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Paclitaxel and Erlotinib-co-loaded Solid Lipid Core Nanocapsules: Assessment of Physicochemical Characteristics and Cytotoxicity in Non-small Cell Lung Cancer

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Abstract

Purpose

Lung cancer is the leading cause of cancer-related deaths. The aim of this study was to design solid lipid core nanocapsules (SLCN) comprising a solid lipid core and a PEGylated polymeric corona for paclitaxel (PTX) and erlotinib (ERL) co-delivery to non-small cell lung cancer (NSCLC), and evaluate their physicochemical characteristics and in vitro activity in NCI-H23 cells.

Methods

PTX/ERL-SLCN were prepared by nanoprecipitation and sonication and physicochemically characterized by dynamic light scattering, transmission electron microscopy, differential scanning calorimetry, X-ray diffraction, and Fourier-transform infrared spectroscopy. In vitro release profiles at pH 7.4 and pH 5.0 were studied and analyzed. In vitro cytotoxicity and cellular uptake and apoptosis assays were performed in NCI-H23 cells.

Results

PTX/ERL-SLCN exhibited appropriately-sized spherical particles with a high payload. Both PTX and ERL showed pH-dependent and sustained release in vitro profiles. PTX/ERL-SLCN demonstrated concentration- and time-dependent uptake by NCI-H23 cells and caused dose-dependent cytotoxicity in the cells, which was remarkably greater than that of not only the free individual drugs but also the free drug cocktail. Moreover, well-defined early and late apoptosis were observed with clearly visible signs of apoptotic nuclei.

Conclusion

PTX/ERL-SLCN could be employed as an optimal approach for combination chemotherapy of NSCLC.

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Abbreviations

ABS:

Acetate buffer solution

DDAB:

Didodecyldimethylammonium bromide

DLS:

Dynamic light scattering

DMEM:

Dulbecco’s Modified Eagle’s medium

DMSO:

Dimethyl sulfoxide

DSC:

Differential scanning calorimetry

EGFR:

Epidermal growth factor receptor

ERL:

Erlotinib

FACS:

Fluorescence-activated cell sorting

FBS:

Fetal bovine serum

FTIR:

Fourier-transform infrared spectroscopy

GMS:

Glyceryl monostearate

HPLC:

High-performance liquid chromatography

LC:

Loading capacity

LE:

Loading efficiency

MTT:

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

MWCO:

Molecular weight cut-off

NSCLC:

Non-small cell lung cancer

PBS:

Phosphate-buffered saline

PDI:

Polydispersity index

PEG:

Poly(ethylene glycol)

PTX:

Paclitaxel

SCLC:

Small cell lung cancer

SL:

Soya lecithin

SLCN:

Solid lipid core nanocapsules

TEM:

Transmission electron microscopy

TKI:

Tyrosine kinase inhibitor

XRD:

X-ray diffraction

References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. Ca-Cancer J Clin. 2015;65:87–108.

    Article  PubMed  Google Scholar 

  2. Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83(5):584–94.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Zarogoulidis K, Zarogoulidis P, Darwiche K, Boutsikou E, Machairiotis N, Tsakiridis K, et al. Treatment of non-small cell lung cancer (NSCLC). J Thorac Dis. 2013;5(S4):S389–96.

  4. Cosaert J, Quoix E. Platinum drugs in the treatment of non-small cell lung cancer. Br J Cancer. 2002;87(8):825–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Langer CJ, Manola J, Bernardo P, Kugler JW, Bonomi P, Cella D, et al. Cisplatin-based therapy for elderly patients with advanced non-small-cell lung cancer: implications of eastern cooperative oncology group 5592, a randomized trial. J Natl Cancer Inst. 2002;94(3):173–81.

  6. Rosell R, Crino L. Pemetrexed combination therapy in the treatment of non-small cell lung cancer. Semin Oncol. 2002;29:23–9.

  7. Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczesna A, Juhasz E, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicenter, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2010;11(6):521–9.

  8. Sandler A, Ettinger DS. Gemcitabine: single-agent and combination therapy in non-small cell lung cancer. Oncologist. 1999;4(3):241–51.

    CAS  PubMed  Google Scholar 

  9. Chen YM, Perng RP, Lee YC, Shih JF, Lee CS, Tsai CM, et al. Paclitaxel plus carboplatin, compared with paclitaxel plus gemcitabine, shows similar efficacy while more cost-effective: a randomized phase II study of combination chemotherapy against inoperable non-small cell lung cancer previously untreated. Ann Oncol. 2002;13(1):108–15.

  10. Freco FA. Paclitaxel-based combination chemotherapy in advanced non-small cell lung cancer. Lung Cancer. 2001;34:S53–6.

    Article  Google Scholar 

  11. Ramalingam S. First-line chemotherapy for advanced-stage non-small-cell lung cancer: focus on docetaxel. Clin Lung Cancer. 2005;7(Suppl 3):S77–82.

    Article  CAS  PubMed  Google Scholar 

  12. Yang XQ, Li CY, MF X, Zhao H, Wang D. Comparison of first-line chemotherapy based on irinotecan or other drugs to treat non-small cell lung cancer in stage IIIB/IV: a systematic review and meta-analysis. BMC Cancer. 2015;15:949.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Grunberg SM, Crowley JJ, Livingston RB, Muggia FM, MacDonald JS, Williamson SK, et al. Treatment of non-small-cell lung cancer with vinblastine and very high-dose cisplatin. A southwest oncology group study. Cancer Chemother Pharmacol. 1991;28(3):211–3.

  14. Faller BA, Pandit TN. Safety and efficacy of vinorelbine in the treatment of non-small cell lung cancer. Clin Med Insights Oncol. 2011;5:131–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Monnet I, de Cremoux H, Soulie P, Saltiel-Voisin S, Bekradda M, Saltiel JC, et al. Oxaliplatin plus vinorelbine in advanced non-small-cell lung cancer: final results of a multicenter phase II study. Ann Oncol. 2002;13:103–7.

  16. Ardizzoni A, Antonelli G, Grossi F, Tixi L, Cafferata M, Rosso R. The combination of etoposide and cisplatin in non-small-cell lung cancer (NSCLC). Ann Oncol. 1999;10(suppl 5):S13–7.

    Article  PubMed  Google Scholar 

  17. Sculier JP, Ghisdal L, Berghmans T, Branle F, Lafitte JJ, Vallot F, et al. The role of mitomycin in the treatment of non-small cell lung cancer: a systematic review with meta-analysis of the literature. Br J Cancer. 2001;84(9):1150–5.

  18. Hesketh PJ, Tansan S, Caquioa PB, Hesketh A, Blanchard R, DiMartino N, et al. Treatment of advanced non-small cell lung cancer with very high-dose cisplatin combined with etoposide and mitomycin C. Cancer. 1993;71(3):717–20.

  19. Cullen MH, Billingham LJ, Woodroffe CM, Chetiyawardana AD, Gower NH, Joshi R, et al. Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life. J Clin Oncol. 1999;17(10):3188–94.

  20. Babiak A, Hetzel J, Godde F, Konig HH, Pietsch M, Hetzel M, et al. Vinorelbine for second-line chemotherapy in NSCLC – a phase II trial. Br J Cancer. 2007;96:1052–6.

  21. Choi JY, Thapa RK, Yong CS, Kim JO. Nanoparticle-based combination drug delivery systems for synergistic cancer treatment. J Pharm Invest. 2016;46(4):325–39.

    Article  CAS  Google Scholar 

  22. Lilenbaum RC, Herndon JE, List MA, Desch C, Watson DM, Miller AA, et al. Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: the cancer and leukemia group B (study 9730). J Clin Oncol. 2005;23(1):190–6.

  23. Chen YM, Shih JF, Lee CS, Chen MC, Lin WC, Tsai CM, et al. Study of docetaxel and ifosfamide combination chemotherapy in non-small-cell lung cancer patients failing previous chemotherapy with or without paclitaxel. Lung Cancer. 2003;39(2):209–14.

  24. Sekine I, Saijo N. Novel combination chemotherapy in the treatment of non-small cell lung cancer. Expert Opin Pharmacother. 2000;1(6):1131–61.

    Article  CAS  PubMed  Google Scholar 

  25. Tran TH, Thapa RK, Nguyen HT, Pham TT, Ramasamy T, Kim DS, et al. Combined phototherapy in anti-cancer treatment: therapeutics design and perspectives. J Pharm Invest. 2016;46(6):505–17.

  26. Lilenbaum R, Villaflor VM, Langer C, O’Byrne K, O’Brien M, Ross HJ, et al. Single-agent versus combination chemotherapy in patients with advances non-small cell lung cancer and a performance status of 2: prognostic factors and treatment selection based on two large randomized clinical trials. J Thorac Oncol. 2009;4(7):869–74.

  27. Santos FN, de Castria TB, Cruz MRS, Riera R. Chemotherapy for advances non-small cell lung cancer in the elderly population. (review) Cochrane Database Syst Rev. 2015; https://doi.org/10.1002/14651858.CD010463.pub2.

  28. Ramalingam S, Belani CP. Paclitaxel for non-small cell lung cancer. Expert Opin Pharmacother. 2004;5(8):1771–80.

    Article  CAS  PubMed  Google Scholar 

  29. Chu Q, Vincent M, Logan D, Mackay JA, Evans WK. Taxanes as first-line therapy for advanced non-small cell lung cancer: a systematic review and practice guideline. Lung Cancer. 2005;50:355–74.

    Article  PubMed  Google Scholar 

  30. Grindelli C, Bareschino MA, Schettino C, Rossi A, Maione P, Ciardiello F. Erlotinib in non-small cell lung cancer treatment: current status and future development. Oncologist. 2007;12:840–9.

    Article  Google Scholar 

  31. JL X, Jin B, Ren ZH, Lou YQ, Zhou ZR, Yang QZ, et al. Chemotherapy plus erlotinib versus chemotherapy alone for treating advanced non-small cell lung cancer: a meta-analysis. PLoS One. 2015; https://doi.org/10.1371/journal.pone.0131278.

  32. Leung L, Mok TSK, Loong H. Combining chemotherapy with epidermal growth factor receptor inhibition in advanced non-small cell lung cancer. Ther Adv Med Oncol. 2012;4(4):173–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ma L, Kohli M, Smith A. Nanoparticles for combination drug therapy. ACS Nano. 2013;7(11):9518–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hu CMJ, Aryal S, Zhang L. Nanoparticle-assisted combination therapies for effective cancer treatment. Ther Del. 2010;1(2):323–34.

    Article  CAS  Google Scholar 

  35. Gupta B, Yong CS, Kim JO. Solid matrix-based lipid nanoplatforms as carriers for combinational therapeutics in cancer. J Pharm Invest. 2017;47(6):461–73.

    Article  CAS  Google Scholar 

  36. Sharma A, Sharma US. Liposomes in drug delivery: progress and limitations. Int J Pharm. 1997;154:123–40.

    Article  CAS  Google Scholar 

  37. Sercombe L, Veerati T, Moheimani F, SY W, Sood AK, Hua S. Advances and challenges of liposome assisted drug delivery. Front Pharmacol. 2015;6:Article 286.

    Article  PubMed  Google Scholar 

  38. Puri A, Loomis K, Smith B, Lee JH, Yavlovich A, Heldman E, et al. Lipid-based nanoparticles as pharmaceutical drug carriers: from concepts to clinic. Crit Rev Ther Drug Carrier Syst. 2009;26(6):523–80.

  39. Krishnamurthy S, Vaiyapuri R, Zhang L, Chan JM. Lipid-coated polymeric nanoparticles for cancer drug delivery. Biomater Sci. 2015;3:923–36.

    Article  CAS  PubMed  Google Scholar 

  40. Gupta B, Poudel BK, Pathak S, Tak JW, Lee HH, Jeong JH, et al. Effects of formulation variables on the particle size and drug encapsulation of imatinib-loaded solid lipid nanoparticles. AAPS PharmSciTech. 2016;17(3):652–62.

  41. Varshosaz J, Ghaffari S, Khoshayand MR, Atyabi F, Azarmi S, Kobarfard F. Development and optimization of solid lipid nanoparticles of amikacin by central composite design. J Liposome Res. 2010;20(2):97–104.

    Article  CAS  PubMed  Google Scholar 

  42. Emami J, Mohiti H, Hamishehkar H, Varshosaz J. Formulation and optimization of solid lipid nanoparticle formulation for pulmonary delivery of budesonide using Taguchi and box-Behnken design. Res Pharm Sci. 2015;10(1):17–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Hao J, Fang X, Zhou Y, Wang J, Guo F, Li F, et al. Development and optimization of solid lipid nanoparticle formulation for ophthalmic delivery of chloramphenicol using a box-Behnken design. Int J Nanomedicine. 2011;6:683–92.

  44. Gupta B, Pathak S, Poudel BK, Regmi S, Ruttala HB, Gautam M, et al. Folate receptor-targeted hybrid lipid-core nanocapsules for sequential delivery of doxorubicin and tanespimycin. Colloids Surf B: Biointerfaces. 2017;155:83–92.

  45. Kobayashi H, Watanabe R, Choyke PL. Improving conventional enhanced permeability and retention (EPR) effects; what is the appropriate target? Theranostics. 2014;4(1):81–9.

    Article  CAS  Google Scholar 

  46. Gupta B, Poudel BK, Tran TH, Pradhan R, Cho HJ, Jeong JH, et al. Modulation of pharmacokinetic and cytotoxicity profile of imatinib base by employing optimized nanostructured lipid carriers. Pharm Res. 2015;32(9):2912–27.

  47. Gupta B, Ramasamy T, Poudel BK, Pathak S, Regmi S, Choi JY, et al. Development of bioactive PEGylated nanostructured platforms for sequential delivery of doxorubicin and imatinib to overcome drug resistance in metastatic tumors. ACS Appl Mater Interfaces. 2017;9:9280–90.

  48. Korsmeyer RW, Gurny R, Doelker E, Buri P, Peppas NA. Mechanisms of solute release from porous hydrophilic polymers. Int J Pharm. 1983;15:25–35.

    Article  CAS  Google Scholar 

  49. Rejman J, Oberle V, Zuhorn IS, Hoekstra D. Size-dependent internalization of particles via the pathways of clathrin- and caveolae-mediated endocytosis. Biochem J. 2004;377(1):159–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments and Disclosures

This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2015R1A2A2A01004118, 2015R1A2A2A04004806, and by the Medical Research Center Program (2015R1A5A2009124) through the NRF funded by MSIP).

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Authors and Affiliations

  1. College of Pharmacy, Yeungnam University, 214-1, Dae-Dong, Gyeongsan, 712-749, South Korea

    Biki Gupta, Bijay Kumar Poudel, Shobha Regmi, Shiva Pathak, Hima Bindu Ruttala, Milan Gautam, Gyeong Jin An, Jee-Heon Jeong, Chul Soon Yong & Jong Oh Kim

  2. College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University,, 55, Hanyangdaehak-ro Sangnok-gu, Ansan, 426-791, South Korea

    Han-Gon Choi

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  1. Biki Gupta
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Correspondence to Chul Soon Yong or Jong Oh Kim.

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Gupta, B., Poudel, B.K., Regmi, S. et al. Paclitaxel and Erlotinib-co-loaded Solid Lipid Core Nanocapsules: Assessment of Physicochemical Characteristics and Cytotoxicity in Non-small Cell Lung Cancer. Pharm Res 35, 96 (2018). https://doi.org/10.1007/s11095-017-2337-6

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