Bersani, Sara (2008) Studio di sistemi supramolecolari per il delivery di proteine terapeutiche. [Tesi di dottorato]
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Novel strategies for site-specific protein modification have been investigated by using low molecular weight linkers.
In the first part of the study, glycoside-derivatives have been obtained by conjugation of alkyl chains and then activated with a maleimido function for selective derivatization of cysteines. The linkers were used to modify the free cysteins (Cys) of serum albumin (HSA) and recombinant human granulocyte colony-stimulating factor (rh-G-CSF). Hydrazide polyethylenglycole (PEG-Hz) was conjugated to the aldehydes groups generated by selective oxidation of the glycosides with periodate. This PEGylation strategy yielded "flag-type" bioconjugates as several PEG chains are attached to the glycosidic residues of the semi-synthetic neo-glycoprotein. The PEG-Hz conjugation to the oxidized glycosides yields pH-dependent cleavable hydrazone bonds which allow for PEG release. Therefore, un-PEGylated active protein can be released over time under physiological conditions.
In the second part of the work preliminary studies of polyethylene methacrylate (PEGMA) radical polymerization from protein surface were conducted in aqueous solution using the Atom Transfer Radical Polymerization (ATRP) technique.
Two different alkyl halide derivatives were synthesized: 2-bromo-isobutyryl-ethoxyethyl-maleimide and 2-bromo-isobutyryl-cadaverine. The linkers were used to modify selectively aminoacids of protein models: HSA, rh-G-CSF and recombinant human growth hormone (rh-GH) and to yield macro-initiators. The synthesized 2-bromo-isobutyryl- derivatives have been characterized by chromatographic and spectrometric techniques. However, preliminary studies of radical polymerization using ATRP from the protein surfaces did not give reasonable results. Therefore more detailed investigation will be worked up in order to set up a convenient polymerization protocol.
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