Internalization and transport of PEGylated lipid-based mixed micelles across Caco-2 cells mediated by scavenger receptor B1

Xiangjie Su; Mercedes Ramírez-Escudero; Feilong Sun; Joep B. van den Dikkenberg; Mies J. van Steenbergen; Roland J. Pieters; Bert J.C. Janssen; Peter M. van Hasselt; Wim E. Hennink; Cornelus F. van Nostrum

doi:10.3390/pharmaceutics13122022

Internalization and transport of PEGylated lipid-based mixed micelles across Caco-2 cells mediated by scavenger receptor B1

Xiangjie Su
, Mercedes Ramírez-Escudero
, Feilong Sun
, Joep B. van den Dikkenberg
, Mies J. van Steenbergen
, Roland J. Pieters
, Bert J.C. Janssen
, Peter M. van Hasselt
, Wim E. Hennink
, Cornelus F. van Nostrum^*

^*Corresponding author for this work

Utrecht University

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

The aim of this study was to get insight into the internalization and transport of PEGylat-ed mixed micelles loaded by vitamin K, as mediated by Scavenger Receptor B1 (SR-B1) that is abun-dantly expressed by intestinal epithelium cells as well as by differentiated Caco-2 cells. Inhibition of SR-B1 reduced endocytosis and transport of vitamin-K-loaded 0%, 30% and 50% PEGylated mixed micelles and decreased colocalization of the micelles with SR-B1. Confocal fluorescence mi-croscopy, fluorescence-activated cell sorting (FACS) analysis, and surface plasmon resonance (SPR) were used to study the interaction between the mixed micelles of different compositions (varying vitamin K loading and PEG content) and SR-B1. Interaction of PEGylated micelles was independent of the vitamin K content, indicating that the PEG shell prevented vitamin K exposure at the surface of the micelles and binding with the receptor and that the PEG took over the micelles’ ability to bind to the receptor. Molecular docking calculations corroborated the dual binding of both vita-min K and PEG with the binding domain of SR-B1. In conclusion, the improved colloidal stability of PEGylated mixed micelles did not compromise their cellular uptake and transport due to the affin-ity of PEG for SR-B1. SR-B1 is able to interact with PEGylated nanoparticles and mediates their subsequent internalization and transport.

Original language	English
Article number	2022
Pages (from-to)	1-22
Journal	Molecular Pharmaceutics
Volume	13
Issue number	12
DOIs	https://doi.org/10.3390/pharmaceutics13122022
Publication status	Published - 26 Nov 2021

Bibliographical note

Funding Information:
Funding: X. Su is supported by a PhD scholarship from China Scholarship Council (CSC) (File no. 201707040097).

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Funding

Funding: X. Su is supported by a PhD scholarship from China Scholarship Council (CSC) (File no. 201707040097).

Keywords

Epithelial transport
Mixed micelles
PEGylation
Scavenger receptor B1
Vitamin K

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Su, X., Ramírez-Escudero, M., Sun, F., van den Dikkenberg, J. B., van Steenbergen, M. J., Pieters, R. J., Janssen, B. J. C., van Hasselt, P. M., Hennink, W. E., & van Nostrum, C. F. (2021). Internalization and transport of PEGylated lipid-based mixed micelles across Caco-2 cells mediated by scavenger receptor B1. Molecular Pharmaceutics, 13(12), 1-22. Article 2022. https://doi.org/10.3390/pharmaceutics13122022

@article{52f9354b5db84c88b4229bd7a677f140,

title = "Internalization and transport of PEGylated lipid-based mixed micelles across Caco-2 cells mediated by scavenger receptor B1",

abstract = "The aim of this study was to get insight into the internalization and transport of PEGylat-ed mixed micelles loaded by vitamin K, as mediated by Scavenger Receptor B1 (SR-B1) that is abun-dantly expressed by intestinal epithelium cells as well as by differentiated Caco-2 cells. Inhibition of SR-B1 reduced endocytosis and transport of vitamin-K-loaded 0\%, 30\% and 50\% PEGylated mixed micelles and decreased colocalization of the micelles with SR-B1. Confocal fluorescence mi-croscopy, fluorescence-activated cell sorting (FACS) analysis, and surface plasmon resonance (SPR) were used to study the interaction between the mixed micelles of different compositions (varying vitamin K loading and PEG content) and SR-B1. Interaction of PEGylated micelles was independent of the vitamin K content, indicating that the PEG shell prevented vitamin K exposure at the surface of the micelles and binding with the receptor and that the PEG took over the micelles{\textquoteright} ability to bind to the receptor. Molecular docking calculations corroborated the dual binding of both vita-min K and PEG with the binding domain of SR-B1. In conclusion, the improved colloidal stability of PEGylated mixed micelles did not compromise their cellular uptake and transport due to the affin-ity of PEG for SR-B1. SR-B1 is able to interact with PEGylated nanoparticles and mediates their subsequent internalization and transport.",

keywords = "Epithelial transport, Mixed micelles, PEGylation, Scavenger receptor B1, Vitamin K",

author = "Xiangjie Su and Mercedes Ram{\'i}rez-Escudero and Feilong Sun and \{van den Dikkenberg\}, \{Joep B.\} and \{van Steenbergen\}, \{Mies J.\} and Pieters, \{Roland J.\} and Janssen, \{Bert J.C.\} and \{van Hasselt\}, \{Peter M.\} and Hennink, \{Wim E.\} and \{van Nostrum\}, \{Cornelus F.\}",

note = "Funding Information: Funding: X. Su is supported by a PhD scholarship from China Scholarship Council (CSC) (File no. 201707040097). Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2021",

month = nov,

day = "26",

doi = "10.3390/pharmaceutics13122022",

language = "English",

volume = "13",

pages = "1--22",

journal = "Molecular Pharmaceutics",

issn = "1543-8384",

publisher = "American Chemical Society",

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Su, X, Ramírez-Escudero, M, Sun, F, van den Dikkenberg, JB, van Steenbergen, MJ , Pieters, RJ , Janssen, BJC, van Hasselt, PM, Hennink, WE & van Nostrum, CF 2021, 'Internalization and transport of PEGylated lipid-based mixed micelles across Caco-2 cells mediated by scavenger receptor B1', Molecular Pharmaceutics, vol. 13, no. 12, 2022, pp. 1-22. https://doi.org/10.3390/pharmaceutics13122022

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T1 - Internalization and transport of PEGylated lipid-based mixed micelles across Caco-2 cells mediated by scavenger receptor B1

AU - Su, Xiangjie

AU - Ramírez-Escudero, Mercedes

AU - Sun, Feilong

AU - van den Dikkenberg, Joep B.

AU - van Steenbergen, Mies J.

AU - Pieters, Roland J.

AU - Janssen, Bert J.C.

AU - van Hasselt, Peter M.

AU - Hennink, Wim E.

AU - van Nostrum, Cornelus F.

N1 - Funding Information: Funding: X. Su is supported by a PhD scholarship from China Scholarship Council (CSC) (File no. 201707040097). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2021/11/26

Y1 - 2021/11/26

N2 - The aim of this study was to get insight into the internalization and transport of PEGylat-ed mixed micelles loaded by vitamin K, as mediated by Scavenger Receptor B1 (SR-B1) that is abun-dantly expressed by intestinal epithelium cells as well as by differentiated Caco-2 cells. Inhibition of SR-B1 reduced endocytosis and transport of vitamin-K-loaded 0%, 30% and 50% PEGylated mixed micelles and decreased colocalization of the micelles with SR-B1. Confocal fluorescence mi-croscopy, fluorescence-activated cell sorting (FACS) analysis, and surface plasmon resonance (SPR) were used to study the interaction between the mixed micelles of different compositions (varying vitamin K loading and PEG content) and SR-B1. Interaction of PEGylated micelles was independent of the vitamin K content, indicating that the PEG shell prevented vitamin K exposure at the surface of the micelles and binding with the receptor and that the PEG took over the micelles’ ability to bind to the receptor. Molecular docking calculations corroborated the dual binding of both vita-min K and PEG with the binding domain of SR-B1. In conclusion, the improved colloidal stability of PEGylated mixed micelles did not compromise their cellular uptake and transport due to the affin-ity of PEG for SR-B1. SR-B1 is able to interact with PEGylated nanoparticles and mediates their subsequent internalization and transport.

AB - The aim of this study was to get insight into the internalization and transport of PEGylat-ed mixed micelles loaded by vitamin K, as mediated by Scavenger Receptor B1 (SR-B1) that is abun-dantly expressed by intestinal epithelium cells as well as by differentiated Caco-2 cells. Inhibition of SR-B1 reduced endocytosis and transport of vitamin-K-loaded 0%, 30% and 50% PEGylated mixed micelles and decreased colocalization of the micelles with SR-B1. Confocal fluorescence mi-croscopy, fluorescence-activated cell sorting (FACS) analysis, and surface plasmon resonance (SPR) were used to study the interaction between the mixed micelles of different compositions (varying vitamin K loading and PEG content) and SR-B1. Interaction of PEGylated micelles was independent of the vitamin K content, indicating that the PEG shell prevented vitamin K exposure at the surface of the micelles and binding with the receptor and that the PEG took over the micelles’ ability to bind to the receptor. Molecular docking calculations corroborated the dual binding of both vita-min K and PEG with the binding domain of SR-B1. In conclusion, the improved colloidal stability of PEGylated mixed micelles did not compromise their cellular uptake and transport due to the affin-ity of PEG for SR-B1. SR-B1 is able to interact with PEGylated nanoparticles and mediates their subsequent internalization and transport.

KW - Epithelial transport

KW - Mixed micelles

KW - PEGylation

KW - Scavenger receptor B1

KW - Vitamin K

U2 - 10.3390/pharmaceutics13122022

DO - 10.3390/pharmaceutics13122022

M3 - Article

C2 - 34959304

AN - SCOPUS:85120174052

SN - 1543-8384

VL - 13

SP - 1

EP - 22

JO - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

IS - 12

M1 - 2022

ER -

Internalization and transport of PEGylated lipid-based mixed micelles across Caco-2 cells mediated by scavenger receptor B1

Abstract

Bibliographical note

Funding

Keywords

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