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

本项目旨在研究可自组装成纳米管的聚合物环肽（CP）偶联物及其作为高功能药物递送系统的应用。由于氢键强，CPs形成大的管状聚集体。将聚合物链连接到多肽上，可以得到长度和直径可调节的易溶纳米管。各种共轭物已经被提出，其中包括响应性和其他功能聚合物链。这些系统的灵活性和多功能性使它们在解决制药科学中的几个问题方面具有吸引力，例如各向异性对细胞相互作用的影响以及目标特异性受体的方便引入。然而，在合成过程中使用的细胞毒性铜配合物限制了它们在生物相关应用中的应用。本项目的关键方面是：1。高分子与多肽偶联高效无铜反应的研究进展，2。载体系统的形状和大小对细胞相互作用的影响；建立反应迅速和具体目标的交付系统。虽然铜催化叠氮化物-炔环加成反应是与肽化学正交和可控自由基聚合的高效反应，但事后铜催化剂的彻底去除仍然是一个挑战。我们的第一个目标是研究无铜反应对聚合物和CP的有效偶联，如环辛基和叠氮化物的环加成或胺与异氰酸酯的反应。随后，将详细研究聚合物- cp共轭物的自组装，建立包括聚合物结构和链长影响在内的结构-性能关系。基于这些知识，我们将改变所得到的纳米管的纵横比，并在体外研究它们与各种细胞类型的相互作用。结果将提高我们对形状对细胞粘附、内吞作用和组织运输的影响的理解。利用RAFT（可逆加成-破碎链转移）聚合和点击化学的潜力，将在第二年合成功能聚合物和嵌段共聚物。这些聚合物将包括隐形块，抑制吞噬作用，pH或热响应聚合物和靶向递送的特异性抗体。在自组装过程中，通过聚合物- cp共轭物的混合，可以方便地制备出附着在CPs上的多功能载体纳米管。这种直接路线的多功能性促进了目标特定配体，隐身基团和响应聚合物的组合。最后，所得到的纳米管将根据其细胞选择性和效率进行体外测试。总之，该项目包括对聚合物- cp偶联的详细研究，以建立一个便捷的途径，以实现高功能和高效的给药系统。

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.