Self-Assembly of Polymer-Cyclic Peptide Conjugates for Multifunctional Drug Carrier Systems

• Applicant: Professor Dr. Johannes Brendel
• Subject Area: Polymer Materials ; Pharmacy ; Preparatory and Physical Chemistry of Polymers
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 254346192

The proposed project aims at the investigation of polymer-cyclic peptide (CP) conjugates which self-assemble into nanotubes and their application as highly functional drug delivery systems. CPs form large tubular aggregates due to strong hydrogen bonds. Attaching polymer chains to the peptides leads to well-soluble nanotubes with adjustable lengths and diameter. A variety of conjugates have already been presented which includes responsive and other functional polymer chains. The flexibility and versatility of these systems make them attractive for addressing several issues in pharmaceutical science such as the effect of anisotropy on cell interactions and the convenient introduction of target specific receptors. However, cytotoxic copper complexes used during the synthesis limit their use for bio-related applications. Key aspects of this project are: 1. the development of highly efficient copper free reactions for the conjugation of polymer and peptide, 2. the effect of shape and size of the carrier system on cell interactions, 3. the creation of responsive and target specific delivery systems. Although copper catalysed azide-alkyne cycloadditions are highly efficient reactions which are orthogonal to peptide chemistry and controlled radical polymerizations, the thorough removal of the copper catalyst afterwards remains challenging. Our fist aim is to investigate copper free reactions for the efficient conjugation of polymer and CP such as the cycloaddition of cyclooctyne and azides or the reaction of amines with isocyanates. Subsequently, the self-assembly of the polymer-CP conjugates will be studied in detail to establish structure-property relations including the effect of polymer structure and chain lengths. Based on this knowledge, we will vary the aspect ratio of the resulting nanotubes and examine their interaction with various cell types in vitro. The results should improve our understanding of shape effects on cell adhesion, endocytosis and transport through tissue. Utilizing the potential of RAFT (reversible addition-fragmentation chain transfer) polymerization and click chemistry functional polymers and block copolymers will be synthesized in the second year. These polymers will comprise stealth blocks, which suppress phagocytosis, pH- or thermoresponsive polymers and specific antibodies for targeted delivery. Attached to CPs multifunctional carrier nanotubes can conveniently be created by mixing of the polymer-CP conjugates during the self-assembly process. The versatility of this straight-forward route facilitates the combination of target specific ligands, stealth groups and responsive polymers. Finally, the resulting nanotubes will be tested in vitro according to their cell selectivity and efficiency. In conclusion, the project involves a detailed investigation of polymer-CP conjugated in order to establish a convenient pathway towards highly functional and efficient drug delivery systems.

• DFG Programme: Research Fellowships
• International Connection: Australia, United Kingdom
• Participating Institution: University of Warwick; Department of Chemistry; Monash University ; Faculty of Pharmacy and Pharmaceutical Sciences
• Host: Professor Sébastien Perrier, Ph.D.