| Autor: |
Slor G; Department of Organic Chemistry, School of Chemistry, Faculty of Exact Sciences, Tel-Aviv University, Tel-Aviv 6997801, Israel.; Tel Aviv University Center for Nanoscience and Nanotechnology, Tel-Aviv University, Tel-Aviv 6997801, Israel., Olea AR; Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 15-21, 08028 Barcelona, Spain., Pujals S; Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 15-21, 08028 Barcelona, Spain.; Department of Electronic and Biomedical Engineering, Faculty of Physics, University of Barcelona, Carrer Martí I Franquès 1, 08028 Barcelona, Spain., Tigrine A; Supramolecular Chemistry Group, Centre of Macromolecular Chemistry (CMaC), Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281 S4, B-9000 Ghent, Belgium., De La Rosa VR; Supramolecular Chemistry Group, Centre of Macromolecular Chemistry (CMaC), Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281 S4, B-9000 Ghent, Belgium., Hoogenboom R; Supramolecular Chemistry Group, Centre of Macromolecular Chemistry (CMaC), Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281 S4, B-9000 Ghent, Belgium., Albertazzi L; Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 15-21, 08028 Barcelona, Spain.; Department of Biomedical Engineering, Institute of Complex Molecular Systems (ICMS), Eindhoven University of Technology (TUE), Eindhoven 5612 AZ, The Netherlands., Amir RJ; Department of Organic Chemistry, School of Chemistry, Faculty of Exact Sciences, Tel-Aviv University, Tel-Aviv 6997801, Israel.; Tel Aviv University Center for Nanoscience and Nanotechnology, Tel-Aviv University, Tel-Aviv 6997801, Israel.; BLAVATNIK Center for Drug Discovery, Tel-Aviv University, Tel-Aviv 6997801, Israel.; ADAMA Center for Novel Delivery Systems in Crop Protection, Tel-Aviv University, Tel-Aviv 6997801, Israel.; The Center for Physics and Chemistry of Living Systems, Tel-Aviv University, Tel-Aviv 6997801, Israel. |
| Abstrakt: |
Enzymatically degradable polymeric micelles have great potential as drug delivery systems, allowing the selective release of their active cargo at the site of disease. Furthermore, enzymatic degradation of the polymeric nanocarriers facilitates clearance of the delivery system after it has completed its task. While extensive research is dedicated toward the design and study of the enzymatically degradable hydrophobic block, there is limited understanding on how the hydrophilic shell of the micelle can affect the properties of such enzymatically degradable micelles. In this work, we report a systematic head-to-head comparison of well-defined polymeric micelles with different polymeric shells and two types of enzymatically degradable hydrophobic cores. To carry out this direct comparison, we developed a highly modular approach for preparing clickable, spectrally active enzyme-responsive dendrons with adjustable degree of hydrophobicity. The dendrons were linked with three different widely used hydrophilic polymers-poly(ethylene glycol), poly(2-ethyl-2-oxazoline), and poly(acrylic acid) using the CuAAC click reaction. The high modularity and molecular precision of the synthetic methodology enabled us to easily prepare well-defined amphiphiles that differ either in their hydrophilic block composition or in their hydrophobic dendron. The micelles of the different amphiphiles were thoroughly characterized and their sizes, critical micelle concentrations, drug loading, stability, and cell internalization were compared. We found that the micelle diameter was almost solely dependent on the hydrophobicity of the dendritic hydrophobic block, whereas the enzymatic degradation rate was strongly dependent on the composition of both blocks. Drug encapsulation capacity was very sensitive to the type of the hydrophilic block, indicating that, in addition to the hydrophobic core, the micellar shell also has a significant role in drug encapsulation. Incubation of the spectrally active micelles in the presence of cells showed that the hydrophilic shell significantly affects the micellar stability, localization, cell internalization kinetics, and the cargo release mechanism. Overall, the high molecular precision and the ability of these amphiphiles to report their disassembly, even in complex biological media, allowed us to directly compare the different types of micelles, providing striking insights into how the composition of the micelle shells and cores can affect their properties and potential to serve as nanocarriers. |
