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Evaluation of the antitumor effects of vitamin K2 (menaquinone-7) nanoemulsions modified with sialic acid-cholesterol conjugate

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Abstract

Numerous studies have recently shown that vitamin K2 (VK2) has antitumor effects in a variety of tumor cells, but there are few reports demonstrating antitumor effects of VK2 in vivo. The antitumor effects of VK2 in nanoemulsions are currently not known. Therefore, we sought to characterize the antitumor potential of VK2 nanoemulsions in S180 tumor cells in the present study. Furthermore, a ligand conjugate sialic acid–cholesterol, with enhanced affinity towards the membrane receptors overexpressed in tumors, was anchored on the surface of the nanoemulsions to increase VK2 distribution to the tumor tissue. VK2 was encapsulated in oil-in-water nanoemulsions, and the physical and chemical stability of the nanoemulsions were characterized during storage at 25 °C. At 25 °C, all nanoemulsions remained physically and chemically stable with little change in particle size. An in vivo study using syngeneic mice with subcutaneously established S180 tumors demonstrated that intravenous or intragastric administration of VK2 nanoemulsions significantly suppressed the tumor growth. The VK2 nanoemulsions modified with sialic acid–cholesterol conjugate showed higher tumor growth suppression than the VK2 nanoemulsions, while neither of them exhibited signs of drug toxicity. In summary, VK2 exerted effective antitumor effects in vivo, and VK2 nanoemulsions modified with sialic acid–cholesterol conjugate enhanced the antitumor activity, suggesting that these VK2 may be promising agents for the prevention or treatment of tumor in patients.

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References

  1. Dam H. The antihæmorrhagic vitamin of the chick.: occurrence and chemical nature. Biochem J. 1935;29(6):1273–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Shearer MJ, Vitamin K. Lancet. 1995;345(8944):229–34.

    Article  CAS  PubMed  Google Scholar 

  3. Mahdinia E, Demirci A, Berenjian A. Production and application of menaquinone-7 (vitamin K2): a new perspective. World J Microbiol Biotechnol. 2017;33(1):2.

    Article  PubMed  Google Scholar 

  4. Buchanan MDGS, Melvin T, et al. Vitamin K2 (menaquinone) supplementation and its benefits in cardiovascular disease osteoporosis, and cancer. Marshall J Med. 2016;2(3):53.

    Article  Google Scholar 

  5. Tsukamoto Y, Ichise H, Kakuda H, Yamaguchi M. Intake of fermented soybean ( natto ) increases circulating vitamin K 2 (menaquinone-7) and γ-carboxylated osteocalcin concentration in normal individuals. J Bone Miner Metab. 2000;18(4):216–22.

    Article  CAS  PubMed  Google Scholar 

  6. Gast GCM, Roos NMD, Sluijs I, Bots ML, Beulens JWJ, Geleijnse JM, et al. A high menaquinone intake reduces the incidence of coronary heart disease. Nutr Metab Cardiovasc Dis. 2009;19(7):504–10.

    Article  CAS  PubMed  Google Scholar 

  7. O’Neil M. The Merck index. Merck & Co; 1989.

  8. Collins MDJD. Distribution of isoprenoid quinone structural types in bacteria and their taxonomic implication. Microbiol Rev. 1981;45(2):316–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Nelsestuen GL, Zytkovicz TH, Howard JB. The mode of action of vitamin K identification of γ-carboxyglutamic acid as a component of prothrombin. J Biol Chem. 1974;249(19):6347.

    CAS  PubMed  Google Scholar 

  10. Villa JK, Diaz MA, Pizziolo VR, Martino HS. Effect of vitamin K in bone metabolism and vascular calcification: a review of mechanisms of action and evidences. Crit Rev Food Sci Nutr. 2016. https://doi.org/10.1080/10408398.2016.1211616

  11. Shea MK, Kritchevsky SB, Hsu FC, Nevitt M, Booth SL, Kwoh CK, et al. The association between vitamin K status and knee osteoarthritis features in older adults: the Health, Aging and Body Composition Study. Osteoarthr Cart. 2015;23(3):370–8.

    Article  CAS  Google Scholar 

  12. Ferland G. Vitamin K and the nervous system: an overview of its actions. Adv Nutr. 2012;3(2):204–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Allison AC. The possible role of vitamin K deficiency in the pathogenesis of Alzheimer’s disease and in augmenting brain damage associated with cardiovascular disease. Med Hypotheses. 2001;57(2):151–5.

    Article  CAS  PubMed  Google Scholar 

  14. Vos M, Esposito G, Edirisinghe JN, Vilain S, Haddad DM, Slabbaert JR, et al. Vitamin K2 is a mitochondrial electron carrier that rescues pink1 deficiency. Science. 2012;336(6086):1306.

    Article  CAS  PubMed  Google Scholar 

  15. Azuma KIS. Aging mechanisms. Vitamin K benefits in aging and cancer. Japan: Springer; 2015.

    Google Scholar 

  16. Li L, Qi Z, Qian J, Bi F, Lv J, Xu L, et al. Induction of apoptosis in hepatocellular carcinoma Smmc-7721 cells by vitamin K(2) is associated with p53 and independent of the intrinsic apoptotic pathway. Mol Cell Biochem. 2010;342(1):125–31.

    Article  CAS  PubMed  Google Scholar 

  17. Otsuka M, Kato N, Shao RX, Hoshida Y, Ijichi H, Koike Y, et al. Vitamin K2 inhibits the growth and invasiveness of hepatocellular carcinoma cells via protein kinase A activation. Hepatology. 2004;40(1):243–51.

    Article  CAS  PubMed  Google Scholar 

  18. Yoshida T, Miyazawa K, Kasuga I, Yokoyama T, Minemura K, Ustumi K, et al. Apoptosis induction of vitamin K2 in lung carcinoma cell lines: the possibility of vitamin K2 therapy for lung cancer. Int J Oncol. 2003;23(3):627.

    CAS  PubMed  Google Scholar 

  19. Yokoyama T, Miyazawa K, Yoshida T, Ohyashiki K. Combination of vitamin K2 plus imatinib mesylate enhances induction of apoptosis in small cell lung cancer cell lines. Int J Oncol 2005;26(1):33–40.

  20. Kawakita H, Tsuchida A, Miyazawa K, Naito M, Shigoka M, Kyo B, et al. Growth inhibitory effects of vitamin K2 on colon cancer cell lines via different types of cell death including autophagy and apoptosis. Int J Mol Med. 2009;23(6):709–16.

    CAS  PubMed  Google Scholar 

  21. Tokita H, Tsuchida A, Miyazawa K, Ohyashiki K, Katayanagi S, Sudo H, et al. Vitamin K2-induced antitumor effects via cell-cycle arrest and apoptosis in gastric cancer cell lines. Int J Mol Med. 2006;17(2):235–43.

    CAS  PubMed  Google Scholar 

  22. Kiely M, Hodgins SJ, Merrigan BA, Tormey S, Kiely PA, O'Connor EM. Real-time cell analysis of the inhibitory effect of vitamin K2 on adhesion and proliferation of breast cancer cells. Nutr Res. 2015;35(8):736.

    Article  CAS  PubMed  Google Scholar 

  23. Duan F, Yu Y, Guan R, Xu Z, Liang H, Hong L. Vitamin K2 induces mitochondria-related apoptosis in human bladder cancer cells via ROS and JNK/p38 MAPK signal pathways. PLoS One. 2016;11(8):e0161886.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Yue X, Akahira JI, Utsunomiya H, Miki Y, Takahashi N, Niikura H, et al. Steroid and xenobiotic receptor (SXR) as a possible prognostic marker in epithelial ovarian cancer. Pathol Int. 2010;60(5):400–6.

    Article  PubMed  Google Scholar 

  25. Lamson DW, Plaza SM. The anticancer effects of vitamin K. Altern Med Rev J Clin Ther. 2003;8(3):303.

    Google Scholar 

  26. Nutter LM, Cheng AL, Hung HL, Hsieh RK, Ngo EO, Liu TW. Menadione: spectrum of anticancer activity and effects on nucleotide metabolism in human neoplastic cell lines. Biochem Pharmacol. 1991;41(9):1283–92.

    Article  CAS  PubMed  Google Scholar 

  27. Kitagawa J, Hara T, Tsurumi H, Ninomiya S, Ogawa K, Adachi S, et al. Synergistic growth inhibition in HL-60 cells by the combination of acyclic retinoid and vitamin K2. J Cancer Res Clin Oncol. 2011;137(5):779–87.

    Article  CAS  PubMed  Google Scholar 

  28. Russo I, Caroppo F, Alaibac M. Vitamins and melanoma. Cancers. 2015;7(3):1371–87.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Zhang H, Ozaki I, Hamajima H, Iwane S, Takahashi H, Kawaguchi Y, et al. Vitamin K2 augments 5-fluorouracil-induced growth inhibition of human hepatocellular carcinoma cells by inhibiting NF-κB activation. Oncol Rep. 2011;25(1):159–66.

    CAS  PubMed  Google Scholar 

  30. Samykutty A, Shetty AV, Dakshinamoorthy G, Kalyanasundaram R, Zheng G, Chen A, et al. Vitamin k2, a naturally occurring menaquinone, exerts therapeutic effects on both hormone-dependent and hormone-independent prostate cancer cells. Evid Based Complement Alternat Med eCAM. 2013;2013(6):287358.

    PubMed  Google Scholar 

  31. Yoshiji H, Kuriyama S, Noguchi R, Yoshii J, Ikenaka Y, Yanase K, et al. Combination of vitamin K2 and the angiotensin-converting enzyme inhibitor, perindopril, attenuates the liver enzyme-altered preneoplastic lesions in rats via angiogenesis suppression. J Hepatol. 2005;42(5):687–93.

    Article  CAS  PubMed  Google Scholar 

  32. Yao Y, Li L, Zhang H, Jia R, Liu B, Zhao X, et al. Enhanced therapeutic efficacy of vitamin K2 by silencing BCL-2 expression in SMMC-7721 hepatocellular carcinoma cells. Oncol Lett. 2012;4(1):163–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Xia J, Matsuhashi S, Hamajima H, Iwane S, Takahashi H, Eguchi Y, et al. The role of PKC isoforms in the inhibition of NF-κB activation by vitamin K2 in human hepatocellular carcinoma cells. J Nutr Biochem. 2012;23(12):1668–75.

    Article  CAS  PubMed  Google Scholar 

  34. Ogawa M, Nakai S, Deguchi A, Nonomura T, Masaki T, Uchida N, et al. Vitamins K2, K3 and K5 exert antitumor effects on established colorectal cancer in mice by inducing apoptotic death of tumor cells. Int J Oncol. 2007;31(2):323.

    CAS  PubMed  Google Scholar 

  35. Habu D, Shiomi S, Tamori A, Takeda T, Tanaka T, Kubo S, et al. Role of vitamin K2 in the development of hepatocellular carcinoma in women with viral cirrhosis of the liver. JAMA. 2004;292(3):358–61.

    Article  CAS  PubMed  Google Scholar 

  36. Schurgers LJ, Vermeer C. Differential lipoprotein transport pathways of K-vitamins in healthy subjects. Biochim Biophys Acta. 2002;1570(1):27–32.

    Article  CAS  PubMed  Google Scholar 

  37. Rapoport N, Nam KH, Gupta R, Gao Z, Mohan P, Payne A, et al. Ultrasound-mediated tumor imaging and nanotherapy using drug loaded, block copolymer stabilized perfluorocarbon nanoemulsions. J Control Release. 2011;153(1):4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Meng Y, Zou C, Madiyalakan R, Woo T, Huang M, Yang X, et al. Water-soluble and biocompatible sono/photosensitizer nanoparticles for enhanced cancer therapy. Nanomedicine. 2017;5(10):1559–69.

    Article  Google Scholar 

  39. Zheng JS, Zheng SY, Zhang YB, Yu B, Zheng W, Yang F, et al. Sialic acid surface decoration enhances cellular uptake and apoptosis-inducing activity of selenium nanoparticles. Colloids Surf B Biointerfaces. 2011;83(1):183.

    Article  CAS  PubMed  Google Scholar 

  40. She Z, Zhang T, Wang X, Li X, Song Y, Cheng X, et al. The anticancer efficacy of pixantrone-loaded liposomes decorated with sialic acid–octadecylamine conjugate. Biomaterials. 2014;35(19):5216–25.

    Article  CAS  PubMed  Google Scholar 

  41. Zhou S, Zhang T, Bo P, Xiang L, Liu X, Ling H, et al. Targeted delivery of epirubicin to tumor-associated macrophages by sialic acid-cholesterol conjugate modified liposomes with improved antitumor activity. Int J Pharm. 2017;523(1):203–16.

    Article  CAS  PubMed  Google Scholar 

  42. Liu Y, Huang L, Liu F. Paclitaxel nanocrystals for overcoming multidrug resistance in cancer. Mol Pharm. 2010;7(3):863.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Nakamura H, Fang J, Maeda H. Development of next-generation macromolecular drugs based on the EPR effect: challenges and pitfalls. Expert Opin Drug Deliv. 2014;12(4):1–12.

    Google Scholar 

  44. Whiteside TL, editor. Immune suppression in cancer: effects on immune cells, mechanisms and future therapeutic intervention. Seminars in cancer biology. Elsevier; 2006.

  45. Couzin-Frankel J. Cancer immunotherapy. Science. 2013;342(6165):1432–3.

    Article  CAS  PubMed  Google Scholar 

  46. D DW. Studies correlating the growth rate of a tumor and its metastases and providing evidence for tumor-related systemic growth-retarding factors. Cancer Res. 1972;32(2):374–9.

    Google Scholar 

  47. Roth H, Kitta D, Jones GRN, Osswald H, Kunz W. Polyamine responses in a solid transplanted tumor (S180) in liver and in urine during endotoxin-induced tumor injury in the mouse. Cancer. 1981;48(4):945.

    Article  CAS  PubMed  Google Scholar 

  48. Sjövall K, Nilsson B, Einhorn N. Different types of rupture of the tumor capsule and the impact on survival in early ovarian carcinoma. Int J Gynecol Cancer. 2010;4(5):333–6.

    Article  Google Scholar 

  49. Nath D, Hartnell A, Happerfield L, Miles DW, Burchell J, Taylorpapadimitriou J, et al. Macrophage-tumour cell interactions: identification of MUC1 on breast cancer cells as a potential counter-receptor for the macrophage-restricted receptor, sialoadhesin. Immunology. 1999;98(2):213–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Jing S, Song Y, Mei L, Lin X, Yang L, Zhou S, et al. Evaluation of the antitumor effect of dexamethasone palmitate and doxorubicin co-loaded liposomes modified with a sialic acid–octadecylamine conjugate. Eur J Pharm Sci. 2016;93:177–83.

    Article  Google Scholar 

  51. Hong W, Chen D, Zhang X, Zeng J, Hu H, Zhao X, et al. Reversing multidrug resistance by intracellular delivery of Pluronic® P85 unimers. Biomaterials. 2013;34(37):9602–14.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (81373334).

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Authors and Affiliations

  1. College of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, No.103, Shenyang, 110016, China

    Jia Shi, Songlei Zhou, Le Kang, Hu Ling, Yanzhi Song & Yihui Deng

  2. Sungen Biotech Co., Ltd, Shantou, 515000, China

    Jiepeng Chen & Lili Duan

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  1. Jia Shi
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Correspondence to Yanzhi Song or Yihui Deng.

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Animal studies were performed in accordance with the Guidelines for Animal Experimentation of Shenyang Pharmaceutical University and approved by the Animal Ethics Committee of the institution.

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Shi, J., Zhou, S., Kang, L. et al. Evaluation of the antitumor effects of vitamin K2 (menaquinone-7) nanoemulsions modified with sialic acid-cholesterol conjugate. Drug Deliv. and Transl. Res. 8, 1–11 (2018). https://doi.org/10.1007/s13346-017-0424-1

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