Controlled Degradable Nanocarriers for Reprogramming the Tumor Microenvironment Towards Anti-Cancer Immunity

• Applicant: Professor Dr. Lutz Nuhn
• Subject Area: Polymer Materials ; Biological and Biomimetic Chemistry ; Preparatory and Physical Chemistry of Polymers
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 417278389

To effectively combat cancer, material scientists including polymer chemists have evolved nanomedicines as promising therapeutic alternatives. However, these achievements primarily focused on eliminating tumorous cells only.Meanwhile, novel biological mechanisms have been elucidated on how body’s own defense system is turned off during cancer progression. Consequently, novel therapeutic concepts are explored which aim at re-activating the suppressed immune system in the cancer microenvironment and, thus, recruiting body’s own curing machinery.Here, nano-sized carriers could play a pivotal role in future: Due to their size and morphology nanoparticles are intrinsically recognized and processed by many immune cells.In this research proposal I would like to utilize this straightforward access and deliver immune modulating cues via polymer-based nanocarriers into the tumor microenvironment and, thus, initiate natural anti-cancer immunity:1) In Part A immune tolerance mechanisms should be turned off locally. They are caused by an abnormal metabolic profile or distinct cell-cell interactions in the tumor microenvironment (so-called immune checkpoints).2) In Part B the tolerance-inducing behavior of pronounced immune subpopulations should be converted. These regulatory cells have settled in the tumor microenvironment and orchestrate its immunosuppressive state.3) In Part C body’s own innate defense mechanism should be focused to the tumor cells and initiate their elimination.To address these targets a versatile carrier platform is required which should be powerful enough to overcome the therapeutic challenges of effective drug transport and delivery (stability, release, degradation). The establishment of such a platform can only be accessed by an intense interplay between organic and polymer chemistry supplemented by biomedical characterization methods: Due to their intrinsic hydrolytic lability, aliphatic poly(carbonate)-based block copolymers will be implemented as carrier material to provide an opportunity towards long-term degradation in the body. These block copolymers will be equipped with amine reactive side chains (pentafluorophenyl/ squaric ethyl esters) to trigger micellar self-assembly into core-shell structures. The resulting nano-assemblies will covalently be stabilized by reversible core crosslinking. Active drugs will further be covalently immobilized into the core, too. By applying self-immolative linkers this can even be realized in a reversible covalent way. Interestingly, by refined modification of the self-immolative linker motif to the poly(carbonate) backbone, self-immolation can also be passed to the polymer main chain and induce its depolymerization.Consequently, for the first time access to a new class of drug delivery systems can be realized which triggers intracellular carrier self-immolation during drug release simultaneously. These systems can be utilized to address complex issues of cancer immunotherapy.

• DFG Programme: Independent Junior Research Groups