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Pulmonary delivery of osimertinib liposomes for non-small cell lung cancer treatment: formulation development and in vitro evaluation

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Abstract

Osimertinib (OB) is a third-generation irreversible tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR), overexpressed in non-small cell lung cancer. Systemic administration of drug often results in poor drug levels at the primary tumor in the lungs and is associated with systemic side effects. In this study, we developed inhalable OB liposomes that can locally accumulate at the tumor site thereby limiting systemic toxicity. OB was loaded into liposomes via active and passive loading methods. The OB active liposomes achieved a higher encapsulation (78%) compared to passive liposomes (25%). The liposomes (passive and active) exhibited excellent aerosolization performance with an aerodynamic diameter of 4 µm and fine particle fraction of 82%. In H1975 cells, OB active and passive liposomes reduced IC50 by 2.2 and 1.2-fold, respectively, compared to free drug. As the OB active liposomes demonstrated higher cytotoxicity compared to OB passive liposomes, they were further investigated for in vitro anti-cancer activity. The OB active liposomes inhibited tumor cell migration and colonization as determined by the scratch assay and clonogenic assay, respectively. Furthermore, the 3D spheroid studies showed that the liposomes were successful in inhibiting tumor growth. These results highlight the potential of OB liposomes to suppress lung cancer. Owing to these attributes, the inhalable OB liposomes can potentially promote better therapeutic outcomes with limited systemic toxicity.

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Any datasets generated during the current study are available from the corresponding author on reasonable request.

References

  1. König D, Prince SS, Rothschild SI. Targeted therapy in advanced and metastatic non-small cell lung cancer. An update on treatment of the most important actionable oncogenic driver alterations. Cancers (Basel). 2021;13:1–37.

  2. Kunda NK. Antimicrobial peptides as novel therapeutics for non-small cell lung cancer. Drug Discov Today Elsevier Ltd. 2020;25:238–47.

    Article  CAS  Google Scholar 

  3. Zappa C, Mousa SA. Non-small cell lung cancer : current treatment and future advances. Transl Lung Cancer Res. 2016;5:288–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Yuan M, Huang L-L, Chen J-H, Wu J, Xu Q. The emerging treatment landscape of targeted therapy in non-small-cell lung cancer. Signal Transduct Target Ther. 2019;4:61.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Asuncio´n Dı´az-Serrano, Pablo Gella, Elisabeth Jime´nez, Jon Zugazagoitia LP-AR. Targeting EGFR in lung cancer : current standards and developments. Drugs. 2018;78:893–911.

  6. Liu J, Li X, Shao Y, Guo X, He J. The efficacy and safety of osimertinib in treating nonsmall cell lung cancer: a PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore). 2020;99:e21826.

  7. Bartholomew C, Eastlake L, Dunn P, Yiannakis D. Respiratory Medicine Case Reports EGFR targeted therapy in lung cancer; an evolving story. Respir Med Case Reports Elsevier Ltd. 2017;20:137–40.

    CAS  Google Scholar 

  8. Godin-heymann N, Ulkus L, Brannigan BW, Mcdermott U, Lamb J, Maheswaran S, et al. The T790M ‘“ gatekeeper ”’ mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitor. Mol Cancer Ther. 2008;7:874–80.

    Article  CAS  PubMed  Google Scholar 

  9. Odogwu L, Mathieu L, Goldberg KB, Blumenthal GM, Larkins E, Fiero MH, et al. FDA benefit-risk assessment of osimertinib for the treatment of metastatic non-small cell lung cancer harboring epidermal growth factor receptor T790M mutation. Oncologist. 2018;23:353–9.

    Article  CAS  PubMed  Google Scholar 

  10. Jelinek MJ, Aggarwal C. Adjuvant osimertinib: a new standard of care. Oncologist. 2021;26:263–5.

    Article  CAS  PubMed  Google Scholar 

  11. Reddy VP, Walker M, Sharma P, Ballard P, Vishwanathan K. Development, verification, and prediction of osimertinib drug-drug interactions using PBPK modeling approach to inform drug label. CPT Pharmacometrics Syst Pharmacol. 2018;7:321–30.

    Article  CAS  Google Scholar 

  12. European Medicines Agency: TAGRISSO (Osimertinib) Summary of Product Characteristics, 2018. 2018.

  13. Vogel WH, Jennifer P. Management strategies for adverse events associated with EGFR TKIs in non-small cell lung cancer. J Adv Pract Oncol. 2016;7:723–35.

    PubMed  PubMed Central  Google Scholar 

  14. Tran S, DeGiovanni P, Piel B, Rai P. Cancer nanomedicine: a review of recent success in drug delivery. Clin Transl Med [Internet]. Springer Berlin Heidelberg; 2017;6:44. Available from: https://onlinelibrary.wiley.com/doi/abs/https://doi.org/10.1186/s40169-017-0175-0

  15. Zhou X, Shi K, Hao Y, Yang C, Zha R, Yi C, et al. Advances in nanotechnology-based delivery systems for EGFR tyrosine kinases inhibitors in cancer therapy. Asian J Pharm Sci Elsevier BV. 2020;26–41.

  16. Skupin-Mrugalska P. Liposome-based drug delivery for lung cancer. Nanotechnology-based target drug Deliv Syst Lung Cancer [Internet]. Elsevier; 2019. p. 123–60. Available from: https://linkinghub.elsevier.com/retrieve/pii/B978012815720600006X

  17. Clemons TD, Singh R, Sorolla A, Chaudhari N, Hubbard A, Iyer KS. Distinction between active and passive targeting of nanoparticles dictate their overall therapeutic efficacy. Langmuir. 2018;34:15343–9.

    Article  CAS  PubMed  Google Scholar 

  18. Zhang R, Qin X, Kong F, Chen P, Pan G. Improving cellular uptake of therapeutic entities through interaction with components of cell membrane. Drug Deliv Taylor & Francis. 2019;26:328–42.

    CAS  Google Scholar 

  19. Yu X, Trase I, Ren M, Duval K, Guo X, Chen Z. Design of nanoparticle-based carriers for targeted drug delivery. J Nanomater [Internet]. 2016;2016:1–15. Available from: http://www.hindawi.com/journals/jnm/2016/1087250/

  20. Olusanya TOB, Haj Ahmad RR, Ibegbu DM, Smith JR, Elkordy AA. Liposomal drug delivery systems and anticancer drugs. Molecules MDPI. 2018;23:907.

  21. Gu Z, Da Silva CG, van der Maaden K, Ossendorp F, Cruz LJ. Liposome-based drug delivery systems in cancer immunotherapy. Pharmaceutics. 2020;12:1–25.

    Article  CAS  Google Scholar 

  22. Akhter S. Nanotechnology-based inhalation treatments for lung cancer : state of the art. Nanotechnology, Scienece Appl. 2015;8:55–66.

    Article  Google Scholar 

  23. Mangal S, Gao W, Li T, Zhou QT. Pulmonary delivery of nanoparticle chemotherapy for the treatment of lung cancers: challenges and opportunities. Acta Pharmacol Sin Nature Publishing Group. 2017;38:782–97.

    Article  CAS  Google Scholar 

  24. Kuehl PJ, Yingling CM, Dubose D, Burke M, Revelli DA, Chen W, et al. Inhalation delivery dramatically improves the efficacy of topotecan for the treatment of local and distant lung cancer. Drug Deliv Taylor & Francis. 2021;28:767–75.

    CAS  Google Scholar 

  25. Price DN, Kunda NK, Miller EK, Muttil P. Inhaled therapeutics against TB: the promise of pulmonary treatment and prevention strategies in the clinic. Inhal Aerosols. 2019;361–75.

  26. Chang H-I, Yeh M-K. Clinical development of liposome-based drugs: formulation, characterization, and therapeutic efficacy. Int J Nanomed. 2012;7:49–60.

    CAS  Google Scholar 

  27. Zhang J, Leifer F, Rose S, Chun DY, Thaisz J, Herr T, et al. Amikacin liposome inhalation suspension ( ALIS ) penetrates non-tuberculous mycobacterial biofilms and enhances amikacin uptake into macrophages. 2018;9:1–12.

  28. Klein DM, Poortinga A, Verhoeven FM, Bonn D, Bonnet S, Rijn CJM Van. Degradation of lipid based drug delivery formulations during nebulization. Chem Phys Elsevier BV. 2021;547:111192.

  29. Liu Q, Guan J, Qin L, Zhang X, Mao S. Physicochemical properties affecting the fate of nanoparticles in pulmonary drug delivery. Drug Discov Today Elsevier Ltd. 2020;25:150–9.

    Article  CAS  Google Scholar 

  30. Sharma P, Mehta M, Dhanjal DS, Kaur S, Gupta G, Singh H, et al. Emerging trends in the novel drug delivery approaches for the treatment of lung cancer. Chem Biol Interact Elsevier. 2019;309:108720.

  31. Kallus S, Englinger B, Senkiv J, Laemmerer A, Heffeter P, Berger W, et al. Nanoformulations of anticancer FGFR inhibitors with improved therapeutic index. Nanomedicine Nanotechnology, Biol Med Elsevier Inc. 2018;14:2632–43.

  32. Haran G, Cohen R, Bar LK, Barenholz Y. Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases. BBA - Biomembr. 1993;1151:201–15.

    Article  CAS  Google Scholar 

  33. Patil SM, Sawant SS, Kunda NK. Inhalable bedaquiline-loaded cubosomes for the treatment of non-small cell lung cancer (NSCLC). Int J Pharm [Internet]. 2021;607:121046. Available from: https://www.sciencedirect.com/science/article/pii/S0378517321008528

  34. Shukla SK, Kulkarni NS, Chan A, Parvathaneni V, Farrales P, Muth A, et al. Metformin-encapsulated liposome delivery system: an effective treatment approach against breast cancer. Pharmaceutics [Internet]. MDPI AG; 2019;11:559. Available from: https://www.mdpi.com/1999-4923/11/11/559

  35. Nimmano N, Somavarapu S, Taylor KMG. Aerosol characterisation of nebulised liposomes co-loaded with erlotinib and genistein using an abbreviated cascade impactor method. Int J Pharm Elsevier. 2018;542:8–17.

    Article  CAS  Google Scholar 

  36. Vartak R, Patil SM, Saraswat A, Patki M, Kunda NK, Patel K. Aerosolized nanoliposomal carrier of remdesivir: an effective alternative for COVID-19 treatment in vitro. Nanomedicine [Internet]. Future Medicine; 2021;16:1187–202. Available from: https://doi.org/10.2217/nnm-2020-0475

  37. Parvathaneni V, Kulkarni NS, Shukla SK, Farrales PT, Kunda NK, Muth A, et al. Systematic development and optimization of inhalable pirfenidone liposomes for non-small cell lung cancer treatment. Pharmaceutics [Internet]. 2020;12:206. Available from: https://www.mdpi.com/1999-4923/12/3/206

  38. Pereira S, Lee J, Rubio N, Hassan HAFM, Suffian IBM, Wang JTW, et al. Cationic liposome- multi-walled carbon nanotubes hybrids for dual siPLK1 and doxorubicin delivery in vitro. Pharm Res. 2015;32:3293–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kunda NK, Alfagih IM, Miyaji EN, Figueiredo DB, Gonçalves VM, Ferreira DM, et al. Pulmonary dry powder vaccine of pneumococcal antigen loaded nanoparticles. Int J Pharm [Internet]. Elsevier B.V.; 2015 [cited 2015 Sep 29];495:903–12. Available from: http://www.sciencedirect.com/science/article/pii/S0378517315302325

  40. Somchai P, Phongkitkarun K, Kueanjinda P, Jamnongsong S, Vaeteewoottacharn K, Luvira V, et al. Novel analytical platform for robust identification of cell migration inhibitors. Sci Rep Nature Research. 2020;10:1–12.

    CAS  Google Scholar 

  41. Munshi A, Hobbs M, Meyn RE. Clonogenic cell survival assay. Methods Mol Med United States. 2005;110:21–8.

    Google Scholar 

  42. Franken NAP, Rodermond HM, Stap J, Haveman J, van Bree C. Clonogenic assay of cells in vitro. Nat Protoc. 2006;1:2315–9.

    Article  CAS  PubMed  Google Scholar 

  43. Tang ZH, Jiang XM, Guo X, Fong CMV, Chen X, Lu JJ. Characterization of osimertinib (AZD9291)-resistant non-small cell lung cancer NCI-H1975/OSIR cell line. Oncotarget. 2016;7:81598–610.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Tchoryk A, Taresco V, Argent RH, Ashford M, Gellert PR, Stolnik S, et al. Penetration and uptake of nanoparticles in 3D tumor spheroids. Bioconjug Chem American Chemical Society. 2019;30:1371–84.

    Article  CAS  Google Scholar 

  45. Ekert JE, Johnson K, Strake B, Pardinas J, Jarantow S, Perkinson R, et al. Three-dimensional lung tumor microenvironment modulates therapeutic compound responsiveness in vitro - Implication for drug development. PLoS ONE. 2014;9:1–14.

    Article  CAS  Google Scholar 

  46. Owens DE, Peppas NA. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm. 2006;307:93–102.

    Article  CAS  PubMed  Google Scholar 

  47. Van Rijt SH, Bein T, Meiners S. Medical nanoparticles for next generation drug delivery to the lungs. Eur Respir J. 2014;765–74.

  48. Dabbagh A, Abu Kasim NH, Yeong CH, Wong TW, Abdul Rahman N. Critical parameters for particle-based pulmonary delivery of chemotherapeutics. J Aerosol Med Pulm Drug Deliv Mary Ann Liebert Inc. 2018;139–54.

  49. Westover D, Zugazagoitia J, Cho BC, Lovly CM, Paz-Ares L. Mechanisms of acquired resistance to first-and second-generation EGFR tyrosine kinase inhibitors. Ann Oncol Elsevier Masson SAS. 2018;i10–9.

  50. Fatima MT, Islam Z, Ahmad E, Barreto GE, Md Ashraf G. Ionic gradient liposomes: recent advances in the stable entrapment and prolonged released of local anesthetics and anticancer drugs. Biomed Pharmacother. 2018;34–43.

  51. Lu X, Liu S, Han M, Yang X, Sun K, Wang H, et al. Afatinib-loaded immunoliposomes functionalized with cetuximab: a novel strategy targeting the epidermal growth factor receptor for treatment of non-small-cell lung cancer. Int J Pharm. 2019;560:126–35.

    Article  CAS  PubMed  Google Scholar 

  52. Trummer BJ, Iyer V, Balu-Iyer SV, O’Connor R, Straubinger RM. Physicochemical properties of epidermal growth factor receptor inhibitors and development of a nanoliposomal formulation of gefitinib. J Pharm Sci. 2012;101:2763–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Environmental Risk Assessment Data Osimertinib. 2017.

  54. Bharate SS. Recent developments in pharmaceutical salts: FDA approvals from 2015 to 2019. Drug Discov Today Elsevier Ltd. 2021;26:384–98.

    Article  CAS  Google Scholar 

  55. Pauli G, Tang WL, Li SD. Development and characterization of the solvent-assisted active loading technology (SALT) for liposomal loading of poorly water-soluble compounds. Pharmaceutics. 2019;11:465.

    Article  CAS  PubMed Central  Google Scholar 

  56. Fritze A, Hens F, Kimpfler A, Schubert R, Peschka-Süss R. Remote loading of doxorubicin into liposomes driven by a transmembrane phosphate gradient. Biochim Biophys Acta - Biomembr. 2006;1758:1633–40.

    Article  CAS  Google Scholar 

  57. Skupin-Mrugalska P, Minko T. Development of liposomal vesicles for osimertinib delivery to egfr mutation—positive lung cancer cells. Pharmaceutics. 2020;12:1–17.

    Article  CAS  Google Scholar 

  58. Gupta V, Gupta N, Shaik IH, Mehvar R, McMurtry IF, Oka M, et al. Liposomal fasudil, a rho-kinase inhibitor, for prolonged pulmonary preferential vasodilation in pulmonary arterial hypertension. J Control Release Elsevier BV. 2013;167:189–99.

  59. Sur S, Fries AC, Kinzler KW, Zhou S, Vogelstein B. Remote loading of preencapsulated drugs into stealth liposomes. PNAS. 2014;111:1–6.

    Article  Google Scholar 

  60. Fugit KD, Anderson BD. Dynamic, nonsink method for the simultaneous determination of drug permeability and binding coefficients in liposomes. Mol Pharm American Chemical Society. 2014;11:1314–25.

    Article  CAS  Google Scholar 

  61. Shibata H, Izutsu K, Yomota C, Okuda H, Goda Y. Investigation of factors affecting in vitro doxorubicin release from PEGylated liposomal doxorubicin for the development of in vitro release testing conditions. Drug Dev Ind Pharm. Taylor & Francis. 2015;41:1376–86.

  62. Maritim S, Boulas P, Lin Y. Comprehensive analysis of liposome formulation parameters and their influence on encapsulation, stability and drug release in glibenclamide liposomes. Int J Pharm. Elsevier B.V.; 2021;592:120051.

  63. Wiggins NA. The development of a mathematical approximation technique to determine the mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of drug particles in an inhalation aerosol sprat. Drug Dev Ind Pharm. 1991;17:1971–86.

    Article  CAS  Google Scholar 

  64. Taira MC, Chiaramoni NS, Pecuch KM, Alonso-Romanowski S. Stability of liposomal formulations in physiological conditions for oral drug delivery. Drug Deliv. 2004;11:123–8.

    Article  CAS  PubMed  Google Scholar 

  65. Akbarzadeh A, Rezaei-Sadabady R, Davaran S, Joo SW, Zarghami N, Hanifehpour Y, et al. Liposome: classification, preparation, and applications. Nanoscale Res Lett. 2013;8:1.

  66. Kim SM, Kwon O-J, Hong YK, Kim JH, Solca F, Ha S-J, et al. Activation of IL-6R/JAK1/STAT3 signaling induces de novo resistance to irreversible EGFR inhibitors in non-small cell lung cancer with T790M resistance mutation. Mol Cancer Ther United States. 2012;11:2254–64.

    Article  CAS  Google Scholar 

  67. Schreier H. Pulmonary delivery of liposomal drugs. J Liposome Res. 1994;4:229–38.

    Article  CAS  Google Scholar 

  68. Hu X, Chen S, Yin H, Wang Q, Duan Y, Jiang L, et al. Chitooligosaccharides-modified PLGA nanoparticles enhance the antitumor efficacy of AZD9291 (Osimertinib) by promoting apoptosis. Int J Biol Macromol. 2020;162:262–72.

    Article  CAS  PubMed  Google Scholar 

  69. Hulkower KI, Herber RL. Cell migration and invasion assays as tools for drug discovery. 2011;107–24.

  70. Hsiao S-H, Chou Y-T, Lin S-E, Hsu R-C, Chung C-L, Kao Y-R, et al. Brain metastases in patients with non-small cell lung cancer: the role of mutated- EGFRs with an exon 19 deletion or L858R point mutation in cancer cell dissemination. Oncotarget. 2017;8:53405–18.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Hong SS, Oh KT, Choi HG, Lim SJ. Liposomal formulations for nose-to-brain delivery: recent advances and future perspectives. Pharmaceutics. 2019;11:1–18.

    Article  CAS  Google Scholar 

  72. Yang X. Clonogenic assay to test cancer therapies. Bio-Protoc. 2012;2:187–9.

    Google Scholar 

  73. Jensen C, Teng Y. Is it time to start transitioning from 2D to 3D cell culture?. Front Mol Biosci 2020;33.

  74. Nath S, Devi GR. Three-dimensional culture systems in cancer research: focus on tumor spheroid model. Pharmacol Ther. 2016;163:94–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Edmondson R, Broglie JJ, Adcock AF, Yang L. Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors. Assay Drug Dev Technol. 2014;12:207–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Chen W, Yu D, Sun SY, Li F. Nanoparticles for co-delivery of osimertinib and selumetinib to overcome osimertinib-acquired resistance in non-small cell lung cancer. Acta Biomater.Acta Materialia Inc. 2021;129:258–68.

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Acknowledgements

The author(s) would like to acknowledge the Imaging Facility of CUNY Advanced Science Research Centre for instrument use and technical assistance in acquiring TEM images. Figures 1, 2, and 4, Table 2, and parts of methods (3.2, 3.3.1, and 3.4) are reproduced with permission from Respiratory Drug Delivery 2021, RDD Online, ISBN: 978–1-942,911–55-5. Original Reference: Formulation Development of Inhalable Osimertinib Liposomes for the Treatment of Non-Small Cell Lung Cancer. Sawant et al. Respiratory Drug Delivery 2021.Volume 1, 2021: 265–270. Editors: Richard N. Dalby, Joanne Peart, Julie D. Suman, Paul M. Young, Daniela Traini. Publisher: Davis Healthcare International, River Grove, IL, USA.

Funding

This study was supported by start-up funds provided to NKK by the College of Pharmacy and Health Sciences (CPHS), St. John’s University. SMP was supported by teaching assistantships from the Department of Pharmaceutical Sciences, CPHS, St. John’s University.

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  1. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Jamaica, NY, 11439, USA

    Shruti S. Sawant, Suyash M. Patil, Snehal K. Shukla, Nishant S. Kulkarni, Vivek Gupta & Nitesh K. Kunda

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  1. Shruti S. Sawant
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Contributions

Conceptualization, supervision, funding acquisition, project administration, N.K.K.; resources, N.K.K. and V.G.; methodology, software, validation, investigation, visualization, N.K.K., S.S.S., S.M.P.; formal analysis, N.K.K., S.S.S., N.S.K., S.M.P.; data curation, N.K.K., S.S.S., S.M.P., N.S.K.; writing – original draft preparation, N.K.K., S.S.S;. writing – review and editing, N.K.K., S.S.S., S.K.S., S.M.P., N.S.K., V.G.

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Correspondence to Nitesh K. Kunda.

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Sawant, S.S., Patil, S.M., Shukla, S.K. et al. Pulmonary delivery of osimertinib liposomes for non-small cell lung cancer treatment: formulation development and in vitro evaluation. Drug Deliv. and Transl. Res. 12, 2474–2487 (2022). https://doi.org/10.1007/s13346-021-01088-0

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