Nanoparticles that do not adhere to mucus provide uniform and long-lasting drug delivery to airways following inhalation

Science Advances

Volumn 3, Issue 4, 2017, Pages

  Schneider, Craig S ^a,b,e   Xu, Qingguo ^a,c,e   Boylan, Nicholas J ^a,b,e   Chisholm, Jane ^a,b   Tang, Benjamin C ^a   Schuster, Benjamin S ^a   Henning, Andreas ^a,b   Ensign, Laura M ^a,b,c   Lee, Ethan ^b   Adstamongkonkul, Pichet ^a   Simons, Brian W ^a   Wang, Sho Yu S ^a,b   Gong, Xiaoqun ^a,d   Yu, Tao ^a   Boyle, Michael P ^a   Suk, Jung Soo ^a,c   Hanes, Justin ^a,b,c,f  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b Johns Hopkins University   (United States)

^c JOHNS HOPKINS UNIVERSITY   (United States)

^d TIANJIN UNIVERSITY   (China)

^e AMGEN INC   (United States)

^f UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BIOLOGICAL ORGANS; BODY FLUIDS; CONTROLLED DRUG DELIVERY; DRUG PRODUCTS; PARTICLE SIZE; PATHOLOGY; SODIUM COMPOUNDS; TARGETED DRUG DELIVERY;

ACUTE LUNG INFLAMMATIONS; AVERAGE DIAMETER; DEXAMETHASONE SODIUM PHOSPHATE; MUCUS-PENETRATING PARTICLES; PERCEIVED BENEFITS; PULMONARY DRUG DELIVERY; RETENTION TIME; UNIFORM DISTRIBUTION;

DRUG DELIVERY;

BIODEGRADABLE PLASTIC; DEXAMETHASONE; NANOPARTICLE;

ANIMAL; BAGG ALBINO MOUSE; CHEMISTRY; DRUG DELIVERY SYSTEM; FEMALE; HUMAN; INHALATIONAL DRUG ADMINISTRATION; METABOLISM; MOUSE; PATHOLOGY; PNEUMONIA; PROCEDURES; RESPIRATORY MUCOSA;

ADMINISTRATION, INHALATION; ANIMALS; BIODEGRADABLE PLASTICS; DEXAMETHASONE; DRUG DELIVERY SYSTEMS; FEMALE; HUMANS; MICE; MICE, INBRED BALB C; NANOPARTICLES; PNEUMONIA; RESPIRATORY MUCOSA;

EID: 85020262019     PISSN: None     EISSN: 23752548     Source Type: Journal    
DOI: 10.1126/sciadv.1601556     Document Type: Article

References (73)

1. S. Azarmi, W. H. Roa, R. Löbenberg, Targeted delivery of nanoparticles for the treatment of lung diseases. Adv. Drug Deliv. Rev. 60, 863–875 (2008).
2. W. Yang, J. I. Peters, R. O. Williams III, Inhaled nanoparticles—A current review. Int. J. Pharm. 356, 239–247 (2008).
3. D. A. Edwards, A. Ben-Jebria, R. Langer, Recent advances in pulmonary drug delivery using large, porous inhaled particles. J. Appl. Physiol. 85, 379–385 (1998).
4. J. S. Suk, S. K. Lai, N. J. Boylan, M. R. Dawson, M. P. Boyle, J. Hanes, Rapid transport of muco-inert nanoparticles in cystic fibrosis sputum treated with N-acetyl cysteine. Nanomedicine 6, 365–375 (2011).
5. J. Panyam, V. Labhasetwar, Biodegradable nanoparticles for drug and gene delivery to cells and tissue. Adv. Drug Deliv. Rev. 55, 329–347 (2003).
6. E. Allémann, J.-C. Leroux, R. Gurny, Polymeric nano- and microparticles for the oral delivery of peptides and peptidomimetics. Adv. Drug Deliv. Rev. 34, 171–189 (1998).
7. B. S. Schuster, A. J. Kim, J. C. Kays, M. M. Kanzawa, W. B. Guggino, M. P. Boyle, S. M. Rowe, N. Muzyczka, J. S. Suk, J. Hanes, Overcoming the cystic fibrosis sputum barrier to leading adeno-associated virus gene therapy vectors. Mol. Ther. 22, 1484–1493 (2014).
8. R. Langer, Drug delivery and targeting. Nature 392, 5–10 (1998).
9. O. C. Farokhzad, R. Langer, Nanomedicine: Developing smarter therapeutic and diagnostic modalities. Adv. Drug Deliv. Rev. 58, 1456–1459 (2006).
10. B. Kwong, H. Liu, D. J. Irvine, Induction of potent anti-tumor responses while eliminating systemic side effects via liposome-anchored combinatorial immunotherapy. Biomaterials 32, 5134–5147 (2011).
11. Y.-T. Kim, J.-M. Caldwell, R. V. Bellamkonda, Nanoparticle-mediated local delivery of methylprednisolone after spinal cord injury. Biomaterials 30, 2582–2590 (2009).
12. J. A. MacKay, D. F. Deen, F. C. Szoka Jr., Distribution in brain of liposomes after convection enhanced delivery; modulation by particle charge, particle diameter, and presence of steric coating. Brain Res. 1035, 139–153 (2005).
13. S. K. Lai, K. Hida, S. T. Man, C. Chen, C. Machamer, T. A. Schroer, J. Hanes, Privileged delivery of polymer nanoparticles to the perinuclear region of live cells via a non-clathrin, non-degradative pathway. Biomaterials 28, 2876–2884 (2007).
14. F. Yuan, M. Leunig, S. K. Huang, D. A. Berk, D. Papahadjopoulos, R. K. Jain, Microvascular permeability and interstitial penetration of sterically stabilized (stealth) liposomes in a human tumor xenograft. Cancer Res. 54, 3352–3356 (1994).
15. C. Prego, M. García, D. Torres, M. J. Alonso, Transmucosal macromolecular drug delivery. J. Control. Release 101, 151–162 (2005).
16. L. K. Medina-Kauwe, J. Xie, S. Hamm-Alvarez, Intracellular trafficking of nonviral vectors. Gene Ther. 12, 1734–1751 (2005).
17. K. Surendrakumar, G. P. Martyn, E. C. M. Hodgers, M. Jansen, J. A. Blair, Sustained release of insulin from sodium hyaluronate based dry powder formulations after pulmonary delivery to beagle dogs. J. Control. Release 91, 385–394 (2003).
18. X.-B. Liu, J.-X. Ye, L.-H. Quan, C.-Y. Liu, X.-L. Deng, M. Yang, Y.-H. Liao, Pulmonary delivery of scutellarin solution and mucoadhesive particles in rats. Eur. J. Pharm. Biopharm. 70, 845–852 (2008).
19. M. Sakagami, K. Sakon, W. Kinoshita, Y. Makino, Enhanced pulmonary absorption following aerosol administration of mucoadhesive powder microspheres. J. Control. Release 77, 117–129 (2001).
20. M. Sakagami, W. Kinoshita, K. Sakon, J.-I. Sato, Y. Makino, Mucoadhesive beclomethasone microspheres for powder inhalation: Their pharmacokinetics and pharmacodynamics evaluation. J. Control. Release 80, 207–218 (2002).
21. H. Yamamoto, Y. Kuno, S. Sugimoto, H. Takeuchi, Y. Kawashima, Surface-modified PLGA nanosphere with chitosan improved pulmonary delivery of calcitonin by mucoadhesion and opening of the intercellular tight junctions. J. Control. Release 102, 373–381 (2005).
22. A. Bernkop-Schnürch, S. Dünnhaupt, Chitosan-based drug delivery systems. Eur. J. Pharm. Biopharm. 81, 463–469 (2012).
23. V. M. Leitner, G. F. Walker, A. Bernkop-Schnürch, Thiolated polymers: Evidence for the formation of disulphide bonds with mucus glycoproteins. Eur. J. Pharm. Biopharm. 56, 207–214 (2003).
24. I. Bravo-Osuna, C. Vauthier, A. Farabollini, G. F. Palmieri, G. Ponchel, Mucoadhesion mechanism of chitosan and thiolated chitosan-poly(isobutyl cyanoacrylate) core-shell nanoparticles. Biomaterials 28, 2233–2243 (2007).
25. J. S. Suk, S. K. Lai, Y.-Y. Wang, L. M. Ensign, P. L. Zeitlin, M. P. Boyle, J. Hanes, The penetration of fresh undiluted sputum expectorated by cystic fibrosis patients by nonadhesive polymer nanoparticles. Biomaterials 30, 2591–2597 (2009).
26. B. S. Schuster, J. S. Suk, G. F. Woodworth, J. Hanes, Nanoparticle diffusion in respiratory mucus from humans without lung disease. Biomaterials 34, 3439–3446 (2013).
27. H. O. Alpar, S. Somavarapu, K. N. Atuah, V. W. Bramwell, Biodegradable mucoadhesive particulates for nasal and pulmonary antigen and DNA delivery. Adv. Drug Deliv. Rev. 57, 411–430 (2005).
28. A. J. Shah, M. D. Donovan, Formulating gels for decreased mucociliary transport using rheologic properties: Polyacrylic acids. AAPS PharmSciTech 8, E48–E53 (2007).
29. A. J. Shah, M. D. Donovan, Rheological characterization of neutral and anionic polysaccharides with reduced mucociliary transport rates. AAPS PharmSciTech 8, E40–E47 (2007).
30. A. Henning, M. Schneider, N. Nafee, L. Muijs, E. Rytting, X. Wang, T. Kissel, D. Grafahrend, D. Klee, C.-M. Lehr, Influence of particle size and material properties on mucociliary clearance from the airways. J. Aerosol Med. Pulm. Drug Deliv. 23, 233–241 (2010).
31. V. Gerber, P. Gehr, R. Straub, M. Frenz, M. King, V. Im Hof, Mucus quality on horse tracheal epithelium: Microscopic grading based on transparency. Respir. Physiol. 107, 67–74 (1997).
32. J. C. Lay, M. R. Stang, P. E. Fisher, J. R. Yankaskas, W. D. Bennett, Airway retention of materials of different solubility following local intrabronchial deposition in dogs. J. Aerosol Med. 16, 153–166 (2003).
33. S. S. Olmsted, J. L. Padgett, A. I. Yudin, K. J. Whaley, T. R. Moench, R. A. Cone, Diffusion of macromolecules and virus-like particles in human cervical mucus. Biophys. J. 81, 1930–1937 (2001).
34. S. K. Lai, D. E. O’Hanlon, S. Harrold, S. T. Man, Y.-Y. Wang, R. Cone, J. Hanes, Rapid transport of large polymeric nanoparticles in fresh undiluted human mucus. Proc. Natl. Acad. Sci. U.S.A. 104, 1482–1487 (2007).
35. N. N. Sanders, S. C. De Smedt, E. Van Rompaey, P. Simoens, F. De Baets, J. Demeester, Cystic fibrosis sputum: A barrier to the transport of nanospheres. Am. J. Respir. Crit. Care Med. 162, 1905–1911 (2000).
36. N. Nafee, A. Husari, C. K. Maurer, C. Lu, C. de Rossi, A. Steinbach, R. W. Hartmann, C.-M. Lehr, M. Schneider, 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 192, 131–140 (2014).
37. J. Kirch, A. Schneider, B. Abou, A. Hopf, U. F. Schaefer, M. Schneider, C. Schall, C. Wagner, C.-M. Lehr, Optical tweezers reveal relationship between microstructure and nanoparticle penetration of pulmonary mucus. Proc. Natl. Acad. Sci. U.S.A. 109, 18355–18360 (2012).
38. Y.-Y. Wang, S. K. Lai, J. S. Suk, A. Pace, R. Cone, J. Hanes, Addressing the PEG mucoadhesivity paradox to engineer nanoparticles that “slip” through the human mucus barrier. Angew. Chem. Int. Ed. 47, 9726–9729 (2008).
39. E. A. Nance, G. F. Woodworth, K. A. Sailor, T.-Y. Shih, Q. Xu, G. Swaminathan, D. Xiang, C. Eberhart, J. Hanes, A dense poly(ethylene glycol) coating improves penetration of large polymeric nanoparticles within brain tissue. Sci. Transl. Med. 4, 149ra119 (2012).
40. L. Illum, S. S. Davis, The organ uptake of intravenously administered colloidal particles can be altered using a non-ionic surfactant (Poloxamer 338). FEBS Lett. 167, 79–82 (1984).
41. M. Yang, S. K. Lai, Y.-Y. Wang, W. Zhong, C. Happe, M. Zhang, J. Fu, J. Hanes, Biodegradable nanoparticles composed entirely of safe materials that rapidly penetrate human mucus. Angew. Chem. Int. Ed. 50, 2597–2600 (2011).
42. T. Ishihara, N. Izumo, M. Higaki, E. Shimada, T. Hagi, L. Mine, Y. Ogawa, Y. Mizushima, Role of zinc in formulation of PLGA/PLA nanoparticles encapsulating betamethasone phosphate and its release profile. J. Control. Release 105, 68–76 (2005).
43. T. Ishihara, M. Takahashi, M. Higaki, Y. Mizushima, Efficient encapsulation of a water-soluble corticosteroid in biodegradable nanoparticles. Int. J. Pharm. 365, 200–205 (2009).
44. W. Möller, K. Felten, K. Sommerer, G. Scheuch, G. Meyer, P. Meyer, K. Häussinger, W. G. Kreyling, Deposition, retention, and translocation of ultrafine particles from the central airways and lung periphery. Am. J. Respir. Crit. Care Med. 177, 426–432 (2008).
45. W. M. Foster, D. M. Walters, M. Longphre, K. Macri, L. M. Miller, Methodology for the measurement of mucociliary function in the mouse by scintigraphy. J. Appl. Physiol. 90, 1111–1118 (2001).
46. M. Geiser, Update on macrophage clearance of inhaled micro- and nanoparticles. J. Aerosol Med. Pulm. Drug Deliv. 23, 207–217 (2010).
47. L. M. Ensign, B. C. Tang, Y.-Y. Wang, T. A. Tse, T. Hoen, R. Cone, J. Hanes, Mucus-penetrating nanoparticles for vaginal drug delivery protect against herpes simplex virus. Sci. Transl. Med. 4, 138ra79 (2012).
48. L. M. Ensign, T. E. Hoen, K. Maisel, R. A. Cone, J. S. Hanes, Enhanced vaginal drug delivery through the use of hypotonic formulations that induce fluid uptake. Biomaterials 34, 6922–6929 (2013).
49. K. Maisel, L. Ensign, M. Reddy, R. Cone, J. Hanes, Effect of surface chemistry on nanoparticle interaction with gastrointestinal mucus and distribution in the gastrointestinal tract following oral and rectal administration in the mouse. J. Control. Release 197, 48–57 (2015).
50. Q. Xu, L. M. Ensign, N. J. Boylan, A. Schön, X. Gong, J.-C. Yang, N. W. Lamb, S. Cai, T. Yu, E. Freire, J. Hanes, Impact of surface polyethylene glycol (PEG) Density on biodegradable nanoparticle transport in mucus ex vivo and distribution in vivo. ACS Nano 9, 9217–9227 (2015).
51. J. S. Suk, Q. Xu, J. Hanes, L. M. Ensign, PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv. Drug Deliv. Rev. 99(Pt A), 28–51 (2016).
52. N. Kim, G. A. Duncan, J. Hanes, J. S. Suk, Barriers to inhaled gene therapy of obstructive lung diseases: A review. J. Control. Release 240, 465–488 (2016).
53. S. K. Lai, J. S. Suk, A. Pace, Y.-Y. Wang, M. Yang, O. Mert, J. Chen, J. Kim, J. Hanes, Drug carrier nanoparticles that penetrate human chronic rhinosinusitis mucus. Biomaterials 32, 6285–6290 (2011).
54. S. K. Lai, Y.-Y. Wang, K. Hida, R. Cone, J. Hanes, Nanoparticles reveal that human cervicovaginal mucus is riddled with pores larger than viruses. Proc. Natl. Acad. Sci. U.S.A. 107, 598–603 (2010).
55. Y.-Y. Wang, S. K. Lai, L. M. Ensign, W. Zhong, R. Cone, J. Hanes, The microstructure and bulk rheology of human cervicovaginal mucus are remarkably resistant to changes in pH. Biomacromolecules 14, 4429–4435 (2013).
56. G. A. Duncan, J. Jung, A. Joseph, A. L. Thaxton, N. E. West, M. P. Boyle, J. Hanes, J. S. Suk, Microstructural alterations of sputum in cystic fibrosis lung disease. JCI Insight 1, e88198 (2016).
57. H. Derendorf, Pharmacokinetic and pharmacodynamic properties of inhaled corticosteroids in relation to efficacy and safety. Respir. Med. 91, 22–28 (1997).
58. T. M. Allen, P. R. Cullis, Drug delivery systems: Entering the mainstream. Science 303, 1818–1822 (2004).
59. U. Griesenbach, E. W. F. W. Alton; UK Cystic Fibrosis Gene Therapy Consortium, Gene transfer to the lung: Lessons learned from more than 2 decades of CF gene therapy. Adv. Drug Deliv. Rev. 61, 128–139 (2009).
60. U. Griesenbach, E. W. F. W. Alton, Cystic fibrosis gene therapy: Successes, failures and hopes for the future. Expert Rev. Respir. Med. 3, 363–371 (2009).
61. J. S. Suk, A. J. Kim, K. Trehan, C. S. Schneider, L. Cebotaru, O. M. Woodward, N. J. Boylan, M. P. Boyle, S. K. Lai, W. B. Guggino, J. Hanes, Lung gene therapy with highly compacted DNA nanoparticles that overcome the mucus barrier. J. Control. Release 178, 8–17 (2014).
62. P. Mastorakos, A. L. da Silva, J. Chisholm, E. Song, W. K. Choi, M. P. Boyle, M. M. Morales, J. Hanes, J. S. Suk, Highly compacted biodegradable DNA nanoparticles capable of overcoming the mucus barrier for inhaled lung gene therapy. Proc. Natl. Acad. Sci. U.S.A. 112, 8720–8725 (2015).
63. D. J. Smith, E. A. Gaffney, J. R. Blake, A viscoelastic traction layer model of muco-ciliary transport. Bull. Math. Biol. 69, 289–327 (2007).
64. G. R. Fulford, J. R. Blake, Muco-ciliary transport in the lung. J. Theor. Biol. 121, 381–402 (1986).
65. R. Cone, Mucus, in Mucosal Immunology, M. E. Lamm, J. R. McGhee, L. Mayer, J. Mestecky, J. Bienenstock, Eds. (Academic Press, 1999), pp. 43–64.
66. B. Button, L.-H. Cai, C. Ehre, M. Kesimer, D. B. Hill, J. K. Sheehan, R. C. Boucher, M. Rubinstein, A periciliary brush promotes the lung health by separating the mucus layer from airway epithelia. Science 337, 937–941 (2012).
67. B. F. Dickey, Biochemistry. Walking on solid ground. Science 337, 924–925 (2012).
68. Q. Xu, N. J. Boylan, S. Cai, B. Miao, H. Patel, J. Hanes, Scalable method to produce biodegradable nanoparticles that rapidly penetrate human mucus. J. Control. Release 170, 279–286 (2013).
69. J. Iravani, A. Van As, Mucus transport in the tracheobronchial tree of normal and bronchitic rats. J. Pathol. 106, 81–93 (1972).
70. D. Yager, T. Cloutier, H. Feldman, J. Bastacky, J. M. Drazen, R. D. Kamm, Airway surface liquid thickness as a function of lung volume in small airways of the guinea pig. J. Appl. Physiol. 77, 2333–2340 (1994).
71. D. F. Rogers, Physiology of airway mucus secretion and pathophysiology of hypersecretion. Respir. Care 52, 1134–1149 (2007).
72. P. R. Sears, C. W. Davis, M. Chua, J. K. Sheehan, Mucociliary interactions and mucus dynamics in ciliated human bronchial epithelial cell cultures. Am. J. Physiol. Lung Cell. Mol. Physiol. 301, L181–L186 (2011).
73. S. I. Rennard, G. Basset, D. Lecossier, K. M. O’Donnell, P. Pinkston, P. G. Martin, R. G. Crystal, Estimation of volume of epithelial lining fluid recovered by lavage using urea as marker of dilution. J. Appl. Physiol. 60, 532–538 (1986).