Skip to main content
SpringerLink
Log in

Effect of thymoquinone-loaded lipid–polymer nanoparticles as an oral delivery system on anticancer efficiency of doxorubicin

  • Original Research
  • Published:
Journal of Nanostructure in Chemistry Aims and scope Submit manuscript

Abstract

In this study, thymoquinone (TQ) was encapsulated into lipid–polymer nanoparticles (LPNPs) consisting of phosphatidylcholine (PC) and poly lactide–co-glycolide (PLGA) to enhance anticancer and oral delivery efficiency of TQ. We also co-delivered TQ nanoparticles with free doxorubicin (DOX) to increase DOX efficiency. Single emulsion solvent evaporation method was exploited to prepare PLGA-TQ and PLGA-PC-TQ NPs. The physicochemical properties of synthetized NPs and their cellular uptake across Caco-2 cells were assessed. Cytotoxicity of different formulations of TQ and their co-delivery with free DOX were determined by MTT assay on colon cancer cell lines (C26). Cell migration was also evaluated by wound healing migration assay. LPNPs containing TQ with an average diameter of 184 nm and 60% loading efficiency showed more release at simulated intestinal fluid pH of 6.8 compared to polymeric NPs. At an acidic pH, however, the release of TQ from PLGA-PC was about 2% after 120 h. The cytotoxicity studies indicated that PLGA-PC-TQ NPs improved anticancer activity of DOX more than TQ NPs. Uptake of PLGA-PC-TQ through the Caco-2 cells was 2.5 times greater compared to NPs without PC. PLGA-PC-TQ NPs also exhibited significantly greater reduction of cancer cell migration. The results demonstrate that co-delivery of PLGA-PC encapsulated TQ through oral administration and free DOX could improve anticancer efficiency of DOX.

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

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

Similar content being viewed by others

References

  1. Ma, W., Guo, Q., Li, Y., Wang, X., Wang, J., Tu, P.: Co-assembly of doxorubicin and curcumin targeted micelles for synergistic delivery and improving anti-tumor efficacy. Eur. J. Pharm. Biopharm. 112, 209–223 (2017)

    Article  CAS  Google Scholar 

  2. Wu H, L.S., Gong J, et al: VCPA, a novel synthetic derivative of α-tocopheryl succinate, sensitizes human gastric cancer to doxorubicin-induced apoptosis via ROS-dependent mitochondrial dysfunction. Cancer Lett. 393, 22–32 (2017).

  3. Kaur, A.K., M. : Doxorubicin: a critical review on toxicity. J. Pharm. Res. 5(5), 2890–2894 (2012)

    CAS  Google Scholar 

  4. Oroojalian, F., Babaei, M., Taghdisi, S.M., Abnous, K., Ramezani, M., Alibolandi, M.: Encapsulation of thermo-responsive gel in pH-sensitive polymersomes as dual-responsive smart carriers for controlled release of doxorubicin. JCR. 288, 45–61 (2018)

    Article  CAS  Google Scholar 

  5. Chen, Q.K., H., Dai, Z., Liu, Z, : Nanoscale theranostics for physical stimulus-responsive cancer therapies. Biomaterials 73, 214–230 (2015)

    Article  CAS  Google Scholar 

  6. Jardim, G.L., D.; Valença, W.; Lima, D.; Cavalcanti, B.; Pessoa, C.; Rafique, J.; Braga, A.; Jacob, C.; da Silva Júnior, E.; et al: Synthesis of Selenium-Quinone Hybrid Compounds with Potential Antitumor Activity via Rh-Catalyzed C-H Bond Activation and Click Reactions. Molecules. 23(1), 83 (2017)

  7. Fang, J., Zhang, S., Xue, X., Zhu, X., Song, S., Wang, B., Jiang, L., Qin, M., Liang, H., Gao, L.: Quercetin and doxorubicin co-delivery using mesoporous silica nanoparticles enhance the efficacy of gastric carcinoma chemotherapy. Int. J. Nanomed. 13, 5113–5126 (2018)

    Article  CAS  Google Scholar 

  8. Langroodi, F., Ghahestani, Z., Alibolandi, M., Ebrahimian, M., Hashemi, M.: Evaluation of the effect of crocetin on antitumor activity of doxorubicin encapsulated in PLGA nanoparticles. Nanomed. J. 3, 23–34 (2016)

    CAS  Google Scholar 

  9. Pishavar, E., Oroojalian, F., Ramezani, M., Hashemi, M.: Cholesterol-conjugated PEGylated PAMAM as an efficient nanocarrier for plasmid encoding interleukin-12 immunogene delivery towards colon cancer cells. Biotechnol. Prog. 36(3), e2952 (2019)

    PubMed  Google Scholar 

  10. Ghazanfary, S., Oroojalian, F., Yazdian-Robati, R., Dadmehr, M., Sahebkar, A.: Density functional theory study of antioxidant adsorption onto single-wall boron nitride nanotubes: design of new antioxidant delivery systems. CCHTS. 22(7), 470–482 (2019)

    Article  CAS  Google Scholar 

  11. Rashidi, A., Omidi, M., Choolaei, M., Nazarzadeh, M., Yadegari, A., Haghierosadat, F., Oroojalian, F., Azhdari, M.: Electromechanical properties of vertically aligned carbon nanotube. Adv. Mat. Res. 705, 332–336 (2013)

    Google Scholar 

  12. M, A.: Thymoquinone in the clinical treatment of cancer: Fact or fiction? Phcog. Rev. 7, 117–120 (2013).

  13. Woo CC, K.A., Sethi G, Tan K: Thymoquinone: potential cure for inflammatory disorders and cancer. Biochem. Pharmacol. 38, 443–451 (2012).

  14. Banerjee S., P.S., Azmi A., Wang Z., Philip P., Kucuk O: Review on molecular and therapeutic potential of thymoquinone in cancer. Nutr. Cancer. 62, 938–946 (2010).

  15. Bhattacharya S., A.M., Patra P., Mukherjee S., Ghosh S., Mazumdar M., Chattopadhyay S., Das T.,, Chattopadhyay D., A.A.: PEGylated- thymoquinone-nanoparticle mediated retardation of breast cancer cell migration by deregulation of cytoskeletal actin polymerization through miR-34a. Biomaterials. 51, 91–107 (2015).

  16. Badary OA, A.-S.O., Nagi MN, Al-Rikabi AC, Elmazar M: Inhibition of benzo(a)pyreneinduced forestomach carcinogenesis in mice by thymoquinone. Eur. J. Cancer. Prev. 8, 435–440 (1999).

  17. Kommineni N, S.R., Bulbake U, Khan W.: Cabazitaxel and thymoquinone co-loaded lipospheres as a synergistic combination for breast cancer. Chem. Phys. Lipids. 224, 104707(2019)

  18. Fatfat, M., Fakhoury, I., Habli, Z., Mismar, R., Gali-Muhtasib, H.: Thymoquinone enhances the anticancer activity of doxorubicin against adult T-cell leukemia in vitro and in vivo through ROS-dependent mechanisms. Life Sci. 232, 116628 (2019)

    Article  CAS  Google Scholar 

  19. Effenberger-Neidnicht K, S.R.: Combinatorial effects of thymoquinone on the anti-cancer activity of doxorubicin. Cancer Chemother. Pharmacol. 67(4), 867–874 (2011).

  20. Badary O., A.-S.O., Nagi M., Al-Bekairi A: Acute and subchronic toxicity of thymoquinone in mice. Drug Dev. Res. 44, 56-61 (1998)

  21. Dhadde, S.B., Patil, J.S., Chandakavathe, B.N., Thippeswamy, B., Kavatekar, M.G.: Relevance of Nanotechnology in Solving Oral Drug Delivery Challenges: A Perspective Review. Crit Rev Ther. 37(5) (2020).

  22. Jana, P., Shyam, M., Singh, S., Jayaprakash, V., Dev, A.: Biodegradable polymers in drug delivery and oral vaccination. Eur. Polym. J. 142, 110155 (2020)

    Article  Google Scholar 

  23. Liang, H., Friedman, J. M.,&Nacharaju, P: Fabrication of biodegradable PEG–PLA nanospheres for solubility, stabilization, and delivery of curcumin. Artif. Cells. Nanomed. Biotechnol. 45, 297–304 (2017).

  24. N. Csaba, M.G.-F.a.J.A., Adv: Nanoparticles for nasal vaccination. Drug. Deliv. Rev. 61(2), 140–157(2009).

  25. Ghitman, J., Biru, E.I., Stan, R., Iovu, H.: Review of hybrid PLGA nanoparticles: Future of smart drug delivery and theranostics medicine. Mater. Des.108805 (2020).

  26. Hashemi, M., Shamshiri, A., Saeedi, M., Tayebi, L., Yazdian-Robati, R.: Aptamer-conjugated PLGA nanoparticles for delivery and imaging of cancer therapeutic drugs. Arch. Biochem. Biophys. 108485 (2020).

  27. Jose, C., Amra, K., Bhavsar, C., Momin, M., Omri, A.: Polymeric lipid hybrid nanoparticles: properties and therapeutic applications. Crit. Rev. Ther. Drug. 35(6), 555–588 (2018)

    Article  Google Scholar 

  28. Mukherjee, A., Waters, A.K., Kalyan, P., Achrol, A.S., Kesari, S., Yenugonda, V.M.: Lipid–polymer hybrid nanoparticles as a next-generation drug delivery platform: state of the art, emerging technologies, and perspectives. Int. J. Nanomedicine. 14, 1937 (2019)

    Article  CAS  Google Scholar 

  29. Yu F, A.M., Zheng X, Li N, Xia J, Li Y, Li D, Hou Zh, Qi Zh, and Chen X D: PEG–lipid–PLGA hybrid nanoparticles loaded with berberine–phospholipid complex to facilitate the oral delivery efficiency. Drug Deliv. 24(1), 258–833 (2017).

  30. Ghahestani, Z., Langroodi, F., Mokhtarzadeh, A., Ramezani, M., Hashemi, M.: Evaluation of anti-cancer activity of PLGA nanoparticles containing crocetin. Artif. Cells. Nanomed. Biotechnol. 45 (2016).

  31. Ahmad, R., Kaus, N.H.M., Hamid, S.: Synthesis and characterization of PLGA-PEG thymoquinone nanoparticles and its cytotoxicity effects in tamoxifen-resistant breast cancer cells. In Cancer Biology and Advances in Treatment. 65–82 (2020).

  32. Mona, M., Mottaleb, A.: Biodegradable thymoquinone nanoparticles for higher therapeutic efficiency in murine colorectal cancer. Ijppr. Human 7, 436–450 (2016)

    Google Scholar 

  33. Oroojalian, F., Jahanafrooz, Z., Chogan, F., Rezayan, A.H., Malekzade, E., Rezaei, S.J.T., Nabid, M.R., Sahebkar, A.: Synthesis and evaluation of injectable thermosensitive penta-block copolymer hydrogel (PNIPAAm-PCL-PEG-PCL-PNIPAAm) and star-shaped poly (CL─ CO─ LA)-b-PEG for wound healing applications. J. Cell. Biochem. 20(10), 17194–17207 (2019)

    Article  Google Scholar 

  34. Zhao, L., Wientjes, M., Au, J.: Evaluation of combination chemotherapy: integration of nonlinear regression, curve shift, isobologram, and combination index analyses. Clin. Cancer Res. 10, 7994–8004 (2005)

    Article  Google Scholar 

  35. Karimisani, I., Marashi, S., Kalalinia, F.: Solamargine inhibits migration and invasion of human hepatocellular carcinoma cells through down-regulation of matrix metalloproteinases 2 and 9 expression and activity. Toxicol In Vitro. 29(5), 893–900 (2015)

    Article  Google Scholar 

  36. Alibolandi, M., Alabdollah, F., Sadeghi, F., Mohammadi, M., Abnous, K., Ramezani, M., Hadizadeh, F. (2016) Dextran-b-poly (Lactide-co-Glycolide) polymersome for oral delivery of insulin: in vitro and in vivo evaluation. JCR. 227.

  37. Nkabinde, L., Shoba-Zikhali, L., Semete-Makokotlela, B., Kalombo, M., Swai, H., Hayeshi, R., Naicker, B., Hillie, K., Hamman, J.: Permeation of PLGA Nanoparticles Across Different in vitro Models. Curr. Drug Deliv. 9 (2012).

  38. Ana Rute Neves , S.M., Marcela A. Segundo and Salette Reis Nanoscale Delivery of Resveratrol towards Enhancement of Supplements and Nutraceuticals. Nutrients. 8(3), 131 (2015).

  39. Yu, F., Ao, M., Zheng, X., Li, N., Xia, J., Li, Y., Li, D., Hou, Z., Qi, Z., Chen, X.D.: PEG–lipid–PLGA hybrid nanoparticles loaded with berberine–phospholipid complex to facilitate the oral delivery efficiency. Drug Deliv. 24(1), 825–833 (2017)

    Article  CAS  Google Scholar 

  40. Araste, F., Abnous, K., Hashemi, M., Dehshahri, A., Detampel, P., Alibolandi, M., Ramezani, M.: Na+/K+ ATPase-targeted delivery to metastatic breast cancer models. Eur. J. Pharm. Sci. 143, 105207 (2020)

    Article  CAS  Google Scholar 

  41. Odeh F., I.S., Abu-Dahab R., Mahmoud I., Al Bawab A: Thymoquinone in liposomes: a studyn of loading efficiency and biological activity towards breast cancer. Drug Deliv. 19(8), 371–377 (2012).

  42. Mahmoud, Y.K., Abdelrazek, H.M.: Cancer: Thymoquinone antioxidant/pro-oxidant effect as potential anticancer remedy. Biomed. Pharmacother. 115, 108783 (2019)

    Article  CAS  Google Scholar 

  43. Imran, M., Rauf, A., Khan, I.A., Shahbaz, M., Qaisrani, T.B., Fatmawati, S., Abu-Izneid, T., Imran, A., Rahman, K.U., Gondal, T.A.: Thymoquinone: a novel strategy to combat cancer: a review. Biomed. Pharmacother. 106, 390–402 (2018)

    Article  CAS  Google Scholar 

  44. Schneider-Stock R., F.I., Zaki A., El-Baba C., Gali-Muhtasib H: Thymoquinone: fifty years of success in the battle against cancer models. Drug. Discov. Today. 19, 18–30 (2014).

  45. Bose, R.J., Lee, S.H., Park, H.: Lipid-based surface engineering of PLGA nanoparticles for drug and gene delivery applications. Biomater. Res. 20, 34 (2016)

    Article  Google Scholar 

  46. Park JH, L.S., Kim JH, Kyeongsoon Park K: Polymeric nanomedicine for cancer therapy. Prog. Polym. Sci. 33, 113-137 (2008)

  47. He, C., Yin, L., Tang, C., Yin, C.: Size-dependent absorption mechanism of polymeric nanoparticles for oral delivery of protein drugs. Biomaterials 33(33), 8569–8578 (2012)

    Article  CAS  Google Scholar 

  48. Öztürk, A.A., Banderas, L.M., Otero, M.D.C., Yenilmez, E., Şenel, B., Yazan, Y.: Dexketoprofen trometamol-loaded poly-lactic-co-glycolic acid (PLGA) nanoparticles: Preparation, in vitro characterization and cyctotoxity. Trop. J. Pharm. Res. 18(1), 1–11 (2019)

    Article  Google Scholar 

  49. Öztürk, A.A., Yenilmez, E., Özarda, M.G.: Clarithromycin-loaded poly (lactic-co-glycolic acid)(PLGA) nanoparticles for oral administration: effect of polymer molecular weight and surface modification with chitosan on formulation, nanoparticle characterization and antibacterial effects. Polymers 11(10), 1632 (2019)

    Article  Google Scholar 

  50. Ma, T., Wang, L., Yang, T., Ma, G., Wang, S.: Homogeneous PLGA-lipid nanoparticle as a promising oral vaccine delivery system for ovalbumin. Asian. J. Pharm. Sci. 9(3), 129–136 (2014)

    Article  Google Scholar 

  51. Des Rieux, A.R., E.G.; Gullberg, E.; Preat, V.; Schneider, Y.J.; Artursson, P: Transport of nanoparticles across an in vitro model of the human intestinal follicle associated epithelium. Eur. J. Pharm. Sci. 25, 455–465 (2005).

  52. Ibrahim, W.N., Rosli, L.M.B.M.: Formulation, cellular uptake and cytotoxicity of thymoquinone-loaded PLGA nanoparticles in malignant melanoma cancer cells. Int. J. Nanomedicine. 15, 8059 (2020)

    Article  CAS  Google Scholar 

  53. Pishavar, E., Ramezani, M., Hashemi, M.: Co-delivery of doxorubicin and TRAIL plasmid by modified PAMAM dendrimer in colon cancer cells, in vitro and in vivo evaluation. Drug. Dev. Ind. Pharm. 45(12), 1931–1939 (2019)

    Article  CAS  Google Scholar 

  54. Tiana, B., Dinga, Y., Hana, J., Zhanga, J., Hanc, H., Hana, J.: N-acetyl-d-glucosamine decorated polymeric nanoparticles for targeted delivery of doxorubicin: Synthesis, characterization and in vitro evaluation. Colloids Surf B. Biointerfaces. 130, 246–254 (2015)

    Article  Google Scholar 

  55. Wei R, C.L., Zheng M, et al: Reduction-responsive disassemblable core-cross-linked micelles based on poly(ethylene glycol)-b-poly(N-2-hydroxypropyl methacrylamide)-lipoic acid conjugates for triggered intracellular anticancer drug release. Biomacromolecules. 13(8), 2429–2438 (2012).

  56. Wang CH, W.C., Hsiue GH: Polymeric micelles with a pH-responsive structure as intracellular drug carriers. JCR. 108(1), 140–149 (2005).

  57. L. Zhang, Z.C., H. Wang, S. Wu, K. Zhao, H. Sun, D. Kong, C. Wang, X. Leng and D. Zhu, : Preparation and evaluation of PCL-PEG-PCL polymeric nanoparticles for doxorubicin delivery against breast cancer. RSC. Adv. (2016).

  58. Hilgers, A.R., Conradi, R.A., Burton, P.S.: Caco-2 cell monolayers as a model for drug transport across the intestinal mucosa. Pharm. Res. 7(9), 902–910 (1990)

    Article  CAS  Google Scholar 

  59. Luo, Q., Jiang, M., Kou, L., Zhang, L., Li, G., Yao, Q., Shang, L., Chen, Y.: Ascorbate-conjugated nanoparticles for promoted oral delivery of therapeutic drugs via sodium-dependent vitamin C transporter 1 (SVCT1). Artif. Cells. Nanomed. Biotechnol. 46, 1–11 (2017)

    Google Scholar 

  60. Chehl N, C.G., Gong Q, Yeo CJ, Arafat HA: Anti-inflammatory effects of the Nigella sativa seed extract, thymoquinone, in pancreatic cancer cells. HPB (Oxford) 11(5), 373–381 (2009).

  61. Torres MP, P.M., Chakraborty S, Smith LM, Das S, Arafat HA, Batra SK.: Effects of thymoquinone in the expression of mucin 4 in pancreatic cancer cells: implications for the development of novel cancer therapies. Mol. Cancer. Ther. 9(5), 1419–1431 (2010).

  62. Woo CC, L.S., Gee V, et al. : Anticancer activity of thymoquinone in breast cancer cells: Possible involvement of PPAR g pathway. Biochem. Pharmacol. 82(5), 464–475 (2011).

  63. Paramasivam A, R.S., Vijayashree Priyadharsini J, Jayaraman G: Thymoquinone inhibits the migration of mouse neuroblastoma (Neuro-2a) cells by down-regulating MMP-2 and MMP-9. CJNM. 14(2), 0904–0912 (2016).

Download references

Acknowledgements

This project was funded by Mashhad University of Medical Sciences, Mashhad, Iran (Grant no. 951129).

Author information

Author notes

  1. Mahboubeh Ebrahimian equal first authors.

Authors and Affiliations

  1. School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

    Faezeh Abbaspour Moghaddam & Mahboubeh Ebrahimian

  2. Department of Advanced Sciences and Technologies, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran

    Fatemeh Oroojalian

  3. Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran

    Fatemeh Oroojalian

  4. Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran

    Rezvan Yazdian-Robati

  5. Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

    Fatemeh Kalalinia & Maryam Hashemi

  6. Marquette University School of Dentistry, Milwaukee, WI, 53233, USA

    Lobat Tayebi

  7. Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

    Maryam Hashemi

Authors
  1. Faezeh Abbaspour Moghaddam
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mahboubeh Ebrahimian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fatemeh Oroojalian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rezvan Yazdian-Robati
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fatemeh Kalalinia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lobat Tayebi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Maryam Hashemi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Lobat Tayebi or Maryam Hashemi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

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

Moghaddam, F.A., Ebrahimian, M., Oroojalian, F. et al. Effect of thymoquinone-loaded lipid–polymer nanoparticles as an oral delivery system on anticancer efficiency of doxorubicin. J Nanostruct Chem 12, 33–44 (2022). https://doi.org/10.1007/s40097-021-00398-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40097-021-00398-6

Keywords

Search

Navigation