ROS响应型多肽水凝胶的制备及其肿瘤治疗应用探索

Most of anticancer drugs damage normal cells as well as cancer cells, often resulting in severe toxic side effects, so there is an urgent need to solve this problem for tumor therapy. Present studies have demonstrated that self-assembly in situ induced by tumor specific stimuli could selectively induce cancer cell death, thus providing an alternative method to solve this issue. This project aims employing tumor over-expressed ROS as stimuli to prepare ROS responsive novel peptide hydrogels through rational molecular design, and explore their tumor inhibition effect in vitro and in vivo. The synthesized peptide precursors would be converted into gelators under ROS oxidation in vitro or in cancer cells. The resulting gelators in vitro would self-assemble into hydrogels as self-delivery systems for anticancer drugs and in cancer cells would self-assemble into fibers in situ inducing cancer cell death.The properties of the new ROS induced hydrogels would be characterized through multiple analyze methods; the behavior of ROS responsive peptides in vivo tissue distribution and tumor-targeted self-assembly would be investigated by radiolabel method; and their application of self-assembly in situ selectively killing cancer cells would be studied by tumor inhibition assays in vitro and in vivo. Through the study, we would develop a new ROS responsive peptide self-assembled system, realizing their application for improving drug selectively and reducing toxic side effects, as well as provide a new and referential approach for drug delivery and cancer therapy.

大多数抗肿瘤药物分子在杀伤肿瘤细胞的同时也会损害正常细胞，从而导致严重的毒副作用，成为肿瘤治疗领域亟待解决的问题。近期研究表明，肿瘤细胞特有环境下诱导的原位自组装能选择性诱导癌细胞死亡，为解决这一问题提供了新的模式。本项目拟利用肿瘤细胞内过表达的ROS作为刺激因子，通过合理的分子设计制备ROS响应的新型自组装多肽水凝胶体系。合成的小分子多肽凝胶前体分子能够在ROS作用下转化形成凝胶因子，进而自组装形成水凝胶或纳米纤维。借用多种分析手段对得到的新型ROS响应性水凝胶的性能进行表征，利用放射性核素标记的方法研究小分子多肽体内组织分布及肿瘤靶向富集组装，通过体内外抑瘤实验探索其选择性在癌细胞内自组装并杀伤癌细胞的应用。通过该研究，我们将建立一种全新的ROS响应的小分子多肽自组装体系，利用该体系实现其提高药物分子选择性并降低毒副作用的目的，为药物递送、癌症治疗提供新的可借鉴的思路和方法。

目前，化疗仍然是癌症治疗的主要手段之一。但是，传统癌症化疗往往又面临很多局限和挑战，包括药物溶解性差、生物利用度低、毒副作用大以及肿瘤耐药等。为了解决这些问题，本项目构建了多个基于多肽自组装的纳米药物体系并对其体内外抗肿瘤应用进行了探索研究。具体研究内容包括四个部分：（i）制备了ROS响应的新型自组装多肽水凝胶体系，其能在过氧化氢作用下发生凝胶到溶液的转变，实现了对抗癌药物的体外可控性释放；（ii）制备了酶促自组装的多肽前药分子，其能选择性在高表达碱性磷酸酶的癌细胞表面自组装成纳米药物纤维，实现了对特定癌细胞的选择性杀伤；（iii）制备了紫杉醇和抗癌短肽构成的前药分子，其能通过分子内酯建水解自组装形成无载体超分子水凝胶，实现了双组分药物联合治疗并克服了肿瘤耐药；（iv）制备了含有光敏剂及抗癌短肽一体化的多肽纳米平台，其能通过分子内非共价相互作用形成超分子纳米棒，实现了光声成像引导下的肿瘤光热-化疗联合治疗。体内外抗癌研究结果表明，经过合理设计的自组装多肽纳米药物能够显著提高抗癌药物的溶解性、靶向性以及抗肿瘤疗效，从而在一定程度上能够降低化疗药物对正常组织及细胞的毒副作用。通过本项目的研究，进一步拓宽了自组装多肽纳米材料在抗癌药物靶向递送、肿瘤联合治疗以及诊疗一体化等领域的应用，能够为新型纳米药物载体的设计以及癌症靶向治疗提供新的方法和思路。