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Uptake Pathway of Apple-derived Nanoparticle by Intestinal Cells to Deliver its Cargo

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Abstract

Purpose

Food-derived nanoparticles exert cytoprotective effects on intestinal cells by delivering their cargo, which includes macromolecules such as microRNAs and proteins, as well as low-molecular weight compounds. We previously reported that apple-derived nanoparticles (APNPs) downregulate the expression of human intestinal transporter OATP2B1/SLCO2B1 mRNA. To verify the involvement of the cargo of APNPs in affecting the expression of transporters, we characterized the uptake mechanism of APNPs in intestinal cells.

Methods

The uptake of fluorescent PKH26-labeled APNPs (PKH-APNPs) into Caco-2, LS180, and HT-29MTX cells was evaluated by confocal microscopy and flow cytometry.

Results

The uptake of PKH-APNPs was prevented in the presence of clathrin-dependent endocytosis inhibitors, chlorpromazine and Pitstop2. Furthermore, PKH-APNPs were incorporated by the HT29-MTX cells, despite the disturbance of the mucus layer. Additionally, the decrease in SLCO2B1 mRNA by APNPs was reversed by Pitstop 2 in Caco-2 cells, indicating that APNPs decrease SLCO2B1 by being incorporated via clathrin-dependent endocytosis.

Conclusions

We demonstrated that clathrin-dependent endocytosis was mainly involved in the uptake of APNPs by intestinal cells, and that the cargo in the APNPs downregulate the mRNA expression of SLCO2B1. Therefore, APNPs could be a useful tool to deliver large molecules such as microRNAs to intestinal cells.

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Abbreviations

APNPs:

Apple-derived nanoparticles

miRNA:

microRNA

NPs:

Nanoparticles

OATP2B1:

Organic anion-transporting polypeptide 2B1

PKH-APNPs:

PKH26-labeled APNPs

References

  1. Tamai I. Oral drug delivery utilizing intestinal OATP transporters. Adv Drug Deliv Rev. 2012;64(6):508–14.

    Article  CAS  Google Scholar 

  2. Chen M, Zhou SY, Fabriaga E, Zhang PH, Zhou Q. Food-drug interactions precipitated by fruit juices other than grapefruit juice: an update review. J Food Drug Anal. 2018;26(2S):S61–71.

    Article  CAS  Google Scholar 

  3. Bailey DG, Spence JD, Munoz C, Arnold JM. Interaction of citrus juices with felodipine and nifedipine. Lancet. 1991;337(8736):268–9.

    Article  CAS  Google Scholar 

  4. Guo LQ, Fukuda K, Ohta T, Yamazoe Y. Role of furanocoumarin derivatives on grapefruit juice-mediated inhibition of human CYP3A activity. Drug Metab Dispos. 2000;28(7):766–71.

    CAS  PubMed  Google Scholar 

  5. Imanaga J, Kotegawa T, Imai H, Tsutsumi K, Yoshizato T, Ohyama T, et al. The effects of the SLCO2B1 c.1457C > T polymorphism and apple juice on the pharmacokinetics of fexofenadine and midazolam in humans. Pharmacogenet Genomics. 2011;21(2):84–93.

    Article  CAS  Google Scholar 

  6. Shirasaka Y, Shichiri M, Mori T, Nakanishi T, Tamai I. Major active components in grapefruit, orange, and apple juices responsible for OATP2B1-mediated drug interactions. J Pharm Sci. 2013;102(1):280–8.

    Article  CAS  Google Scholar 

  7. Shirasaka Y, Mori T, Murata Y, Nakanishi T, Tamai I. Substrate- and dose-dependent drug interactions with grapefruit juice caused by multiple binding sites on OATP2B1. Pharm Res. 2014;31(8):2035–43.

    Article  CAS  Google Scholar 

  8. Yang C, Zhang M, Lama S, Wang L, Merlin D. Natural-lipid nanoparticle-based therapeutic approach to deliver 6-shogaol and its metabolites M2 and M13 to the colon to treat ulcerative colitis. J Control Release. 2020;323:293–310.

    Article  CAS  Google Scholar 

  9. Zhuang X, Deng ZB, Mu J, Zhang L, Yan J, Miller D, et al. Ginger-derived nanoparticles protect against alcohol-induced liver damage. J Extracell Vesicles. 2015;4:28713.

    Article  Google Scholar 

  10. Zhang M, Viennois E, Xu C, Merlin D. Plant derived edible nanoparticles as a new therapeutic approach against diseases. Tissue Barriers. 2016;4(2):e1134415.

    Article  Google Scholar 

  11. Aquilano K, Ceci V, Gismondi A, De Stefano S, Iacovelli F, Faraonio R, et al. Adipocyte metabolism is improved by TNF receptor-targeting small RNAs identified from dried nuts. Commun Biol. 2019;2:317.

    Article  Google Scholar 

  12. Raimondo S, Saieva L, Cristaldi M, Monteleone F, Fontana S, Alessandro R. Label-free quantitative proteomic profiling of colon cancer cells identifies acetyl-CoA carboxylase alpha as antitumor target of Citrus Limon-derived nanovesicles. J Proteome. 2018;173:1–11.

    Article  CAS  Google Scholar 

  13. Ju S, Mu J, Dokland T, Zhuang X, Wang Q, Jiang H, et al. Grape exosome-like nanoparticles induce intestinal stem cells and protect mice from DSS-induced colitis. Mol Ther. 2013;21(7):1345–57.

    Article  CAS  Google Scholar 

  14. Raimondo S, Naselli F, Fontana S, Monteleone F, Lo Dico A, Saieva L, et al. Citrus Limon-derived nanovesicles inhibit cancer cell proliferation and suppress CML xenograft growth by inducing TRAIL-mediated cell death. Oncotarget. 2015;6(23):19514–27.

    Article  Google Scholar 

  15. Wang B, Zhuang X, Deng ZB, Jiang H, Mu J, Wang Q, et al. Targeted drug delivery to intestinal macrophages by bioactive nanovesicles released from grapefruit. Mol Ther. 2014;22(3):522–34.

    Article  CAS  Google Scholar 

  16. Shandilya S, Rani P, Onteru SK, Singh D. Small interfering RNA in Milk Exosomes is resistant to digestion and crosses the intestinal barrier in vitro. J Agric Food Chem. 2017;65(43):9506–13.

    Article  CAS  Google Scholar 

  17. Mu J, Zhuang X, Wang Q, Jiang H, Deng ZB, Wang B, et al. Interspecies communication between plant and mouse gut host cells through edible plant derived exosome-like nanoparticles. Mol Nutr Food Res. 2014;58(7):1561–73.

    Article  CAS  Google Scholar 

  18. Zhang M, Wang X, Han MK, Collins JF, Merlin D. Oral administration of ginger-derived nanolipids loaded with siRNA as a novel approach for efficient siRNA drug delivery to treat ulcerative colitis. Nanomedicine (Lond). 2017;12(16):1927–43.

    Article  CAS  Google Scholar 

  19. Fujita D, Arai T, Komori H, Shirasaki Y, Wakayama T, Nakanishi T, et al. Apple-derived nanoparticles modulate expression of organic-anion-transporting polypeptide (OATP) 2B1 in Caco-2 cells. Mol Pharm. 2018;15(12):5772–80.

    Article  CAS  Google Scholar 

  20. Wikman A, Karlsson J, Carlstedt I, Artursson P. A drug absorption model based on the mucus layer producing human intestinal goblet cell line HT29-H. Pharm Res. 1993;10(6):843–52.

    Article  CAS  Google Scholar 

  21. Wang Q, Zhuang X, Mu J, Deng ZB, Jiang H, Zhang L, et al. Delivery of therapeutic agents by nanoparticles made of grapefruit-derived lipids. Nat Commun. 2013;4:1867.

    Article  Google Scholar 

  22. Hillaireau H, Couvreur P. Nanocarriers' entry into the cell: relevance to drug delivery. Cell Mol Life Sci. 2009;66(17):2873–96.

    Article  CAS  Google Scholar 

  23. Canton I, Battaglia G. Endocytosis at the nanoscale. Chem Soc Rev. 2012;41(7):2718–39.

    Article  CAS  Google Scholar 

  24. Rejman J, Oberle V, Zuhorn IS, Hoekstra D. Size-dependent internalization of particles via the pathways of clathrin- and caveolae-mediated endocytosis. Biochem J. 2004;377(Pt 1):159–69.

    Article  CAS  Google Scholar 

  25. Ju Y, Guo H, Edman M, Hamm-Alvarez SF. Application of advances in endocytosis and membrane trafficking to drug delivery. Adv Drug Deliv Rev. 2020;157:118–41.

  26. Zhang L, Hou D, Chen X, Li D, Zhu L, Zhang Y, et al. Exogenous plant MIR168a specifically targets mammalian LDLRAP1: evidence of cross-kingdom regulation by microRNA. Cell Res. 2012;22(1):107–26.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan

    Mayumi Arai, Hisakazu Komori, Daichi Fujita & Ikumi Tamai

Authors
  1. Mayumi Arai
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  2. Hisakazu Komori
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  3. Daichi Fujita
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  4. Ikumi Tamai
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Correspondence to Ikumi Tamai.

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Arai, M., Komori, H., Fujita, D. et al. Uptake Pathway of Apple-derived Nanoparticle by Intestinal Cells to Deliver its Cargo. Pharm Res 38, 523–530 (2021). https://doi.org/10.1007/s11095-021-03018-8

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  • DOI: https://doi.org/10.1007/s11095-021-03018-8

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