不同形貌双靶向聚醚—聚酯磁性胶束对肿瘤治疗的研究

发布时间：2018-04-15 12:15

本文选题：药物载体 + 棒状胶束　；参考：《西南交通大学》2017年硕士论文

【摘要】：目前,精准有效地将化疗药物通过药物输送系统递送到肿瘤部位仍然是临床应用上的挑战,也引起了越来越多学者的关注。具有主动靶向和磁靶向的杆状细菌形貌的共聚物胶束纳米载体能够有效的实现在血液中的长循环,通过增强肿瘤部位药物的富集量,进一步降低对其它正常组织的毒副作用。因此,考虑将主动靶向、磁靶向和特殊的杆状细菌形貌相结合,构建一个双靶向的棒状纳米载体,使其能在药物传递领域具有更好的应用。在本论文中,我们首先合成了具有主动靶向的苯硼酸修饰的聚乙二醇-聚己内酯(PBA-PEG-PCL)以及无靶向的单甲氧基聚乙二醇-聚己内酯(mPEG-PCL)共聚物材料。通过在胶束制备过程中加入不同浓度的氯化钠溶液,制备出球形胶束 mPEG-PCL(S_1)、PBA-PEG-PCL(S_2)和棒状胶束 mPEG-PCL(R_1)、PBA-PEG-PCL(R_2),并用动态激光散射纳米粒度仪(DLS)、激光共聚焦显微镜(CLSM)、透射电子显微镜(TEM)对所制备的胶束粒径和形貌进行表征。所得到的胶束都具有明显的球形或棒状形貌,球形胶束粒径大小约为110 nm,棒状胶束宽度约为20 nm,长度约为600 nm。考察所制备的胶束在0.9%氯化钠溶液中120h内的稳定性,可以看出胶束的平均粒径大小和粒径的分布没有发生显著变化,说明所制备的胶束能够在长时间内保持良好的稳定性。随后考察了所制备胶束的生物相容性,所制备的球形和棒状载药胶束均表现出良好的生物相容性,说明可以临床用作药物传输系统。体外肿瘤生长抑制结果显示S_1@DOX,R_1@DOX,S_2@DOX和R_2@DOX载药胶束都能够抑制A549/HepG2细胞的增殖,其中R_2@DOX的效果最好。在考察不同形貌的胶束对A549/HepG2细胞内在化的影响时,可以发现棒状胶束更容易被肿瘤细胞摄取,将共聚物材料修饰上PBA小分子配体后,一定程度上加强了高表达细胞的细胞膜上的受体和配体的结合,这种胶束靶向和形貌两者共同作用促进细胞对载药胶束的摄取。最后我们通过在BALB/C小鼠右后背处建立小鼠肝癌H22肿瘤模型,对不同形貌的载药胶束考察了体内的抗肿瘤效果。药代动力学结果说明,棒状载药胶束相比于球形载药胶束在血液中的循环时间有所延长;既有主动靶向又有磁靶向的棒状胶束组R_2@DOX/Fe_3O_4,其DOX在肿瘤部位的富集量明显增加,而在其它正常组织富集量最少;21d治疗结束后,该实验组小鼠的体重下降最不明显,肿瘤体积和肿瘤重量最小,说明肿瘤增殖最为缓慢;组织学分析结果同样发现,该组能明显引起肿瘤细胞的凋亡,进一步从组织学上证明了该组的抑瘤效果最突出。
[Abstract]:At present, accurate and effective chemotherapy drug delivery to the tumor site is still the challenge through the clinical application of drug delivery systems have attracted more and more attention. The copolymer micelle nano carrier with active targeting and magnetic targeting of the rod-shaped bacteria morphology can achieve long circulating in the blood effectively, by increasing the enrichment the amount of tumor drug, to further reduce the other normal tissue toxicity. Therefore, considering active targeting, magnetic targeting and bacterial morphology combined with the construction of special rod, rod like nano carrier to a double target, which has better application in the field of drug delivery in this paper., we first synthesized with polyethylene glycol phenyl boronic acid to the active target modified polycaprolactone (PBA-PEG-PCL) and methoxy polyethylene glycol to non target polycaprolactone (mPEG-PCL) copolymer materials. In the preparation process of micelles with different concentrations of Sodium Chloride Solution, preparation of spherical micelles of mPEG-PCL (S_1), PBA-PEG-PCL (S_2) and mPEG-PCL (R_1) micelles, PBA-PEG-PCL (R_2), and the use of a dynamic laser scattering particle size analyzer (DLS), laser confocal microscope (CLSM), transmission electron microscope (TEM) of the prepared micellar particle size and morphology were characterized. The micelle has obvious spherical or rod like morphology, spherical micelle particle size is about 110 nm, width of rodlike micelles is about 20 nm, the length is about 600 nm. on stability of the prepared micelles in 120h in 0.9% Sodium Chloride Solution, we can see that the average particle size of the micelles and particle size distribution did not change significantly, shows that the prepared micelles can keep good stability in a long time. The effects of the biological compatibility of the micelles, the prepared spherical and Rod like micelles exhibit good biocompatibility, can be used as clinical drug delivery system in vitro inhibition of tumor growth. The results showed that S_1@DOX, R_1@DOX, S_2@DOX and R_2@DOX micelles are able to inhibit the proliferation of A549/HepG2 cells, and the effect of R_2@DOX is the best. The morphologies of the micelles effect on A549/HepG2 cell internalization when can be found more easily micelles of tumor cell uptake, the copolymer material modified PBA small molecule ligands, to some extent strengthen the binding of receptor and ligand expression on the cell membrane of the interaction of the micelle morphology and targeting both promote the cellular uptake of drug loaded micelles. Finally we used mouse H22 liver cancer model in BALB/C mice right at the back, the micelles with different morphologies were investigated in vivo anti-tumor effect. Pharmacokinetics. The results illustrate that rod like micelles compared to spherical micelles in the blood circulation time prolonged; both active targeting and magnetic target group to R_2@DOX/Fe_3O_4 micelles, the DOX increased significantly in the accumulation of the site of the tumor, whereas in other normal tissues the concentration of at least 21d; after the end of treatment, the in the experimental group, the weight loss is not obvious, the tumor volume and tumor weight minimum, indicating most slow tumor proliferation; histological analysis also found that the group could obviously induce apoptosis of tumor cells, further histologically proved the most prominent anti-tumor effect of the group.

【学位授予单位】：西南交通大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O631;TQ460.1

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