Design of macromolecularly engineered amino-acid-derived zwitterionic polymers for cellular targeting

• Applicant: Professorin Dr. Meike Leiske
• Subject Area: Polymer Materials ; Biomaterials
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 535904448

The aim of this project is the development of site-specific zwitterionic polymers based on natural compounds (i.e., amino acids) to target cancer cells specifically. In modern oncology it is a major challenge to deliver therapeutically active agents more safely and directly to the tumor. To overcome this, polymers serve as drug delivery platforms in different ways: (i) polymer nanoparticles, (ii) stimuli responsive polymer drug conjugates, or (iii) therapeutic polymers. Independent from the aimed mechanism of delivery, a high degree of cell or tissue specificity of the polymer carriers is indispensable. Hydrophilic non-ionic stealth polymers (e.g., poly(ethylene glycol)s) have gained interest due to their favourable protein adsorption and high blood circulation times. While stealth properties are advantageous to decrease unwanted cellular interactions, they can also reduce the association with the target tissue and cells. One promising alternative is the incorporation of natural, low-fouling compounds, such as proteinogenic amino acids into polymer chains by the monomer approach. Due to their bioderived nature, amino-acid-containing polymers represent interesting candidates for the development of materials for applications in the biomedical field. Latest molecular biological research on cancer cells has revealed the overexpression of various amino acid transporters. The potential of zwitterionic amino-acid-derived polymers to target cancer cells via interaction with these transporters can be exploited for the targeting therapy of tumors. Within this project, zwitterionic, amino-acid-derived polymers will be established as potential materials to target cancer cells. Due to their chemical versatility, the use of amino-acid-derived polymers enables to different pathways to maximise cellular recognition: (i) modifications to the polymer structure by changes to side-chain chemistry, (ii) the design of betaine-like amino-acid-derived polymers from amino acids, or (iii) manipulations to the macromolecular structure by copolymerization with non-ionic monomers. In this project, we will use the mentioned synthetic strategies to design optimized zwitterionic polymers with high site-specificity. For the evaluation of their potential to serve as site-specific materials, the evaluation of their in vitro properties is indispensable. For this reason their association with (i) cancer cells and non-cancerous cells, and (ii) with proteins will be studied. By this combination of valuable in vitro evaluation and precise polymer development it will be possible to design site-specific materials and understand their in vitro behaviour. Only the best-performing candidates will be tested in vivo to gain information about their biodistribution and blood circulation times. The results will prove valuable for the design of optimised drug carriers based on amino-acid-derived polymers.

• DFG Programme: Research Grants