Martin K. Kræmer

PhD defence by Martin K. Kræmer

On Friday 21 February, Martin K. Kræmer will defend his PhD thesis "Prodrugs and Linker Systems for Degradation in Diseased Tissue as part of Liposomal Drug Delivery Systems"

Time: 13:00
Place: Building 421, aud. 71

Supervisor: Professor Thomas Lars Andresen

Evaluation board: 
Associate Professor Andrew James Urquhart, DTU Health Tech
Professor David H. Thompson, Purdue University
Senior Researcher Dennis Christensen, Statens Serum Institut

Chairman: Senior Researcher Ladan Parhamifar

Abstract:
Cancer is a complex disease with a significant burden to the global health. To turn the immune system against cancer has long been a goal in immunology and oncology. Accordingly, immunotherapy is an emerging strategy to combat cancer. During this decade, biomaterials sciences have been increasingly involved in developing methods and materials that engineer the immune system to combat cancer. Immunotherapy has shown its great potential as a cancer therapy by eradicating tumors through co-administration of adjuvants and tumor-antigens, designed with inspiration from vaccines against natural pathogens such as viruses. However, both adjuvants and antigens must act controlled and specifically on the immune system to induce an anti-tumor immune response. Although potent adjuvants, such as Toll-like receptor (TLR) agonists, exert their immunostimulatory effects at a low dose, challenges still exist with toxicity. Moreover, ensuring an anti-tumor immune response requires presentation of tumor-specific antigens to the immune system.
This thesis addresses these challenges in three parts. The first part uses liposomes as drug delivery vehicles to reduce adjuvant toxicity and investigates how potent imidazoquinoline TLR7/8 agonists can be modified to obtain high encapsulation efficiencies, reduce toxicity, and retain agonist potencies. The second part explores how such agonists can be designed to utilize protein binding for specific transportation. The final part investigates how antigens can be designed for optimal presentation to the immune system when using liposomes as a drug delivery platform.
This thesis describes a promising strategy to efficiently encapsulate imidazoquinoline TLR7/8 agonists in liposomes. More specifically, the first part describes the development of novel imidazoquinoline TLR7/8 agonists that obtain high liposomal encapsulation efficiencies by remote loading while retaining agonist potencies. Imidazoquinoline 42 was loaded with an encapsulation efficiency of >95%, exhibited reduced cytotoxicity and drug precipitation upon liposomal formulation, and showed greater potency in vitro in liposomal form than R848.
The second part presents peptide-conjugate strategies to deliver imidazoquinolines to act as T cell conjugated immunostimulatory agents.
The third and final part describes how the design of lipopeptide antigens influence antigen presentation when delivered by a liposome. Reducible linkers between lipids and peptide antigens markedly increased the strength and duration of antigen presentation.
Taken together, the research presented in this thesis adds to the emerging field that uses synthetic nanoparticles for subunit vaccines and T-cell conjugated agents for cancer immunotherapy.

Time

Fri 21 Feb 20
13:00 - 16:00

Organizer

DTU Sundhedsteknologi

Where

Building 421, aud. 71