【摘要】：聚合物納米材料可以通過(guò)調(diào)節(jié)聚合物的組成和聚集態(tài)的形成條件達(dá)到作為藥物載體的目的。當(dāng)其作為藥物載體時(shí),可以裝載藥物分子保護(hù)其在到達(dá)組織之前不被外界環(huán)境所破壞。載藥聚合物中所含雙硫鍵在腫瘤細(xì)胞中高谷胱甘肽(GSH)下能被還原成硫醇,實(shí)現(xiàn)藥物的定點(diǎn)釋放。本論文以生物相容性良好的聚乙二醇為原料,設(shè)計(jì)合成還原型HNTs-聚合物納米材料載藥體系。同時(shí)以雙鍵聚乙二醇為原料設(shè)計(jì)合成基于雙硫鍵的還原型核交聯(lián)膠束載藥體系。具體工作如下:⑴設(shè)計(jì)合成還原型HNTs-PAA-MPEG納米材料載藥體系采用原子轉(zhuǎn)移自由基聚合反應(yīng)(ATRP),合成了兩親性嵌段聚合物MPEG-b-PtBA,酸解得到末端帶羧基的嵌段聚合物MPEG-PAA。HNTs表面經(jīng)過(guò)共價(jià)修飾,引入雙硫鍵。末端帶氨基的納米管和末端帶羧基的聚合物MPEG-PAA經(jīng)過(guò)溶液中的靜電結(jié)合得到含雙硫鍵的還原型HNTs-PAA-MPEG納米材料。通過(guò)核磁、凝膠滲透色譜對(duì)聚合物結(jié)構(gòu)和分子量及分子量分布進(jìn)行表征,證明成功合成了單分散性?xún)捎H聚合物。通過(guò)紅外、掃描電鏡和熱重分析表明,聚合物成功接枝到HNTs表面,并且聚合物所含羧基量越多,接枝到HNTs表面的聚合物量越多。通過(guò)包載和釋放阿霉素研究了HNTs-PAA-MPEG納米材料的載藥和藥物釋放行為。結(jié)果表明,在還原性GSH存在下,HNTs-PAA-MPEG納米材料能夠較快的釋放出藥物。因此,含雙硫鍵的HNTs-PAA-MPEG納米材料有望作為一種還原型藥物載體。⑵設(shè)計(jì)合成基于雙硫鍵的還原型核交聯(lián)膠束載藥體系通過(guò)自由基聚合,調(diào)控三個(gè)單體的加入量,形成側(cè)鏈以聚乙二醇甲基丙烯酸酯作為親水鏈段、乙酸-N-琥珀酰亞胺酯作為交聯(lián)鏈段、MA6-Chol作為疏水鏈段的不同比例不同分子量的聚合物(MPEG-NSA-Chol)。用核磁和凝膠滲透色譜對(duì)聚合物結(jié)構(gòu)和分子量及分子量分布進(jìn)行表征,證明成功合成了不同比例不同分子量的聚合物。隨后通過(guò)胱胺和乙酸-N-琥珀酰亞胺酯反應(yīng)得到交聯(lián)的聚合物。同時(shí),利用熒光光譜儀、動(dòng)態(tài)光散射儀和透射電鏡對(duì)聚合物水溶液自組裝行為進(jìn)行研究。結(jié)果表明:交聯(lián)后的聚合物膠束結(jié)構(gòu)更穩(wěn)定,尺寸更小(10-30 nm)。此外與聚合物載藥膠束相對(duì)比,交聯(lián)載藥膠束在還原性GSH存在下,能夠更快的釋放出藥物。因此,這種基于雙硫鍵的還原型核交聯(lián)膠束也很有潛質(zhì)成為一種穩(wěn)定的還原型藥物載體。
[Abstract]:Polymer nanomaterials can be used as drug carriers by adjusting the composition of polymers and the formation conditions of aggregation states. When it is used as a drug carrier, it can be loaded with drug molecules to protect it from environmental damage before reaching the tissue. The disulfide bond contained in the drug-loaded polymer can be reduced to mercaptan under glutathione (GSH) in tumor cells to realize the targeted release of the drug. In this paper, a novel drug delivery system of reduced HNTs- polymer nanomaterials was designed and synthesized from polyethylene glycol (PEG) with good biocompatibility. At the same time, double bond polyethylene glycol was used as raw material to design and synthesize reductive nuclear crosslinked micelle drug loading system based on disulfide bond. The main work is as follows: 1. The drug loading system of reduced HNTs-PAA-MPEG nanomaterials was designed and synthesized. The amphiphilic block polymer MPEG-b-PtBA was synthesized by atom transfer radical polymerization (ATRP),). The surface of block polymer MPEG-PAA.HNTs with carboxyl group at the end was covalently modified by acidolysis. The disulfide bond is introduced. The reduced HNTs-PAA-MPEG nanomaterials containing disulfide bonds were obtained by electrostatic binding of terminal amino nanotubes and carboxyl group polymer MPEG-PAA. The structure, molecular weight and molecular weight distribution of the polymer were characterized by NMR and gel permeation chromatography. It was proved that the monodisperse amphiphilic polymer was successfully synthesized. Infrared scanning electron microscopy and thermogravimetric analysis showed that the polymer was grafted onto the surface of HNTs and the more carboxyl group the polymer was grafted to the surface of HNTs the more the polymer was grafted to the surface of HNTs. Drug loading and drug release behavior of HNTs-PAA-MPEG nanomaterials were studied by encapsulating and releasing adriamycin. The results showed that HNTs-PAA-MPEG nanoparticles could release drugs rapidly in the presence of reductive GSH. Therefore, HNTs-PAA-MPEG nanomaterials with disulfide bonds are expected to be used as a reductive drug carrier .2 to design and synthesize reductive nuclear cross-linked micelle drug carrier system based on disulfide bond. The amount of three monomers can be regulated by free radical polymerization. The side chain was formed with poly (ethylene glycol) methacrylate as hydrophilic segment and acetic acid-N-succinimide as crosslinking segment MA6-Chol as hydrophobic polymer (MPEG-NSA-Chol). The structure, molecular weight and molecular weight distribution of polymers were characterized by NMR and gel permeation chromatography. The crosslinked polymer was obtained by the reaction of cysteamine with acetic acid-N-succinimide ester. At the same time, the self-assembly behavior of polymer aqueous solution was studied by fluorescence spectrometer, dynamic light scattering instrument and transmission electron microscope. The results show that the crosslinked polymer micelles have more stable structure and smaller size (10-30 nm). In addition, in the presence of reductive GSH, the cross-linked drug carrier micelles can release the drug more quickly than the polymer loaded micelles. Therefore, the reduced nuclear crosslinked micelles based on disulfide bond have the potential to become a stable drug carrier.
【學(xué)位授予單位】：河南師范大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：TB383.1;TQ460.1

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本文編號(hào)：2162193