Innovative cleavable and bioorthogonal conjugation chemistries for application in core-crosslinked polymeric micelles and bioconjugates

Matt Timmers

Research output: ThesisDoctoral thesis 1 (Research UU / Graduation UU)


The choice of chemistry is very important in drug development. In polymeric micelles, covalent crosslinking and covalent encapsulation can enhance the circulation kinetics of these drugs compared to free drug. This covalent bond between drug and carrier can be chosen to improve the therapeutic index of a drug by introducing selective bonds which are sensitive to for example the acidic environment of the tumor microenvironment. Here, linkers based on the trityl and silyl group are explored as there are acid sensitive and can be tuned with relatively simply chemical modifications. These linker could be applied to achieve tunable, acid sensitive release of the native drug from core-crosslinked polymeric micelles. In parallel, the chemical possibilities of novel click compound TMTHSI are explored, as this is a promising reagent for biocoinjugates, surface modification or other applications of click chemistry. This TMTHSI compound can be produced at large scale, is remarkably stable against very acidic conditions, and can be used to functionalize antibodies. Besides, a bifunctional reagent could be made which binds specifically to the N-terminus of native proteins. The combination of the core-crosslinked micelles and this new click reagent led to the development of micelles in which large hydrophilic siRNA could be entrapped, and released with a reductive glutathion trigger. All these results combined underline the importance of choosing the right chemistry for a core-crosslinked polymeric micelle platform.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Utrecht University
  • Vermonden, Tina, Primary supervisor
  • Hennink, Wim, Supervisor
  • Rijcken, Cristianne, Co-supervisor, External person
  • Liskamp, Rob, Co-supervisor, External person
Award date29 Nov 2023
Place of PublicationUtrecht
Print ISBNs978-94-6473-279-5
Electronic ISBNs978-94-6473-279-5
Publication statusPublished - 29 Nov 2023


  • Nanomedicine
  • controlled release
  • click chemistry
  • bioconjugates
  • polymeric micelles


Dive into the research topics of 'Innovative cleavable and bioorthogonal conjugation chemistries for application in core-crosslinked polymeric micelles and bioconjugates'. Together they form a unique fingerprint.

Cite this