SpringerLink
Log in

Antitumor Immunotherapy of Sialic Acid and/or GM1 Modified Coenzyme Q10 Submicron Emulsion

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

Immunotherapy is a novel therapeutic approach for controlling and killing tumor cells by stimulating or reconstituting the immune system, among which T cells serve as immune targets. Herein, we used coenzyme Q10 (CoQ10), which has both immune activation and avoids adverse reactions, as a model drug and developed four CoQ10 submicron emulsions modified with sialic acid (SA) and/or monosialotetrahexosyl ganglioside (GM1). On the one hand, SA interacts with L-selectins on the surface of T cells after entering the circulatory system, leading to activation of T cells and enhancement of antitumor immune responses. On the other hand, owing to its immune camouflage, GM1 can prolong the circulation time of the preparation in the body, thereby increasing the accumulation of the drug at the tumor site. In vitro and in vivo experiments showed that SA-modified preparations exhibited stronger immune activation and inhibition of tumor proliferation. Pharmacokinetic experiments showed that GM1-modified preparations have longer circulation times in vivo. However, SA and GM1 co-modification did not produce a synergistic effect on the preparation. In conclusion, the SA-modified CoQ10 submicron emulsion (Q10-SE) showed optimal antitumor efficacy when administered at a medium dose (6 mg CoQ10 kg−1).

Graphical Abstract

In this study, the submicron emulsion model was used as a carrier, and the tumor-bearing mice were used as animal models. In addition, CoQ10 submicron emulsion was modified with SA-CH with active targeting function and/or GM1 with long-circulation function to explore the antitumor effects of different doses of CoQ10 submicron emulsion, and to screen the best tumor immunotherapy formulations of CoQ10.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Abbreviations

Q10-E:

CoQ10 submicron emulsion

Q10-SE:

SA-CH modified CoQ10 submicron emulsion

Q10-GE:

GM1 modified CoQ10 submicron emulsion

Q10-SGE:

SA-CH and GM1 co-modified CoQ10 submicron emulsion

DiR-E:

DiR submicron emulsion

DiR-SE:

SA-CH modified DiR submicron emulsion

DiR-GE:

GM1 modified DiR submicron emulsion

DiR-SGE:

SA-CH and GM1 co-modified DiR submicron emulsion

References

  1. Mattiuzzi C, Lippi G. Current cancer epidemiology. JJoe health G. 2019;9(4):217.

  2. Fu L, ** W, Zhang J, Zhu L, Lu J, Zhen Y, et al. Repurposing non-oncology small-molecule drugs to improve cancer therapy: Current situation and future directions. Acta Pharm Sin B. 2022;12(2):532–57.

    Article  CAS  PubMed  Google Scholar 

  3. Bidram E, Esmaeili Y, Ranji-Burachaloo H, Al-Zaubai N, Zarrabi A, Stewart A, et al. A concise review on cancer treatment methods and delivery systems. J Drug Deliv Sci. 2019;54. https://doi.org/10.1016/j.jddst.2019.101350

  4. Siva S, MacManus MP, Martin RF, Martin OA. Abscopal effects of radiation therapy: a clinical review for the radiobiologist. JCl 2015;356(1):82-90.

  5. Dai WBY, Wang X, Song G, Liu TZ, He B, Zhang H, et al. Combination antitumor therapy with targeted dualnanomedicines. Adv Drug Deliver Rev. 2017;115:23–45.

    Article  CAS  Google Scholar 

  6. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1–10.

    Article  PubMed  Google Scholar 

  7. Crane FL. Isolation of a quinone from beef heart mitochondria. JBBA 1957;25:220–1.

  8. Cirilli I, Damiani E, Dludla PV, Hargreaves I, Marcheggiani F, Millichap LE, et al. Role of coenzyme Q10 in health and disease: an update on the last 10 years (2010–2020). Antioxidants (Basel). 2021;10(8):1325. https://doi.org/10.3390/antiox10081325

  9. Fotino AD, Thompson-Paul AM, Bazzano LA. Effect of coenzyme Q10 supplementation on heart failure: a meta-analysis. JTAjocn 2013;97(2):268–75.

  10. Mills EL, Kelly B, O'Neill LA. Mitochondria are the powerhouses of immunity. JNi 2017;18(5):488-98.

  11. Lee SK, Lee JO, Kim JH, Kim N, You GY, Moon JW, et al. Coenzyme Q10 increases the fatty acid oxidation through AMPK-mediated PPARalpha induction in 3T3-L1 preadipocytes. Cell Signal. 2012;24(12):2329–36.

    Article  CAS  PubMed  Google Scholar 

  12. Weinberg SE, Sena LA, Chandel NS. Mitochondria in the regulation of innate and adaptive immunity. JI 2015;42(3):406-17.

  13. Ron-Harel N, Santos D, Ghergurovich JM, Sage PT, Reddy A, Lovitch SB, et al. Mitochondrial biogenesis and proteome remodeling promote one-carbon metabolism for T cell activation. Cell Metab. 2016;24(1):104–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fouad AA, Al-Mulhim AS, Jresat I. Therapeutic effect of coenzyme Q10 against experimentally-induced hepatocellular carcinoma in rats. Environ Toxicol Pharmacol. 2013;35(1):100–8.

    Article  CAS  PubMed  Google Scholar 

  15. Liu H-T, Huang Y-C, Cheng S-B, Huang Y-T, Lin P-T. Effects of coenzyme Q10 supplementation on antioxidant capacity and inflammation in hepatocellular carcinoma patients after surgery: a randomized, placebo-controlled trial. JNj 2015;15(1):1–9.

  16. Garg S, Dhavala S, Krumova K, Kiebish M, Vishnudas V, Gesta S, et al. Membrane fluidity in cancer cell membranes as a therapeutic target: validation using bpm 31510. Biophys J. 2015;108(2):246a-a.

  17. Chawla SP, Hendifar A, Chua VS, Quon D, Narasimhan V, Lavinski Y, et al. Phase 1 study of bpm 31510 (ubidecaranone) in advanced solid tumors: updated analysis of a novel treatment with promising activity. Ann Oncol. 2012;23:166.

    Article  Google Scholar 

  18. Sun J, Patel CB, Jang T, Merchant M, Chen C, Kazerounian S, et al. High levels of ubidecarenone (oxidized CoQ10) delivered using a drug-lipid conjugate nanodispersion (BPM31510) differentially affect redox status and growth in malignant glioma versus non-tumor cells. Sci Rep. 2020;10(1):13899.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Varki A. Sialic acids in human health and disease. Trends Mol Med. 2008;14(8):351–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kelm S, Schauer RJIroc. Sialic acids in molecular and cellular interactions. 1997;175:137-240.

  21. Lehmann F, Tiralongo E, Tiralongo JJC, CMLS MLS. Sialic acid-specific lectins: occurrence, specificity and function. 2006;63(12):1331-54.

  22. Bi S, Baum LGJBeBA-GS. Sialic acids in T cell development and function. 2009;1790(12):1599-610.

  23. Ehrhardt C, Kneuer C, Bakowsky UJAddr. Selectins—an emerging target for drug delivery. 2004;56(4):527–49.

  24. Meijer SL, Dols A, Hu HM, Chu Y, Romero P, Urba WJ, et al. Reduced L-selectin (CD62LLow) expression identifies tumor-specific type 1 T cells from lymph nodes draining an autologous tumor cell vaccine. Cell Immunol. 2004;227(2):93–102.

    Article  CAS  PubMed  Google Scholar 

  25. Zhou S, Zhang T, Peng B, Luo X, Liu X, Hu L, et al. Targeted delivery of epirubicin to tumor-associated macrophages by sialic acid-cholesterol conjugate modified liposomes with improved antitumor activity. 2017;523(1):203-16.

  26. DeNinno MP. The synthesis and glycosidation of N-acetylneuraminic acid. JS 1991;1991(08):583-93.

  27. ** A-p, Xu Z-X, Liu F-L, Xu Y-L. Neuroprotective effects of monosialotetrahexosylganglioside. JNRR 2015;10(8):1343.

  28. Gabizon A, Papahadjopoulos D. Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors. JPotnaos 1988;85(18):6949-53.

  29. Park KJJoCR. Attenuating the immunogenicity of PEGylated liposomes by gangliosides. 2017;100(250):116.

  30. Zhang T, Zhou SL, Kang L, Luo X, Liu Y, Song YZ, et al. The effect of monosialylganglioside mix modifying the PEGylated liposomal epirubicin on the accelerated blood clearance phenomenon. Asian J Pharm Sci. 2017;12(2):134–42.

    Article  PubMed  Google Scholar 

  31. Wang Y, Wang C, Deng Y, Song YJEJoPS. A new application of monosialotetrahexosylganglioside in pharmaceutics: preparation of freeze-thaw-resistant coenzyme Q10 emulsions. 2021;159:105701.

  32. Zheng JS, Zheng SY, Zhang YB, Yu B, Zheng WJ, Yang F, et al. Sialic acid surface decoration enhances cellular uptake and apoptosis-inducing activity of selenium nanoparticles. Colloid Surface B. 2011;83(1):183–7.

    Article  CAS  Google Scholar 

  33. Müller R, Schmidt S, Buttle I, Akkar A, Schmitt J, Brömer SJIjop. SolEmuls®—novel technology for the formulation of iv emulsions with poorly soluble drugs. 2004;269(2):293–302.

  34. Wang Y, Wang C, Deng Y, Song Y. A new application of monosialotetrahexosylganglioside in pharmaceutics: preparation of freeze-thaw-resistant coenzyme Q10 emulsions. Eur J Pharm Sci. 2021;159: 105701.

    Article  CAS  PubMed  Google Scholar 

  35. Dorfmüller Th. Dynamic light scattering — applications of photon correlation spectroscopy. Berichte der Bunsengesellschaft für physikalische Chemie. 1985;91:498–9.

    Article  Google Scholar 

  36. Sui DZ, Meng XM, Li CZ, Tang XY, Qin Y, Zhang N, et al. The fate of sialic acid and peg modified epirubicin liposomes in aged versus young cells and tumor mice models. Pharmaceutics. 2022;14(3):545. https://doi.org/10.3390/pharmaceutics14030545

  37. Cheon IS, Park SM, Lee HJ, Hong JE, Ji SY, Shim BS, et al. Functional characteristics of porcine peripheral T cells stimulated with IL-2 or IL-2 and PMA. Res Vet Sci. 2014;96(1):54–61.

    Article  CAS  PubMed  Google Scholar 

  38. Ye YX, Zhang YX, Lu XY, Huang XY, Zeng XF, Lai XQ, et al. The anti-inflammatory effect of the SOCC blocker SK&F 96365 on mouse lymphocytes after stimulation by Con A or PMA/ionomycin. Immunobiology. 2011;216(9):1044–53.

    Article  CAS  PubMed  Google Scholar 

  39. Ding JQ, Zhao D, Hu YW, Liu MQ, Liao XR, Zhao BW, et al. Terminating the renewal of tumor-associated macrophages: a sialic acid-based targeted delivery strategy for cancer immunotherapy. Int J Pharmaceut. 2019;571:118706. https://doi.org/10.1016/j.ijpharm.2019.118706

  40. Shi J, Zhou S, Kang L, Ling H, Chen J, Duan L, et al. Evaluation of the antitumor effects of vitamin K2 (menaquinone-7) nanoemulsions modified with sialic acid-cholesterol conjugate. Drug Deliv Transl Res. 2018;8(1):1–11.

    Article  PubMed  Google Scholar 

  41. Qiu Q, Lu M, Li C, Luo X, Liu X, Hu L, et al. Novel self-assembled ibrutinib-phospholipid complex for potently peroral delivery of poorly soluble drugs with pH-dependent solubility. AAPS PharmSciTech. 2018;19(8):3571–83.

    Article  CAS  PubMed  Google Scholar 

  42. Luo X, Hu L, Zheng H, et al. Neutrophil-mediated delivery of pixantrone-loaded liposomes decorated with poly(sialic acid)-octadecylamine conjugate for lung cancer treatment. Drug Deliv. 2018;25:1200–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Chen M, Wu WJ, Wang S, Lai XX, Liu MY, Sun YM, et al. Neutrophils as emerging immunotherapeutic targets: indirect treatment of tumors by regulating the tumor immune environment based on a sialic acid derivative-modified nanocomplex platform. Int J Pharmaceut. 2022;620.

  44. Ding J, Sui D, Liu M, et al. Sialic acid conjugate-modified liposomes enable tumor homing of epirubicin via neutrophil/monocyte infiltration for tumor therapy. Acta Biomaterialia. 2021;134:702–15.

    Article  CAS  PubMed  Google Scholar 

  45. Drummond DC, Meyer O, Hong K, et al. Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors. Pharmacol Rev. 1999;51:691–743.

    CAS  PubMed  Google Scholar 

  46. Ziegler SF, Ramsdell F, Hjerrild KA, et al. Molecular characterization of the early activation antigen CD69: a type II membrane glycoprotein related to a family of natural killer cell activation antigens. Eur J Immunol. 1993;23:1643–8.

    Article  CAS  PubMed  Google Scholar 

  47. Kimura MY, Hayashizaki K, Tokoyoda K, Takamura S, Motohashi S, Nakayama T. Crucial role for CD 69 in allergic inflammatory responses: CD 69‐Myl9 system in the pathogenesis of airway inflammation. JIr 2017;278(1):87–100.

  48. Hayashizaki K, Kimura MY, Tokoyoda K, Hosokawa H, Shinoda K, Hirahara K, et al. Myosin light chains 9 and 12 are functional ligands for CD69 that regulate airway inflammation. 2016;1(3):eaaf9154-eaaf.

  49. Witherden DA, Abernethy NJ, Kimpton WG, Cahill RNJEjoi. Changes in thymic export of L‐selectin+ γδ and αβ T cells during fetal and postnatal development. 1994;24(5):1234–9.

  50. Tedder TF, Steeber DA, Chen A, Engel PJTFJ. The selecting: vascular adhesion molecules. 1995;9(10):866–73.

    CAS  Google Scholar 

  51. Gajbhiye V, Ganesh N, Barve J, Jain NKJEJoPS. Synthesis, characterization and targeting potential of zidovudine loaded sialic acid conjugated-mannosylated poly (propyleneimine) dendrimers. 2013;48(4–5):668–79.

  52. Chen M, Wu W, Wang S, Lai X, Liu M, Sun Y, et al. Neutrophils as emerging immunotherapeutic targets: indirect treatment of tumors by regulating the tumor immune environment based on a sialic acid derivative-modified nanocomplex platform. 2022;620:121684.

  53. Qiu Q, Li C, Song Y, Shi T, Luo X, Zhang H, et al. Targeted delivery of ibrutinib to tumor-associated macrophages by sialic acid-stearic acid conjugate modified nanocomplexes for cancer immunotherapy. 2019;92:184-95.

  54. Chiu GN, Bally MB, Mayer LDJBeBA-B. Selective protein interactions with phosphatidylserine containing liposomes alter the steric stabilization properties of poly (ethylene glycol). 2001;1510(1-2):56-69.

  55. Fischer HC, Hauck TS, Gómez-Aristizábal A, Chan WCJAM. Exploring primary liver macrophages for studying quantum dot interactions with biological systems. 2010;22(23):2520-4.

  56. Khlebtsov N, Dykman L. Biodistribution and toxicity of engineered gold nanoparticles: a review of in vitro and in vivo studies. JCSR 2011;40(3):1647-71.

  57. **ao J-H, Zhang Y, Liang G-Y, Liu R-M, Li X-G, Zhang L-T, et al. Synergistic antitumor efficacy of antibacterial helvolic acid from Cordyceps taii and cyclophosphamide in a tumor mouse model. 2017;242(2):214-22.

  58. Damia G, D’Incalci MJEJoC. Contemporary pre-clinical development of anticancer agents–what are the optimal preclinical models? 2009;45(16):2768–81.

  59. Liu M, Luo X, Qiu Q, Kang L, Li T, Ding J, et al. Redox-and pH-sensitive glycan (polysialic acid) derivatives and F127 mixed micelles for tumor-targeted drug delivery. 2018;15(12):5534–45.

  60. Byrne JD, Betancourt T, Brannon-Peppas LJAddr. Active targeting schemes for nanoparticle systems in cancer therapeutics. 2008;60(15):1615-26.

  61. Raker VK, Becker C, Landfester K, Steinbrink KJC. Targeted activation of T cells with IL-2-coupled nanoparticles. 2020;9(9):2063.

  62. Donia M, Hansen M, Sendrup SL, Iversen TZ, Ellebæk E, Andersen MH, et al. Methods to improve adoptive T-cell therapy for melanoma: IFN-γ enhances anticancer responses of cell products for infusion. 2013;133(2):545-52.

  63. Levy M, Schutze W, Fuhrer C, Benita SJJom. Characterization of diazepam submicron emulsion interface: role of oleic acid. 1994;11(1):79-92.

  64. Chen JX, Chen SQ, Yang XB, Wang SM, Wu WY. Efficacy and safety of Brucea javanica oil emulsion injection as adjuvant therapy for cancer: an overview of systematic reviews and meta-analyses. Phytomedicine. 2022;102.

  65. Ting YW, Chiou YS, Pan MH, Ho CT, Huang QR. In vitro and in vivo anti-cancer activity of tangeretin against colorectal cancer was enhanced by emulsion-based delivery system. J Funct Foods. 2015;15:264–73.

    Article  CAS  Google Scholar 

  66. Mohammadzadeh V, Rahiman N, Hosseinikhah SM, Barani M, Rahdar A, Jaafari MR, et al. Novel EPR-enhanced strategies for targeted drug delivery in pancreatic cancer: an update. Journal of Drug Delivery Science and Technology. 2022;73.

  67. Kalyane D, Raval N, Maheshwari R, Tambe V, Kalia K, Tekade RK. Employment of enhanced permeability and retention effect (EPR): nanoparticle-based precision tools for targeting of therapeutic and diagnostic agent in cancer. Mater Sci Eng C Mater Biol Appl. 2019;98:1252–76.

    Article  CAS  PubMed  Google Scholar 

  68. Varki A, Gagneux PJAotNYAoS. Multifarious roles of sialic acids in immunity. 2012;1253(1).

  69. Ajit, Glycobiology VJ. Since there are PAMPs and DAMPs, there must be SAMPs? Glycan “self-associated molecular patterns” dampen innate immunity, but pathogens can mimic them. 2011.

  70. Zhang KM, Zhao HR. Perspectives in the stability of emulsion explosive. Adv Colloid Interface Sci. 2022;307: 102745.

    Article  CAS  PubMed  Google Scholar 

  71. Ouyang J, Meng Y. Quantitative effect of droplet size and emulsion viscosity on the storage stability of asphalt emulsion. Constr Build Mater. 2022;342.

Download references

Funding

This study was supported by the Career Development Support Plan for Young and Middle-aged Teachers at the Shenyang Pharmaceutical University (ZDN2021009).

Author information

Author notes

  1. **anmin Meng and Na Yan contributed equally to this work.

Authors and Affiliations

  1. College of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, , Liaoning, 110016, People’s Republic of China

    **anmin Meng, Na Yan, Tiantian Guo, Meng Chen, Dezhi Sui, Mingqi Wang, Kaituo Zhang, **nrong Liu, Yihui Deng & Yanzhi Song

Authors
  1. **anmin Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Na Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tiantian Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Meng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dezhi Sui
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mingqi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kaituo Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. **nrong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yihui Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yanzhi Song
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: **anmin Meng, Na Yan, Yihui Deng, and Yanzhi Song; data curation: **anmin Meng, Na Yan, and Yanzhi Song; acquisition: Na Yan, Tiantian Guo, Mingqi Wang, and Kaituo Zhang; writing: **anmin Meng; analysis: Dezhi Sui and Meng Chen; supervision: **nrong Liu. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Yanzhi Song.

Ethics declarations

Conflict of Interest

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.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 787 KB)

Rights and permissions

Springer Nature or its licensor 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

Meng, X., Yan, N., Guo, T. et al. Antitumor Immunotherapy of Sialic Acid and/or GM1 Modified Coenzyme Q10 Submicron Emulsion. AAPS PharmSciTech 23, 283 (2022). https://doi.org/10.1208/s12249-022-02426-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-022-02426-2

Keywords

Search

Navigation