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

该项目旨在研究聚合物-环肽(CP)自组装成纳米管的偶联物及其作为高功能药物输送系统的应用。由于强氢键，CP形成大的管状聚集体。将多聚物链连接到多肽上，可以得到长度和直径可调的可溶性纳米管。人们已经提出了各种偶联物，其中包括响应性和其他功能性的高分子链。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方便地引入靶向特异性受体。然而，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使用。该项目的关键方面是：1.开发用于聚合物和多肽偶联的高效无铜反应；2.载体系统的形状和大小对细胞相互作用的影响；3.创建响应性和靶向性的特定递送系统。虽然铜催化的叠氮化-炔环加成反应是与多肽化学和可控自由基聚合正交的高效反应，但随后铜催化剂的彻底去除仍然具有挑战性。我们的第一个目标是研究聚合物与CP之间的无铜反应，例如环辛炔与叠氮化合物的环加成反应或胺与异氰酸酯的反应。随后，将详细研究聚合物-CP偶联物的自组装，以建立结构-性质关系，包括聚合物结构和链长的影响。基于这些知识，我们将改变所得到的纳米管的长宽比，并在体外检测它们与各种细胞类型的相互作用。这一结果应该会加深我们对形状对细胞黏附、内吞和组织运输的影响的理解。利用RAFT(可逆加成-断裂链转移)聚合和点击化学的潜力，第二年将合成功能聚合物和嵌段共聚物。这些聚合物将包括抑制吞噬作用的隐形块、pH或温度响应性聚合物和靶向递送的特定抗体。通过在自组装过程中将聚合物-CP偶联物混合，可以方便地制备附着在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、隐形基团和响应性聚合物的结合。最后，将根据其细胞选择性和效率对生成的纳米管进行体外测试。总之，该项目涉及到对聚合物-CP共轭的详细研究，以建立一条通往高功能和高效药物输送系统的便捷途径。

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.