Design of drug carriers based on biodegradable polyrotaxanes

在本研究中，我们首次将可生物降解聚轮烷作为新型生物材料进行了研究。详细地，我们设计了可生物降解的聚轮烷，并阐明了其具体特性，包括生物降解性和与生物组分的物理相互作用。我们合成了一种聚轮烷，其中许多α-环糊精（α-CDs）通过肽键连接在聚乙二醇（PEG）链上，聚乙二醇（PEG）链上有酶水解氨基酸（l -苯丙氨酸）。我们已经澄清了聚轮烷在生理条件下形成松散堆积的缔合并保持其棒状结构。体外降解实验表明，蛋白酶的末端水解是完成的，并且由于松散排列的结合而伴有超分子解离。基于这一特点，我们将模型药物（茶碱）引入聚轮烷的α-CDs中，通过超分子解离来研究药物的释放。更多n.获得的药物-聚轮烷偶联物在生理条件下形成特定的结合，这取决于药物和/或偶联物中聚轮烷末端的相互作用。体外降解实验发现，药物固定的α-CDs通过水解聚轮烷末端肽键完全释放，没有任何空间位阻。此外，我们已经合成了寡肽端聚轮烷，并澄清了在膜结合金属肽酶存在下的完全水解和超分子解离，该酶水解不太可能水解具有更高分子量的底物。这一结果表明酶对可生物降解部分的识别是维持的。生物可降解聚轮烷的另一种方法是用于植入式材料。我们已经合成了末端含有酯键的可水解聚轮烷，并通过末端酯水解证明了完全的超分子解离。这种解离速率可以通过化学修饰如聚轮烷中羟基的乙酰化来控制。利用可水解的聚轮烷，我们设计了α-CDs的羟基与另一个聚乙二醇交联的超分子结构水凝胶。通过改变α-CDs和PEG在水凝胶制备中的摩尔比，可以控制水凝胶的侵蚀时间和形貌。从这些结果中，我们发现在高水膨胀状态的水凝胶中，酯水解的稳定性增强。这种异常现象可能是由于聚轮烷的结构特点：酯键可能包含在α-CDs的腔内。因此，我们可以在本研究项目中建立具有一些新功能的可生物降解聚轮烷的设计。少

In this research, we have studied biodegradable polyrotaxanes as new biomaterials for the first time in the world. In detail, we designed biodegradable polyrotaxanes and clarified those specific characteristics including biodegradability and physical interaction with biological components.We have synthesized a polyrotaxane in which many α-cyclodextrins (α-CDs) are threaded onto a poly (ethylene glycol)(PEG) chain capped with enzymatically hydrolyzable amino acid (L-phenylalanine) via peptide bonds. We have clarified that the polyrotaxanes form loosely packed association and maintain their rod-like structure in physiological conditions. In vitro degradation experiments revealed that the terminal hydrolysis by a proteinase is completed and accompanied by supramolecular dissociation due to the loosely packed association. Based on this characteristic, we have introduced a model drug (theophylline) into the α-CDs in the polyrotaxane to examine drug release via the supramolecular dissociatio … More n. The obtained drug-polyrotaxane conjugate formed a specific association under physiological conditions, depending on interactions between drugs and/or terminals of the polyrotaxane in the conjugate. From in vitro degradation tests, it was found that drug-immobilized α-CDs are completely released by hydrolysis of the terminal peptide linkages in the polyrotaxane without any steric hindrance. Further, we have synthesized oligopeptide-terminated polyrotaxanes and clarified complete hydrolysis and supramolecular dissociation in the presence of membrane-bound metalloexopeptidaase that hydrolyzes unlikely substrates with higher molecular weight. This result suggests that enzymatic recognition of the biodegradable moiety is maintained.Another approaches to biodegradable polyrotaxanes have been focused for implantable materials. We have synthesized hydolyzable polyrotaxanes that contain ester linkages at the terminals and demonstrated complete-supramolecular dissociation via the terminal ester hydrolysis. This dissociation rate can be controlled by chemical modification such as acethylation of hydroxyl groups in the polyrotaxanes. By using the hydrolyzable polyrotaxanes, we designed supramolecular-structured hydrogels in which hydroxyl groups of α-CDs are cross-linked with another PEG.By changing molar ratio of α-CDs and PEG on the hydrogel preparation, erosion time and profile of the hydrogels can be controlled. From these results, we found that enhanced stability of ester hydrolysis in the hydrogels with highly water swollen state. Such an anomalous phenomenon maybe due to the structural characteristic of the polyrotaxanes : ester linkages may be included within the cavity of α-CDs.Therefore, we could establish the design of biodegradable polyrotaxanes with some new functions in this research project. Less