University of Groningen Endocytosis of nanomedicines Francia, Valentina

University of Groningen

Endocytosis of nanomedicines

Francia, Valentina

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from

it. Please check the document version below.

Document Version

Publisher's PDF, also known as Version of record

Publication date:

2018

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):

Francia, V. (2018). Endocytosis of nanomedicines: Dissecting the pathways of uptake of nanosized drug

carriers by cells. University of Groningen.

Copyright

Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policy

If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.

12.

Endocytosis of

Nanomedicines

Dissecting the Pathways of Uptake of

Nano-sized Drug Carriers by Cells

2018

Paranymphs : Keni Yang

Harita Yedavally

Cover design : Valentina Francia

Layout

: Valentina Francia

Printing

: Gildeprint

The work presented in this thesis was partly funded by the European Research

Council (ERC) under the European Union's Horizon 2020 research and innovation

programme under grant agreement Nº637614 (NanoPaths). Printing of this thesis

was financially supported by the University of Groningen, Faculty of Faculty of

Science and Engineering and the University Library.

© 2018, Valentina Francia

ISBN (printed version)

: 978-94-034-1038-8

ISBN (digital version)

: 978-94-034-1037-1

All rights reserved. No part of this thesis may be reproduced or transmitted in any

form by any means without permission of the author.

Endocytosis of nanomedicines

Dissecting the Pathways of Uptake of Nano-sized Drug Carriers by Cells

PhD thesis

to obtain the degree of PhD at the

University of Groningen

on the authority of the

Rector Magnificus Prof. E. Sterken

and in accordance with

the decision by the College of Deans.

This thesis will be defended in public on

Tuesday 25 September 2018 at 09.00 hours

by

Valentina Francia

born on 14 June 1987

in Milan, Italy

Supervisor

Prof. K. Poelstra

Co-supervisor

Dr. A. Salvati

Assessment Committee

Prof. M. Schmidt

Prof. R.M. Schiffelers

Prof. S.C. de Smedt

Table of Contents

CHAPTER 1. NANOMEDICINE

1

1

G

ENERAL DEFINITION AND PROPERTIES

2

2

T

HE BIOLOGICAL INTERACTIONS OF NANOMEDICINES

4

3

T

HE BIODISTRIBUTION OF NANOMEDICINES

6

4

T

ARGETING STRATEGIES OF NANOMEDICINES

8

5

S

UCCESSFUL EXAMPLES IN THE MARKET

14

6

P

ROBLEMS OF DRUG DELIVERY OF NANOMEDICINES AND FUTURE PERSPECTIVES

17

B

IBLIOGRAPHY

26

AIM OF THE THESIS

35

B

IBLIOGRAPHY

38

CHAPTER 2. ENDOCYTOSIS MECHANISMS

41

1

C

LATHRIN

-

MEDIATED

E

NDOCYTOSIS

(CME)

43

2

C

LATHRIN

-

INDEPENDENT ENDOCYTOSIS

(CIE)

46

3

M

EMBRANE

C

URVATURE AND

BAR

PROTEINS

55

4

V

IRUSES AND

T

OXIN UPTAKE

62

5.

F

INAL REMARKS

:

HOW ENDOCYTOSIS HAS BEEN STUDIED IN THIS THESIS

64

B

IBLIOGRAPHY

66

CHAPTER 3. LIMITS AND CHALLENGES IN USING TRANSPORT INHIBITORS TO

CHARACTERIZE HOW NANO-SIZED DRUG CARRIERS ENTER CELLS

75

A

BSTRACT

75

B

ACKGROUND

76

R

ESULTS AND DISCUSSION

78

C

ONCLUSIONS

91

M

ETHODS

92

A

CKNOWLEDGEMENTS

95

B

IBLIOGRAPHY

96

S

UPPLEMENTARY

I

NFORMATION

99

CHAPTER 4. SILICA NANOPARTICLES ARE INTERNALIZED BY CELLS VIA DIFFERENT

MECHANISMS WHEN COATED BY DIFFERENT CORONAS IN LOW OR HIGH SERUM

CONTENT

109

A

BSTRACT

109

B

ACKGROUND

110

R

ESULTS AND DISCUSSION

111

C

ONCLUSION

119

M

ETHODS

121

A

CKNOWLEDGEMENTS

125

B

IBLIOGRAPHY

126

CHAPTER 5. MECHANISMS OF UPTAKE AND MEMBRANE CURVATURE GENERATION FOR

CELL INTERNALIZATION OF NANO-SIZED OBJECTS

133

A

BSTRACT

133

B

ACKGROUND

,

RESULTS AND DISCUSSION

134

M

ETHODS

143

A

CKNOWLEDGEMENTS

146

B

IBLIOGRAPHY

146

S

UPPLEMENTARY

I

NFORMATION

149

CHAPTER 6: EFFECT OF THE DEVELOPMENT OF A CELL BARRIER ON NANOPARTICLE

UPTAKE IN ENDOTHELIAL CELLS

159

A

BSTRACT

159

B

ACKGROUND

160

R

ESULTS AND DISCUSSION

161

C

ONCLUSIONS

171

M

ETHODS

172

A

CKNOWLEDGEMENTS

177

B

IBLIOGRAPHY

179

S

UPPLEMENTARY

I

NFORMATION

183

CHAPTER 7.GENERAL DISCUSSION AND FUTURE PERSPECTIVES

209

B

IBLIOGRAPHY

219

NEDERLANDSE SAMENVATTING

223

B

IBLIOGRAPHY

232

ACKNOWLEDGEMENTS

235