Light-sensitive polymeric nanoparticles based on photo-cleavable chromophores [Elektronische Ressource] / Daniel Klinger

Daniel Defoe

Informations

• Publié par: johannes_gutenberg-universitat_mainz
• Publié le: 01 janvier 2012
• Nombre de lectures: 28
• Langue: English
• Poids de l'ouvrage: 11 Mo

Extrait

Light-Sensitive
Polymeric Nanoparticles
Based on
Photo-Cleavable Chromophores



Dissertation



zur Erlangung des Grades
“Doktor der Naturwissenschaften”
dem Fachbereich Chemie, Pharmazie und Geowissenschaften
der Johannes Gutenberg-Universität Mainz
vorgelegt von



Daniel Klinger

geboren in Mainz
Mainz 2011














Abstract
This thesis focuses on the design, synthesis and characterization of novel photo-sensitive
microgels and nanoparticles as potential materials for the loading and light-triggered
release/accessibility of functional compounds. In order to realize this concept, different
approaches to irradiation-dependent response mechanisms have been investigated.
Novel light-cleavable divinyl functionalized monomeric crosslinkers based on
o-nitrobenzyl derivatives were synthesized and used for the preparation of either PMMA or
hydroxyl functionalized PHEMA microgels swellable and degradable in organic solvents. By
the introduction of anionic MAA moieties into the PHEMA microgels, this concept was
successfully transferred to double stimuli-responsive p(HEMA-co-MAA) hydrogel
nanoparticles exhibiting a pH-dependent swelling and light-induced degradation behavior in
aqueous media. This sensitivity to two orthogonal triggers is proposed to combine a pH-
induced post-formation loading mechanism with a pH- and light-triggered release. In addition,
a new class of enzyme- and light-sensitive PAAm microgels based on (meth-)acrylate
functionalized dextrans as photo- and enzymatically degradable macromolecular crosslinkers
was developed by introducing a photo-labile linker between the enzymatically degradable
dextran chain and the polymerizable vinyl moieties. Here, the water solubility of the
crosslinkers is assumed to enable an in situ loading approach of hydrophilic compounds.
A different approach to the loading of microgels is based on photo-labile covalent
microgel-drug conjugates. The first step to the realization of this concept was achieved by the
development of a novel functional monomer consisting of a doxorubicin molecule covalently
attached to a radically polymerizable methacrylate group via a photo-cleavable linker.
Moreover, in order to enable the release of hydrophobic substances in aqueous media,
hydrophobic nanoparticles consisting of a photo-resist polymer were designed to be
degradable upon irradiation in water. Light-triggered conversion of the initial hydrophobic
polymer into hydrophilic PMAA induced in situ particle dissolution and release of nile red.
Since the introduction of a stimuli-responsive shell around a microgel is assumed to prevent
leakage of embedded compounds, studies on non-stimuli-responsive shell formation around
preformed microgel seed particles and the formation of microgel cores in polymeric shells
were conducted to investigate potential synthetic pathways to this approach.
In a last attempt, the surface of PHEMA and p(HEMA-co-MAA) microgels was
functionalized with cinnamoyl groups in order to trigger the (reversible) particles interaction
with each other by light-induced [2+2] cycloaddition reactions. Table of Contents
Table of Contents

1 Introduction ...................................................................................... 1

2 Motivation ........................ 3

3 Theoretical Part ................................................................................ 5
3.1 Polymeric gels: from macro to micro ....................... 5
3.2 Synthesis of Microgels ............................................................................. 8
3.2.1 Microgel preparation in homogeneous phase .... 8
3.2.2 Microgel preparation in heterogeneous phase .................................... 9
3.2.2.1 Microgels by dispersion / precipitation polymerization ..... 9
3.2.2.2 Microgel synthesis in dispersed droplets .......................................................... 11
3.3 Stimuli-responsive microgels: features and applications ....................... 14
3.3.1 Microgels for loading and release applications ................................ 14
3.3.1.1 Network characteristics .................................................... 15
3.3.2 Different approaches to stimuli-responsive microgels ..................... 25
3.3.2.1 Stimuli-responsive microgels based on triggered changes in the
physico-chemical parameters of the network-forming polymer ....................... 26
3.3.2.2 Stimuli-responsive microgels based on cleavable crosslinking points ............. 38
3.4 Photochemistry in polymeric nanoscale materials ................................. 46
3.4.1 Light as a trigger ............................................................................... 46
3.4.2 Photoreactions in polymers .............................................................. 47
3.4.2.1 Types of chromophores in polymeric materials ............................................... 48
3.4.2.2 Photoreactions of o-nitrobenzyl derivatives ..................... 50


i Table of Contents
4 Outline ............................................................................................ 53

5 Results and Discussion ................................... 56
5.1 Photo-sensitive microgels based on light-cleavable
monomeric crosslinkers .......................................... 56
5.1.1 Photo-sensitive polymeric gel nanoparticles .................................... 57
5.1.1.1 Photo-sensitive PMMA microgels: light-triggered swelling
and degradation ............................................................................................... 58
5.1.1.2 Photo-sensitive PHEMA microgels: light-triggered swelling .......................... 80
5.1.2 Photo-sensitive hydrogel nanoparticles ............................................ 85
5.1.2.1 Anionic hydrogel nanoparticles containing methacrylic acid groups ............... 86
5.1.2.2 Dual stimuli-responsive p(HEMA-co-MAA) microgels: pH-dependent
swelling and light-induced degradation .......................................................... 106
5.2 Photo-sensitive hydrogel nanoparticles based on light-cleavable
polymeric crosslinkers .......................................................................... 126
5.2.1 Enzymatically degradable nanogels based on dextran-
methacrylates as macromolecular crosslinkers .............................. 127
5.2.2 Enzymatically- and light-degradable nanogels
based on functionalized dextrans as crosslinkers ........................... 146
5.3 Light-sensitive microgel-doxorubicin conjugates: labile drug
attachment via a photo-cleavable linker ............................................... 163
5.4 Photo-resist nanoparticles: light-induced degradation of
hydrophobic polymers in aqueous dispersion ...................................... 174
5.5 Towards stimuli-responsive core/shell nanoparticles
containing a microgel core.................................................................... 186


ii Table of Contents
5.5.1 PAAm/PMMA core/shell nanoparticles by seeded
dispersion polymerization. ............................................................. 188
5.5.2 PAAm/PU core/shell nanoparticles by free radical
polymerization of AAm in preformed nanocapsules ..................... 195
5.5.2.1 Preparation of a light-sensitive polyurethane as potential material
for photo-cleavable nanocapsules ................................................................... 198
5.6 Surface functionalization of microgels with
photo-reactive chromophores ............................................................... 202
5.6.1 Surface modification of PHEMA and p(HEMA-co-MAA)
microgels with cinnamoyl groups. ................................................. 203
5.6.2 Self-healing hydrogel thin films from photo-reactive microgels ... 207

6 Conclusion and Outlook ............................................................... 209

7 Experimental Part ......................................... 214
7.1 Materials ............................................................... 214
7.2 Instrumentation ..................... 214
7.3 Synthesis of light-cleavable monomeric crosslinkers .......................... 215
7.4 Synthesis of enzymatically degradable macromolecular
cross-linkers .......................................................................................... 220
7.5 Synthesis of enzymatically and light-degradable
macromolecular crosslinkers ................................................................ 221
7.6 Synthesis of doxorubicin-methacrylate containing a
photo-labile linker ................................................................................. 223


iii Table of Contents
7.7 Synthesis of a light-sensitive monomer for the preparation
of polymeric photo-resist nanoparticles ............................................... 227
7.8 Synthesis of a photo-degradable polyurethane by p