發(fā)布時(shí)間：2018-06-19 13:08

  本文選題：納米粒子 + β-環(huán)糊精��； 參考：《南京大學(xué)》2017年博士論文

【摘要】：紫杉醇(PTX)因其在水中的溶解度較低,臨床治療效果受到嚴(yán)重的制約。為解決這一問(wèn)題,將PTX溶解于聚氧乙烯蓖麻油／乙醇溶液中來(lái)提高PTX的溶解度,獲得了商業(yè)化的抗癌藥物泰素(Taxol(?))。但是,該藥物中有乙醇和聚氧乙烯蓖麻油等有機(jī)穩(wěn)定劑的加入,導(dǎo)致治療過(guò)程中出現(xiàn)嚴(yán)重的毒副作用。因此,我們有必要設(shè)計(jì)一種新型的PTX傳輸體系,有效地實(shí)現(xiàn)PTX到腫瘤部位的傳輸并且阻止藥物快速地從腫瘤部位流失。在腫瘤治療手段中,聯(lián)合治療可以大大增強(qiáng)腫瘤治療效果。其中將光熱療法和傳統(tǒng)的化療相結(jié)合,利用協(xié)同效應(yīng)來(lái)治療腫瘤的方式,相對(duì)于普通化療,可以在降低藥劑量的同時(shí)達(dá)到相同療效,這對(duì)于存在劑量依賴的毒副作用的化療藥物是非常有意義的,因此光療-化療聯(lián)合治療是更為理想的治療策略。納米粒子的尺寸、形狀以及表面化學(xué)性質(zhì)影響著粒子在體內(nèi)的靶向效果。當(dāng)納米粒子的尺寸和形狀一定時(shí),表面化學(xué)性質(zhì)在細(xì)胞攝取和體內(nèi)循環(huán)效果起著主要作用。為了達(dá)到延長(zhǎng)納米粒子在體內(nèi)的循環(huán)時(shí)間的目的,已有多種方式將PEG或者兩性離子聚合物修飾到納米粒子的表面。然而,系統(tǒng)地針對(duì)PEG修飾的納米粒子與兩性離子修飾的納米粒子在生物體內(nèi)應(yīng)用的對(duì)比研究還很少。針對(duì)上述聚合物納米藥物傳輸體系存在的問(wèn)題,本論文進(jìn)行了以下三個(gè)方面的研究：(1)基于紫杉醇(PTX)和聚丙烯酸修飾的β-環(huán)糊精(PCDAA)之間的主客體關(guān)系,我們?cè)O(shè)計(jì)了一種用于癌癥治療的納米組裝給藥系統(tǒng),成功制備了PCDAA-PTX納米粒子,其中PCDAA作為抗癌藥物PTX的載體。通過(guò)這樣的設(shè)計(jì),PTX在水中的溶解性得到大幅度提高,從之前的0.34μg/ml提高到36.02 μg/ml。該納米粒子呈現(xiàn)球狀且其粒徑約170 nm。荷瘤小鼠近紅外成像結(jié)果顯示,PCDAA-PTX納米粒子在腫瘤部位有增強(qiáng)富集作用。體內(nèi)抗腫瘤實(shí)驗(yàn)表明：與商業(yè)化抗腫瘤藥物Taxol(?)相比,PCDAA-PTX納米粒子的抗腫瘤效果明顯增強(qiáng)。(2)利用具有良好生物相容性和可生物降解的殼聚糖(chitosan, CS)作為載體材料,將其與在近紅外區(qū)域具有很好的光熱效應(yīng)的W_(18)O_(49) (WO)納米粒子的進(jìn)行高效復(fù)合,制備了尺寸均一且穩(wěn)定的CS-W_(18)O_(49)(CS-WO)復(fù)合納米微球,再進(jìn)一步將化療藥物阿霉素(DOX)負(fù)載到CS-WO復(fù)合納米粒子體系中,制備出具有良好生物相容性的CS-WO-DOX復(fù)合納米粒子,進(jìn)行了熱療和化療的聯(lián)合治療,考察了CS-WO-DOX復(fù)合納米粒子在抗腫瘤方面的效果。研究表明,CS-WO-DOX復(fù)合納米粒子不僅可以顯著增強(qiáng)WO納米粒子的生物相容性和穩(wěn)定性,降低藥物DOX的生物毒性,還能很好地保留WO納米粒子特殊的光學(xué)性質(zhì),同時(shí)具備對(duì)抗癌藥物DOX的輸送與緩釋功能,增強(qiáng)了抗腫瘤效果。(3)通過(guò)可控自由基聚合方法分別合成了兩種兩性離子型聚合物聚羧酸甜菜堿(PCB)和聚2-甲基丙烯酰氧基乙基磷酰膽堿(PMPC),并控制其與非離子型聚乙二醇(PEG)具有相似的聚合度。將三種聚合物分別接枝到聚乙烯亞胺(PEI)的支鏈上,分別形成PEI-PCB、PEI-PMP、PEI-PEG接枝共聚物。進(jìn)一步地將這三種接枝數(shù)目相同的PEI接枝共聚物分別包覆到大小為110 nm的牛血清蛋白-聚間丙烯酰胺基苯硼酸(BSA-PAPBA)納米粒子表面,從而研究表面修飾對(duì)納米粒子在生物體內(nèi)分布情況的影響。與未經(jīng)表面修飾的BSA-PAPBA納米粒子相比,經(jīng)接枝共聚物修飾過(guò)的納米粒子在小鼠體內(nèi)的循環(huán)時(shí)間大大延長(zhǎng),從而使得納米粒子在腫瘤區(qū)域的富集量顯著增加,每克腫瘤中納米粒子的富集量最高達(dá)到了注射計(jì)量的10%。在這三種不同表面修飾的納米粒子中,采用PEI-PMPC修飾的納米粒子在腫瘤富集程度和抗腫瘤效果方面顯示出最好的性能。因此,在藥物傳輸系統(tǒng)中,通過(guò)對(duì)納米粒子進(jìn)行表面修飾從而提高其在腫瘤中的富集效果具有非常大的應(yīng)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.
【學(xué)位授予單位】：南京大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：TB383.1;TQ460.4

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