Skip to main content
Log in

In vitro Anti-cancer Efficacy and Cellular Interaction of Cubic Phases Containing Cinnamic Acid, Poly(ethyleneimine), and Doxorubicin

  • Research Paper
  • Nanobiotechnology
  • Published:
Biotechnology and Bioprocess Engineering Aims and scope Submit manuscript

Abstract

Folate-decorated monoolein (MO) cubosomes containing poly(ethyleneimine) (PEI), cinnamic acid (CA), and doxorubicin (DOX) were prepared to deliver the anticancer drug specifically to cancer cells (KB cells) and boost the anti-cancer efficacy without causing an acute toxicity. Hydrophobically modified (Hm) gelatin (Gel)-folate (FA) conjugate (HmGel-FA) was prepared through amidation reaction among Gel, decanoyl chloride, and FA. HmGel-FA and Pluronic F127 were used as stabilizers for the cubosomal particles. According to the measurement of air/water interfacial tension, the surface activity was greater in the order of HmGel > HmGel-FA > Gel. Since it was reported that PEI and CA formed a self-assembly in the water channel of cubosomes and the dissolving property of the self-assembly was dependent on the pH value of medium, they were included in the water channel as a controller for DOX release. On the TEM micrographs of the cubosomes, water channels were surrounded by MO bilayers, and the payload (i.e. PEI, CA, DOX) had little effect on the structure. The in vitro anti-cancer efficacy of folate-decorated cubosomes containing PEI, CA, and DOX was higher than that of folate-free ones. According to flow cytometric analysis and confocal laser scanning microscopy, DOX fluorescence intensity was greater in the order of KB cells treated with folate-decorated cubosomes containing PEI, CA, and DOX > folate-free ones > free DOX. The folate-decorated cubosomes would be able to target the cancer cells and subsequently the receptor-mediated endocytosis would take place.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Seddon, J. M. and R. H. Templer (1993) Cubic phases of self-assembled amphiphilic aggregates. Philos. Trans. Phys. Sci. Eng. 344: 377–401.

    CAS  Google Scholar 

  2. Lindblom, G. and L. Rilfors (1989) Cubic phases and isotropic structures formed by membrane lipids—possible biological relevance. Biochim. Biophys. Acta. 988: 221–256.

    Article  CAS  Google Scholar 

  3. Choi, J. H., H. Y. Lee, J. C. Kim, and Y. C. Kim (2007) Monoolein cubic phases containing hydrophobically modified poly (N-isopropylacrylamide). J. Ind. Eng. Chem. 13: 380–386.

    CAS  Google Scholar 

  4. Nazaruk, E., M. Szlęzak, E. Górecka, R. Bilewicz, Y. M. Osornio, P. Uebelhart, and E. M. Landau (2014) Design and assembly of pH-sensitive lipidic cubic phase matrices for drug release. Langmuir. 30: 1383–1390.

    Article  CAS  Google Scholar 

  5. Negrini, R., A. Sánchez-Ferrer, and R. Mezzenga (2014) Influence of electrostatic interactions on the release of charged molecules from lipid cubic phases. Langmuir. 30: 4280–4288.

    Article  CAS  Google Scholar 

  6. Zhang, H. and J. C. Kim (2016) Reduction-responsive monoolein cubic phase containing hydrophobically modified poly (ethylene imine) and dithiodipropionic acid. Colloids Surf. A Physicochem. Eng. Asp. 506: 526–534.

    Article  CAS  Google Scholar 

  7. Rahanyan-Kägi, N., S. Aleandri, C. Speziale, R. Mezzenga, and E. M. Landau (2015) Stimuli-responsive lipidic cubic phase: triggered release and sequestration of guest molecules. Chemistry. 21: 1873–1877.

    Article  Google Scholar 

  8. Zhang, H. and J. C. Kim (2016) Concentration and temperature-sensitive assembling behavior of polyethyleneimine–cinnamic acid conjugate and its release-controlling property in monoolein cubic phase. J. Ind. Eng. Chem. 36: 215–223.

    Article  CAS  Google Scholar 

  9. Kim, J. A., D. Park, and J. C. Kim (2018) pH-sensitive self-assembling property of poly (ethyleneimine)/cinnamic acid mixture and its effect on pH-dependent release of monoolein cubic phase. Int. J. Polym. Mater. 67: 438–444.

    Article  CAS  Google Scholar 

  10. Park, D. and J. C. Kim (2019) Monoolein cubic phases containing cinnamic acid, poly(ethyleneimine) and gold nanoparticle and their UV- and NIR-responsive release property. Int. J. Pharm. 554: 420–428.

    Article  CAS  Google Scholar 

  11. Park, D., S. J. Lee, and J. C. Kim (2018) pH-sensitive self-assembled microspheres composed of poly(ethyleneimine) and cinnamic acid. Appl. Biochem. Biotechnol. 184: 253–263.

    Article  CAS  Google Scholar 

  12. Park, D. and J. C. Kim (2017) UV light and thermo-sensitive disassembling and release property of the assembly of cinnamic acid and poly(ethyleneimine). Soft Mater. 15: 282–291.

    Article  CAS  Google Scholar 

  13. Allen, T. M. (2002) Ligand-targeted therapeutics in anticancer therapy. Nat. Rev. Cancer. 2: 750–763.

    Article  CAS  Google Scholar 

  14. Toffoli, G., C. Cernigoi, A. Russo, A. Gallo, M. Bagnoli, and M. Boiocchi (1997) Overexpression of folate binding protein in ovarian cancers. Int. J. Cancer. 74: 193–198.

    Article  CAS  Google Scholar 

  15. Guo, H. and J. C. Kim (2015) Upper critical solution temperature behavior of cinnamic acid and polyethyleneimine mixture and its effect on temperature-dependent release of liposome. Int. J. Pharm. 494: 172–179.

    Article  CAS  Google Scholar 

  16. Sudimack, J. and R. J. Lee (2000) Targeted drug delivery via the folate receptor. Adv. Drug Deliv. Rev. 41: 147–162.

    Article  CAS  Google Scholar 

  17. Matsuda, M., M. Ueno, Y. Endo, M. Inoue, M. Sasaki, and T. Taguchi (2012) Enhanced tissue penetration-induced high bonding strength of a novel tissue adhesive composed of cholesteryl group-modified gelatin and disuccinimidyl tartarate. Colloids Surf. B Biointerfaces. 91: 48–56.

    Article  CAS  Google Scholar 

  18. Caffrey, M. (1987) Kinetics and mechanism of transitions involving the lamellar, cubic, inverted hexagonal, and fluid isotropic phases of hydrated monoacylglycerides monitored by time-resolved x-ray diffraction. Biochemistry. 26: 6349–6363.

    Article  CAS  Google Scholar 

  19. Zhao, X. Y., J. Zhang, L. Q. Zheng, and H. L. Dong (2005) Studies of cubosomes as a sustained drug delivery system. J. Dispers. Sci. Technol. 25: 795–799.

    Article  Google Scholar 

  20. Driever, C. D., X. Mulet, A. P. R. Johnston, L. J. Waddington, H. Thiisen, F. Caruso, and C. J. Drummond (2011) Converging layer-by-layer polyelectrolyte microcapsule and cubic lyotropic liquid crystalline nanoparticle approaches for molecular encapsulation. Soft Matter. 7: 4257–4266.

    Article  CAS  Google Scholar 

  21. Hassan, F., A. P. R. S. Islam, M. M. Mu, H. Ito, N. Koide, I. Mori, T. Yoshida, and T. Yokochi (2005) Lipopolysaccharide prevents doxorubicin-induced apoptosis in RAW 264.7 macrophage cells by inhibiting p53 activation. Mol. Cancer Res. 3: 373–379.

    Article  CAS  Google Scholar 

  22. Pan, X. Q., A. P. R. H. Wang, and R. J. Lee (2003) Antitumor activity of folate receptor-targeted liposomal doxorubicin in a KB oral carcinoma murine xenograft model. Pharm. Res. 20: 417–422.

    Article  CAS  Google Scholar 

  23. Nakagawa, K., A. P. R. S. Iwamoto, M. Nakajima, A. Shono, and K. Satoh (2004) Microchannel emulsification using gelatin and surfactant-free coacervate microencapsulation. J. Colloid Interface Sci. 278: 198–205.

    Article  CAS  Google Scholar 

  24. Toledano, O. and A. P. R. S. Magdassi (1998) Emulsification and foaming properties of hydrophobically modified gelatin. J. Colloid Interface Sci. 200: 235–240.

    Article  CAS  Google Scholar 

  25. Zhang, Y., A. P. R. N. Kohler, and M. Zhang (2002) Surface modification of superparamagnetic magnetite nanoparticles and their intracellular uptake. Biomaterials. 23: 1553–1561.

    Article  CAS  Google Scholar 

  26. Ghosh, P., A. P. R. G. Han, M. De, C. K. Kim, and V. M. Rotello (2008) Gold nanoparticles in delivery applications. Adv. Drug Deliv. Rev. 60: 1307–1315.

    Article  CAS  Google Scholar 

  27. Schmidt, H. H., A. P. R. T. D. Warner, M. Nakane, U. Förstermann, and F. Murad (1992) Regulation and subcellular location of nitrogen oxide synthases in RAW264.7 macrophages. Mol. Pharmacol. 41: 615–624.

    CAS  PubMed  Google Scholar 

  28. Alle, M., B. reddy G, T. H. Kim, S. H. Park, S. H. Lee, and J. C. Kim (2020) Doxorubicin-carboxymethyl xanthan gum capped gold nanoparticles: Microwave synthesis, characterization, and anti-cancer activity. Carbohydr. Polym. 229: 115511.

    Article  Google Scholar 

Download references

Acknowledgments

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2015R1D1A1A01057279) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (No. 2018R1A6A1A03025582).

The authors declare no conflict of interest.

Neither ethical approval nor informed consent was required for this study.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jin-Chul Kim.

Additional information

Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Park, D., Park, S.H. & Kim, JC. In vitro Anti-cancer Efficacy and Cellular Interaction of Cubic Phases Containing Cinnamic Acid, Poly(ethyleneimine), and Doxorubicin. Biotechnol Bioproc E 25, 235–245 (2020). https://doi.org/10.1007/s12257-019-0123-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12257-019-0123-5

Keywords

Navigation