Biodegradable paclitaxel loaded nanoparticles and stent coatings as local delivery systems for the prevention of restenosis [Elektronische Ressource] / vorgelegt von Ulrich Westedt

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Biodegradable Paclitaxel-loaded Nanoparticles and Stent Coatings as Local Delivery Systems for the Prevention of Restenosis Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften (Dr. rer. nat.) dem Fachbereich Pharmazie der Philipps-Universit t Marburg vorgelegt von Ulrich Westedt aus Brome / Niedersachsen Marburg/Lahn 2004 Vom Fachbereich Pharmazie der Philipps-Universit t Marburg als Dissertation am 13.01.2004 angenommen. Erstgutachter: Prof. Dr. T. Kissel Zweitgutachter: Prof. Dr. U. Bakowsky Tag der m ndlich Pr fung 13. Januar 2004 Biodegradable Paclitaxel-loaded Nanoparticles and Stent Coatings as Local Delivery Systems for the Prevention of Restenosis von Ulrich Westedt Die vorliegende Arbeit entstand auf Anregung und unter der Leitung von Herrn Prof. Dr. Thomas Kissel am Institut f r Pharmazeutische Technologie und Biopharmazie der Philipps-Universit t Marburg TABLE OF CONTENTS 1. INTRODUCTION ............................................................................................. 1 .......................... 2 RESTENOSIS: INCIDENCE AND PATHOPYSIOLOGY ....................... 2 RATIONALE FOR LOCAL DRUG DELIVERY ...................................... 4 DRUG ELUTING STENTS.......................................... 5 POROUS BALLOON CATHETER-BASED DRUG DELIVERY ........... 8 PACLITAXEL FOR PREVENTION OF RESTENOSIS............

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Biodegradable Paclitaxel-loaded
Nanoparticles and Stent Coatings
as Local Delivery Systems
for the Prevention of Restenosis


Dissertation

zur
Erlangung des Doktorgrades
der Naturwissenschaften
(Dr. rer. nat.)



dem Fachbereich Pharmazie der
Philipps-Universit t Marburg


vorgelegt von
Ulrich Westedt
aus Brome / Niedersachsen


Marburg/Lahn 2004


















Vom Fachbereich Pharmazie der Philipps-Universit t Marburg als Dissertation am
13.01.2004 angenommen.

Erstgutachter: Prof. Dr. T. Kissel
Zweitgutachter: Prof. Dr. U. Bakowsky
Tag der m ndlich Pr fung 13. Januar 2004
Biodegradable Paclitaxel-loaded
Nanoparticles and Stent Coatings
as Local Delivery Systems
for the Prevention of Restenosis






von
Ulrich Westedt
Die vorliegende Arbeit
entstand auf Anregung und unter der Leitung von

Herrn Prof. Dr. Thomas Kissel

am Institut f r Pharmazeutische Technologie und Biopharmazie
der Philipps-Universit t Marburg
TABLE OF CONTENTS
1. INTRODUCTION ............................................................................................. 1 .......................... 2
RESTENOSIS: INCIDENCE AND PATHOPYSIOLOGY ....................... 2
RATIONALE FOR LOCAL DRUG DELIVERY ...................................... 4
DRUG ELUTING STENTS.......................................... 5
POROUS BALLOON CATHETER-BASED DRUG DELIVERY ........... 8
PACLITAXEL FOR PREVENTION OF RESTENOSIS......................... 10
OBJECTIVES OF THIS WORK................................................................ 11
REFERENCES ............................................................. 13

2. DEPOSITION OF NANOPARTICLES IN THE ARTERIAL VESSEL
BY POROUS BALLOON CATHETERS: LOCALIZATION BY
CONFOCAL LASER SCANNING MICROSCOPY AND
TRANSMISSION ELECTRON MICROSCOPY......................................25
SUMMARY.................................................................. 26
INTRODUCTION........................ 27
MATERIALS AND METHODS ................................................................ 28
RESULTS AND DISCUSSION. 31
CONCLUSIONS .......................................................................................... 37
REFERENCES............................. 38
3. EFFECTS OF DIFFERENT APPLICATION PARAMETERS ON
PENETRATION CHARACTERISTICS AND ARTERIAL VESSEL
WALL INTEGRITY AFTER LOCAL NANOPARTICLE DELIVERY
USING A POROUS BALLOON CATHETER ..........................................42
SUMMARY.................................................................. 43
INTRODUCTION........................ 44
MATERIALS AND METHODS ................................................................ 45
RESULTS AND DISCUSSION. 49
CONCLUSIONS .......................................................................................... 55
REFERENCES............................. 56

4. PACLITAXEL LOADED NANOPARTICLES FROM
BIODEGRADABLE POLY(VINYL ALCOHOL)-GRAFT-
POLY(LACTIDE-CO-GLYCOLIDE) FOR CATHETER BASED
LOCAL TREATMENT OF RESTENOSIS................................................61
SUMMARY.................................................................................................. 62
INTRODUCTION........................ 63
MATERIALS AND METHODS ................................................................ 64
RESULTS AND DISCUSSION. 70
CONCLUSIONS .......................................................................................... 79
REFERENCES............................. 79

5. PACLITAXEL RELEASING STENTS FOR THE TREATMENT OF
RESTENOSIS: BIODEGRADABLE COATINGS CONSISTING OF
POLY(VINYL ALCOHOL)-GRAFT-POLY(LACTIDE-CO-
GLYCOLIDE) .................................................................................................85
SUMMERY.. 86
INTRODUCTION........................................................................................ 87
MATERIALS AND METHODS................................ 88
RESULTS AND DISCUSSION ................................. 94
CONCLUSIONS ........................................................ 104
REFERENCES........................................................... 104

6. SUMMARY AND OUTLOOK FOR FURTHER STUDIES .................109
SUMMARY................................................................................................ 110
OUTLOOK FOR FURTHER STUDIES.................................................. 114
ZUSAMMENFASSUNG .......................................... 116
AUSBLICK ................................................................ 121
REFERENCES / LITERATURSTELLEN............................................... 123

7. APPENDICES................................................................................................126
LIST OF PUBLICATIONS....... 127
CURRICULUM VITAE............................................................................ 129
Chapter 1 1









CHAPTER 1

INTRODUCTION











Chapter 1 2
INTRODUCTION
In this work, nanoparticles and films consisting of biodegradable comb
polyesters, poly(vinyl alcohol)-graft-poly(lactide-co-glycolide) (PVA-g-PLGA)
[1,2], have been investigated as delivery systems for paclitaxel to prevent the
pathogenesis of postangioplastic restenosis. A more detailed introduction
dealing with the specific objectives of each research topic is provided in the
following chapters. This chapter serves as a general introduction explaining the
basic problems that arise from percutaneous revascularization interventions and
local drug delivery strategies to reduce restenosis. At the end of the chapter the
objectives of this work are outlined.

RESTENOSIS: INCIDENCE AND PATHOPYSIOLOGY
Percutaneous transluminal (coronary) angioplasty, PT(C)A is a very
useful technique for the treatment of vascular occlusions. Unfortunately, its
success is often limited by the development of a secondary arterial obstruction,
also known as restenosis. According to both clinical and angiographic
definitions, 25 ? 35 % of successfully treated atherosclerotic lesions re occlude
within 3 ? 6 months [3], generating increased costs for additional
revascularization procedures, atherectomy or bypass surgery [4]. Restenosis is
primarily attributed to neointimal hyperplasia. Balloon angioplasty denudes the
endothelial layer which normally prevents of blood components from interaction
with tissue factors and subendothelial parts of the injured vessel wall. When
such interactions occur, platelet aggregation and the activation of the
coagulation cascade leads to thrombus formation [5]. This, in turn, stimulates
the release of cytokines and growth factors, such as platelet-derived growth
factor (PDGF), basic fibroblast growth factor (bFGF), transforming growth
factor b (TGFb), thrombin, and angiotensinII [6-10]. Consequently,
Chapter 1 3
mononuclear leukocytes enter the arterial wall followed by a transformation to
macrophages.

Treatment Restenosis
EEL
PT(C)A
Media
IEL
Intima
EEL
Intima
Stenting
IEL
Intima
Treatment Restenosis
Fig. 1: Possible mechanisms of restenosis after PT(C)A and stenting. PTA leads
to plaque disruptions, and dissections penetrating the media through the
internal elastic lamina (IEL). Restenosis, caused by arterial remodelling, is
characterized by shrinkage of the area circumscribed by the external elastic
lamina (EEL), and intimal hyperplasia. Stenting also enlarges the cross-
sectional area of the vessel wall. Stents prevent vessel shrinkage, however
intimal hyperplasia can be excessive (adapted from [11]).

These macrophages produce additional vascular smooth muscle cell (VSMC)
activation elements. Vascular trauma by angioplasty catheter and stents
application induces necrosis and the activation of VSMC in the media and
myofibroblasts in the adventitia. Subsequently, cells migrate into the intima,
where they proliferate and secrete extracellular matrix. VSMC proliferation is