Skip to main content
SpringerLink
Log in

Intracellular cholesterol efflux effects of mannose-beta cyclodextrin conjugates on cholesterol-laden foam cells

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

Abstract

Lipid-laden foam cells within the arterial walls play a key role in the development of atherosclerotic lesions at early disease stages, and they have been recognized as attractive targets for developing targeted therapeutics in atherosclerosis. Herein, we developed mannose-conjugated beta-cyclodextrin (MAN-βCD) and evaluated its targeting ability and intracellular cholesterol efflux toward cholesterol-laden foam cells. The synthesized MAN-βCD showed effective cholesterol extraction ability in aqueous conditions. The nontoxic and cytocompatible MAN-βCD specifically targeted cholesterol-laden foam cells with positive CD206 expressions and was internalized into the cells via receptor-mediated endocytosis. Additionally, the internalized MAN-βCD exhibited effective lipid droplet (LD) reduction within the cholesterol-laden foam cells, leading to remarkable prevention of LD accumulation. Therefore, the specific delivery of MAN-βCD into CD206-expressing lipid-laden foam cells provides a promising prevention strategy in the progression of atherosclerotic plaques.

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

Similar content being viewed by others

References

  1. Juhl AD, Wüstner D (2022) Pathways and mechanisms of cellular cholesterol efflux-insight from imaging. Front Cell Dev Biol 10:834408. https://doi.org/10.3389/fcell.2022.834408

    Article  PubMed  PubMed Central  Google Scholar 

  2. McLean KJ, Hans M, Munro AW (2012) Cholesterol, an essential molecule: diverse roles involving cytochrome P450 enzymes. Biochem Soc Trans 40:587–593. https://doi.org/10.1042/BST20120077

    Article  CAS  PubMed  Google Scholar 

  3. Luo J, Yang H, Song BL (2020) Mechanisms and regulation of cholesterol homeostasis. Nat Rev Mol Cell Biol 21:225–245. https://doi.org/10.1038/s41580-019-0190-7

    Article  CAS  PubMed  Google Scholar 

  4. Beckers L, Heeneman S, Wang L et al (2007) Disruption of hedgehog signalling in ApoE - /- mice reduces plasma lipid levels, but increases atherosclerosis due to enhanced lipid uptake by macrophages. J Pathol 212:420–428. https://doi.org/10.1002/path.2193

    Article  CAS  PubMed  Google Scholar 

  5. Rader DJ, Puré E (2005) Lipoproteins, macrophage function, and atherosclerosis: beyond the foam cell? Cell Metab 1:223–230. https://doi.org/10.1016/j.cmet.2005.03.005

    Article  CAS  PubMed  Google Scholar 

  6. Javadifar A, Rastgoo S, Banach M et al (2021) Foam cells as therapeutic targets in atherosclerosis with a focus on the regulatory roles of non-coding RNAs. Int J Mol Sci 22:2529. https://doi.org/10.3390/ijms22052529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chistiakov DA, Melnichenko AA, Myasoedova VA et al (2017) Mechanisms of foam cell formation in atherosclerosis. J Mol Med (Berl) 95:1153–1165. https://doi.org/10.1007/s00109-017-1575-8

    Article  CAS  PubMed  Google Scholar 

  8. Maxfield FR, Tabas I (2005) Role of cholesterol and lipid organization in disease. Nature 438:612–621. https://doi.org/10.1038/nature04399

    Article  CAS  PubMed  Google Scholar 

  9. Hetherington I, Totary-Jain H (2022) Anti-atherosclerotic therapies: milestones, challenges, and emerging innovations. Mol Ther 30:3106–3117. https://doi.org/10.1016/j.ymthe.2022.08.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Prospective Studies Collaboration (2007) Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 370:1829–1839. https://doi.org/10.1016/S0140-6736(07)61778-4

  11. Emerging Risk Factors Collaboration (2009) Major lipids, apolipoproteins, and risk of vascular disease. JAMA 302:1993–2000. https://doi.org/10.1001/jama.2009.1619

  12. Dawson LP, Lum M, Nerleker N et al (2022) Coronary atherosclerotic plaque regression: JACC state-of-the-art review. J Am Coll Cardiol 79:66–82. https://doi.org/10.1016/j.jacc.2021.10.035

    Article  PubMed  Google Scholar 

  13. He H, Wang J, Yannie PJ et al (2020) Nanoparticle-based “Two-pronged” approach to regress atherosclerosis by simultaneous modulation of cholesterol influx and efflux. Biomaterials 260:120333. https://doi.org/10.1016/j.biomaterials.2020.120333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kim BJ (2018) What do we get from recent statin and CETP inhibitors trials? J Lipid Atheroscler 7:12–20. https://doi.org/10.12997/jla.2018.7.1.12

    Article  CAS  Google Scholar 

  15. Feig JE, Hewing B, Smith JD et al (2014) High-density lipoprotein and atherosclerosis regression: evidence from preclinical and clinical studies. Circ Res 114:205–213. https://doi.org/10.1161/CIRCRESAHA.114.300760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Damiano MG, Mutharasan RK, Tripathy S et al (2013) Templated high density lipoprotein nanoparticles as potential therapies and for molecular delivery. Adv Drug Deliv Rev 65:649–662. https://doi.org/10.1016/j.addr.2012.07.013

    Article  CAS  PubMed  Google Scholar 

  17. Rosenson RS, Brewer HB Jr, Ansell BJ et al (2016) Dysfunctional HDL and atherosclerotic cardiovascular disease. Nat Rev Cardiol 13:48–60. https://doi.org/10.1038/nrcardio.2015.124

    Article  CAS  PubMed  Google Scholar 

  18. Tuteja S, Rader DJ (2014) High-density lipoproteins in the prevention of cardiovascular disease: changing the paradigm. Clin Pharmacol Ther 96:48–56. https://doi.org/10.1038/clpt.2014.79

    Article  CAS  PubMed  Google Scholar 

  19. Khera AV, Rader DJ (2010) Future therapeutic directions in reverse cholesterol transport. Curr Atheroscler Rep 12:73–81. https://doi.org/10.1007/s11883-009-0080-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Degoma EM, Rader DJ (2011) Novel HDL-directed pharmacotherapeutic strategies. Nat Rev Cardiol 8:266–277. https://doi.org/10.1038/nrcardio.2010.200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kontush A, Chapman MJ (2010) Antiatherogenic function of HDL particle subpopulations: focus on antioxidative activities. Curr Opin Lipidol 21:312–318. https://doi.org/10.1097/MOL.0b013e32833bcdc1

    Article  CAS  PubMed  Google Scholar 

  22. Vickers KC, Palmisano BT, Shoucri BM et al (2011) MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol 13:423–433. https://doi.org/10.1038/ncb2210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ma X, Song Q, Gao X (2018) Reconstituted high-density lipoproteins: novel biomimetic nanocarriers for drug delivery. Acta Pharm Sin B 8:51–63. https://doi.org/10.1016/j.apsb.2017.11.006

    Article  PubMed  Google Scholar 

  24. Kuai R, Li D, Chen YE et al (2016) High-density lipoproteins: nature’s multifunctional nanoparticles. ACS Nano 10:3015–3041. https://doi.org/10.1021/acsnano.5b07522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Huang H, Cruz W, Chen J et al (2015) Learning from biology: synthetic lipoproteins for drug delivery. Wiley Interdiscip Rev Nanomed Nanobiotechnol 7:298–314. https://doi.org/10.1002/wnan.1308

    Article  CAS  PubMed  Google Scholar 

  26. Huang JL, Jiang G, Song QX et al (2017) Lipoprotein-biomimetic nanostructure enables efficient targeting delivery of siRNA to Ras-activated glioblastoma cells via macropinocytosis. Nat Commun 8:15144. https://doi.org/10.1038/ncomms15144

    Article  PubMed  PubMed Central  Google Scholar 

  27. Davis ME, Brewster ME (2004) Cyclodextrin-based pharmaceutics: past, present and future. Nat Rev Drug Discov 3:1023–1035. https://doi.org/10.1038/nrd1576

    Article  CAS  PubMed  Google Scholar 

  28. Narayanan G, Shen J, Matai I et al (2022) Cyclodextrin-based nanostructures. Prog Mater Sci 124:100869. https://doi.org/10.1016/j.pmatsci.2021.100869

    Article  CAS  Google Scholar 

  29. Irie T, Fukunaga K, Pitha J (1992) Hydroxypropylcyclodextrins in parenteral use. I: lipid dissolution and effects on lipid transfers in vitro. J Pharm Sci 81:521–523. https://doi.org/10.1002/jps.2600810609

    Article  CAS  PubMed  Google Scholar 

  30. Ohvo H, Slotte JP (1996) Cyclodextrin-mediated removal of sterols from monolayers: effects of sterol structure and phospholipids on desorption rate. Biochemistry 35:8018–8024. https://doi.org/10.1021/bi9528816

    Article  CAS  PubMed  Google Scholar 

  31. Zidovetzki R, Levitan I (2007) Use of cyclodextrins to manipulate plasma membrane cholesterol content: evidence, misconceptions and control strategies. Biochim Biophys Acta 1768:1311–1324. https://doi.org/10.1016/j.bbamem.2007.03.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Dai Y, Zhong J, Li J et al (2022) Interaction mechanism of cholesterol/β-cyclodextrin complexation by combined experimental and computational approaches. Food Hydrocoll 130:107725. https://doi.org/10.1016/j.foodhyd.2022.107725

    Article  CAS  Google Scholar 

  33. Park S, Ahn JW, Jo Y et al (2020) Label-free tomographic imaging of lipid droplets in foam cells for machine-learning-assisted therapeutic evaluation of targeted nanodrugs. ACS Nano 14:1856–1865. https://doi.org/10.1021/acsnano.9b07993

    Article  CAS  PubMed  Google Scholar 

  34. Kim H, Kumar S, Kang DW et al (2020) Affinity-driven design of cargo-switching nanoparticles to leverage a cholesterol-rich microenvironment for atherosclerosis therapy. ACS Nano 14:6519–6531. https://doi.org/10.1021/acsnano.9b08216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Song JW, Nam HS, Ahn JW et al (2021) Macrophage targeted theranostic strategy for accurate detection and rapid stabilization of the inflamed high-risk plaque. Theranostics 11:8874–8893. https://doi.org/10.7150/thno.59759

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chinetti-Gbaguidi G, Baron M, Bouhlel MA et al (2011) Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARγ and LXRα pathways. Circ Res 108:985–995. https://doi.org/10.1161/CIRCRESAHA.110.233775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Choi JY, Ryu J, Kim HJ et al (2018) Therapeutic effects of targeted PPARɣ activation on inflamed high-risk plaques assessed by serial optical imaging in vivo. Theranostics 8:45–60. https://doi.org/10.7150/thno.20885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kim JB, Park K, Ryu J et al (2016) Intravascular optical imaging of high-risk plaques in vivo by targeting macrophage mannose receptors. Sci Rep 6:22608. https://doi.org/10.1038/srep22608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Weis WI, Taylor ME, Drickamer K (1998) The C-type lectin superfamily in the immune system. Immunol Rev 163:19–34. https://doi.org/10.1111/j.1600-065x.1998.tb01185.x

    Article  CAS  PubMed  Google Scholar 

  40. Song M, Li L, Zhang Y et al (2017) Carboxymethyl-β-cyclodextrin grafted chitosan nanoparticles as oral delivery carrier of protein drugs. React Funct Polym 117:10–15. https://doi.org/10.1016/j.reactfunctpolym.2017.05.008

    Article  CAS  Google Scholar 

  41. Vainio S, Ikonen E (2003) Macrophage cholesterol transport: a critical player in foam cell formation. Ann Med 35:146–155. https://doi.org/10.1080/07853890310008198

    Article  CAS  PubMed  Google Scholar 

  42. Song YJ, Jung SY, Park K (2022) In vitro therapeutic effects of folate receptor-targeted delivery of anti-atherogenic nanodrug on macrophage foam cells. Macromol Res 30:703–706. https://doi.org/10.1007/s13233-022-0082-0

    Article  CAS  Google Scholar 

  43. Wang H, Wang H, Xiong W et al (2006) Evaluation on the phagocytosis of apoptotic spermatogenic cells by Sertoli cells in vitro through detecting lipid droplet formation by oil red O staining. Reproduction 132:485–492. https://doi.org/10.1530/rep.1.01213

    Article  CAS  PubMed  Google Scholar 

  44. Greenspan P, Mayer EP, Fowler SD (1958) Nile red: a selective fluorescent stain for intracellular lipid droplets. J Cell Biol 100:965–973. https://doi.org/10.1083/jcb.100.3.965

    Article  Google Scholar 

  45. Zhang C, Zhang PQ, Guo S et al (2020) Application of biomimetic cell-derived nanoparticles with mannose modification as a novel vaccine delivery platform against teleost fish viral disease. ACS Biomater Sci Eng 6:6770–6777. https://doi.org/10.1021/acsbiomaterials.0c01302

    Article  CAS  PubMed  Google Scholar 

  46. Pooresmaeil M, Namazi H, Salehi R (2020) Synthesis of photoluminescent glycodendrimer with terminal β-cyclodextrin molecules as a biocompatible pH-sensitive carrier for doxorubicin delivery. Carbohydr Polym. https://doi.org/10.1016/j.carbpol.2020.116658

    Article  PubMed  Google Scholar 

  47. Jang S, Lee S, Park H (2020) β-cyclodextrin inhibits monocytic adhesion to endothelial cells through nitric oxide-mediated depletion of cell adhesion molecules. Molecules 25:3575. https://doi.org/10.3390/molecules25163575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Jeong D, Ko WK, Kim SJ et al (2021) Lobeglitazone exerts anti-inflammatory effect in lipopolysaccharide-induced bone-marrow derived macrophages. Biomedicines 9:1432. https://doi.org/10.3390/biomedicines9101432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ma KL, Ruan XZ, Powis SH et al (2008) Inflammatory stress exacerbates lipid accumulation in hepatic cells and fatty livers of apolipoprotein E knockout mice. Hepatology 48:770–781. https://doi.org/10.1002/hep.22423

    Article  CAS  PubMed  Google Scholar 

  50. Wang FY, Ching TT (2021) Oil Red O staining for lipid content in Caenorhabditis elegans. Bio Protoc 11:e4124. https://doi.org/10.21769/BioProtoc.4124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Coisne C, Hallier-Vanuxeem D, Boucau MC et al (2016) β-cyclodextrins decrease cholesterol release and ABC-associated transporter expression in smooth muscle cells and aortic endothelial cells. Front Physiol 7:185. https://doi.org/10.3389/fphys.2016.00185

    Article  PubMed  PubMed Central  Google Scholar 

  52. Zimmer S, Grebe A, Bakke SS et al (2016) Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming. Sci Transl Med. https://doi.org/10.1126/scitranslmed.aad6100

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This research was supported by grants from the National Research Foundation of Korea (NRF-2019M3A9E2066883 and 2021R1A4A1022206). Woojeong Lee was supported by a grant from the Chung-Ang University Graduate Research Scholarship in 2022. Additionally, we thank the BT Research Facility Centre at Chung-Ang University.

Author information

Authors and Affiliations

  1. Department of Systems Biotechnology, Chung-Ang University, Anseong, 17546, Korea

    Woojeong Lee, Yong Geun Lim, Yeong Jun Song & Kyeongsoon Park

Authors
  1. Woojeong Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yong Geun Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yeong Jun Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kyeongsoon Park
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kyeongsoon Park.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

Ethical approval

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

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 760 kb)

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

Lee, W., Lim, Y.G., Song, Y.J. et al. Intracellular cholesterol efflux effects of mannose-beta cyclodextrin conjugates on cholesterol-laden foam cells. Biotechnol Bioproc E (2024). https://doi.org/10.1007/s12257-024-00101-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12257-024-00101-w

Keywords

Search

Navigation