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Sorafenib Loaded Inhalable Polymeric Nanocarriers against Non-Small Cell Lung Cancer

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Abstract

Purpose

This exploration is aimed at developing sorafenib (SF)-loaded cationically-modified polymeric nanoparticles (NPs) as inhalable carriers for improving the therapeutic efficacy of SF against non-small cell lung cancer (NSCLC).

Methods

The NPs were prepared using a solvent evaporation technique while incorporating cationic agents. The optimized NPs were characterized by various physicochemical parameters and evaluated for their aerosolization properties. Several in-vitro evaluation studies were performed to determine the efficacy of our delivery carriers against NSCLC cells.

Results

Optimized nanoparticles exhibited an entrapment efficiency of ~40%, <200 nm particle size and a narrow poly-dispersity index. Cationically-modified nanoparticles exhibited enhanced cellular internalization and cytotoxicity (~5-fold IC50 reduction vs SF) in various lung cancer cell types. The inhalable nanoparticles displayed efficient aerodynamic properties (MMAD ~ 4 μM and FPF >80%). In-vitro evaluation also resulted in a superior ability to inhibit cancer metastasis. 3D-tumor simulation studies further established the anti-cancer efficacy of NPs as compared to just SF.

Conclusion

The localized delivery of SF-loaded nanoparticles resulted in improved anti-tumor activity as compared to SF alone. Therefore, this strategy displays great potential as a novel treatment approach against certain lung cancers.

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Abbreviations

ATCC:

American type culture collection

DCM:

Dichloromethane

DMSO :

Dimethyl sulfoxide

DSC:

Differential scanning calorimetry

ERK:

Extracellular signaling-regulated kinase

FPF:

Fine particle fraction

FT-IR:

Fourier transform- Infrared

GSD:

Geometric standard deviation

MEK:

Mitogen-activated protein kinase

MMAD:

Mass median aerodynamic diameter

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NGI:

Next generation impactor

NP:

Nanoparticle

NSCLC:

Non-small cell lung cancer

PBS:

Phosphate buffer saline

PDI:

Polydispersity index

PEI:

Polyethyleneimine

p-ERK:

Phosphorylated extracellular signaling-regulated kinase

PLA:

Poly-L-arginine

PVA:

Poly (vinyl alcohol)

RPMI:

Roswell park memorial institute

SF:

Sorafenib

TEM:

Transmission electron microscopy

References

  1. Nexavar (sorafenib) FDA Approval History. Drugs.com. Available from: https://www.drugs.com/history/nexavar.html Accessed 24 November 2019.

  2. Blumenschein G. Sorafenib in lung cancer: clinical developments and future directions. J Thorac Oncol. 2008;3:S124–7.

    PubMed  Google Scholar 

  3. Liang Y, Chen J, Yu Q, Ji T, Zhang B, Xu J, et al. Phosphorylated ERK is a potential prognostic biomarker for Sorafenib response in hepatocellular carcinoma. Cancer Med. 2017;6:2787–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Sheng X, Huang T, Qin J, Li Q, Wang W, Deng L, et al. Preparation, pharmacokinetics, tissue distribution and antitumor effect of sorafenib-incorporating nanoparticles in vivo. Oncol Lett. 2017;14:6163–9.

    PubMed  PubMed Central  Google Scholar 

  5. Chen C, Ju R, Shi J, Chen W, Sun F, Zhu L, et al. Carboxyamidotriazole synergizes with Sorafenib to combat non–small cell lung cancer through inhibition of NANOG and aggravation of apoptosis. J Pharmacol Exp Ther. 2017;362:219–29.

    PubMed  Google Scholar 

  6. Zhang Y-N, Wu X-Y, Zhong N, Deng J, Zhang L, Chen W, et al. Stimulatory effects of sorafenib on human non-small cell lung cancer cells in vitro by regulating MAPK/ERK activation. Mol Med Rep. 2014;9:365–9.

    CAS  PubMed  Google Scholar 

  7. Spigel DR, Rubin MS, Gian VG, Shipley DL, Burris HA, Kosloff RA, et al. Sorafenib and continued erlotinib or sorafenib alone in patients with advanced non-small cell lung cancer progressing on erlotinib: a randomized phase II study of the Sarah Cannon Research Institute (SCRI). Lung Cancer. 2017;113:79–84.

    PubMed  Google Scholar 

  8. Paz-Ares L, Hirsh V, Zhang L, de Marinis F, Yang JC-H, Wakelee HA, et al. Monotherapy Administration of Sorafenib in patients with non–small cell lung cancer (MISSION) trial: a phase III, multicenter, placebo-controlled trial of Sorafenib in patients with relapsed or refractory predominantly nonsquamous non–small-cell lung cancer after 2 or 3 previous treatment regimens. J Thorac Oncol. 2015;10:1745–53.

    CAS  PubMed  Google Scholar 

  9. Scagliotti G, Novello S, von Pawel J, Reck M, Pereira JR, Thomas M, et al. Phase III study of carboplatin and paclitaxel alone or with Sorafenib in advanced non–small-cell lung cancer. J Clin Oncol. 2010;28:1835–42.

    CAS  PubMed  Google Scholar 

  10. Molina JR, Dy GK, Foster NR, Allen Ziegler KL, Adjei A, Rowland KM, et al. A randomized phase II study of pemetrexed (PEM) with or without sorafenib (S) as second-line therapy in advanced non-small cell lung cancer (NSCLC) of nonsquamous histology: NCCTG N0626 study. J Clin Oncol. 2011;29:7513.

    Google Scholar 

  11. Shukla SK, Gupta V. Utilizing nanotechnology to recuperate sorafenib for lung cancer treatment: challenges and future perspective. Ther Deliv. 2020.

  12. Wang X, Fan J, Liu Y, Zhao B, Jia Z, Zhang Q. Bioavailability and pharmacokinetics of sorafenib suspension, nanoparticles and nanomatrix for oral administration to rat. Int J Pharm. 2011;419:339–46.

    CAS  PubMed  Google Scholar 

  13. Zhang H, Zhang F-M, Yan S-J. Preparation, in vitro release, and pharmacokinetics in rabbits of lyophilized injection of sorafenib solid lipid nanoparticles. Int J Nanomedicine. 2012;7:2901–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Villarroel MC, Pratz KW, Xu L, Wright JJ, Smith BD, Rudek MA. Plasma protein binding of sorafenib, a multi kinase inhibitor: in vitro and in cancer patients. Investig New Drugs. 2012;30:2096–102.

    CAS  Google Scholar 

  15. Tod M, Mir O, Bancelin N, Coriat R, Thomas-Schoemann A, Taieb F, et al. Functional and clinical evidence of the influence of Sorafenib binding to albumin on Sorafenib disposition in adult cancer patients. Pharm Res. 2011;28:3199–207.

    CAS  PubMed  Google Scholar 

  16. Kamaly N, Yameen B, Wu J, Farokhzad OC. Degradable controlled-release polymers and polymeric nanoparticles: mechanisms of controlling drug release. Chem Rev. 2016;116:2602–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Masood F. Polymeric nanoparticles for targeted drug delivery system for cancer therapy. Mater Sci Eng C. 2016;60:569–78.

    CAS  Google Scholar 

  18. Wang Y-H, Fu Y-C, Chiu H-C, Wang C-Z, Lo S-P, Ho M-L, et al. Cationic nanoparticles with quaternary ammonium-functionalized PLGA–PEG-based copolymers for potent gene transfection. J Nanopart Res. 2013;15:2077.

    Google Scholar 

  19. Stylianopoulos T, Soteriou K, Fukumura D, Jain RK. Cationic nanoparticles have superior transvascular flux into solid tumors: insights from a mathematical model. Ann Biomed Eng. 2013;41:68–77.

    PubMed  Google Scholar 

  20. Abdelaziz HM, Gaber M, Abd-Elwakil MM, Mabrouk MT, Elgohary MM, Kamel NM, et al. Inhalable particulate drug delivery systems for lung cancer therapy: nanoparticles, microparticles, nanocomposites and nanoaggregates. J Control Release. 2018;269:374–92.

    CAS  PubMed  Google Scholar 

  21. Liu J, Boonkaew B, Arora J, Mandava SH, Maddox MM, Chava S, et al. Comparison of Sorafenib-loaded poly (lactic/glycolic) acid and DPPC liposome nanoparticles in the in vitro treatment of renal cell carcinoma. J Pharm Sci. 2015;104:1187–96.

    CAS  PubMed  Google Scholar 

  22. Marques MRC, Loebenberg R, Almukainzi M. Simulated biological fluids with possible application in dissolution testing. Dissolution Technol. 2011;18:15–28.

    CAS  Google Scholar 

  23. Takezawa K, Okamoto I, Yonesaka K, Hatashita E, Yamada Y, Fukuoka M, et al. Sorafenib inhibits non-small cell lung cancer cell growth by targeting B-RAF in KRAS wild-type cells and C-RAF in KRAS mutant cells. Cancer Res. 2009;69:6515–21.

    CAS  PubMed  Google Scholar 

  24. Abdelrahim ME, Chrystyn H. Aerodynamic characteristics of nebulized terbutaline sulphate using the Next Generation Impactor (NGI) and CEN method. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2009;22:19–28.

    PubMed  Google Scholar 

  25. Vaidya B, Shukla SK, Kolluru S, Huen M, Mulla N, Mehra N, et al. Nintedanib-cyclodextrin complex to improve bio-activity and intestinal permeability. Carbohydr Polym. 2019;204:68–77.

    CAS  PubMed  Google Scholar 

  26. 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. 2019;11:559.

    PubMed Central  Google Scholar 

  27. Niu Z, Tedesco E, Benetti F, Mabondzo A, Montagner IM, Marigo I, et al. Rational design of polyarginine nanocapsules intended to help peptides overcoming intestinal barriers. J Control Release. 2017;263:4–17.

    CAS  PubMed  Google Scholar 

  28. Tunki L, Kulhari H, Vadithe LN, Kuncha M, Bhargava S, Pooja D, et al. Modulating the site-specific oral delivery of sorafenib using sugar-grafted nanoparticles for hepatocellular carcinoma treatment. Eur J Pharm Sci. 2019;104978.

  29. Erbetta CDC, Alves RJ, Resende JM, Freitas RF d S, de Sousa RG. Synthesis and characterization of Poly(D,L-Lactide-co-Glycolide) Copolymer. J Biomater Nanobiotechnol. 2012;3:208–225.

    CAS  Google Scholar 

  30. Lin Y-T, Chao CC-K. Identification of the β-catenin/JNK/prothymosin-alpha axis as a novel target of sorafenib in hepatocellular carcinoma cells. Oncotarget. 2015;6:38999–9017.

    PubMed  PubMed Central  Google Scholar 

  31. Vaidya B, Parvathaneni V, Kulkarni NS, Shukla SK, Damon JK, Sarode A, et al. Cyclodextrin modified erlotinib loaded PLGA nanoparticles for improved therapeutic efficacy against non-small cell lung cancer. Int J Biol Macromol. 2019;122:338–47.

    CAS  PubMed  Google Scholar 

  32. Ferreira LP, Gaspar VM, Mano JF. Design of spherically structured 3D in vitro tumor models -advances and prospects. Acta Biomater. 2018;75:11–34.

    CAS  PubMed  Google Scholar 

  33. Kulkarni NS, Parvathaneni V, Shukla SK, Barasa L, Perron JC, Yoganathan S, et al. Tyrosine kinase inhibitor conjugated quantum dots for non-small cell lung cancer (NSCLC) treatment. Eur J Pharm Sci. 2019;133:145–59.

    CAS  PubMed  Google Scholar 

  34. Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 2008;7:3129–40.

    CAS  PubMed  Google Scholar 

  35. Galvao J, Davis B, Tilley M, Normando E, Duchen MR, Cordeiro MF. Unexpected low-dose toxicity of the universal solvent DMSO. FASEB J. 2014;28:1317–30.

    CAS  PubMed  Google Scholar 

  36. Mehta A, Dalle Vedove E, Isert L, Merkel OM. Targeting KRAS mutant lung cancer cells with siRNA-loaded bovine serum albumin nanoparticles. Pharm Res. 2019;36:133.

    PubMed  Google Scholar 

  37. Hsu F, Caluwe AD, Anderson D, Nichol A, Toriumi T, Ho C. Patterns of spread and prognostic implications of lung cancer metastasis in an era of driver mutations. Curr Oncol. 2017;24:228–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Chanvorachote P, Chamni S, Ninsontia C, Phiboonchaiyanan PP. Potential anti-metastasis natural compounds for lung cancer. Anticancer Res. 2016;36:5707–17.

    CAS  PubMed  Google Scholar 

  39. Sahai E. Illuminating the metastatic process. Nat Rev Cancer. 2007;7:737–49.

    CAS  PubMed  Google Scholar 

  40. Zheng G, Zhao R, Xu A, Shen Z, Chen X, Shao J. Co-delivery of sorafenib and siVEGF based on mesoporous silica nanoparticles for ASGPR mediated targeted HCC therapy. Eur J Pharm Sci. 2018;111:492–502.

    CAS  PubMed  Google Scholar 

  41. Hu B, Sun D, Sun C, Sun Y-F, Sun H-X, Zhu Q-F, et al. A polymeric nanoparticle formulation of curcumin in combination with sorafenib synergistically inhibits tumor growth and metastasis in an orthotopic model of human hepatocellular carcinoma. Biochem Biophys Res Commun. 2015;468:525–32.

    CAS  PubMed  Google Scholar 

  42. Chen Y, Liu Y-C, Sung Y-C, Ramjiawan RR, Lin T-T, Chang C-C, et al. Overcoming sorafenib evasion in hepatocellular carcinoma using CXCR4-targeted nanoparticles to co-deliver MEK-inhibitors. Sci Rep. 2017;7:44123.

    PubMed  PubMed Central  Google Scholar 

  43. Gao D-Y, Lin T-T, Sung Y-C, Liu YC, Chiang W-H, Chang C-C, et al. CXCR4-targeted lipid-coated PLGA nanoparticles deliver sorafenib and overcome acquired drug resistance in liver cancer. Biomaterials. 2015;67:194–203.

    CAS  PubMed  Google Scholar 

  44. Poojari R, Kini S, Srivastava R, Panda D. Intracellular interactions of electrostatically mediated layer-by-layer assembled polyelectrolytes based sorafenib nanoparticles in oral cancer cells. Colloids Surf B: Biointerfaces. 2016;143:131–8.

    CAS  PubMed  Google Scholar 

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ACKNOWLEDGMENTS AND DISCLOSURES

This study was supported by start-up funds provided to VG by College of Pharmacy and Health Sciences (CPHS), St. John’s University. SKS, NSK, and VP were supported by teaching assistantships from CPHS, Dept. of Pharmaceutical Sciences. All authors declare no conflict of interest in this work.

The author(s) would like to acknowledge the Imaging Facility of CUNY Advanced Science Research Center for instrument use, scientific and technical assistance.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, 8000 Utopia Parkway, Queens, New York, 11439, USA

    Snehal K. Shukla, Nishant S. Kulkarni, Pamela Farrales, Dipti D. Kanabar, Vineela Parvathaneni, Nitesh K. Kunda, Aaron Muth & Vivek Gupta

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  1. Snehal K. Shukla
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Correspondence to Vivek Gupta.

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Shukla, S.K., Kulkarni, N.S., Farrales, P. et al. Sorafenib Loaded Inhalable Polymeric Nanocarriers against Non-Small Cell Lung Cancer. Pharm Res 37, 67 (2020). https://doi.org/10.1007/s11095-020-02790-3

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