还原和低氧双重敏感聚合物载体的制备及其用于抗肿瘤药物的靶向传输

Polymer drug vectors have shown great potentials in tumor therapy, but the clinical applications were limited owing to instability during transport and storage and high toxicity. It has been proven a key solution to these problems by developing novel intelligent drug delivery systems. Aiming at highly efficient and safe transportation of chemotherapy drug, the present research proposes to develop a novel hypoxia and reduction dual-sensitive polymer vectors. Thanks to the hypoxic-sensitivity of nitro imidazole group and redox-sensitive of disulfide linkage, the drug-loading particles will be gifted to stability of structure and properties during blood circulation. The dual sensitivity cross-linking drug-loading micelles avoid the leakage and premature release of drug-loaded in blood circulation, and was endowed long circulation property in vivo, whereas a burst drug release will be triggered in a reductant-enriched and hypoxia environment such as in cytoplasm of tumor cell via EPR effect and endocytosis. We will focus on the synthesis of three triblock polypeptides through ring opening polymerization (ROP) of amino acid anhydride and aminolysis reactions, the way of obtaining hypoxia and reduction dual-sensitive drug carrier nanoparticles after cross-linking the sub-surface of micelles, and the exploration and evaluation of the controlled-release behavior and anti-tumor effect in vitro and in vivo. The novel tumor targeted drug release carrier will improve the drug efficacy and reduce the adverse effect simultaneously. This proposed project can provide ideas for the development of new-style polymer controlled-release system, and progress the research on tumor treatment.

聚合物药物载体在肿瘤治疗中具有重要应用前景，然而传输和储存时不稳定及药物毒副作用大等缺点制约了其在临床上的应用，发展智能型载药体系是解决瓶颈问题的关键。本课题拟制备具有还原和低氧双重敏感的新型聚合物载药体系，实现药物的高效安全传输。双重敏感性设计增强载药粒子在血液循环中结构的稳定性，减少药物渗漏，延长循环时间；经EPR效应在低氧的肿瘤组织富集并通过胞吞作用进入细胞(还原环境)后，快速释放所负载药物，实现药物的肿瘤靶向释放。课题主要研究内容包括：（1）通过氨基酸酸酐开环聚合反应和胺解反应等手段合成聚氨基酸三嵌段共聚物；（2）制备低氧敏感型载药胶束；（3）胶束亚表层交联捆绑作用获得双重敏感性载药体系；（4）体内和体外实验研究载药体系的控释性能并评价其抑瘤效果。期望本课题的实施不仅制备出新型的具有优异性能的双重敏感型药物载体，且为聚合物控释体系研究提供新思路，促进肿瘤治疗的进展。

聚合物药物载体在肿瘤治疗中具有重要应用前景，如何实现对化疗药物的稳定递送和智能控释已经成为肿瘤化疗研究中的科学难题。本课题拟制备具有还原和低氧双重敏感的新型聚合物载药体系，实现药物的高效安全传输。前期研究表明我们初步得到了低氧敏感的嵌段共聚物，并通过对不同的合成路线制备目标聚合物进行了积极的探索。本项目主要进行了以下研究：1）通过调控聚合物氨基酸嵌段的聚合度来尝试赋予嵌段共聚物低氧敏感的药物控释性能；2）通过反应条件优化和反应原料调整以得到低氧敏感的嵌段共聚物；3）通过调整反应线路制备合成低氧敏感的嵌段共聚物。通过开展上述深入而广泛的探索，制备了低氧敏感性能优越的目标聚合物，目前正在进行生物学实验。本课题的顺利开展，制备出新型的具有优异性能的双重敏感型药物载体，为聚合物控释体系研究提供新思路，促进肿瘤治疗的进展。