分级制导肿瘤细胞核的纳米囊泡输药系统

Nowadays, chemotherapy is still a principal approach for clinical cancer treatment. Thereinto, the key to improve curative effect is to enhance specific targting of drug delivery for malignant tumor, especially very susceptible nuclei of tumor cells. This nuclear targeting will make it possible to increase drug efficacy, and to decrease side effect and drug resistance. As a result, a novel stepping nucleus-targted nanovesicle as drug delivery system to tumor cell is designed. In detail, encapsulated drugs are specificly transported to tumor tissue by RGD-targeting acid-sensitive nanovesicle, and then released fully. Secondly, transactivating transcriptional activator peptide (TATp) will induce anticancer drug-doxorubicine (DOX) to pass through cell or nuclear membrance for high enrichment within nuclei. All the performances of acid-responsive poly(ethylene glycol)-b-poly[2-(diisopropylamino)ethyl aspartate] nanovesicle loading TATp-modified DOX as drug carrier will be systematically studied, including biocompatibility, cytotoxicity, tumor targeting, drug loading and release efficiency. Particularly, the nucleus-targeted behaviors for tumor cells will become an important point. In a word, our goal is to achieve the specific targeting for neoplastic cell nucleus and greatly enhanced efficacy.

作为癌症治疗的主要手段，提高化疗疗效的关键仍在于增强药物传输的特异性，发展药物对于肿瘤细胞内部高度"敏感"区域- - 特别是细胞核的特异性靶向，以提高药效、降低毒副作用并减少癌细胞产生抗药性的可能。基于此，本课题设计了一种针对肿瘤细胞核靶向的"分级制导"纳米囊泡输药体系，即首先通过RGD靶向的纳米酸敏聚合物囊泡将药物定向地输送至肿瘤组织，在细胞间和细胞内发生特异性地"暴释"，然后TATp跨膜肽引导阿霉素分子穿越细胞膜和核膜，以促进在细胞核区域的高度富集。主要研究经过靶向修饰的聚乙二醇-b-聚（L-天冬氨酸）酸敏化共聚物囊泡的生物相容性、细胞毒性、组织靶向性和载药释药性能，重点针对肿瘤细胞核的特异性传输进行系统分析。由此，可望获得对肿瘤细胞核的高度靶向，大幅度地提高阿霉素的药效，为癌症治疗和智能化药物输送系统的研究提供一定的理论依据及应用价值。

作为癌症治疗的主要手段，提高化疗疗效的关键仍在于增强药物传输的特异性，发展药物对于肿瘤细胞内部高度“敏感”区域——特别是细胞核的特异性靶向，以提高药效、降低毒副作用并减少癌细胞产生抗药性的可能。基于此，本项目研究并开发了一种针对肿瘤细胞核靶向的“分级制导”纳米囊泡输药体系。主要研究经过靶向修饰的聚乙二醇-b-聚（L-天冬氨酸）酸敏化共聚物囊泡的生物相容性、细胞毒性、组织靶向性和载药释药性能，重点针对肿瘤细胞核的特异性传输进行系统分析。截止目前，已完成酸敏纳米载药囊泡及其对照组-单甲基聚乙二醇-b-聚乳酸乙醇酸无规共聚物纳米载药囊泡的合成、制备与表征，并进行了肿瘤药物阿霉素的细胞摄取和细胞毒性实验。结果表明，该酸敏囊泡的粒径在200nm左右，具有极佳的pH响应性。此外，还进行了负载1,1,1,3,3-五氟丁烷的聚合物纳米囊和负载全氟辛溴的聚乙二醇-b-聚（D,L-丙交酯）纳米囊泡的超声造影研究。前者被证实能够被低强度超声触发高对比度的相转变，后者则具有良好的体内超声显像效果。申请人还对Γ-聚谷氨酸微波辅助快速降解的动力学和相关机制进行了研究。