Lipid-polymer conjugates for innate immune activation

Over the past years, immunotherapy has caused innovative breakthroughs in the oncology field and may likely conquer the treatment landscape in the future. Due to extensive research, immunotherapy is a fast evolving domain which has the potential to develop more effective, more precise and more personalized treatment strategies, compared to the traditional therapies (e.g. chemotherapy). In this context, triggering of Toll like receptors (TLRs) on immune cells was explored to redirect the immune system against cancer. Particularly, small molecule TLR agonists hold promise as potent vaccine adjuvants to generate a strong immune response and immunological memory which in turn promises long-term protection. Unfortunately, numerous small molecule TLR agonists rapidly enter systemic circulation and have to deal with an unfavourable safety profile. The general aim of this thesis is to design potent but safe delivery system for small molecule imidazoquinoline TLR7/8 agonists. The latter are highly potent at triggering innate immune activation, but suffer from an unfavourable pharmacokinetic profile, upon local administration, and will rapidly enter the systemic circulation and cause off target toxicity. Hereto, we will covalently conjugate TLR7/8 agonist to lipid polymer conjugates with the intention to bind to albumin and thereby hitchhike the albumin flow in the interstitial tissue towards the immune inducing sites in the draining lymph nodes. In this thesis, the influence of macromolecular design and conjugation chemistry on the immunobiological behaviour in vitro and in vivo will be investigated.

Jaar van publicatie:2021

Toegankelijkheid:Open