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

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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.

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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(2):87–108.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed Central  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

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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).

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Authors and Affiliations

  1. College of Pharmacy, Dalian Medical University, Dalian, 116044, People’s Republic of China

    Qingqing Zhai, Hailong Li, Yanlin Song, Ruijiao Wu, Chuanfang Tang, Xiaodong Ma, Zhihao Liu, Jinyong Peng, Jianbin Zhang & Zeyao Tang

  2. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People’s Republic of China

    Zhihao Liu

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  1. Qingqing Zhai
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Correspondence to Jianbin Zhang or Zeyao Tang.

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Zhai, Q., Li, H., Song, Y. et al. Preparation and Optimization Lipid Nanocapsules to Enhance the Antitumor Efficacy of Cisplatin in Hepatocellular Carcinoma HepG2 Cells. AAPS PharmSciTech 19, 2048–2057 (2018). https://doi.org/10.1208/s12249-018-1011-6

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