Представлено новое направление биотехнологии, основанное на использовании наноаэрозолей для лечения и диагностики легочных заболеваний. В обзоре описаны методы генерации бионаноаэрозолей (БНА), которые сохраняют структуру и биологическую активность молекул. Разработанный автором метод генерации использует электрогидродинамическое распыление растворов лекарств с последующей нейтрализацией заряженных нанокластеров в газовой фазе. Он позволяет превращать в БНА практически любое вещество, растворимое в воде или в спирте (включая пептиды, белки, ДНК) без изменения его функциональных свойств. Представлены методы дозиметрии наноаэрозольных лекарств, приведены примеры использования БНА антибиотиков и других лекарств для лечения инфекционных и системных заболеваний лабораторных животных. Описаны особенности лекарственных БНА, их преимущества по сравнению с другими способами введения лекарства и возможные побочные эффекты. Показано, что наноаэрозольные частицы, образующиеся в выдыхаемом воздухе при высыхании микрокапель легочной жидкости, могут быть использованы для неинвазивной диагностики легочных заболеваний. Разработаны специальные фильтры и одноразовые приспособления для сбора таких микрокапель из выдыхаемого воздуха. Продемонстрирована принципиальная возможность неинвазивной диагностики туберкулеза легких по выдыхаемым антителам, специфичным к секретируемым антигенам микобактерии. Аналогичные устройства, успешно примененные для анализа нозокомиальных инфекций в клинике, можно использовать для обеспечения биобезопасности на транспорте, в промышленных и жилых помещениях.
бионаноаэрозоли, генератор, лечение бионаноаэрозолями, выдыхаемый воздух, неинвазивная диагностика
1. Ehn M., Thornton J. A., Kleist E. et al. A large source of low-volatility secondary organic aerosol. Nature, 2014, vol. 506, pp. 476-479.
2. Julin J., Murphy B. N., Patoulias D., Fountoukis C., Olenius T., Pandis S. N., Riipinen I. Impacts of future european emission reductions on aerosol particle number concentrations accounting for effects of ammonia, amines, and organic species. Environ. Sci. Technol., 2018, vol. 52, pp. 692-700.
3. Lin K., Marr L. C. Aerosolization of Ebola virus surrogates in wastewater systems. Environ. Sci. Technol., 2017, vol. 51, pp. 2669-2675.
4. Biskos G., Vons V., Yurteri C.U., Schmidt-Ott A. Generation and sizing of particles for aerosol-based nanotechnology. KONA Powder and Particle Journal, 2008, vol. 26, pp. 13-35.
5. Samodurova A.V., Vosel’ S.V., Baklanov A.M., Onishchuk A.A., Karasev V.V. A study of homogeneous nucleation of ibuprofen in a flow chamber. Determination of the surface tension of critical nuclei. Colloid J., 2013, vol. 75, pp. 397-408.
6. Onischuk A.A., Tolstikova T.G., Baklanov A.M., Khvostov M.V., Sorokina I.V., Zhukova N.A., An’kov S.V., Borovkova O.V., Dultseva G.G., Boldyrev V.V., Fomin V.M., Steven Huang G. Generation, inhalation delivery and anti-hypertensive effect of nisoldipine nanoaerosol. J. Aerosol Sci., 2014, vol. 78, pp. 41-54.
7. Rajapaksa A.E, Ho J.J., Qi A., Bischof R., Nguyen T.H., Tate M., Piedrafita D., McIntosh M. P., Yeo L.Y., Meeusen E., Coppel R. L., Friend J. R. Effective pulmonary delivery of an aerosolized plasmid DNA vaccine via surface acoustic wave nebulization. Respiratory Research, 2014, vol. 15, pp. 1-12.
8. Lee S.H., Heng D., Nga W.K., Chan H.K., Tan R.B.H. Nano spray drying: A novel method for preparing protein nanoparticles for protein therapy. Int. J. Pharmaceutics, 2011, vol. 403, pp. 192-200.
9. Morozov V.N., Kanev I.L., Mikheev A.Y., Shlyapnikova E.A., Shlyapnikov Y.M., Nwabueze A.O., Propst C. N., van Hoek M. L. Biological nanoaerosols: from delivering drugs to collecting lung liquid in exhaled air. New Approaches combating Cancer & Aging, 2016, vol. 3, pp. 11-14.
10. International Commission on Radiological Protection. Human respiratory model for radiological protection. Ann ICRP, 1994, vol. 24, pp. 1-3.
11. Kebarle P., Verkerk U.H. Electrospray: from ions in solution to ions in the gas phase, what we know now. Mass Spectrom. Rev., 2009, vol. 28, pp. 898-917.
12. Fu H., Patel A.C., Holtzman M.J., Chen D.R. A new electrospray aerosol generator with high particle transmission efficiency. Aerosol Sci. Technol., 2011, vol. 45, pp. 1176-1183.
13. Ijesebaert J. C., Geerse K.B., Marijnisseen J.C.M., Lammers J.W.J., Zanen P. Electro-hydrodynamic atomization of drug solutions for inhalation purposes. J. Appl. Physiol., 2001, vol. 91, pp. 2735-2741.
14. Morozov V.N. Generation of biologically active nano-aerosol by an electrospray-neutralization method. J. Aerosol Sci., 2011, vol. 42, pp. 341-354.
15. Morozov V.N., Kanev I.L., Mikheev A.Y., Shlyapnikova E.A., Shlyapnikov Y.M., Nikitin M.P., Nikitin P.I., Nwabueze A.O., van Hoek M.L. Generation and delivery of nanoaerosols from biological and biologically active substances. J. Aerosol Sci., 2014, vol. 69, pp. 48-61.
16. Propst C.N., Nwabueze A.O., Kanev I.L., Pepin R.E., Gutting B.W., Morozov V.N., van Hoek M.L. Nanoaerosols reduce required effective dose of liposomal levofloxacin against pulmonary murine Francisella tularensis subsp. novicida infection. J. Nanobiotechnology, 2016, vol. 14, pp. 1-10.
17. Morozov V.N., Kanev I.L. Dry lung as a physical model in studies of aerosol deposition. Lung, 2015, vol. 193, pp. 799-804.
18. Kim C. S. Methods of calculating lung delivery and deposition of aerosol particles. Respiratory care, 2000, vol. 45, pp. 695-671.
19. Onischuk A.A., Tolstikova T.G., Sorokina I.V., Zhukova N.A., Baklanov A.M., Karasev V.V., Borovkova O.V., Dultseva G.G, Boldyrev V.V., Fomin V.M. Analgesic effect from ibuprofen nanoparticles inhaled by male mice. J Aerosol Med. Pulm. Drug Delivery, 2009, vol. 22, pp. 1-8.
20. Onischuk A.A., Tolstikova T.G., An’kov S.V., Baklanov A.M., Valiulin S.V., Khvostov M.V., Sorokina I.V., Dultseva G.G., Zhukova N.A. Ibuprofen, indomethacin and diclofenac sodium nanoaerosol: Generation, inhalation delivery and biological effects in mice and rats. J. Aerosol Sci., 2016, vol. 100, pp. 164-177.
21. Shlyapnikova E.A., Kanev I.L., Novikova N.N., Litvinova E.G., Shlyapnikov Y.M., Morozov V.N. Inhalation of bleomycin nanoaerosol does not induce fibrosis in mice. European J. Nanomedicine, 2016, vol. 8, pp. 213-224.
22. Garbuzenko O.B., Mainelis G., Taratula O., Minko T. Inhalation treatment of lung cancer: the influence ofcomposition, size and shape of nanocarriers on their lung accumulation and retention. Cancer Biol. Med., 2014, vol. 11, pp. 44-55.
23. Kuzmov A., Minko T. Nanotechnology approaches for inhalation treatment of lung diseases. Journal of Controlled Release, 2015, vol. 219, pp. 500-518.
24. Yang X., Zhao C., Gao Z., Su X. A novel regulator of lung inflammation and immunity: pulmonary parasympathetic inflammatory reflex. Q. J. Med., 2014, vol. 107, pp. 789-792.
25. Tracey K.J. The inflammatory reflex. Nature, 2002, vol. 420, pp. 853-859.
26. Bleomycin Chemotherapy. Academic Press, ed. I. Branimir, M. Sikic, S. Rozencweig, K. Carter, 1985, 335 p.
27. Sheykh Z.V., Krutskevich A.O., Drebushevskiy N.S., Shvayko S.N., Dunaev A.P., Alekseev V.G. Pulmonary cytotoxicity induced by bleomycin and methotrexate. Vestnik Rentgenologii i Radiologii, 2015, vol. 3, pp. 46-51. (In Russ.)
28. Mouratis M.A., Aidinis V. Modeling pulmonary fibrosis with bleomycin. Current Opinion in Pulmonary Medicine, 2011, vol. 17, pp. 355-361.
29. Wall D.A., Lanutti A. T. High levels of exopeptidase activity are present in rat and canine bronchoalveolar lavage fluid. Int. J. Pharmaceutics, 1993, vol. 97, pp. 171-181.
30. Stone K.C., Mercer R.R., Gehr, P., Stockstill B., Crapo J.D. Allometric relationships of cell numbers and size in the mammalian lung. Am. J. Resp. Cell Mol.Biol., 1992, vol. 6, pp. 235-243.
31. Coty J.B., Vauthie C. Characterization of nanomedicines: A reflection on a field under construction needed for clinical translation success. Journal of Controlled Release, 2018, vol. 275, 254-268.
32. Pelaz B., Alexiou C., Alvarez-Puebla R. A. et al. Diverse applications of nanomedicine. ACS Nano, 2017, vol. 11, pp. 2313-2381.
33. Zhou Y., Peng Z., Seven E. S., Leblanc R. M. Crossing the blood-brain barrier with nanoparticles. J. Controlled Release, 2018, vol. 270, pp. 290-303.
34. Kozlovskaya L., Abou-Kaoud M., Stepensky D. Quantitative analysis of drug delivery to the brain via nasal route J. Controlled Release, 2014, vol. 189, pp. 133-140.
35. Xi J., Zhang Z., Si X. A. Improving intranasal delivery of neurological nanomedicine to the olfactory region using magnetophoretic guidance of microsphere carriers. Int. J. Nanomedicine, 2015, vol. 10, pp. 1211-1222.
36. Dasa S. C., Stewart P. J. The influence of lung surfactant liquid crystalline nanostructures on respiratory drug delivery. Int. J. Pharmaceutics, 2016, vol. 514, pp. 465-474.
37. Austin P.R., Timmerman S.W. Design and operation of clean rooms. Business News Publishing Co, Detroit (USA), 1965, pp. 235-251.
38. Vladimirskiy M.A., Shipina L.K., Makeeva E.S., Alyapkina Y.S., Mikheev A.Y., Morozov V.N. Application of water-soluble nanofilters for collection of airborne M. tuberculosis DNA in hospital wards. J. Hospital Infect., 2016, vol. 93, pp. 100-104.
39. Johnson G.R., Morawska L. The mechanism of breath aerosol formation J. Aerosol Med. Pulm. Drug Deliv., 2009, 22, pp. 229-237.
40. Haslbeck K., Schwarz K., Hohlfeld J.M., Seume J.R., Koch W. Submicron droplet formation in the human lung. J. Aerosol Sci., 2010, vol. 41, pp. 429-438.
41. Bondesson E., Jonsson L.T., Bengtsson T., Wollmer P. Exhaled breath condensate - site and mechanism of formation. J. Breath Res., 2009, vol. 3, p. 016005.
42. Namati E., Thiesse J., de Ryk J., McLennan G. Alveolar dynamics during respiration. Are pores of Kohn a pathway to recruitment? Am. J. Respir. Cell. Mol. Biol., 2008, vol. 38, pp. 572-578.
43. Holmgren E., Gerth E., Ljungstrom A.C., Almstrand P., Larsson B., Bake A.C., Olin A.C. Effects of breath holding at low and high lung volumes on amount of exhaled particles. Respir. Physiol. Neurobiol., 2013, vol. 185, pp. 228-234.
44. Edwards D.A., Man J.C., Brand P., Katstra J.P., Sommerer K., Stone H.A., Nardell E., Scheuch G. Inhaling to mitigate exhaled bioaerosols. Proc. Natl. Acad. Sci., 2004, vol. 101, pp. 17383-17388.
45. Kubán P., Foret F. Exhaled breath condensate: Determination of non-volatile compounds and their potential for clinical diagnosis and monitoring. A review Anal. Chim. Acta, 2013, vol. 805, pp. 1-18.
46. Effros R. M., Biller J., Foss B., Hoagland K., Dunning M. B., Castillo D., Bosbous M., Sun F., Shaker R. A simple method for estimating respiratory solute dilution in exhaled breath condensates. Am. J. Respir. Crit. Care Med., 2003, vol. 168, pp. 1500-1505.
47. Muccillia V., Salettia R., Cunsoloa V., Hob J., Gilic E., Contec E., Sichilic S., Foti V. C. S. Protein profile of exhaled breath condensate determined by high resolution mass spectrometry. J. Pharm. Biomed. Anal., 2015, vol. 105, pp. 134-49.
48. Tinglev S., Ullah G., Ljungkvist E., Viklund A.C., Olin O., Beck O. Characterization of exhaled breath particles collected by an electret filter technique. J. Breath Res., 2016, p. 026001.
49. Ullah S., Sandqvist S., Beck O. Measurement of lung phosphatidylcholines in exhaled breath particles by a convenient collection procedure. Anal. Chem., 2015, vol. 87, pp. 11553-11560.
50. Morozov V.N., Nikolaev A.A., Shlyapnikov Y.M., Mikheev A.Y., Shlyapnikova E.A., Bagdasaryan T.R., Burmistrova I.A., Smirnova T.G., Andrievskaya I.Y., Larionova E.E., Lyadova I. V. Non-invasive approach to diagnosis of pulmonary tuberculosis using exhaled air. J. Breath Res., 2018, vol. 12, p. 036010.
51. Beck O., Stephanson N., Sandqvist S., Frank J. Detection of drugs of abuse in exhaled breath using a device for rapid collection: comparison with plasma, urine and self-reporting in 47 drug users. J. Breath Res., 2013, vol. 7, p. 026006.
52. Mikheev A.Y., Kanev I.L., Morozova T.Y., Morozov V.N. Water-soluble filters from ultra-thin polyvinylpirrolidone nanofibers. J. Membr. Sci., 2013, vol. 448, pp. 151-159.
53. Basmanov P.I., Kirichenko V.N., Filatov Y.N., Yurov Y.L. Highly Efficient Cleaning of Gases from Aerosols with Petryanov’s Filters, Moscow, 2002, 193 p. (In Russ.)
54. Morozov V.N., Vsevolodov N.N. Electrospray-neutralization method for manufacturing free and supported nanomats. Adv. Materials, 2007, vol. 19, pp. 4381-4386.
55. Marple V.A., Liu B.Y.H. Characteristics of laminar jet impactors. Environ. Sci. Technol., 1974, vol. 8, pp. 648-654.
56. Papineni R.S., Rosenthal F.S. The size distribution of droplets in the exhaled breath of healthy human subjects. J. Aerosol. Med., 1997, vol. 10, pp. 105-116.
57. Almstrand A.C., Ljungström E., Lausmaa J., Bake B., Sjövall P., Olin A. C. Airway monitoring by collection and mass spectrometric analysis of exhaled particles. Anal. Chem., 2009, vol. 81, pp. 662-668.
58. Miller A., Frey G., King G., Sunderman C. A handheld electrostatic precipitator for sampling airborne particles and nanoparticles. Aerosol Sci. Technol., 2010, vol. 44, pp. 417-427.
59. Morozov V.N., Mikheev A.Y. A collection system for dry solid residues from exhaled breath for analysis via atomic force microscopy. J. Breath Res., 2017, vol. 11, p. 016006.
60. Morozov V.N., Mikheev A.Y., Shlyapnikov Y.M., Nikolaev A.A, Lyadova I.V. Non-invasive lung disease diagnostics. Perspectives and technical challenges. J. Breath Res., 2018, vol. 12, p. 017103.
61. Mikheev A.Y., Shlyapnikov Y.M., Kanev I.L., Avseenko A.V., Morozov V. N. Filtering and optical properties of free standing electrospun nanomats from nylon-4,6. European Polymer Journal, 2016, vol. 75, pp. 317-328.
62. Morozov V.N., Groves, S., Turell M. J., Bailey C., Three minutes-long electrophoretically assisted zeptomolar microfluidic immunoassay with magnetic beads detection. J. Am. Chem. Soc., 2007, vol. 129, pp. 12628-12629.
63. Shlyapnikov Y.M., Morozov V.N. Titration of trace amounts of immunoglobulins in a microarray-based assay with magnetic labels. Anal. Chim. Acta, 2017, vol. 966, pp. 47-53.
