Skip to main content

Advertisement

SpringerLink
Log in

A facile and simple synthesis of a cytotoxic tocotrienol-based nanoemulsion against MCF-7 and A549 cancer cell lines

  • Research
  • Published:
Colloid and Polymer Science Aims and scope Submit manuscript

Abstract

Tocotrienol is a subfamily of natural vitamin E with multiple biological activities, including antioxidants, antiproliferative, proapoptotic, antiangiogenic, and anti-inflammatory properties. Despite numerous biological activities, the application of tocotrienol is hampered by its poor solubility, resulting in low bioavailability, and in turn, limits its therapeutic effectivity. To address these limitations, the present study focuses on the development of tocotrienol nanoemulsion, followed by an in vitro anticancer evaluation of the formula. The tocotrienol nanoemulsion was prepared by a combination of high-speed homogenization with ultrasonication, using food-grade canola oil and Tween 80 as oil phases and surfactants, respectively. The formulated nanoemulsion observed an encapsulation efficiency of 90.26% with particle size and zeta potential of 145 ± 0.06 nm and −25.27 ± 0.01 mV, respectively. The FTIR spectra show no interference between the active compounds and the excipients, indicating that tocotrienol was successfully loaded into the nanoemulsion. Besides, the tocotrienol nanoemulsions demonstrated higher antioxidant ABTS (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical scavenging activity than the free form of tocotrienol at the same concentration (p < 0.05). In the in vitro cytotoxicity studies, there was a decrease in cell viability observed against MCF-7 breast and A549 lung cancer cell lines for tocotrienol nanoemulsion. Overall, it suggests that nanoemulsion-based natural component delivery systems have substantial implications in developing and designing encapsulated biologically active systems. The potent cytotoxicity of tocotrienol-loaded nanoemulsion under aqueous phases provides insight into the development of nanoemulsion systems for enhancing the bioavailability and activity of tocotrienol as well as other lipophilic compounds in water systems, particularly for anticancer therapeutic.

Graphical Abstract

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

No datasets were generated or analyzed during the current study.

References

  1. Ahsan H, Ahad A, Iqbal J, Siddiqui WA (2014) Pharmacological potential of tocotrienols: a review. Nutr Metab 11:1–22. https://doi.org/10.1186/1743-7075-11-52

    Article  CAS  Google Scholar 

  2. Aggarwal BB, Sundaram C, Prasad S, Kannappan R (2010) Tocotrienols, the vitamin E of the 21st century: it’s potential against cancer and other chronic diseases. Biochem Pharmacol 80:1613–1631. https://doi.org/10.1016/j.bcp.2010.07.043.Tocotrienols

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Nakatomi T, Itaya-Takahashi M, Horikoshi Y et al (2023) The difference in the cellular uptake of tocopherol and tocotrienol is influenced by their affinities to albumin. Sci Rep 13:1–11. https://doi.org/10.1038/s41598-023-34584-z

    Article  CAS  Google Scholar 

  4. Banasaz S, Morozova K, Ferrentino G, Scampicchio M (2020) Encapsulation of lipid-soluble bioactives by nanoemulsions. Molecules 25:1–29. https://doi.org/10.3390/molecules25173966

    Article  CAS  Google Scholar 

  5. Goh PS, Ng MH, Choo YM et al (2015) Production of nanoemulsions from palm-based tocotrienol rich fraction by microfluidization. Molecules 20:19936–19946. https://doi.org/10.3390/molecules201119666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kofler M, Sommer PF, Bolliger HR et al (1962) Physicochemical properties and assay of the tocopherols. Vitam Horm 20:407–440. https://doi.org/10.1016/S0083-6729(08)60727-X

    Article  CAS  Google Scholar 

  7. Blokhina O, Virolainen E, Fagerstedt KV (2003) Antioxidants, oxidative damage and oxygen deprivation stress: a review. Ann Bot 91:179–194. https://doi.org/10.1093/aob/mcf118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Pierpaoli E, Viola V, Pilolli F et al (2010) γ- and δ-tocotrienols exert a more potent anticancer effect than α-tocopheryl succinate on breast cancer cell lines irrespective of HER-2/neu expression. Life Sci 86:668–675. https://doi.org/10.1016/j.lfs.2010.02.018

    Article  CAS  PubMed  Google Scholar 

  9. Zaffarin ASM, Ng SF, Ng MH et al (2020) Pharmacology and pharmacokinetics of vitamin E: nanoformulations to enhance bioavailability. Int J Nanomedicine 15:9961–9974. https://doi.org/10.2147/IJN.S276355

    Article  Google Scholar 

  10. Yap SP, Yuen KH, Lim AB (2003) Infuence of route of administration on the absorption and disposition of alpha, gamma, and delta-tocotrienols in rats. J Pharm Pharmacol 55:53–58. https://doi.org/10.1211/002235702450

    Article  PubMed  Google Scholar 

  11. Hasan ZAA, Idris Z, Gani SSA, Basri M (2018) In vitro safety evaluation of palm tocotrienol-rich fraction nanoemulsion for topical application. J Oil Palm Res 30:150–162. https://doi.org/10.21894/jopr.2018.0004

    Article  CAS  Google Scholar 

  12. Chong WT, Tan CP, Cheah YK et al (2018) Optimization of process parameters in preparation of tocotrienol-rich red palm oil-based nanoemulsion stabilized by Tween80-Span 80 using response surface methodology. PLoS ONE 13:1–22. https://doi.org/10.1371/journal.pone.0202771

    Article  CAS  Google Scholar 

  13. Jaiswal M, Dudhe R, Sharma PK (2015) Nanoemulsion: an advanced mode of drug delivery system. 3 Biotech 5:123–127. https://doi.org/10.1007/s13205-014-0214-0

    Article  PubMed  Google Scholar 

  14. Sánchez-López E, Guerra M, Dias-Ferreira J et al (2019) Current applications of nanoemulsions in cancer therapeutics. Nanomaterials. https://doi.org/10.3390/nano9060821

    Article  PubMed  PubMed Central  Google Scholar 

  15. Shaker DS, Ishak RAH, Ghoneim A, Elhuoni MA (2019) Nanoemulsion: a review on mechanisms for the transdermal delivery of hydrophobic and hydrophilic drugs. Sci Pharm. https://doi.org/10.3390/scipharm87030017

    Article  Google Scholar 

  16. Date AA, Desai N, Dixit R, Nagarsenker M (2010) Self-nanoemulsifying drug delivery systems: formulation insights, applications and advances. Nanomedicine 5:1595–1616. https://doi.org/10.2217/nnm.10.126

    Article  CAS  PubMed  Google Scholar 

  17. Saffarionpour S (2019) Preparation of food flavor nanoemulsions by high- and low-energy emulsification approaches. Food Eng Rev 11:259–289. https://doi.org/10.1007/s12393-019-09201-3

    Article  Google Scholar 

  18. Karsli GT, Sahin S, Oztop MH (2022) High-pressure-homogenized clove and thyme oil emulsions: formulation, stability, and antioxidant capacity. ACS Food Sci Technol 2:1832–1839. https://doi.org/10.1021/acsfoodscitech.2c00231

    Article  CAS  Google Scholar 

  19. Safaya M, Rotliwala YC (2020) Nanoemulsions: a review on low energy formulation methods, characterization, applications and optimization technique. Mater Today Proc 27:454–459. https://doi.org/10.1016/j.matpr.2019.11.267

    Article  CAS  Google Scholar 

  20. Himanath G, Shruthy R, Preetha R, Sreejit V (2021) Nanoemulsion with coconut oil and soy lecithin as a stable delivery system for lycopene and its incorporation into yogurt to enhance antioxidant properties and maintain quality. ACS Food Sci Technol 1:1538–1549. https://doi.org/10.1021/acsfoodscitech.1c00117

    Article  CAS  Google Scholar 

  21. McClements DJ (2012) Edible delivery systems for nutraceuticals: designing functional foods for improved health. Ther Deliv 3:801–803. https://doi.org/10.4155/tde.12.56

    Article  CAS  PubMed  Google Scholar 

  22. Mushtaq A, Mohd Wani S, Malik AR et al (2023) Recent insights into nanoemulsions: their preparation, properties and applications. Food Chem X 18:100684. https://doi.org/10.1016/j.fochx.2023.100684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ledet GA, Biswas S, Kumar VP et al (2017) Development of orally administered γ tocotrienol (GT3) nanoemulsion for radioprotection. Int J Mol Sci. https://doi.org/10.3390/ijms18010028

    Article  Google Scholar 

  24. Chong WT, Tan CP, Cheah YK, Lai OM (2022) In-vitro and in-vivo evaluations of tocotrienolrich nanoemulsified system on skin wound healing. PLoS ONE 17:1–20. https://doi.org/10.1371/journal.pone.0267381

    Article  CAS  Google Scholar 

  25. Schreiner TB, Santamaria-Echart A, Colucci G et al (2023) Saponin-based natural nanoemulsions as alpha-tocopherol delivery systems for dermal applications. J Mol Liq. https://doi.org/10.1016/j.molliq.2023.123371

    Article  Google Scholar 

  26. Pham J, Nayel A, Hoang C, Elbayoumi T (2016) Enhanced effectiveness of tocotrienol-based nano-emulsified system for topical delivery against skin carcinomas. Drug Deliv 23:1514–1524. https://doi.org/10.3109/10717544.2014.966925

    Article  CAS  PubMed  Google Scholar 

  27. Steuber N, Vo K, Wadhwa R et al (2016) Tocotrienol nanoemulsion platform of curcumin elicit elevated apoptosis and augmentation of anticancer efficacy against breast and ovarian carcinomas. Int J Mol Sci 17:1–17. https://doi.org/10.3390/ijms17111792

    Article  CAS  Google Scholar 

  28. Raviadaran R, Ng MH, Chandran D et al (2021) Stable W/O/W multiple nanoemulsion encapsulating natural tocotrienols and caffeic acid with cisplatin synergistically treated cancer cell lines (A549 and HEP G2) and reduced toxicity on normal cell line (HEK 293). Mater Sci Eng C. https://doi.org/10.1016/j.msec.2020.111808

    Article  Google Scholar 

  29. Montes de Oca-Ávalos JM, Candal RJ, Herrera ML (2017) Colloidal properties of sodium caseinate-stabilized nanoemulsions prepared by a combination of a high-energy homogenization and evaporative ripening methods. Food Res Int 100:143–150. https://doi.org/10.1016/j.foodres.2017.06.035

    Article  CAS  PubMed  Google Scholar 

  30. Ullah N, Amin A, Alamoudi RA et al (2022) Fabrication and optimization of essential-oil-loaded nanoemulsion using Box-Behnken design against Staphylococos aureus and Staphylococos epidermidis isolated from oral cavity. Pharmaceutics 14:1–22. https://doi.org/10.3390/pharmaceutics14081640

    Article  CAS  Google Scholar 

  31. Ali H, Nazzal S (2009) Journal of Pharmaceutical and Biomedical Analysis Development and validation of a reversed-phase HPLC method for the simultaneous analysis of simvastatin and tocotrienols in combined dosage forms. 49:950–956. https://doi.org/10.1016/j.jpba.2009.02.009

    Article  CAS  Google Scholar 

  32. Nenandis N, Wang L-F, Tsimidou M, Zhang H-Y (2004) Estimation of scavenging activity of phenolic compounds using the ABTS•+ assay, Journal of agricultural and food chemistry.pdf. J Agric Food Chem 52:4669–4674

    Article  Google Scholar 

  33. Kassem MGA, Ahmed AMM, Abdel-Rahman HH, Moustafa AHE (2019) Use of Span 80 and Tween 80 for blending gasoline and alcohol in spark ignition engines. Energy Rep 5:221–230. https://doi.org/10.1016/j.egyr.2019.01.009

    Article  Google Scholar 

  34. Bose S, Du Y, Takhistov P, Michniak-Kohn B (2013) Formulation optimization and topical delivery of quercetin from solid lipid based nanosystems. Int J Pharm 441:56–66. https://doi.org/10.1016/j.ijpharm.2012.12.013

    Article  CAS  PubMed  Google Scholar 

  35. Danaei M, Dehghankhold M, Ataei S et al (2018) Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics 10:1–17. https://doi.org/10.3390/pharmaceutics10020057

    Article  CAS  Google Scholar 

  36. Jusril NA, Abu Bakar SI, Khalil KA et al (2022) Development and optimization of nanoemulsion from ethanolic extract of Centella asiatica (NanoSECA) using D-optimal mixture design to improve blood-brain barrier permeability. Evidence-based Complement Altern Med. https://doi.org/10.1155/2022/3483511

    Article  Google Scholar 

  37. Ali HH, Hussein AA (2017) Oral nanoemulsions of candesartan cilexetil: formulation, characterization and in vitro drug release studies. AAPS Open. https://doi.org/10.1186/s41120-017-0016-7

    Article  Google Scholar 

  38. Hong IK, Kim SI, Lee SB (2018) Effects of HLB value on oil-in-water emulsions: droplet size, rheological behavior, zeta-potential, and creaming index. J Ind Eng Chem 67:123–131. https://doi.org/10.1016/j.jiec.2018.06.022

    Article  CAS  Google Scholar 

  39. Yang F, Wu W, Chen S, Gan W (2017) The ionic strength dependent zeta potential at the surface of hexadecane droplets in water and the corresponding interfacial adsorption of surfactants. Soft Matter 13:638–646. https://doi.org/10.1039/c6sm02174c

    Article  CAS  PubMed  Google Scholar 

  40. Büsing A, Ternes W (2011) Separation of α-tocotrienol oxidation products and eight tocochromanols by HPLC with DAD and fluorescence detection and identification of unknown peaks by DAD, PBI-EIMS, FTIR, and NMR. Anal Bioanal Chem 401:2843–2854. https://doi.org/10.1007/s00216-011-5352-1

    Article  CAS  PubMed  Google Scholar 

  41. Zhang H, Ma J, Miao Y et al (2015) Analysis of carbonyl value of frying oil by Fourier transform infrared spectroscopy. J Oleo Sci 64:375–380. https://doi.org/10.5650/jos.ess14201

    Article  CAS  PubMed  Google Scholar 

  42. Sahu M, Reddy VRM, Kim B et al (2022) Fabrication of Cu2ZnSnS4 light absorber using a cost-effective mechanochemical method for photovoltaic applications. Mater (Basel) 15:1–16. https://doi.org/10.3390/ma15051708

    Article  CAS  Google Scholar 

  43. Alam A, Ansari MJ, Alqarni MH et al (2023) Antioxidant, antibacterial, and anticancer activity of ultrasonic nanoemulsion of cinnamomum Cassia L. essential oil. Plants2 12:1–15. https://doi.org/10.3390/plants12040834

    Article  CAS  Google Scholar 

  44. Sneha K, Kumar A (2022) Nanoemulsions: techniques for the preparation and the recent advances in their food applications. Innov Food Sci Emerg Technol 76:102914. https://doi.org/10.1016/j.ifset.2021.102914

    Article  CAS  Google Scholar 

  45. Pavoni L, Perinelli DR, Ciacciarelli A et al (2020) Properties and stability of nanoemulsions: how relevant is the type of surfactant? J Drug Deliv Sci Technol 58:101772. https://doi.org/10.1016/j.jddst.2020.101772

    Article  CAS  Google Scholar 

  46. Thanasukarn P, Pongsawatmanit R, McClements DJ (2006) Impact of fat and water crystallization on the stability of hydrogenated palm oil-in-water emulsions stabilized by a nonionic surfactant. J Agric Food Chem 54:3591–3597. https://doi.org/10.1021/jf0524630

    Article  CAS  PubMed  Google Scholar 

  47. Ghosh S, Coupland JN (2008) Factors affecting the freeze-thaw stability of emulsions. Food Hydrocoll 22:105–111. https://doi.org/10.1016/j.foodhyd.2007.04.013

    Article  CAS  Google Scholar 

  48. Mota Ferreira L, Gehrcke M, Ferrari Cervi V et al (2016) Pomegranate seed oil nanoemulsions with selective antiglioma activity: optimization and evaluation of cytotoxicity, genotoxicity and oxidative effects on mononuclear cells. Pharm Biol 54:2968–2977. https://doi.org/10.1080/13880209.2016.1199039

    Article  CAS  PubMed  Google Scholar 

  49. Azeem A, Rizwan M, Ahmad FJ et al (2009) Nanoemulsion components screening and selection: a technical note. AAPS PharmSciTech 10:69–76. https://doi.org/10.1208/s12249-008-9178-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Peh HY, Tan WSD, Liao W, Wong WSF (2016) Vitamin E therapy beyond cancer: tocopherol versus tocotrienol. Pharmacol Ther 162:152–169. https://doi.org/10.1016/j.pharmthera.2015.12.003

    Article  CAS  PubMed  Google Scholar 

  51. Azizkhani M, Jafari Kiasari F, Tooryan F et al (2021) Preparation and evaluation of food-grade nanoemulsion of tarragon (Artemisia dracunculus L.) essential oil: antioxidant and antibacterial properties. J Food Sci Technol 58:1341–1348. https://doi.org/10.1007/s13197-020-04645-6

    Article  CAS  PubMed  Google Scholar 

  52. Sundararajan B, Moola AK, Vivek K, Kumari BDR (2018) Formulation of nanoemulsion from leaves essential oil of Ocimum basilicum L. and its antibacterial, antioxidant and larvicidal activities (Culex quinquefasciatus). Microb Pathog 125:475–485. https://doi.org/10.1016/j.micpath.2018.10.017

    Article  CAS  PubMed  Google Scholar 

  53. da Silva BD, do Rosário DKA, Neto LT et al (2023) Antioxidant, antibacterial and antibiofilm activity of nanoemulsion-based natural compound delivery systems compared with non-nanoemulsified versions. Foods 12:1–12. https://doi.org/10.3390/foods12091901

    Article  CAS  Google Scholar 

  54. Nie Y, Pan Y, Jiang Y et al (2023) Stability and bioactivity evaluation of black pepper essential oil nanoemulsion. Heliyon 9:e14730. https://doi.org/10.1016/j.heliyon.2023.e14730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Liu T, Gao Z, Zhong W et al (2022) Preparation, characterization, and antioxidant activity of nanoemulsions incorporating lemon essential oil. Antioxidants 11:1–13. https://doi.org/10.3390/antiox11040650

    Article  CAS  Google Scholar 

  56. Aggarwal V, Kashyap D, Sak K et al (2019) Molecular mechanisms of action of tocotrienols in cancer: recent trends and advancements. Int J Mol Sci. https://doi.org/10.3390/ijms20030656

    Article  PubMed  PubMed Central  Google Scholar 

  57. Pang KL, Mai CW, Chin KY (2023) Molecular mechanism of tocotrienol-mediated anticancer properties: a systematic review of the involvement of endoplasmic reticulum stress and unfolded protein response. Nutrients. https://doi.org/10.3390/nu15081854

    Article  PubMed  PubMed Central  Google Scholar 

  58. Shin-Kang S, Ramsauer VP, Lightner J et al (2011) Tocotrienols inhibit AKT and ERK activation and suppress pancreatic cancer cell proliferation by suppressing the ErbB2 pathway. Free Radic Biol Med 51:1164–1174. https://doi.org/10.1016/j.freeradbiomed.2011.06.008

    Article  CAS  PubMed  Google Scholar 

  59. Shibata A, Nakagawa K, Sookwong P et al (2008) Tocotrienol inhibits secretion of angiogenic factors from human colorectal adenocarcinoma cells by suppressing hypoxia-inducible factor-1α. J Nutr 138:2136–2142. https://doi.org/10.3945/jn.108.093237

    Article  CAS  PubMed  Google Scholar 

  60. Abedinpour N, Ghanbariasad A, Taghinezhad A, Osanloo M (2021) Preparation of nanoemulsions of Mentha piperita essential oil and investigation of their cytotoxic effect on human breast cancer lines. Bionanoscience 11:428–436. https://doi.org/10.1007/s12668-021-00827-4

    Article  Google Scholar 

  61. Aslan B, Ozpolat B, Sood AK, Lopez-Berestein G (2013) Nanotechnology in cancer therapy. J Drug Target 21:904–913. https://doi.org/10.3109/1061186X.2013.837469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank PT. DKSH for the Zeta Sizer Instrument.

Funding

This work was supported by Badan Pengelola Dana Perkebunan Kelapa Sawit (BPDPKS) through Grant Riset Sawit 2023 (PRJ-03/DPKS/DIT.IV/2023).

Author information

Authors and Affiliations

  1. Research Center for Vaccine and Drug, National Research and Innovation Agency (BRIN), Bogor, 16911, Indonesia

    A’liyatur Rosyidah, Riyona Desvy Pratiwi, Sjaikhurrizal El Muttaqien, Siti Irma Rahmawati, Asep Bayu, Nunik Gustini, Peni Ahmadi & Masteria Yunovilsa Putra

  2. Department of Pharmaceutical Technology, Faculty of Pharmacy, University Malaya, Kuala Lumpur, 50603, Malaysia

    Sui Ling Janet Tan

Authors
  1. A’liyatur Rosyidah
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Riyona Desvy Pratiwi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sjaikhurrizal El Muttaqien
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Siti Irma Rahmawati
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Asep Bayu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sui Ling Janet Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nunik Gustini
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Peni Ahmadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Masteria Yunovilsa Putra
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AR: conceptualization, methodology, investigation, validation, writing—original draft; RDP: investigation, validation, writing—original draft; SEM: investigation, writing—review and editing; SIR: methodology, validation, writing—original draft; AB: conceptualization, funding acquisition, validation, writing—review and editing; SLJT: writing—review and editing; NG: methodology and investigation; PA: writing—review and editing; MYP: resources, writing—review and editing.

Corresponding authors

Correspondence to A’liyatur Rosyidah or Asep Bayu.

Ethics declarations

Ethics approval

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rosyidah, A., Pratiwi, R.D., Muttaqien, S.E. et al. A facile and simple synthesis of a cytotoxic tocotrienol-based nanoemulsion against MCF-7 and A549 cancer cell lines. Colloid Polym Sci (2024). https://doi.org/10.1007/s00396-024-05245-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00396-024-05245-y

Keywords

Search

Navigation