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• W3136207940 abstract "This thesis investigates pharmaceutical suitability of core crosslinked flower-like micelles for local and systemic applications. First, we demonstrated crosslinking of micelles composed of hydrophilic PEG shell and hydrophobic N-isopropylacrylamide core using native chemical ligation. In a follow-up study, circulation kinetics, biodistribution, and occurrence of accelerated blood clearance (ABC) phenomenon upon ... read more injection of flower-like micelles was compared to star-like micelles. Immunocompetent mice were used for this study and both types of micelles were injected twice and the time interval between the injection was one week. Determination of concentration of micelles and anti-PEG antibodies in plasma samples showed that first, flower-like micelles circulate significantly longer than star-like micelles upon the first injection. Second, both types of micelles induce production of anti-PEG IgM. Third, the anti-PEG IgM induced by injection of star-like micelles cause rapid clearance of the second dose of star-like micelles but not flower-like micelles. Forth, the anti-PEG IgM induced upon injection of flower-like micelles reduced circulation time of the second dose of star-like micelles but not flower-like micelles. Taken together, the results of this study show the great potential of looped PEG in preventing recognition by anti-PEG antibodies and thereby opsonization and clearance of PEGylated nanocarriers. These findings propose that for clinical application of pegylated nanoparticles especially the ones that are repeatedly administered, the surface should be decorated with looped PEG. To investigated suitability of flower-like micelles for local pharmaceutical applications, formulation of flower-like micelles into enzyme-responsive hydrogel were investigated. The target enzyme was matrix metalloproteinase (MMP) which is upregulated in many diseased tissues. Micelles with an excess of thioester functionalities in the core were prepared. Two novel pentablock copolymers having a peptide midblock (consisting of either L- or D- amino acids) and cysteine functionalities in the outer blocks were synthesized by ATRP as linker. Upon mixing the micelles with the linker (either D or L peptide), the excess of thioester functionalities in the micellar cores reacted with cysteine functionalities in the linker resulting in a hydrogel. Both types of hydrogels were incubated with collagenase as a model for MMP’s. Only the gel crosslinked by a L-peptide linker showed degradation upon exposure to collagenase in a concentration dependent manner. Moreover, we investigated the rheological characteristics of dense dispersions of core crosslinked flower-like micelles at a range of temperature from 10 to 40 °C. An effective volume fraction (φ) was defined to compare packing of micelles at different concentrations and temperatures. We observed that for a dense micellar dispersion, φ can be above the maximum random packing fraction for monodisperse hard spheres Φ_rcp≈0.64 possibly due to compressible deformation of the relatively soft micelles. When the storage modulus of different micellar dispersions at different concentrations and temperatures is plotted as a function of φ, the data points collapse on a master curve. This indicates that the effective volume fraction of the micellar dispersions is the main parameter controlling their rheological properties. A glassy state was observed at φ≥ 1.2 independent from temperature which is well described by a disordered lattice model. show less" @default.
• W3136207940 created "2021-03-29" @default.
• W3136207940 creator A5072625120 @default.
• W3136207940 date "2021-01-29" @default.
• W3136207940 modified "2023-09-23" @default.
• W3136207940 title "Core crosslinked flower-like micelles for systemic and local pharmaceutical applications" @default.
• W3136207940 doi "https://doi.org/10.33540/596" @default.
• W3136207940 hasPublicationYear "2021" @default.
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