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AAPS PharmSciTech

, Volume 19, Issue 5, pp 2048–2057 | Cite as

Preparation and Optimization Lipid Nanocapsules to Enhance the Antitumor Efficacy of Cisplatin in Hepatocellular Carcinoma HepG2 Cells

  • Qingqing Zhai
  • Hailong Li
  • Yanlin Song
  • Ruijiao Wu
  • Chuanfang Tang
  • Xiaodong Ma
  • Zhihao Liu
  • Jinyong Peng
  • Jianbin Zhang
  • Zeyao Tang
Research Article

Abstract

This work aimed to develop and optimize several lipid nanocapsule formulations (LNCs) to encapsulate cisplatin (CDDP) for treatment of hepatocellular carcinoma. By comparing the effect of oil/surfactant ratio, lecithin content, and oil/surfactant type on LNC characteristics, two LNCs were selected as optimal formulations: HS15-LNC (Solutol HS 15/MCT/lecithin, 54.5:42.5:3%, w/w) and EL-LNC (Cremophor EL/MCT/lecithin, 54.5:42.5:3%, w/w). Both LNCs could effectively encapsulate CDDP with the encapsulation efficiency of 73.48 and 78.84%. In vitro release study showed that both LNCs could sustain the release CDDP. Moreover, cellular uptake study showed that C6-labeled LNCs could be effectively internalized by HepG2 cells. Cellular cytotoxicity study revealed that both LNCs showed negligible cellular toxicity when their concentrations were below 313 μg/mL. Importantly, CDDP-loaded LNCs exhibited much stronger cell killing potency than free CDDP, with the IC50 values decreased from 17.93 to 3.53 and 5.16 μM after 72-h incubation. In addition, flow cytometric analysis showed that the percentage of apoptotic cells was significantly increased after treatment with LNCs. Therefore, the prepared LNC formulations exhibited promising anti-hepatocarcinoma effect, which could be beneficial to hepatocellular carcinoma therapy.

KEY WORDS

lipid nanocapsule hepatocellular carcinoma cisplatin solutol HS 15 cremophor EL 

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant No. 81603186) and Educational Committee Foundation of Liaoning Province (Grant No. L2016026).

References

  1. 1.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.CrossRefPubMedGoogle Scholar
  2. 2.
    Mohamed NK, Hamad MA, Hafez MZ, Wooley KL, Elsabahy M. Nanomedicine in management of hepatocellular carcinoma: challenges and opportunities. Int J Cancer. 2017;140(7):1475–84.CrossRefPubMedGoogle Scholar
  3. 3.
    Zhao J, Zhao J, Jiao H. Synergistic growth-suppressive effects of quercetin and cisplatin on HepG2 human hepatocellular carcinoma cells. Appl Biochem Biotechnol. 2014;172(2):784–91.CrossRefPubMedGoogle Scholar
  4. 4.
    Cai Y, Xu Y, Chan HF, Fang X, He C, Chen M. Glycyrrhetinic acid mediated drug delivery carriers for hepatocellular carcinoma therapy. Mol Pharm. 2016;13(3):699–709.CrossRefPubMedGoogle Scholar
  5. 5.
    Shah M, Ullah N, Choi MH, Kim MO, Yoon SC. Amorphous amphiphilic P (3HV-co-4HB)-b-mPEG block copolymer synthesized from bacterial copolyester via melt transesterification: nanoparticle preparation, cisplatin-loading for cancer therapy and in vitro evaluation. Eur J Pharm Biopharm. 2012;80(3):518–27.CrossRefPubMedGoogle Scholar
  6. 6.
    Liu C-L, Lim Y-P, Hu M-L. Fucoxanthin enhances cisplatin-induced cytotoxicity via NFκB-mediated pathway and downregulates DNA repair gene expression in human hepatoma HepG2 cells. Marine Drugs. 2013;11(1):50–66.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Wu S, Zhang T, Du J. Ursolic acid sensitizes cisplatin-resistant hepg2/DDP cells to cisplatin via inhibiting nrf2/are pathway. Drug Design, Development and Therapy. 2016;10:3471–81.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Salimi F, Dilmaghani KA, Alizadeh E, Akbarzadeh A, Davaran S. Enhancing cisplatin delivery to hepatocellular carcinoma HepG2 cells using dual sensitive smart nanocomposite. Artif Cells Nanomed Biotechnol. 2017:1–10.Google Scholar
  9. 9.
    Chang TW, Lin CY, Tzeng YJ, Lur HS. Synergistic combinations of tanshinone IIA and trans-resveratrol toward cisplatin-comparable cytotoxicity in HepG2 human hepatocellular carcinoma cells. Anticancer Res. 2014;34(10):5473–80.PubMedGoogle Scholar
  10. 10.
    Shi H, Cheng Q, Yuan S, Ding X, Liu Y. Human serum albumin conjugated nanoparticles for pH and redox-responsive delivery of a prodrug of cisplatin. Chem Eur J. 2015;21(46):16547–54.CrossRefPubMedGoogle Scholar
  11. 11.
    Zhang C, Nance EA, Mastorakos P, Chisholm J, Berry S, Eberhart C, et al. Convection enhanced delivery of cisplatin-loaded brain penetrating nanoparticles cures malignant glioma in rats. J Control Release. 2017;263:112–9.  https://doi.org/10.1016/j.jconrel.2017.03.007.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Song J, Xu T, Zhang Y, Guo H, Ren W, Zhu S, et al. 3-octadecylcarbamoylacrylic acid-cisplatin nanocomplexes for the development of novel liposome formulation. Drug delivery. 2016;23(9):3285–93.CrossRefPubMedGoogle Scholar
  13. 13.
    Mattheolabakis G, Taoufik E, Haralambous S, Roberts ML, Avgoustakis K. In vivo investigation of tolerance and antitumor activity of cisplatin-loaded PLGA-mPEG nanoparticles. Eur J Pharm Biopharm. 2009;71(2):190–5.CrossRefPubMedGoogle Scholar
  14. 14.
    Hwang PA, Lin XZ, Kuo KL, Hsu FY. Fabrication and cytotoxicity of fucoidan-cisplatin nanoparticles for macrophage and tumor cells. Materials. 2017;10(3):291.CrossRefPubMedCentralGoogle Scholar
  15. 15.
    Cheng Q, Shi H, Huang H, Cao Z, Wang J, Liu Y. Oral delivery of a platinum anticancer drug using lipid assisted polymeric nanoparticles. Chem Commun. 2015;51(99):17536–9.CrossRefGoogle Scholar
  16. 16.
    Cafaggi S, Russo E, Stefani R, Leardi R, Caviglioli G, Parodi B, et al. Preparation and evaluation of nanoparticles made of chitosan or N-trimethyl chitosan and a cisplatin–alginate complex. J Control Release. 2007;121(1):110–23.CrossRefPubMedGoogle Scholar
  17. 17.
    Saliou B, Thomas O, Lautram N, Clavreul A, Hureaux J, Urban T, et al. Development and in vitro evaluation of a novel lipid nanocapsule formulation of etoposide. Eur J Pharm Sci. 2013;50(2):172–80.CrossRefPubMedGoogle Scholar
  18. 18.
    Zhang Y, Zhang W, Löbler M, Schmitz KP, Saulnier P, Perrier T, et al. Inner ear biocompatibility of lipid nanocapsules after round window membrane application. Int J Pharm. 2011;404(1):211–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Maupas C, Moulari B, Béduneau A, Lamprecht A, Pellequer Y. Surfactant dependent toxicity of lipid nanocapsules in HaCaT cells. Int J Pharm. 2011;411(1):136–41.CrossRefPubMedGoogle Scholar
  20. 20.
    Paese K, Ortiz M, Frank LA, Kulkamp-Guerreiro IC, Rolim CM, Barros DM, et al. Production of isotonic, sterile, and kinetically stable lipid-core nanocapsules for injectable administration. AAPS PharmSciTech. 2017;18(1):212–23.  https://doi.org/10.1208/s12249-016-0493-3.CrossRefPubMedGoogle Scholar
  21. 21.
    Weyland M, Manero F, Paillard A, Gree D, Viault G, Jarnet D, et al. Mitochondrial targeting by use of lipid nanocapsules loaded with SV30, an analogue of the small-molecule Bcl-2 inhibitor HA14-1. J Control Release. 2011;151(1):74–82.CrossRefPubMedGoogle Scholar
  22. 22.
    Tran TH, Nguyen TD, Poudel BK, Nguyen HT, Kim JO, Yong CS, et al. Development and evaluation of artesunate-loaded chitosan-coated lipid nanocapsule as a potential drug delivery system against breast cancer. AAPS PharmSciTech. 2015;16(6):1307–16.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Roger E, Lagarce F, Benoit JP. Development and characterization of a novel lipid nanocapsule formulation of Sn38 for oral administration. Eur J Pharm Biopharm. 2011;79(1):181–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Groo AC, Bossiere M, Trichard L, Legras P, Benoit J-P, Lagarce F. In vivo evaluation of paclitaxel-loaded lipid nanocapsules after intravenous and oral administration on resistant tumor. Nanomedicine. 2015;10(4):589–601.CrossRefPubMedGoogle Scholar
  25. 25.
    Hureaux J, Lagarce F, Gagnadoux F, Rousselet M-C, Moal V, Urban T, et al. Toxicological study and efficacy of blank and paclitaxel-loaded lipid nanocapsules after iv administration in mice. Pharm Res. 2010;27(3):421–30.CrossRefPubMedGoogle Scholar
  26. 26.
    Tian J, Pang X, Yu K, Liu L, Zhou J. Preparation, characterization and in vivo distribution of solid lipid nanoparticles loaded with cisplatin. Pharmazie. 2008;63(8):593–7.PubMedGoogle Scholar
  27. 27.
    Bannister SJ, Sternson LA, Repta AJ. Urine analysis of platinum species derived from cis-dichlorodiammineplatinum (II) by high-performance liquid chromatography following derivatization with sodium diethyldithiocarbamate. J Chromatogr A. 1979;173(2):333–42.CrossRefGoogle Scholar
  28. 28.
    Zhang J, Lv Y, Zhao S, Wang B, Tan M, Xie H, et al. Effect of lipolysis on drug release from self-microemulsifying drug delivery systems (SMEDDS) with different core/shell drug location. AAPS PharmSciTech. 2014;15(3):731–40.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Heurtault B, Saulnier P, Pech B, Proust J-E, Benoit J-P. A novel phase inversion-based process for the preparation of lipid nanocarriers. Pharm Res. 2002;19(6):875–80.  https://doi.org/10.1023/A:1016121319668.CrossRefPubMedGoogle Scholar
  30. 30.
    Matsaridou I, Barmpalexis P, Salis A, Nikolakakis I. The influence of surfactant HLB and oil/surfactant ratio on the formation and properties of self-emulsifying pellets and microemulsion reconstitution. AAPS PharmSciTech. 2012;13(4):1319–30.  https://doi.org/10.1208/s12249-012-9855-7.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Peng L-C, Liu C-H, Kwan C-C, Huang K-F. Optimization of water-in-oil nanoemulsions by mixed surfactants. Colloids Surf A Physicochem Eng Asp. 2010;370(1):136–42.  https://doi.org/10.1016/j.colsurfa.2010.08.060.CrossRefGoogle Scholar
  32. 32.
    Roy U, Ding H, Pilakka-Kanthikeel S, Raymond AD, Atluri V, Yndart A, et al. Preparation and characterization of anti-HIV nanodrug targeted to microfold cell of gut-associated lymphoid tissue. Int J Nanomedicine. 2015;10:5819–35.  https://doi.org/10.2147/IJN.S68348.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Li S, Li C, Jin S, Liu J, Xue X, Eltahan AS, et al. Overcoming resistance to cisplatin by inhibition of glutathione S-transferases (GSTs) with ethacraplatin micelles in vitro and in vivo. Biomaterials. 2017;144:119–29.CrossRefPubMedGoogle Scholar
  34. 34.
    Hatahet T, Morille M, Shamseddin A, Aubert-Pouëssel A, Devoisselle JM, Bégu S. Dermal quercetin lipid nanocapsules: influence of the formulation on antioxidant activity and cellular protection against hydrogen peroxide. Int J Pharm. 2017;518(1):167–76.  https://doi.org/10.1016/j.ijpharm.2016.12.043.CrossRefPubMedGoogle Scholar
  35. 35.
    Torge A, Wagner S, Chaves PS, Oliveira EG, Guterres SS, Pohlmann AR, et al. Ciprofloxacin-loaded lipid-core nanocapsules as mucus penetrating drug delivery system intended for the treatment of bacterial infections in cystic fibrosis. Int J Pharm. 2017;527(1):92–102.  https://doi.org/10.1016/j.ijpharm.2017.05.013.CrossRefPubMedGoogle Scholar
  36. 36.
    de Andrade DF, Zuglianello C, Pohlmann AR, Guterres SS, Beck RC. Assessing the in vitro drug release from lipid-core nanocapsules: a new strategy combining dialysis sac and a continuous-flow system. AAPS PharmSciTech. 2015;16(6):1409–17.  https://doi.org/10.1208/s12249-015-0330-0.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Zhang J, Lv Y, Wang B, Zhao S, Tan M, Lv G, et al. Influence of microemulsion–mucin interaction on the fate of microemulsions diffusing through pig gastric mucin solutions. Mol Pharm. 2015;12(3):695–705.CrossRefPubMedGoogle Scholar
  38. 38.
    Lv X, Liu T, Ma H, Tian Y, Li L, Li Z, et al. Preparation of essential oil-based microemulsions for improving the solubility, pH stability, photostability, and skin permeation of quercetin. AAPS PharmSciTech. 2017:1–8.Google Scholar
  39. 39.
    Duan X, He C, Kron SJ, Lin W. Nanoparticle formulations of cisplatin for cancer therapy. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology. 2016;8(5):776–91.  https://doi.org/10.1002/wnan.1390.PubMedCrossRefGoogle Scholar
  40. 40.
    Vhora I, Khatri N, Desai J, Thakkar HP. Caprylate-conjugated cisplatin for the development of novel liposomal formulation. AAPS PharmSciTech. 2014;15(4):845–57.  https://doi.org/10.1208/s12249-014-0106-y.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Wang S, Chen T, Chen R, Hu Y, Chen M, Wang Y. Emodin loaded solid lipid nanoparticles: preparation, characterization and antitumor activity studies. Int J Pharm. 2012;430(1):238–46.CrossRefPubMedGoogle Scholar
  42. 42.
    Lollo G, Vincent M, Ullio-Gamboa G, Lemaire L, Franconi F, Couez D, et al. Development of multifunctional lipid nanocapsules for the co-delivery of paclitaxel and CpG-ODN in the treatment of glioblastoma. Int J Pharm. 2015;495(2):972–80.  https://doi.org/10.1016/j.ijpharm.2015.09.062.CrossRefPubMedGoogle Scholar
  43. 43.
    Teixeira MC, Carbone C, Souto EB. Beyond liposomes: recent advances on lipid based nanostructures for poorly soluble/poorly permeable drug delivery. Prog Lipid Res. 2017;68:1–11.  https://doi.org/10.1016/j.plipres.2017.07.001.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Qingqing Zhai
    • 1
  • Hailong Li
    • 1
  • Yanlin Song
    • 1
  • Ruijiao Wu
    • 1
  • Chuanfang Tang
    • 1
  • Xiaodong Ma
    • 1
  • Zhihao Liu
    • 1
    • 2
  • Jinyong Peng
    • 1
  • Jianbin Zhang
    • 1
  • Zeyao Tang
    • 1
  1. 1.College of PharmacyDalian Medical UniversityDalianPeople’s Republic of China
  2. 2.State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingPeople’s Republic of China

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