Light-Sensitive Polymeric Nanoparticles Based on Photo-Cleavable Chromophores

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 pHinduced 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.

Precisely Controlled Microsphere Design via Visible‐Light Cross‐Linking of Functional Prepolymers

“…[24] This is in contrast to methods of particle synthesis such as dispersion polymerization, where oligomers reach a critical length which leads to enthalpic precipitation as a result of unfavourable polymer-solvent interactions. [25] The mechanism of particle nucleation and growth in the current study appears to proceed analogous to precipitation polymerization for a number of reasons. First, photochemical initiation leads to cross-linking of the pre-polymers, as opposed to growth by monomeric addition, as in the case of dispersion polymerization without cross-linker.…”

Photocontrolled Release of Chemicals from Nano‐ and Microparticle Containers

“…[2] Among the different stimuli, light is of outstanding importance because it can be applied in av ery precise manner by selecting suitable wavelengths,p olarization directions,a nd intensities in an essentially non-contact approach. [7][8][9] Concerning particular applications, they suffer from serious drawbacks.A part from slow degradation kinetics and the formation of unwanted side products during the photolysis reaction with o-nitrobenzyl linkers, these are recognized as reactive chromogenic nitroso carbonyl compounds,r evealing severe cytotoxicity. Nitroaryl groups,t hat is, ortho-nitrobenzyl groups,a re by far the most commonly used photoresponsive linker units.…”

“…Nitroaryl groups,t hat is, ortho-nitrobenzyl groups,a re by far the most commonly used photoresponsive linker units. [7][8][9] Concerning particular applications, they suffer from serious drawbacks.A part from slow degradation kinetics and the formation of unwanted side products during the photolysis reaction with o-nitrobenzyl linkers, these are recognized as reactive chromogenic nitroso carbonyl compounds,r evealing severe cytotoxicity. [10,11] Even in derivatives where the cleavage kinetics have been improved to as much as 95 %degradation in 3h, [12] various issues,such as lengthy syntheses,s ensitivity to sunlight, and reactive side products,r emain challenging.T his limits their applicability for advanced life-science settings.A lternative methods comprise the use of photoresponsive phenacyl, coumarin-4ylmethyl, or arylmethyl groups.M ost common photodegradable compounds are monofunctional, rendering them unsuitable to be part of apolymer backbone.The use of adithianeprotected benzoin derivative (from the arylcarbonylmethyl group), first described by Sheehan and co-workers as alightsensitive protecting group for carboxylic acids, [13] may circumvent such limitations.E stablished for peptide [14] and solidphase synthesis, [15,16] the use of diol benzoin derivatives as an active monomer in the polymerization process of polyesters has,s urprisingly and to the best of our knowledge,n ot been reported thus so far.Inthis study,wefocus on the synthesis of nano-and microparticle containers that can be "opened" with UV light in as imple and well-controlled manner while releasing chemicals on demand within defined periods of time (minutes to hours).…”

Lichtgesteuerte Freisetzung von Chemikalien aus polymeren Nano‐ und Mikropartikelbehältern

“…Die Verwendung von spaltbaren, bifunktionellen Monomereinheiten stellt eine Methode dar,umdie vollständige Zersetzung des polymeren Materials durch externe Auslçser zu ermçglichen. [7][8][9] Bezüglich ihrer Anwendbarkeit haben sie allerdings schwerwiegende Nachteile.N eben ihrer langsamen Abbaukinetik und dem Auftreten unerwünschter Nebenprodukte bei der Photolysereaktion der Nitrobenzyleinheiten, bilden sich reaktive chromogene Nitrosocarbonylverbindungen, was sich wiederum in einer starken Zytotoxizitätmanifestiert. Zahlreiche photoabbaubare Polymere,w ie z.…”

“…B. O-Nitrobenzyl-Gruppen, sind die mit Abstand am häufigsten verwendeten lichtempfindlichen Verknüpfungseinheiten. [7][8][9] Bezüglich ihrer Anwendbarkeit haben sie allerdings schwerwiegende Nachteile.N eben ihrer langsamen Abbaukinetik und dem Auftreten unerwünschter Nebenprodukte bei der Photolysereaktion der Nitrobenzyleinheiten, bilden sich reaktive chromogene Nitrosocarbonylverbindungen, was sich wiederum in einer starken Zytotoxizitätmanifestiert. [10,11] Selbst bei Derivaten, deren Abbau innerhalb von drei Stunden auf bis zu 95 %o ptimiert wurde, [12] bleiben Herausforderungenw ie eine langwierige Synthese,E mpfindlichkeit gegenüber Sonnenlicht und das Auftreten reaktiver Nebenprodukte bestehen.…”