Orthogonal linker chemistries applied in core-crosslinked polymeric micelles

Abstract

CCPMs have shown great potential in preclinical models and even clinical evaluation, with there being a continued need for the development of orthogonal linker chemistries for the crosslinking and triggered release of API cargos, also with increasing API complexity. The aim of this thesis was to expand the toolbox available to this regard: • Implement NCL as a crosslinking tool to obtain CCPMs using two different, well described thermosensitive diblock copolymer systems, namely mPEG-PNIPAM and mPEG-pHPMAmLacn. • Study the crosslinking efficiency and stability of CCPMs formed by two different crosslinking approaches, either by using a small molecule crosslinker or with crossreactive complementary polymers. • Demonstrate improved compatibility of fragile compounds (therapeutic and diagnostic) with CCPMs using NCL as a crosslinking reaction. 15 • Assess the state of the art for the use of AuNCs in biomedical applications in diagnostic, therapeutic and theranostic capacity. • Develop linking technologies, using light induced (AuNC based) and reduction sensitive (disulfide based) release triggers for the release of APIs. • Apply reduction sensitive release linker technology to promising but challenging API classes, namely therapeutic peptides and siRNA, with entrapment in CCPMs. • Keeping an eye on industrial applicability