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基于载体物理特性设计的难溶性抗肿瘤药物纳米传输体系
Alternative TitleNovel Delivery Systems for Insoluble Anti-cancer Drugs: Design based on Carrier’s Physical Properties
岳占国
Subtype博士
Thesis Advisor马光辉
2013-05-01
Degree Grantor中国科学院研究生院
Degree Discipline生物化工
Keyword难溶药物   物理性质   形状   表面电荷   分子组成
Abstract本文以难溶性抗肿瘤药物的给药研究为背景,以紫杉醇和喜树碱为模型药物,通过颗粒型载体的构建,系统地考察了颗粒形状、表面电荷及分子组成对药物输送效率的影响,解决难溶性抗肿瘤药物分散性差、毒副作用高、生物利用度低等问题。1)考察了无机材料氧化铁纳米颗粒作为紫杉醇载体的可行性,发现棒状比球状更易被肿瘤细胞大量摄取,并在此基础上构建了新型的磁性氧化铁纳米管,药物装载率达12.1 wt%,由于其特有的pH敏感性,可在溶酶体的酸性环境中快速降解,从而实现药物的定点靶向释放,其肿瘤细胞杀伤效果比商品注射剂提高了36%。2)考察了有机材料壳聚糖类纳米球作为紫杉醇载体的可行性,发现壳聚糖类纳米球被肿瘤细胞和正常细胞的内吞速率及内吞量都与表面电荷呈正相关。基于上述结论,成功构建出针对肿瘤微酸环境响应的智能电荷翻转体系,在减少巨噬细胞J774A.1摄取的同时使肿瘤细胞的摄取量提高约1.9倍,与商品注射剂相比,其半抑制药物浓度从11.3 ?g/mL降至4.09 ?g/mL,实现了紫杉醇的选择性输送。3)考察了目前药审部门已批准的聚乳酸类生物可降解材料作为紫杉醇载体的特点,重点在于材料的分子组成对肿瘤组织蓄积及肿瘤内输送能力的影响,发现与PLA(聚乳酸)和PLGA(聚(乳酸?羟基乙酸)共聚物)纳米球相比,PELA(PLA-PEG两嵌段)纳米球由于良好的亲水性和变形性,具有血液循环时间长、肿瘤部位聚集量大及肿瘤内3D穿透能力强等优势,其能显著延长荷瘤小鼠的生存时间(商品注射剂组24天后全部死亡,而PELA组仍有70%存活)。4)考察了纳米晶体和氧化石墨烯用于10-羟基喜树碱(HCPT)输送的可行性,在半乳糖化壳聚糖作用下,制备出了HCPT纳米晶体,特异靶向肝癌细胞并通过核孔进入细胞核内部,在10 μg/mL下抑制率达到了65%,而市售注射液却只有17%;利用氧化石墨烯的二维平面结构及强疏水作用,成功装载了HCPT(载药率9.6%),构建了可激活的荧光探针(iProbe),不仅可用于肿瘤的早期诊断,还可用于肿瘤体积的实时监测,同样展现了优于市售注射液的抑瘤效果。
Other AbstractThis thesis systemically investigated the effects of carrier shape, surface charge, and molecular structure on the delivery performance of paclitaxel (PTX) and 10-hydroxycamptothecin (HCPT). The obtained results opened new avenues for solving the prolems associated with insoluble anti-cancer drugs, such as poor dispersibility, high side effects and low bioavailability.1) Having compared the feasibility of spherical and rod-like iron oxide nanoparticles in a view of carcinoma cellular uptake, we found that rod-like nanoparticles could be internalized more quickly and massively. These nanorods were further transformed into a tube structure, so that PTX crystal could be loaded in the void with high efficiency (12.1 wt%). The iron oxide-based complex also possessed a low pH-activated release profile and increased the anticancer efficacy 36% to commercial injection.2) With the investigation addressing the feasibility of chitosan-based NPs as PTX carrier, we found that the cellular uptake of NPs was positively related to their surface charge both in carcinoma and normal cell lines. Based on these results, a tumor microenvironment sensitive charge-reversal delivery system was fabricated, which could reduce the cellular uptake by macrophages as well as improve the internalization by cancer cells (1.9 times). The IC50 of charge-reversal system was reduced to 4.09 ?g/mL from 11.3 ?g/mL of commercial injection.3) We explored the features of FDA proved poly (lactic acid) (PLA)-related materials as PTX carrier. The inherent relationship between the molecular structure and the delivery performance was investigated. Compared with PLA and poly (lactide-co-glycolide) (PLGA) NPs, poly-ethylene glycol-co-poly-lactide (PELA) ones owned prior hydrophilicity and deformability and possessed the advantages of longer blood circulation time, more tumor accumulation, and better intratumoral delivery ability. Finally, the superior PELA NPs could remarkably prolong the survival time of tumor-bearing mice. All mice died after 24 days in commercial injection group while still 70% survived in treatment group.4) We tested the feasibility of nanocrystallites and graphene oxide (GO) for HCPT delivery. With the template effect of galactosylated chitosan, we successfully prepared HCPT nanocrystallites, which could target liver carcinoma and enter in the nucleus. Their cytotoxicity arrived at 65% at the drug concentration of 10 μg/mL, while it was only 17% in commercial injection. Based on large specific surface area and strong hydrophobicity, we also successfully loaded graphene oxide with HCPT (9.6 wt%), which was further developed as an inducible cancer probe. This theragnosis system could detect tumors at an early stage, monitor tumor development and exhibit better tumor suppression effect.
Pages152
Language中文
Document Type学位论文
Identifierhttp://ir.ipe.ac.cn/handle/122111/8251
Collection研究所(批量导入)
Recommended Citation
GB/T 7714
岳占国. 基于载体物理特性设计的难溶性抗肿瘤药物纳米传输体系[D]. 中国科学院研究生院,2013.
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