Research Article

Development of a dry powder for inhalation of nanoparticles codelivering cisplatin and ABCC3 siRNA in lung cancer

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Department of Pharmaceutics, Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390001, India

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Denish Bardoliwala

Department of Pharmaceutics, Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390001, India

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Rohan Lalani

Department of Pharmaceutics, Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390001, India

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Sushilkumar Patil

Department of Pharmaceutics, Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390001, India

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Saikat Ghosh

Department of Pharmaceutics, Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390001, India

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Ankit Javia

Department of Pharmaceutics, Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390001, India

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Ambikanandan Misra

https://orcid.org/0000-0002-9100-3789

Department of Pharmaceutics, Faculty of Pharmacy, Kalabhavan Campus, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, 390001, India

Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS University, Mumbai, Maharashtra, 400056, India

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Published Online:10 Aug 2021https://doi.org/10.4155/tde-2020-0117

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Abstract

Background: The current study sought to formulate a dry powder inhalant (DPI) for pulmonary delivery of lipopolymeric nanoparticles (LPNs) consisting of cisplatin and siRNA for multidrug-resistant lung cancer. siRNA against ABCC3 gene was used to silence drug efflux promoter. Results & discussion: The formulation was optimized through the quality by design system by nanoparticle size and cisplatin entrapment. The lipid concentration, polymer concentration and lipid molar ratio were selected as variables. The DPI was characterized by in vitro deposition study using the Anderson cascade impactor. DPI formulation showed improved pulmonary pharmacokinetic parameters of cisplatin with higher residence time in lungs. Conclusion: Local delivery of siRNA and cisplatin to the lung tissue resulted into an enhanced therapeutic effectiveness in combating drug resistance.

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Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. Torre LA, Siegel RL, Jemal A. Lung cancer statistics. In: Lung Cancer and Personalized Medicine. Ahmad AGadgeel S (Eds). Springer, NY, USA, 1–19 (2016).
Google Scholar
2. Creixell M, Peppas NA. Co-delivery of siRNA and therapeutic agents using nanocarriers to overcome cancer resistance. Nano Today 7(4), 367–379 (2012). • Advantages of combinatorial approach in lung cancer are detailed in this paper.
Medline CASGoogle Scholar
3. Peters GJ. Cancer drug resistance: a new perspective. Cancer Drug Resist. 1, 1–5 (2018).
Google Scholar
4. Patel NR, Pattni BS, Abouzeid AH, Torchilin VP. Nanopreparations to overcome multidrug resistance in cancer. Adv. Drug Deliv. Rev. 65(13–14), 1748–1762 (2013). •• The role of nanocarriers for overcoming drug resistance in cancer is evaluated.
Medline CASGoogle Scholar
5. Hu B, Zhong L, Weng Y et al. Therapeutic siRNA: state of the art. Signal. Transduct. Target. Ther. 5(1), 1–25 (2020).
MedlineGoogle Scholar
6. Szakács G, Paterson JK, Ludwig JA et al. Targeting multidrug resistance in cancer. Nat. Rev. Drug Discov. 5(3), 219–234 (2006). •• Different targets on the tumor cell surface are identified and their use for the drug targeting is described.
Medline CASGoogle Scholar
7. Tian Z, Liang G, Cui K et al. Insight into the prospects for RNAi therapy of cancer. Front. in Pharmacol. 12, 308 (2021).
Google Scholar
8. Chalbatani GM, Dana H, Gharagouzloo E et al. Small interfering RNAs (siRNAs) in cancer therapy: a nano-based approach. Int. J. Nanomed. 14, 3111–3128 (2019).
Medline CASGoogle Scholar
9. Cao F, Wan C, Xie L et al. Localized RNA interference therapy to eliminate residual lung cancer after incomplete microwave ablation. Thorac. Cancer 10(6), 1369–1377 (2019).
Medline CASGoogle Scholar
10. Saad M, Garbuzenko OB, Minko T. Co-delivery of siRNA and an anticancer drug for treatment of multidrug-resistant cancer. Nanomedicine (Lond). 3(6), 761–776 (2008).
Medline CASGoogle Scholar
11. Kandil R, Merkel OM. Pulmonary delivery of siRNA as a novel treatment for lung diseases. Ther. Deliv. 10(4), 203–206 (2019).
CASGoogle Scholar
12. Das M, Musetti S, Huang L. RNA interference-based cancer drugs: the roadblocks, and the ‘delivery’ of the promise. Nucleic Acid Ther. 29(2), 61–66 (2019).
Medline CASGoogle Scholar
13. Adjei A. Inhalation Delivery of Therapeutic Peptides and Proteins. Adjei A (Ed). CRC Press, FL, USA (1997).
Google Scholar
14. Islam N, Gladki E. Dry powder inhalers (DPIs) – a review of device reliability and innovation. Int. J. Pharm. 360(1–2), 1–11 (2008). •• Development of a dry powder inhalant for targeted pulmonary delivery of nanocarriers is described. The crucial role played by device and powder characteristics in pulmonary delivery is discussed.
Medline CASGoogle Scholar
15. Kasper JC. Lyophilization of nucleic acid nanoparticles [Doctoral thesis]. https://edoc.ub.uni-muenchen.de/14425/1/Kasper_Julia_Christina.pdf
Google Scholar
16. Pfeifer C, Hasenpusch G, Uezguen S et al. Dry powder aerosols of polyethylenimine (PEI)-based gene vectors mediate efficient gene delivery to the lung. J. Control. Release. 154(1), 69–76 (2011).
Medline CASGoogle Scholar
17. Telko MJ, Hickey AJ. Dry powder inhaler formulation. Respir. Care 50(9), 1209–1227 (2005). • Formulation characteristics of dry powders for effective pulmonary targeting.
MedlineGoogle Scholar
18. 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. 38(6), 782–797 (2017).
Medline CASGoogle Scholar
19. Carvalho TC, Carvalho SR, Mcconville JT. Formulations for pulmonary administration of anticancer agents to treat lung malignancies. J. Aerosol. Med. Pulm. Drug. Deliv. 24(2), 61–80 (2011).
Medline CASGoogle Scholar
20. Jensen DK, Jensen LB, Koocheki S et al. Design of an inhalable dry powder formulation of DOTAP-modified PLGA nanoparticles loaded with siRNA. J. Control Release. 157(1), 141–148 (2012).
Medline CASGoogle Scholar
21. Rosière R, Berghmans T, De Vuyst P et al. The position of inhaled chemotherapy in the care of patients with lung tumors: clinical feasibility and indications according to recent pharmaceutical progresses. Cancers 11(3), 329 (2019).
CASGoogle Scholar
22. Akbarzadeh A, Rezaei-Sadabady R, Davaran S et al. Liposome: classification, preparation, and applications. Nanoscale Res. Lett. 8(1), 102 (2013).
MedlineGoogle Scholar
23. Gautschi O, Mack PC, Heighway J, et al. Molecular biology of lung cancer as the basis for targeted therapy. In: Lung Cancer. Pandya KJBrahmer JRHidalgo M (Eds). CRC Press, FL, USA, 11–34 (2016).
Google Scholar
24. Hadinoto K, Sundaresan A, Cheow WS. Lipid–polymer hybrid nanoparticles as a new generation therapeutic delivery platform: a review. Eur. J. Pharm. Biopharm. 85(3), 427–443 (2013). •• The role of nanocarriers as a therapeutic delivery platform for various diseases is discussed.
Medline CASGoogle Scholar
25. Zamboni WC, Torchilin V, Patri AK et al. Best practices in cancer nanotechnology: perspective from NCI nanotechnology alliance. Clin. Cancer. Res. 18(12), 3229–3241 (2012).
Medline CASGoogle Scholar
26. Saraswathy M, Gong S. Recent developments in the co-delivery of siRNA and small molecule anticancer drugs for cancer treatment. Materials Today 17(6), 298–306 (2014).
CASGoogle Scholar
27. Schiffelers RM, Ansari A, Xu J et al. Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle. Nucleic Acids Res. 32(19), e149–e149 (2004).
MedlineGoogle Scholar
28. Zhao P, Wang H, Yu M et al. Paclitaxel loaded folic acid targeted nanoparticles of mixed lipid-shell and polymer-core: in vitro and in vivo evaluation. Eur. J. Pharm. Biopharm. 81(2), 248–256 (2012). • Evaluation technique of lipid core shell-type nanoccarriers.
Medline CASGoogle Scholar
29. Zhang L, Zhang L. Lipid–polymer hybrid nanoparticles: synthesis, characterization and applications. Nano Life 1(01n02), 163–173 (2010).
CASGoogle Scholar
30. Patel V, Lalani R, Vhora I et al. Co-delivery of cisplatin and siRNA through hybrid nanocarrier platform for masking resistance to chemotherapy in lung cancer. Drug Deliv. Trans. Res. 1–20 (2020).
MedlineGoogle Scholar
31. Win KY, Feng S-S. Effects of particle size and surface coating on cellular uptake of polymeric nanoparticles for oral delivery of anticancer drugs. Biomater. 26(15), 2713–2722 (2005).
Medline CASGoogle Scholar
32. Mandal B, Bhattacharjee H, Mittal N et al. Core–shell-type lipid–polymer hybrid nanoparticles as a drug delivery platform. Nanomed. Nanotechnol. 9(4), 474–491 (2013).
CASGoogle Scholar
33. Vhora I, Khatri N, Desai J, Thakkar HP. Caprylate-conjugated cisplatin for the development of novel liposomal formulation. AAPS PharmSciTech 15(4), 845–857 (2014).
Medline CASGoogle Scholar
34. Ruozi B, Belletti D, Tombesi A et al. AFM, ESEM, TEM, and CLSM in liposomal characterization: a comparative study. Int. J. of Nanomed. 6, 557 (2011).
Medline CASGoogle Scholar
35. Xu P, Van Kirk EA, Li S et al. Highly stable core-surface-crosslinked nanoparticles as cisplatin carriers for cancer chemotherapy. Colloids Surf. B Biointerfaces 48(1), 50–57 (2006).
Medline CASGoogle Scholar
36. Chougule M, Padhi B, Misra A. Nano-liposomal dry powder inhaler of tacrolimus: preparation, characterization, and pulmonary pharmacokinetics. Int. J. Nanomed. 2(4), 675 (2007).
Medline CASGoogle Scholar
37. Su W-P, Cheng F-Y, Shieh D-B et al. PLGA nanoparticles codeliver paclitaxel and Stat3 siRNA to overcome cellular resistance in lung cancer cells. Int. J. Nanomed. 7, 4269 (2012).
Medline CASGoogle Scholar
38. Longo-Sorbello GS, Saydam G, Banerjee D, Bertino JR. Cytotoxicity and cell growth assays. In: Cell Biology. Elsevier, MA, USA, 315–324 (2006).
Google Scholar
39. Patil S, Lalani R, Bhatt P et al. Hydroxyethyl substituted linear polyethylenimine for safe and efficient delivery of siRNA therapeutics. RSC Adv. 8(62), 35461–35473 (2018).
CASGoogle Scholar
40. Lee J, Reddy R, Barsky L et al. Lung alveolar integrity is compromised by telomere shortening in telomerase-null mice. Am. J. Physiol. Lung Cell Mol. Physiol. 296(1), L57–L70 (2009).
Medline CASGoogle Scholar
41. Fenart L, Casanova A, Dehouck B et al. Evaluation of effect of charge and lipid coating on ability of 60-nm nanoparticles to cross an in vitro model of the blood–brain barrier. J. Pharmacol. Exp. Ther. 291(3), 1017–1022 (1999).
Medline CASGoogle Scholar
42. Troutier A-L, Delair T, Pichot C, Ladavière C. Physicochemical and interfacial investigation of lipid/polymer particle assemblies. Langmuir 21(4), 1305–1313 (2005).
Medline CASGoogle Scholar
43. Stavropoulos K. Synthesis and characterization of lipid-polymer hybrid nanoparticles for combinatorial drug delivery [master’s thesis] (2011). https://core.ac.uk/download/pdf/213394887.pdf
Google Scholar
44. Thevenot J, Troutier A-L, David L et al. Steric stabilization of lipid/polymer particle assemblies by poly (ethylene glycol)-lipids. Biomacromolecules 8(11), 3651–3660 (2007).
Medline CASGoogle Scholar
45. Lim SK, De Hoog H-P, Parikh AN et al. Hybrid, nanoscale phospholipid/block copolymer vesicles. Polymers 5(3), 1102–1114 (2013).
Google Scholar
46. Li J, Wang X, Zhang T et al. A review on phospholipids and their main applications in drug delivery systems. Asian J. Pharm. Sci. 10(2), 81–98 (2015).
Google Scholar
47. Khatri N, Rathi M, Baradia D, Misra A. cRGD grafted siRNA nano-constructs for chemosensitization of gemcitabine hydrochloride in lung cancer treatment. Pharm. Res. 32(3), 806–818 (2015).
Medline CASGoogle Scholar
48. Zhao Y, Lu H, Yan A et al. ABCC3 as a marker for multidrug resistance in non-small cell lung cancer. Sci. Rep. 3, 3120 (2013).
MedlineGoogle Scholar
49. Rabanel J-M, Hildgen P, Banquy X. Assessment of PEG on polymeric particles surface, a key step in drug carrier translation. J. Control. Release. 185, 71–87 (2014).
Medline CASGoogle Scholar
50. Blanco E, Shen H, Ferrari M. Nanoparticle rational design implementation for overcoming delivery barriers. Nat Biotechnol. 33, 941–951 (2015).
Medline CASGoogle Scholar
51. Nakamura K, Yamashita K, Itoh Y et al. Comparative studies of polyethylene glycol-modified liposomes prepared using different PEG-modification methods. Biochim. Biophys. Acta Biomembr. 1818(11), 2801–2807 (2012).
CASGoogle Scholar
52. Zhang L, Hu Y, Jiang X et al. Camptothecin derivative-loaded poly (caprolactone-co-lactide)-b-PEG-b-poly (caprolactone-co-lactide) nanoparticles and their biodistribution in mice. J. Control. Release. 96(1), 135–148 (2004).
Medline CASGoogle Scholar
53. Li X, Li R, Qian X et al. Superior antitumor efficiency of cisplatin-loaded nanoparticles by intratumoral delivery with decreased tumor metabolism rate. Eur. J. Pharm. Biopharm. 70(3), 726–734 (2008).
Medline CASGoogle Scholar
54. Zarogoulidis P, Chatzaki E, Porpodis K et al. Inhaled chemotherapy in lung cancer: future concept of nanomedicine. Int. J. Nanomed. 7, 1551 (2012).
Medline CASGoogle Scholar
55. Kaialy W, Nokhodchi A. Freeze-dried mannitol for superior pulmonary drug delivery via dry powder inhaler. Pharm. Res. 30(2), 458–477 (2013).
Medline CASGoogle Scholar
56. Chougule MB, Padhi BK, Jinturkar KA, Misra A. Development of dry powder inhalers. Recent Pat. Drug Deliv. Formul. 1(1), 11–21 (2007).
Medline CASGoogle Scholar
57. Allison SD, Molina MDC, Anchordoquy TJ. Stabilization of lipid/DNA complexes during the freezing step of the lyophilization process: the particle isolation hypothesis. Biochim Biophy Acta Biomembr. 1468(1), 127–138 (2000).
CASGoogle Scholar
58. Nishiyama N, Okazaki S, Cabral H et al. Novel cisplatin-incorporated polymeric micelles can eradicate solid tumors in mice. Cancer Res. 63(24), 8977–8983 (2003).
Medline CASGoogle Scholar
59. Gryparis EC, Hatziapostolou M, Papadimitriou E, Avgoustakis K. Anticancer activity of cisplatin-loaded PLGA-mPEG nanoparticles on LNCaP prostate cancer cells. Eur. J. Pharm. Biopharm. 67(1), 1–8 (2007).
Medline CASGoogle Scholar
60. Khatri N, Rathi MN, Baradia D, Trehan S, Misra A. In vivo delivery aspects of miRNA, shRNA and siRNA. Crit. Rev. Ther. Drug Carrier Syst. 29(6), 487–527 (2012).
Medline CASGoogle Scholar
61. Nillawar AN, Bardapurkar J, Bardapurkar S. High sensitive C-reactive protein as a systemic inflammatory marker and LDH-3 isoenzyme in chronic obstructive pulmonary disease. Lung India. 29(1), 24 (2012).
MedlineGoogle Scholar

Vol. 12, No. 9

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Received 22 September 2020

Accepted 13 July 2021

Published online 10 August 2021

Published in print September 2021

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Acknowledgments

The authors acknowledge the contribution by following: Prof Paola Luciani and her research group (Former Professor of Institute of Pharmacy, Friedrich schiller university of Jena, Germany) for providing laboratory and technical support; Department of Science and Technology (DST), Government of India and German academic exchange service (DAAD) for financial assistance for this collaborative project between Faculty of Pharmacy, The Maharaja Sayajirao University of Baroda and Friedrich schiller university of Jena, Germany; Dr Bhavin A Vyas of Maliba Pharmacy College for animal studies; & Central salt and marine chemicals research institute (CSMCRI), Bhavnagar for Cryo-TEM & SEM studies. All animal experiments and protocol described in the present study were approved by the Institutional Animal Ethical Committee (IAEC) of Maliba Pharmacy College, Uka Tarsadia University, Bardoli wide protocol MPC/IAEC/02/2019 and with permission from committee for the purpose of control and supervision of experiments on Animals (CPCSEA), Ministry of Social Justice and Empowerment, Government of India.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

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