聚合物载药纳米微粒的功能化及抗肿瘤研究

发布时间：2018-06-19 13:08

本文选题：纳米粒子 + β-环糊精　；参考：《南京大学》2017年博士论文

【摘要】：紫杉醇(PTX)因其在水中的溶解度较低,临床治疗效果受到严重的制约。为解决这一问题,将PTX溶解于聚氧乙烯蓖麻油／乙醇溶液中来提高PTX的溶解度,获得了商业化的抗癌药物泰素(Taxol(?))。但是,该药物中有乙醇和聚氧乙烯蓖麻油等有机稳定剂的加入,导致治疗过程中出现严重的毒副作用。因此,我们有必要设计一种新型的PTX传输体系,有效地实现PTX到肿瘤部位的传输并且阻止药物快速地从肿瘤部位流失。在肿瘤治疗手段中,联合治疗可以大大增强肿瘤治疗效果。其中将光热疗法和传统的化疗相结合,利用协同效应来治疗肿瘤的方式,相对于普通化疗,可以在降低药剂量的同时达到相同疗效,这对于存在剂量依赖的毒副作用的化疗药物是非常有意义的,因此光疗-化疗联合治疗是更为理想的治疗策略。纳米粒子的尺寸、形状以及表面化学性质影响着粒子在体内的靶向效果。当纳米粒子的尺寸和形状一定时,表面化学性质在细胞摄取和体内循环效果起着主要作用。为了达到延长纳米粒子在体内的循环时间的目的,已有多种方式将PEG或者两性离子聚合物修饰到纳米粒子的表面。然而,系统地针对PEG修饰的纳米粒子与两性离子修饰的纳米粒子在生物体内应用的对比研究还很少。针对上述聚合物纳米药物传输体系存在的问题,本论文进行了以下三个方面的研究：(1)基于紫杉醇(PTX)和聚丙烯酸修饰的β-环糊精(PCDAA)之间的主客体关系,我们设计了一种用于癌症治疗的纳米组装给药系统,成功制备了PCDAA-PTX纳米粒子,其中PCDAA作为抗癌药物PTX的载体。通过这样的设计,PTX在水中的溶解性得到大幅度提高,从之前的0.34μg/ml提高到36.02 μg/ml。该纳米粒子呈现球状且其粒径约170 nm。荷瘤小鼠近红外成像结果显示,PCDAA-PTX纳米粒子在肿瘤部位有增强富集作用。体内抗肿瘤实验表明：与商业化抗肿瘤药物Taxol(?)相比,PCDAA-PTX纳米粒子的抗肿瘤效果明显增强。(2)利用具有良好生物相容性和可生物降解的壳聚糖(chitosan, CS)作为载体材料,将其与在近红外区域具有很好的光热效应的W_(18)O_(49) (WO)纳米粒子的进行高效复合,制备了尺寸均一且稳定的CS-W_(18)O_(49)(CS-WO)复合纳米微球,再进一步将化疗药物阿霉素(DOX)负载到CS-WO复合纳米粒子体系中,制备出具有良好生物相容性的CS-WO-DOX复合纳米粒子,进行了热疗和化疗的联合治疗,考察了CS-WO-DOX复合纳米粒子在抗肿瘤方面的效果。研究表明,CS-WO-DOX复合纳米粒子不仅可以显著增强WO纳米粒子的生物相容性和稳定性,降低药物DOX的生物毒性,还能很好地保留WO纳米粒子特殊的光学性质,同时具备对抗癌药物DOX的输送与缓释功能,增强了抗肿瘤效果。(3)通过可控自由基聚合方法分别合成了两种两性离子型聚合物聚羧酸甜菜碱(PCB)和聚2-甲基丙烯酰氧基乙基磷酰胆碱(PMPC),并控制其与非离子型聚乙二醇(PEG)具有相似的聚合度。将三种聚合物分别接枝到聚乙烯亚胺(PEI)的支链上,分别形成PEI-PCB、PEI-PMP、PEI-PEG接枝共聚物。进一步地将这三种接枝数目相同的PEI接枝共聚物分别包覆到大小为110 nm的牛血清蛋白-聚间丙烯酰胺基苯硼酸(BSA-PAPBA)纳米粒子表面,从而研究表面修饰对纳米粒子在生物体内分布情况的影响。与未经表面修饰的BSA-PAPBA纳米粒子相比,经接枝共聚物修饰过的纳米粒子在小鼠体内的循环时间大大延长,从而使得纳米粒子在肿瘤区域的富集量显著增加,每克肿瘤中纳米粒子的富集量最高达到了注射计量的10%。在这三种不同表面修饰的纳米粒子中,采用PEI-PMPC修饰的纳米粒子在肿瘤富集程度和抗肿瘤效果方面显示出最好的性能。因此,在药物传输系统中,通过对纳米粒子进行表面修饰从而提高其在肿瘤中的富集效果具有非常大的应用前景。
[Abstract]:Taxol (PTX) is severely restricted because of its low solubility in water. In order to solve this problem, PTX is dissolved in polyoxyethylene castor oil / ethanol solution to improve the solubility of PTX, and commercial anticancer drugs (Taxol (?)) are obtained. However, there are ethanol and polyoxyethylene castor oil in this drug. The addition of machine stabilizers leads to severe toxic and side effects in the treatment process. Therefore, it is necessary to design a new PTX transmission system to effectively carry out the transmission of PTX into the tumor site and prevent the drug from losing rapidly from the tumor site. In the tumor treatment, the combined treatment can greatly enhance the effect of tumor treatment. Combining phototherapy with traditional chemotherapy and using synergistic effects to treat tumors, compared with conventional chemotherapy, it can reduce the amount of drugs and achieve the same effect, which is very meaningful for a dose dependent side effect of chemotherapy drugs, which is a more ideal treatment for the combination of phototherapy and chemotherapy. Strategy. The size, shape and surface chemical properties of nanoparticles affect the target effect in the body. When the size and shape of the nanoparticles are fixed, the surface chemical properties play a major role in the cell uptake and the effect of circulation in the body. In order to prolong the cycle time of the nanoparticles in the body, there are many ways. PEG or amphoteric ion polymers are modified to the surface of nanoparticles. However, there are few comparative studies on the application of PEG modified nanoparticles and amphoteric ions modified nanoparticles in organisms. In this paper, the following three aspects have been studied in this paper. (1) based on the host and guest relationship between Taxol (PTX) and polyacrylic acid modified beta cyclodextrin (PCDAA), we designed a nano assembly drug delivery system for cancer treatment. The PCDAA-PTX nanoparticles were successfully prepared, in which PCDAA was used as the carrier of the anticancer drug PTX. By such a design, the solubility of PTX in water was greatly improved. The degree increases from 0.34 to 36.02 g/ml to 36.02 mu, and the nanoparticle is spherical and its particle size is about 170 nm. tumor mice near infrared imaging results show that PCDAA-PTX nanoparticles have enhanced enrichment in the tumor site. In vivo antitumor experiments show that PCDAA-PTX nanoparticles are compared with the commercial antitumor drug Taxol (?). (2) using good biocompatibility and biodegradable chitosan (chitosan, CS) as a carrier material and high effective complex of W_ (18) O_ (49) (WO) nanoparticles with good photothermal effect in the near infrared region, a homogeneous and stable CS-W_ (18) O_ (49) (49) (49) (CS-WO) composite Nana is prepared. Rice microspheres were further loaded with the chemotherapeutic drug adriamycin (DOX) into the CS-WO composite nanoparticle system, and the CS-WO-DOX composite nanoparticles with good biocompatibility were prepared. The combined therapy of thermotherapy and chemotherapy was carried out. The anti tumor effect of CS-WO-DOX composite nanoparticles was investigated. The research showed that CS-WO-DOX composite nanoparticles were used. The particles can not only significantly enhance the biocompatibility and stability of WO nanoparticles, reduce the biotoxicity of drug DOX, but also retain the special optical properties of WO nanoparticles, simultaneously have the delivery and release function to the anti-cancer drug DOX, and enhance the anti-tumor effect. (3) two by the controlled radical polymerization method, respectively. The amphoteric ionic polymer polycarboxylic acid betaine (PCB) and poly 2- methyl acryl ethyl phosphachylcholine (PMPC) have a similar degree of polymerization with non ionic polyethylene glycol (PEG). Three kinds of polymers are grafted onto the chain of polyethyleneimine (PEI) to form PEI-PCB, PEI-PMP, PEI-PEG graft copolymers respectively. The three graft copolymers of the same grafted PEI were coated to the surface of the bovine serum protein polyacrylamide based benzyl boric acid (BSA-PAPBA) nanoparticles with the size of 110 nm, respectively. The effect of surface modification on the distribution of nanoparticles in the organism was investigated. The results were compared with the unmodified BSA-PAPBA nanoparticles. The circulation time of the nanoparticles modified by the branched copolymer is greatly extended in the mice, thus the concentration of nanoparticles in the tumor area is increased significantly. The concentration of nanoparticles in each gram of tumor is the highest to the measured 10%. in these three different surface modified nanoparticles, using PEI-PMPC modified nanoparticles. It shows the best performance in tumor enrichment and anti-tumor effect. Therefore, it is very promising in the drug transmission system to improve its enrichment effect in the tumor by surface modification of nanoparticles.
【学位授予单位】：南京大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：TB383.1;TQ460.4

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