J. Pharm. Sci.,  2016, 105(2), 460-475.
[http://dx.doi.org/10.1016/j.xphs.2015.11.015] [PMID: 26869412] 
[165] 
Muralidharan, P.; Mallory, E.; Malapit, M.; Hayes, D., Jr; Mansour, H.M. Inhalable PEGylated phospholipid nanocarriers and pegylated therapeutics for respiratory delivery as aerosolized colloidal dispersions and dry powder inhalers. Pharmaceutics,  2014, 6(2), 333-353.
[http://dx.doi.org/10.3390/pharmaceutics6020333] [PMID: 24955820] 
[166] 
Rattan, R.; Bhattacharjee, S.; Zong, H.; Swain, C.; Siddiqui, M.A.; Visovatti, S.H.; Kanthi, Y.; Desai, S.; Pinsky, D.J.; Goonewardena, S.N. Nanoparticle-macrophage interactions: A balance between clearance and cell-specific targeting. Bioorg. Med. Chem.,  2017, 25(16), 4487-4496.
[http://dx.doi.org/10.1016/j.bmc.2017.06.040] [PMID: 28705434] 
[167] 
Tang, B.C.; Dawson, M.; Lai, S.K.; Wang, Y.Y.; Suk, J.S.; Yang, M.; Zeitlin, P.; Boyle, M.P.; Fu, J.; Hanes, J. Biodegradable polymer nanoparticles that rapidly penetrate the human mucus barrier. Proc. Natl. Acad. Sci. USA,  2009, 106(46), 19268-19273.
[http://dx.doi.org/10.1073/pnas.0905998106] [PMID: 19901335] 
[168] 
Nag, M.; Gajbhiye, V.; Kesharwani, P.; Jain, N.K. Transferrin functionalized chitosan-PEG nanoparticles for targeted delivery of paclitaxel to cancer cells. Colloids Surf. B Biointerfaces,  2016, 148, 363-370.
[http://dx.doi.org/10.1016/j.colsurfb.2016.08.059 ] [PMID:  27632697] 
[169] 
Wen, Z.M.; Jie, J.; Zhang, Y.; Liu, H.; Peng, L.P. A self-assembled polyjuglanin nanoparticle loaded with doxorubicin and anti-Kras siRNA for attenuating multidrug resistance in human lung cancer. Biochem. Biophys. Res. Commun.,  2017, 493(4), 1430-1437.
[http://dx.doi.org/10.1016/j.bbrc.2017.09.132] [PMID: 28958938] 
[170] 
Kolte, A.; Patil, S.; Lesimple, P.; Hanrahan, J.W.; Misra, A. PEGylated composite nanoparticles of PLGA and polyethylenimine for safe and efficient delivery of pDNA to lungs. Int. J. Pharm.,  2017, 524(1-2), 382-396.
[http://dx.doi.org/10.1016/j.ijpharm.2017.03.094] [PMID: 28391040] 
[171] 
Akbarzadeh, A.; Rezaei-Sadabady, R.; Davaran, S.; Joo, S.W.; Zarghami, N.; Hanifehpour, Y.; Samiei, M.; Kouhi, M.; Nejati-Koshki, K. Liposome: Classification, preparation, and applications. Nanoscale Res. Lett.,  2013, 8(1), 102.
[http://dx.doi.org/10.1186/1556-276X-8-102] [PMID: 23432972] 
[172] 
Huang, Z.Y.; Sun, Y.Q.; Hu, H.Y.; Zhuang, R.; Xu, Q.; Chen, D.W. Techniques and methods evaluation on pharmaceutical stability of liposomes. Yao Xue Xue Bao,  2016, 51(3), 356-361.
[PMID:  29858892] 
[173] 
Qi, P.; Cao, M.; Song, L.; Chen, C.; Liu, M.; Li, N.; Wu, D.; Peng, J.; Hu, G.; Zhao, J. The biological activity of cationic liposomes in drug delivery and toxicity test in animal models. Environ. Toxicol. Pharmacol.,  2016, 47, 159-164.
[http://dx.doi.org/10.1016/j.etap.2016.09.015] [PMID: 27694054] 
[174] 
Lin, G.; Zhang, H.; Huang, L. Smart polymeric nanoparticles for cancer gene delivery. Mol. Pharm.,  2015, 12(2), 314-321.
[http://dx.doi.org/10.1021/mp500656v] [PMID: 25531409] 
[175] 
Ding, L.X.; Chai, J.L.; Li, H.; Yang, S.S.; Yu, L.; Li, S.J.; Wang, Z.Q. New progress of study on solid lipid nanoparticles. Medical J. Chinese People’s Health,  2014, 26, 69-71.
[176] 
Jenning, V.; Schäfer-Korting, M.; Gohla, S. Vitamin A-loaded solid lipid nanoparticles for topical use: Drug release properties. J. Control. Release,  2000, 66(2-3), 115-126.
[http://dx.doi.org/10.1016/S0168-3659(99)00223-0] [PMID: 10742573] 
[177] 
Yang, H.; Teng, F.; Wang, P.; Tian, B.; Lin, X.; Hu, X.; Zhang, L.; Zhang, K.; Zhang, Y.; Tang, X. Investigation of a nanosuspension stabilized by Soluplus® to improve bioavailability. Int. J. Pharm.,  2014, 477(1-2), 88-95.
[http://dx.doi.org/10.1016/j.ijpharm.2014.10.025] [PMID: 25455766] 
[178] 
Du, J.; Zhou, Y.; Wang, L.; Wang, Y. Effect of PEGylated chitosan as multifunctional stabilizer for deacetyl mycoepoxydience nanosuspension design and stability evaluation. Carbohydr. Polym.,  2016, 153, 471-481.
[http://dx.doi.org/10.1016/j.carbpol.2016.08.002] [PMID: 27561519] 
[179] 
Wang, Y.; Zheng, Y.; Zhang, L.; Wang, Q.; Zhang, D. Stability of nanosuspensions in drug delivery. J. Control. Release,  2013, 172(3), 1126-1141.
[http://dx.doi.org/10.1016/j.jconrel.2013.08.006] [PMID: 23954372] 
[180] 
Reis, C.P.; Neufeld, R.J.; Ribeiro, A.J.; Veiga, F.; Nanoencapsulation, I.; Nanoencapsulation, I. Methods for preparation of drug-loaded polymeric nanoparticles. Nanomedicine (Lond.),  2006, 2(1), 8-21.
[http://dx.doi.org/10.1016/j.nano.2005.12.003] [PMID: 17292111] 
[181] 
Mao, S.R.; Wang, L.L. Research progress on drug nanocontainer polymericm icelles. J. Shenyang Pharm. Univ.,  2010, 27, 979-985.
Cite As
Mini-Reviews in Medicinal Chemistry

Nano-Strategies for Improving the Bioavailability of Inhaled Pharmaceutical Formulations

Abstract

Graphical Abstract
