Enhancing nanoparticle penetration through airway mucus to improve drug delivery efficacy in the lung

References

• Edwards DA, Ben-Jebria A, Langer R. Recent advances in pulmonary drug delivery using large, porous inhaled particles. J Appl Physiol. 1998;85:379–385.
   PubMed Web of Science ®Google Scholar
• Chow AH, Tong HH, Chattopadhyay P, et al. Particle engineering for pulmonary drug delivery. Pharm Res. 2007;24:411–437.
   PubMed Web of Science ®Google Scholar
• Yang W, Peters JI, Williams RO III. Inhaled nanoparticles—a current review. Int J Pharm. 2008;356:239–247.
   PubMed Web of Science ®Google Scholar
• Azarmi S, Roa WH, Löbenberg R. Targeted delivery of nanoparticles for the treatment of lung diseases. Adv Drug Deliv Rev. 2008;60:863–875.
   PubMed Web of Science ®Google Scholar
• Faraji AH, Wipf P. Nanoparticles in cellular drug delivery. Bioorg Med Chem. 2009;17:2950–2962.
   PubMed Web of Science ®Google Scholar
• Panyam J, Labhasetwar V. Biodegradable nanoparticles for drug and gene delivery to cells and tissue. Adv Drug Deliv Rev. 2003;55:329–347.
   PubMed Web of Science ®Google Scholar
• Cho K, Wang X, Nie S, et al. Therapeutic nanoparticles for drug delivery in cancer. Clin Cancer Res. 2008;14:1310–1316.
   PubMed Web of Science ®Google Scholar
• De Jong WH, Borm PJ. Drug delivery and nanoparticles: applications and hazards. Int. J Nanomed. 2008;3:133–149.
   PubMed Web of Science ®Google Scholar
• Gelperina S, Kisich K, Iseman MD, et al. The potential advantages of nanoparticle drug delivery systems in chemotherapy of tuberculosis. Am J Respir Crit Care Med. 2005;172:1487–1490.
   PubMed Web of Science ®Google Scholar
• Lee J, Cho EC, Cho K. Incorporation and release behavior of hydrophobic drug in functionalized poly (D, L-lactide)-block–poly (ethylene oxide) micelles. J Control Release. 2004;94:323–335.
   PubMed Web of Science ®Google Scholar
• Banerjee SS, Chen D-H. Magnetic nanoparticles grafted with cyclodextrin for hydrophobic drug delivery. Chem Mater. 2007;19:6345–6349.
   Web of Science ®Google Scholar
• Hamidi M, Azadi A, Rafiei P. Hydrogel nanoparticles in drug delivery. Adv Drug Deliv Rev. 2008;60:1638–1649.
   PubMed Web of Science ®Google Scholar
• Malam Y, Loizidou M, Seifalian AM. Liposomes and nanoparticles: nanosized vehicles for drug delivery in cancer. Trends Pharmacol Sci. 2009;30:592–599.
   PubMed Web of Science ®Google Scholar
• Paranjpe M, Müller-Goymann CC. Nanoparticle-mediated pulmonary drug delivery: a review. Int J Mol Sci. 2014;15:5852–5873.
   PubMed Web of Science ®Google Scholar
• Miragoli M, Ceriotti P, Iafisco M, et al. Inhalation of peptide-loaded nanoparticles improves heart failure. Sci Transl Med. 2018;10:eaan6205.
   PubMed Web of Science ®Google Scholar
• Soppimath KS, Aminabhavi TM, Kulkarni AR, et al. Biodegradable polymeric nanoparticles as drug delivery devices. J Control Release. 2001;70:1–20.
   PubMed Web of Science ®Google Scholar
• Park K. Controlled drug delivery systems: past forward and future back. J Control Release. 2014;190:3–8.
   PubMed Web of Science ®Google Scholar
• Hougaard KS, Campagnolo L, Chavatte-Palmer P, et al. A perspective on the developmental toxicity of inhaled nanoparticles. Reprod Toxicol. 2015;56:118–140.
   PubMed Web of Science ®Google Scholar
• Bakand S, Hayes A. Toxicological considerations, toxicity assessment, and risk management of inhaled nanoparticles. Int J Mol Sci. 2016;17:929.
   Web of Science ®Google Scholar
• Randell SH, Boucher RC. Effective mucus clearance is essential for respiratory health. Am J Respir Cell Mol Biol. 2006;35:20–28.
   PubMed Web of Science ®Google Scholar
• Button B, Cai LH, Ehre C, et al. A periciliary brush promotes the lung health by separating the mucus layer from airway epithelia. Science. 2012;337:937–941.
   PubMed Web of Science ®Google Scholar
• Kim N, Duncan GA, Hanes J, et al. Barriers to inhaled gene therapy of obstructive lung diseases: A review. J Control Release. 2016;240:465–488.
   PubMed Web of Science ®Google Scholar
• Kirch J, Guenther M, Doshi N, et al. Mucociliary clearance of micro-and nanoparticles is independent of size, shape and charge—an ex vivo and in silico approach. J Control Release. 2012;159:128–134.
   PubMed Web of Science ®Google Scholar
• Geiser M. Update on macrophage clearance of inhaled micro-and nanoparticles. J Aerosol Med Pulm Drug Deliv. 2010;23:207–217.
   PubMed Web of Science ®Google Scholar
• Zhang J, Wu L, Chan H-K, et al. Formation, characterization, and fate of inhaled drug nanoparticles. Adv Drug Deliv Rev. 2011;63:441–455.
   PubMed Web of Science ®Google Scholar
• Geiser M, Kreyling WG. Deposition and biokinetics of inhaled nanoparticles. Part Fibre Toxicol. 2010;7:2.
   PubMed Web of Science ®Google Scholar
• Fahy JV, Dickey BF. Airway mucus function and dysfunction. N Engl J Med. 2010;363:2233–2247.
   PubMed Web of Science ®Google Scholar
• Duncan GA, Jung J, Hanes J, et al. The mucus barrier to inhaled gene therapy. Mol Ther. 2016;24:2043–2053.
   PubMed Web of Science ®Google Scholar
• Murgia X, Loretz B, Hartwig O, et al. The role of mucus on drug transport and its potential to affect therapeutic outcomes. Adv Drug Deliv Rev. 2018;124:82–97.
   PubMed Web of Science ®Google Scholar
• Cone RA. Barrier properties of mucus. Adv Drug Deliv Rev. 2009;61:75–85.
   PubMed Web of Science ®Google Scholar
• Barbero N, Coletti M, Catalano F, et al. Exploring gold nanoparticles interaction with mucins: a spectroscopic-based study. Int J Pharm. 2018;535:438–443.
   PubMedGoogle Scholar
• Li D, Yamamoto H, Takeuchi H, et al. A novel method for modifying AFM probe to investigate the interaction between biomaterial polymers (Chitosan-coated PLGA) and mucin film. Eur J Pharm Biopharm. 2010;75:277–283.
   PubMed Web of Science ®Google Scholar
• Huckaby JT, Lai SK. PEGylation for enhancing nanoparticle diffusion in mucus. Adv Drug Deliv Rev. 2018;124:125–139.
   PubMed Web of Science ®Google Scholar
• Suk JS. Could recent advances in DNA-loaded nanoparticles lead to effective inhaled gene therapies? Nanomedicine (Lond). 2016;11:193–196.
   PubMed Web of Science ®Google Scholar
• Schuster BS, Suk JS, Woodworth GF, et al. Nanoparticle diffusion in respiratory mucus from humans without lung disease. Biomaterials. 2013;34:3439–3446.
   PubMed Web of Science ®Google Scholar
• de Souza Carvalho C, Daum N, Lehr C-M. Carrier interactions with the biological barriers of the lung: advanced in vitro models and challenges for pulmonary drug delivery. Adv Drug Deliv Rev. 2014;75:129–140.
   PubMed Web of Science ®Google Scholar
• Henry CE, Wang YY, Yang Q, et al. Anti-PEG antibodies alter the mobility and biodistribution of densely PEGylated nanoparticles in mucus. Acta Biomater. 2016;43:61–70.
   PubMed Web of Science ®Google Scholar
• Jensen MA, Wang YY, Lai SK, et al. Antibody-Mediated Immobilization of Virions in Mucus. Bull Math Biol. 2019;81:4069–4099.
   PubMed Web of Science ®Google Scholar
• Schiller JL, Fogle MM, Bussey O, et al. Antibody-mediated trapping in biological hydrogels is governed by sugar-sugar hydrogen bonds. Acta Biomater. 2020;107:91–101.
   PubMed Web of Science ®Google Scholar
• Wang J, Shi X. Molecular dynamics simulation of diffusion of nanoparticles in mucus. Acta Mech Solida Sin. 2017;30:241–247.
   Web of Science ®Google Scholar
• Boucher RC. Cystic fibrosis: a disease of vulnerability to airway surface dehydration. Trends Mol Med. 2007;13:231–240.
   PubMed Web of Science ®Google Scholar
• Rogers DF. Mucociliary dysfunction in COPD: effect of current pharmacotherapeutic options. Pulm Pharmacol Ther. 2005;18:1–8.
   PubMed Web of Science ®Google Scholar
• Duncan GA, Jung J, Joseph A, et al. Microstructural alterations of sputum in cystic fibrosis lung disease. JCI Insight. 2016;1:e88198.
   PubMed Web of Science ®Google Scholar
• Chisholm JF, Shenoy SK, Shade JK, et al. Nanoparticle diffusion in spontaneously expectorated sputum as a biophysical tool to probe disease severity in COPD. Eur Respir J. 2019;54(2):1-11.
   Web of Science ®Google Scholar
• Yuan S, Hollinger M, Lachowicz-Scroggins ME, et al. Oxidation increases mucin polymer cross-links to stiffen airway mucus gels. Sci Transl Med. 2015;7:276ra27.
   PubMed Web of Science ®Google Scholar
• Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005;352:1992–2001.
   PubMed Web of Science ®Google Scholar
• Broughton-Head VJ, Smith JR, Shur J, et al. Actin limits enhancement of nanoparticle diffusion through cystic fibrosis sputum by mucolytics. Pulm Pharmacol Ther. 2007;20:708–717.
   PubMed Web of Science ®Google Scholar
• Kostikas K, Papatheodorou G, Ganas K, et al. pH in expired breath condensate of patients with inflammatory airway diseases. Am J Respir Crit Care Med. 2002;165:1364–1370.
   PubMed Web of Science ®Google Scholar
• Lieleg O, Vladescu I, Ribbeck K. Characterization of particle translocation through mucin hydrogels. Biophys J. 2010;98:1782–1789.
   PubMed Web of Science ®Google Scholar
• Wan F, Herzberg M, Huang Z, et al. A free-floating mucin layer to investigate the effect of the local microenvironment in lungs on mucin-nanoparticle interactions. Acta Biomater. 2020;104:115–123.
   PubMed Web of Science ®Google Scholar
• Matsui H, Randell SH, Peretti SW, et al. Coordinated clearance of periciliary liquid and mucus from airway surfaces. J Clin Invest. 1998;102:1125–1131.
   PubMed Web of Science ®Google Scholar
• Lay JC, Stang MR, Fisher PE, et al. Airway retention of materials of different solubility following local intrabronchial deposition in dogs. J Aerosol Med. 2003;16:153–166.
   PubMedGoogle Scholar
• Reihill JA, Walker B, Hamilton RA, et al. Inhibition of protease-epithelial sodium channel signaling improves mucociliary function in cystic fibrosis airways. Am J Respir Crit Care Med. 2016;194:701–710.
   PubMed Web of Science ®Google Scholar
• Gentzsch M, Mall MA. Ion channel modulators in cystic fibrosis. Chest. 2018;154:383–393.
   PubMed Web of Science ®Google Scholar
• Tagalakis AD, Munye MM, Ivanova R, et al. Effective silencing of ENaC by siRNA delivered with epithelial-targeted nanocomplexes in human cystic fibrosis cells and in mouse lung. Thorax. 2018;73:847–856.
   PubMed Web of Science ®Google Scholar
• S MV, Holmes D, Suara K, et al. Transport and fate of inhaled particles after deposition onto the airway surface liquid: A 3D numerical study. Comput Biol Med. 2020;117:103595.
   PubMed Web of Science ®Google Scholar
• Braeckmans K, Peeters L, Sanders NN, et al. Three-dimensional fluorescence recovery after photobleaching with the confocal scanning laser microscope. Biophys J. 2003;85:2240–2252.
   PubMed Web of Science ®Google Scholar
• Tang BC, Dawson M, Lai SK, et al. Biodegradable polymer nanoparticles that rapidly penetrate the human mucus barrier. Proc Natl Acad Sci U S A. 2009;106:19268–19273.
   PubMed Web of Science ®Google Scholar
• Suk JS, Lai SK, Wang YY, et al. The penetration of fresh undiluted sputum expectorated by cystic fibrosis patients by non-adhesive polymer nanoparticles. Biomaterials. 2009;30:2591–2597.
   PubMed Web of Science ®Google Scholar
• Sanders NN, De Smedt SC, Van Rompaey E, et al. Cystic fibrosis sputum: a barrier to the transport of nanospheres. Am J Respir Crit Care Med. 2000;162:1905–1911.
   PubMed Web of Science ®Google Scholar
• Sanders NN, De Smedt SC, Demeester J. Mobility and stability of gene complexes in biogels. J Control Release. 2003;87:117–129.
   PubMed Web of Science ®Google Scholar
• Kim AJ, Boylan NJ, Suk JS, et al. Use of single-site-functionalized PEG dendrons to prepare gene vectors that penetrate human mucus barriers. Angew Chem Int Ed. 2013;52:3985–3988.
   PubMed Web of Science ®Google Scholar
• Suk JS, Kim AJ, Trehan K, et al. Lung gene therapy with highly compacted DNA nanoparticles that overcome the mucus barrier. J Control Release. 2014;178:8–17.
   PubMed Web of Science ®Google Scholar
• Osman G, Rodriguez J, Chan SY, et al. PEGylated enhanced cell penetrating peptide nanoparticles for lung gene therapy. J Control Release. 2018;285:35–45.
   PubMed Web of Science ®Google Scholar
• Mastorakos P, da Silva AL, Chisholm J, et al. Highly compacted biodegradable DNA nanoparticles capable of overcoming the mucus barrier for inhaled lung gene therapy. Proc Natl Acad Sci U S A. 2015;112:8720–8725.
   PubMed Web of Science ®Google Scholar
• Suk JS, Xu Q, Kim N, et al. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv Drug Deliv Rev. 2016;99:28–51.
   PubMed Web of Science ®Google Scholar
• Schuster BS, Kim AJ, Kays JC, et al. Overcoming the cystic fibrosis sputum barrier to leading adeno-associated virus gene therapy vectors. Mol Ther. 2014;22:1484–1493.
   PubMed Web of Science ®Google Scholar
• Schneider CS, Xu Q, Boylan NJ, et al. Nanoparticles that do not adhere to mucus provide uniform and long-lasting drug delivery to airways following inhalation. Sci Adv. 2017;3:e1601556.
   PubMed Web of Science ®Google Scholar
• Forier K, Messiaen AS, Raemdonck K, et al. Transport of nanoparticles in cystic fibrosis sputum and bacterial biofilms by single-particle tracking microscopy. Nanomedicine (Lond). 2013;8:935–949.
   PubMed Web of Science ®Google Scholar
• Xu Q, Ensign LM, Boylan NJ, et al. Impact of surface polyethylene glycol (PEG) density on biodegradable nanoparticle transport in mucus ex vivo and distribution in vivo. ACS Nano. 2015;9:9217–9227.
   PubMed Web of Science ®Google Scholar
• De Leo V, Ruscigno S, Trapani A, et al. Preparation of drug-loaded small unilamellar liposomes and evaluation of their potential for the treatment of chronic respiratory diseases. Int J Pharm. 2018;545:378–388.
   PubMedGoogle Scholar
• Nafee N, Forier K, Braeckmans K, et al. Mucus-penetrating solid lipid nanoparticles for the treatment of cystic fibrosis: proof of concept, challenges and pitfalls. Eur J Pharm Biopharm. 2018;124:125–137.
   PubMed Web of Science ®Google Scholar
• Yu T, Chisholm J, Choi WJ, et al. Mucus‐penetrating nanosuspensions for enhanced delivery of poorly soluble drugs to mucosal surfaces. Adv Healthc Mater. 2016;5:2745–2750.
   PubMed Web of Science ®Google Scholar
• Huang X, Chisholm J, Zhuang J, et al. Protein nanocages that penetrate airway mucus and tumor tissue. Proc Natl Acad Sci U S A. 2017;114:E6595–e602.
   PubMed Web of Science ®Google Scholar
• Kolte A, Patil S, Lesimple P, et al. PEGylated composite nanoparticles of PLGA and polyethylenimine for safe and efficient delivery of pDNA to lungs. Int J Pharm. 2017;524:382–396.
   PubMed Web of Science ®Google Scholar
• Ge C, Yang J, Duan S, et al. Fluorinated α-helical polypeptides synchronize mucus permeation and cell penetration toward highly efficient pulmonary sirna delivery against acute lung injury. Nano Lett. 2020;20:1738–1746.
   PubMed Web of Science ®Google Scholar
• Kim YC, Hsueh HT, Kim N, et al. Strategy to Enhance Dendritic Cell–Mediated DNA Vaccination in the Lung. Adv Ther; DOI: 10.1002/adtp.202000013.
   Google Scholar
• Griesser J, Hetényi G, Federer C, et al. Highly mucus permeating and zeta potential changing self-emulsifying drug delivery systems: A potent gene delivery model for causal treatment of cystic fibrosis. Int J Pharm. 2019;557:124–134.
   PubMedGoogle Scholar
• da Silva AL, de Oliveira GP, Kim N, et al. Nanoparticle-based thymulin gene therapy therapeutically reverses key pathology of experimental allergic asthma. Sci Adv. 2020;6(24):eaay7973.
   PubMed Web of Science ®Google Scholar
• Leal J, Peng X, et al. Peptides as surface coatings of nanoparticles that penetrate human cystic fibrosis sputum and uniformly distribute in vivo following pulmonary delivery. J Control Release. 2020. DOI: 10.1016/j.jconrel.2020.03.032.
   Google Scholar
• Shan W, Zhu X, Liu M, et al. Overcoming the diffusion barrier of mucus and absorption barrier of epithelium by self-assembled nanoparticles for oral delivery of insulin. ACS Nano. 2015;9:2345–2356.
   PubMed Web of Science ®Google Scholar
• Liu M, Zhang J, Zhu X, et al. Efficient mucus permeation and tight junction opening by dissociable “mucus-inert” agent coated trimethyl chitosan nanoparticles for oral insulin delivery. J Control Release. 2016;222:67–77.
   PubMed Web of Science ®Google Scholar
• Hoogenboom R. Poly(2-oxazoline)s: a polymer class with numerous potential applications. Angew Chem Int Ed. 2009;48:7978–7994.
   PubMed Web of Science ®Google Scholar
• Mansfield ED, Sillence K, Hole P, et al. POZylation: a new approach to enhance nanoparticle diffusion through mucosal barriers. Nanoscale. 2015;7:13671–13679.
   PubMed Web of Science ®Google Scholar
• Mansfield ED, de la Rosa VR, Kowalczyk RM, et al. Side chain variations radically alter the diffusion of poly(2-alkyl-2-oxazoline) functionalised nanoparticles through a mucosal barrier. Biomater Sci. 2016;4:1318–1327.
   PubMed Web of Science ®Google Scholar
• Shan W, Zhu X, Tao W, et al. Enhanced oral delivery of protein drugs using zwitterion-functionalized nanoparticles to overcome both the diffusion and absorption barriers. ACS Appl Mater Interfaces. 2016;8:25444–25453.
   PubMed Web of Science ®Google Scholar
• Poinard B, Lam SAE, Neoh KG, et al. Mucopenetration and biocompatibility of polydopamine surfaces for delivery in an Ex Vivo porcine bladder. J Control Release. 2019;300:161–173.
   PubMed Web of Science ®Google Scholar
• Poinard B, Kamaluddin S, Tan AQQ, et al. Polydopamine coating enhances mucopenetration and cell uptake of nanoparticles. ACS Appl Mater Interfaces. 2019;11:4777–4789.
   PubMed Web of Science ®Google Scholar
• Taipaleenmäki E, Städler B. Recent advancements in using polymers for intestinal mucoadhesion and mucopenetration. Macromol Biosci. 2020;20:e1900342.
   PubMed Web of Science ®Google Scholar
• Beloqui A, Solinís M, Des Rieux A, et al. Dextran-protamine coated nanostructured lipid carriers as mucus-penetrating nanoparticles for lipophilic drugs. Int J Pharm. 2014;468:105–111.
   PubMed Web of Science ®Google Scholar
• Song Y, Shi Y, Zhang L, et al. Synthesis of CSK-DEX-PLGA nanoparticles for the oral delivery of exenatide to improve its mucus penetration and intestinal absorption. Mol Pharm. 2019;16:518–532.
   PubMed Web of Science ®Google Scholar
• Nordgård CT, Draget KI. Co association of mucus modulating agents and nanoparticles for mucosal drug delivery. Adv Drug Deliv Rev. 2018;124:175–183.
   PubMed Web of Science ®Google Scholar
• Conrad C. Application of N-acetylcysteine in pulmonary disorders. In: Fryer RE and Berk M, editors. The therapeutic use of N-acetylcysteine (NAC) in medicine. Springer; 2019. p. 255–276.
   Google Scholar
• Sun F, Tai S, Lim T, et al. Additive effect of dornase alfa and Nacystelyn on transportability and viscoelasticity of cystic fibrosis sputum. Can Respir J. 2002;9:401–406.
   PubMedGoogle Scholar
• Sasse W, Deegen E. On the effectiveness of Sputolysin in horses with chronic bronchial diseases, Tieraerztliche Umschau, 1984;39(12):941-949.
   Google Scholar
• Suk JS, Boylan NJ, Trehan K, et al. N-acetylcysteine enhances cystic fibrosis sputum penetration and airway gene transfer by highly compacted DNA nanoparticles. Mol Ther. 2011;19:1981–1989.
   PubMed Web of Science ®Google Scholar
• Langer R. Drug delivery and targeting. Nature. 1998;392:5–10.
   PubMed Web of Science ®Google Scholar
• Konstan MW, Davis PB, Wagener JS, et al. Compacted DNA nanoparticles administered to the nasal mucosa of cystic fibrosis subjects are safe and demonstrate partial to complete cystic fibrosis transmembrane regulator reconstitution. Hum Gene Ther. 2004;15:1255–1269.
   PubMed Web of Science ®Google Scholar
• Kushwah R, Oliver JR, Cao H, et al. Nacystelyn enhances adenoviral vector-mediated gene delivery to mouse airways. Gene Ther. 2007;14:1243–1248.
   PubMed Web of Science ®Google Scholar
• Ferrari S, Kitson C, Farley R, et al. Mucus altering agents as adjuncts for nonviral gene transfer to airway epithelium. Gene Therapy. 2001;8(18):1380–1386.
   PubMed Web of Science ®Google Scholar
• Pritchard MF, Powell LC, Menzies GE, et al. A new class of safe oligosaccharide polymer therapy to modify the mucus barrier of chronic respiratory disease. Mol Pharm. 2016;13:863–872.
   PubMed Web of Science ®Google Scholar
• Nordgård CT, Nonstad U, Olderøy M, et al. Alterations in mucus barrier function and matrix structure induced by guluronate oligomers. Biomacromolecules. 2014;15:2294–2300.
   PubMed Web of Science ®Google Scholar
• Stern M, Caplen N, Browning J, et al. The effect of mucolytic agents on gene transfer across a CF sputum barrier in vitro. Gene Ther. 1998;5:91–98.
   PubMed Web of Science ®Google Scholar
• Morgan LE, Raclawska D, Emezienna NA, et al. Disulfide disruption reverses mucus dysfunction in allergic airway disease. Nat Commun. 2020;In press.
   Google Scholar
• Dawson M, Wirtz D, Hanes J. Enhanced viscoelasticity of human cystic fibrotic sputum correlates with increasing microheterogeneity in particle transport. J Biol Chem. 2003;278:50393–50401.
   PubMed Web of Science ®Google Scholar
• Sanders NN, Van Rompaey E, De Smedt SC, et al. On the transport of lipoplexes through cystic fibrosis sputum. Pharm Res. 2002;19:451–456.
   PubMed Web of Science ®Google Scholar
• Deacon J, Abdelghany SM, Quinn DJ, et al. Antimicrobial efficacy of tobramycin polymeric nanoparticles for Pseudomonas aeruginosa infections in cystic fibrosis: formulation, characterisation and functionalisation with dornase alfa (DNase). J Control Release. 2015;198:55–61.
   PubMed Web of Science ®Google Scholar
• Wills PJ. Inhaled mannitol in cystic fibrosis. Expert Opin Investig Drugs. 2007;16:1121–1126.
   PubMed Web of Science ®Google Scholar
• Elkins MR, Bye PT. Inhaled hypertonic saline as a therapy for cystic fibrosis. Curr Opin Pulm Med. 2006;12:445–452.
   PubMed Web of Science ®Google Scholar
• Donaldson SH, Bennett WD, Zeman KL, et al. Mucus clearance and lung function in cystic fibrosis with hypertonic saline. N Engl J Med. 2006;354:241–250.
   PubMed Web of Science ®Google Scholar
• Daviskas E, Anderson SD, Eberl S, et al. Inhalation of dry powder mannitol improves clearance of mucus in patients with bronchiectasis. Am J Respir Crit Care Med. 1999;159:1843–1848.
   PubMed Web of Science ®Google Scholar
• Cooney AL, McCray PB, Sinn PL. Cystic fibrosis gene therapy: looking back, looking forward. Genes (Basel). 2018;9:538.
   Web of Science ®Google Scholar
• Hart SL, Harrison PT. Genetic therapies for cystic fibrosis lung disease. Curr Opin Pharmacol. 2017;34:119–124.
   PubMed Web of Science ®Google Scholar
• Murgia X, Pawelzyk P, Schaefer UF, et al. Size-limited penetration of nanoparticles into porcine respiratory mucus after aerosol deposition. Biomacromolecules. 2016;17:1536–1542.
   PubMed Web of Science ®Google Scholar
• Fang Y, Xue J, Gao S, et al. Cleavable PEGylation: a strategy for overcoming the “PEG dilemma” in efficient drug delivery. Drug Deliv. 2017;24:22–32.
   PubMed Web of Science ®Google Scholar
• Pamujula S, Hazari S, Bolden G, et al. Cellular delivery of PEGylated PLGA nanoparticles. J Pharm Pharmacol. 2012;64:61–67.
   PubMed Web of Science ®Google Scholar
• Negron K, Khalasawi N, Lu B, et al. Widespread gene transfer to malignant gliomas with In vitro-to-In vivo correlation. J Control Release. 2019;303:1–11.
   PubMed Web of Science ®Google Scholar