State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, PR China.
Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Department of Pharmacy and Pharmacology, University of South China, Hengyang, Hunan 421001, PR China.
J Control Release. 2022 May;345:278-291. doi: 10.1016/j.jconrel.2022.03.018. Epub 2022 Mar 17.
Inspired by the biological use of a combination of precision and self-assembly to achieve exquisite control and diversity from 20 natural amino acids, there is considerable scope for the development of synthetic precision materials with complex architecture that can access advanced function for biomedical applications. Single cyclic polymers (SCPs) have been shown to offer different and often better performance compared to their linear analogues. Because multicyclic topology in nature offers enhanced effects relative to single cyclization, we hypothesize that multicyclic polymers (MCPs) would access unique features compared to SCPs. However, there are currently quite limited ways to efficiently synthesize MCPs and to precisely modulate the valency of cyclic units. In this work, we report for the first time a straightforward and robust strategy to synthesize MCPs with controllable valency via facile one-pot statistical reversible addition-fragmentation chain transfer (RAFT) copolymerization. We use this strategy to synthesize biocompatible MCPs based on the most classic and important biocompatible polymers of oligo (ethylene glycol) (OEG) and cyclic poly(ε-caprolactone) (cPCL), which can further self-assemble into well-defined nanostructures. We then apply these MCP-based formulations as drug delivery vehicles and demonstrate greater colloidal stability with a low critical micelle concentration (CMC) of 80.3 nM, larger drug loading capacity, higher cellular uptake efficiency, more tumor accumulation, and increased anti-tumor efficacy in murine tumor models compared to SCP-based analogues. We believe this cumulative work demonstrating facile synthesis of MCPs and demonstration of multicyclic topology-enhanced anti-cancer efficiency in vivo provides key technologies and concepts to the burgeoning field of cyclic topology-derived biomaterials.
受生物利用精确性和自组装的结合来实现从 20 种天然氨基酸中获得精致控制和多样性的启发，开发具有复杂结构的合成精密材料具有很大的空间，这些材料可以获得用于生物医学应用的先进功能。已经证明，单环聚合物 (SCP) 与它们的线性类似物相比具有不同的、通常更好的性能。由于自然界中环的多循环拓扑结构相对于单环化提供了增强的效果，我们假设多环聚合物 (MCP) 将具有与 SCP 相比的独特特征。然而，目前高效合成 MCP 并精确调节环单元的价数的方法相当有限。在这项工作中，我们首次报道了一种通过简便的一锅式统计可逆加成-断裂链转移 (RAFT) 共聚来合成具有可控价数的 MCP 的简单而稳健的策略。我们使用该策略合成了基于最经典和最重要的生物相容性聚合物聚乙二醇 (OEG) 和环状聚 (ε-己内酯) (cPCL) 的生物相容性 MCP，它们可以进一步自组装成具有良好定义的纳米结构。然后，我们将这些基于 MCP 的制剂用作药物递送载体，并证明与基于 SCP 的类似物相比，具有更低的临界胶束浓度 (CMC) 80.3 nM、更大的载药能力、更高的细胞摄取效率、更多的肿瘤积累和增强的抗肿瘤功效。我们相信，这项工作综合展示了 MCP 的简便合成方法以及体内多循环拓扑增强抗癌效率的演示，为新兴的环状拓扑衍生生物材料领域提供了关键技术和概念。
