Polymeric drug delivery systems: aspects of core and shell of nanocarriers from polyesters, poly(ester amide)s or poly(2–oxazoline)s

Hydrophobe Wirkstoffe weisen häufig eine schlechten Bioverfügbarkeit und Transporteffizienz auf. Diese Nachteile können durch ein optimiertes Nanoträgersystem kompensiert werden. Hierfür sind polymerbasierte Mizellen und Nanopartikel mit einem hydrophoben Kern besonders geeignet. Die Personalisierung des jeweiligen Polymergrundgerüsts sollte jedoch unter Beachtung der kausalen Zusammenhänge erfolgen. In diesem Zusammenhang wurden in der vorliegenden Dissertation ausgewählte Kandidaten der Polyester, Polyesteramide und Poly(2-ethyl-2-oxazolin)e untersucht. Neben ihrer Synthese, wurden diese Materialien hinsichtlich ihrer Anwendung als Nanocarrier und Struktur–Eigenschafts–Beziehungen bewertet. Die konstante hydrophile-hydrophobe-Balance wurde für wohldefinierte Poly(ɛ–caprolacton)-Analoga mit unterschiedlicher Mikroarchitektur validiert. Trotz unterschiedlicher thermischer Polymereigenschaften wurden vielversprechende Nanopartikel mit gleicher Größe und ausgezeichneter Langzeitstabilität erhalten. Eine Polyesteramid-Bibliothek wurde durch die Polyaddition von acht Dicarbonsäuren und 2,2`-Bis(2-oxazoline) erzeugt. Im Anschluss wurden die geeigneten Materialien in einer Kompatibilitätsstudie mit dem hydrophoben, antientzündlichen Wirkstoff Indomethacin untersucht. Formulierbarkeit des Polymers, aber auch die Kompatibilität der Kernkomponenten in Bulk hatten beide einen signifikanten Einfluss auf die Qualität der beladenen Nanoträger. Die Einführung einer hydrophilen Stealth-Schale erfolgte im Makromonomeransatz durch Kombination der kationischen Ringöffnungspolymerization und einer kontrollierten, radikalischen Polymerisation. Resultierende Kern-Schale-Mizellen basierend auf dem hydrophoben Poly(methylmethacrylat)-Rückgrat und hydrophilien Seitenketten aus Oligo(2-ethyl-2-oxazolin) wurden in Abhängigkeit der variierenden Rückgrat-Endgruppe untersucht. Mittels intravitaler Mikroskopie wurde ein Endgruppeneinfluss auf die Leberzellspezifität in Mausstudien festgestellt

Stealth Effect of Short Polyoxazolines in Graft Copolymers: Minor Changes of Backbone End Group Determine Liver Cell-Type Specificity

Dye-loaded micelles of 10 nm diameter formed from amphiphilic graft copolymers composed of a hydrophobic poly(methyl methacrylate) backbone and hydrophilic poly(2-ethyl-2-oxazoline) side chains with a degree of polymerization of 15 were investigated concerning their cellular interaction and uptake in vitro as well as their interaction with local and circulating cells of the reticuloendothelial system in the liver by intravital microscopy. Despite the high molar mass of the individual macromolecules (Mn ≈ 20 kg mol-1), backbone end group modification by attachment of a hydrophilic anionic fluorescent probe strongly affected the in vivo performance. To understand these effects, the end group was additionally modified by the attachment of four methacrylic acid repeating units. Although various micelles appeared similar in dynamic light scattering and cryo-transmission electron microscopy, changes in the micelles were evident from principal component analysis of the Raman spectra. Whereas an efficient stealth effect was found for micelles formed from polymers with anionically charged or thiol end groups, a hydrophobic end group altered the micelles' structure sufficiently to adapt cell-type specificity and stealth properties in the liver. © 2021 The Authors. Published by American Chemical Society

PMMA-g-OEtOx Graft Copolymers: Influence of Grafting Degree and Side Chain Length on the Conformation in Aqueous Solution

Depending on the degree of grafting (DG) and the side chain degree of polymerization (DP), graft copolymers may feature properties similar to statistical copolymers or to block copolymers. This issue is approached by studying aqueous solutions of PMMA-g-OEtOx graft copolymers comprising a hydrophobic poly(methyl methacrylate) (PMMA) backbone and hydrophilic oligo(2-ethyl-2-oxazoline) (OEtOx) side chains. The graft copolymers were synthesized via reversible addition-fragmentation chain transfer (RAFT) copolymerization of methyl methacrylate (MMA) and OEtOx-methacrylate macromonomers of varying DP. All aqueous solutions of PMMA-g-OEtOx (9% ≤ DG ≤ 34%; 5 ≤ side chain DP ≤ 24) revealed lower critical solution temperature behavior. The graft copolymer architecture significantly influenced the aggregation behavior, the conformation in aqueous solution and the coil to globule transition, as verified by means of turbidimetry, dynamic light scattering, nuclear magnetic resonance spectroscopy, and analytical ultracentrifugation. The aggregation behavior of graft copolymers with a side chain DP of 5 was significantly affected by small variations of the DG, occasionally forming mesoglobules above the cloud point temperature (Tcp), which was around human body temperature. On the other hand, PMMA-g-OEtOx with elongated side chains assembled into well-defined structures below the Tcp (apparent aggregation number (Nagg = 10)) that were able to solubilize Disperse Orange 3. The thermoresponsive behavior of aqueous solutions thus resembled that of micelles comprising a poly(2-ethyl-2-oxazoline) (PEtOx) shell (Tcp > 60 °C)

Maintaining the Hydrophilic–Hydrophobic Balance of Polyesters with Adjustable Crystallinity for Tailor-Made Nanoparticles

To explore the relationship between thermal properties of a polymer and the biological performance of the resulting nanoparticle, all other parameters, including the hydrophobicity, should be kept constant. For this purpose, a gradient and a block copolyester were tailor-made via the triazabicyclodecene catalyzed ring-opening copolymerization of δ-valerolactone (δVL) and δ-decalactone (δDL) to match the hydrophobicity of poly­(ε-caprolactone) (PεCL). The degree of crystallinity of the semicrystalline materials was significantly reduced due to the incorporation of amorphous PδDL segments, as confirmed by dynamic scanning calorimetry. Atomic force microscopy revealed short and randomly oriented crystals in the gradient copolymer but longer and parallel aligned crystals for the block copolymer and PεCL. The stiffness of nanoparticles (<i>D</i>_h ≈ 170 nm) prepared from the polyesters correlated to the bulk crystallinity. The set of nanoparticles with constant hydrophobicity and size will facilitate direct access to the influence of the nanoparticle crystallinity on biological processes such as enzymatic degradation, drug release, and cellular uptake