【摘要】：兩親性嵌段共聚物或接枝共聚物由于其獨(dú)特的結(jié)構(gòu)和性能,在生命科學(xué),材料科學(xué),醫(yī)學(xué)和藥物載體等領(lǐng)域都有十分廣泛的應(yīng)用,尤其在作為靶向藥物載體方面,已成為研究的新領(lǐng)域。具有pH響應(yīng)性的兩親性聚合物作為藥物載體,能夠依托于環(huán)境的pH變化而產(chǎn)生相應(yīng)的相轉(zhuǎn)變,從而促使藥物的釋放行為也具有pH響應(yīng)性,實(shí)現(xiàn)藥物控制釋放及靶向給藥的目的。雖然pH響應(yīng)型嵌段共聚物已經(jīng)具備以上特性,但仍舊存在載藥量低,穩(wěn)定性不持久等問題。提高載藥量,改善膠束在體內(nèi)循環(huán)時的穩(wěn)定性以及更好地實(shí)現(xiàn)靶向給藥也是現(xiàn)在研究中亟待解決的問題。基于此,本文中的工作以聚甲基丙烯酸嵌段為pH響應(yīng)的親水段分別合成了以羥基碳納米管(CNTs-OH)為疏水段的CNTs-g-PMAA接枝聚合物和以改性的端羥基丁二烯-丙烯腈共聚物(HTPBN)為疏水段的H型PMAA2-b-HTPBN-b-PMAA2嵌段共聚物,并對其結(jié)構(gòu)進(jìn)行了表征,研究了其在水溶液中的自組裝行為,對其應(yīng)用于疏水抗癌藥物的負(fù)載和藥物釋放以及生物性能進(jìn)行了研究,具體內(nèi)容如下：第一,pH響應(yīng)型碳納米管接枝聚甲基丙烯酸接枝聚合物的合成自組裝及藥物釋放行為研究。我們采用自由基鏈轉(zhuǎn)移反應(yīng)分別使用一鍋法和分段法兩種方法成功制備了一系列不同配比的CNTs-g-PMAA聚合物,并通過紅外光譜技術(shù)(FT-IR)和核磁共振氫譜技術(shù)(1HNMR)進(jìn)行表征驗(yàn)證。聚合物自組裝成具有特殊核殼結(jié)構(gòu)的納米膠束,經(jīng)表面張力儀,透射電子顯微鏡(TEM),動態(tài)光散射激光粒度儀(DLS)確定膠束的CMC,形狀,大小等。實(shí)驗(yàn)確定在不同環(huán)境下膠束均為球形結(jié)構(gòu),經(jīng)過測量其表面張力得到其CMC值在120.33-251.19 mg/L范圍內(nèi)。zeta電位值測量得到結(jié)果呈電負(fù)性,并且在不同pH環(huán)境中呈現(xiàn)規(guī)律性變化。紫外-可見分光光度計(jì)(UV-vis)和DLS測量結(jié)果均顯示膠束粒徑依賴于pH值變化,轉(zhuǎn)變點(diǎn)約為pH=6.4,具有pH響應(yīng)性。細(xì)胞毒性測量結(jié)果顯示膠束無毒,可用于藥物載體。包覆了10-羥基喜樹堿(HCTP)的載藥膠束在模擬人體環(huán)境中進(jìn)行藥物釋放行為研究,表明其釋放行為與環(huán)境pH有關(guān)。結(jié)果表明CNTs-g-PMAA可用于生物醫(yī)用材料,尤其在增加載藥量方面表現(xiàn)突出。第二,pH響應(yīng)的H型兩親性嵌段共聚物PMAA2-b-HTPBN-b-PMAA2的合成,膠束化以及藥物釋放研究。我們通過原子轉(zhuǎn)移自由基聚合的方法合成新型H型嵌段共聚物PMAA2-b-HTPBN-b-PMAA2,由疏水段HTPBN和聚甲基丙烯酸叔丁酯水解后的聚甲基丙烯酸親水段組成。其結(jié)構(gòu)通過FT-IR和1H NMR得以確定,并用GPC表征手段測量了其相對分子質(zhì)量。共聚物自組裝成的球形納米膠束,CMC值在366-58.0 mg/L, zeta位值測量結(jié)果在-24到-34 mV, Dh采用動態(tài)光散射激光粒度儀(DLS)測量,得到結(jié)果與通過紫外-可見分光光度計(jì)(UV-vis)測得的透光率結(jié)果一致,都說明其具有pH響應(yīng)性。相比起相同分子量的線型聚合物,H型聚合物膠束具有更小的粒徑和CMC值,表明在體內(nèi)循環(huán)時具有更好的穩(wěn)定性。我們采用MTT法進(jìn)行了細(xì)胞毒性研究,空白膠束和載藥膠束毒性明顯低于游離藥物。通過模擬人體環(huán)境的體外藥物釋放行為的研究,我們得到可控的藥物釋放規(guī)律,在病灶部位具有更大的釋放量,釋放行為依賴于外界pH的變化。因此,該嵌段聚合物可以作為疏水藥物載體并應(yīng)用于控制釋放的研究中。
[Abstract]:Amphiphilic block copolymers or graft copolymers have been widely used in life sciences, materials sciences, medicine and drug carriers due to their unique structures and properties, especially in targeting drug carriers. The pH-responsive block copolymers have the above characteristics, but there are still some problems such as low drug loading, unstable stability and so on. The stability of cycling in vivo and the better targeting of drug delivery are also urgent problems to be solved. Based on this, CNTs-g-PMAA graft polymers with hydroxy carbon nanotubes (CNTs-OH) as hydrophobic segments and modified hydroxy-terminated succinic acid as hydrophilic segments were synthesized using polymethacrylic acid as pH-responsive hydrophilic segments, respectively. H-type PMAA2-b-HTPBN-b-PMAA2 block copolymers with hydrophobic segments of ene-acrylonitrile copolymers (HTPBN) were characterized, and their self-assembly behavior in aqueous solution was studied. The loading, drug release and biological properties of the copolymers were studied. Firstly, pH-responsive carbon nanoparticles were prepared. A series of CNTs-g-PMAA polymers with different proportions were successfully prepared by one-pot method and one-step method respectively through free radical chain transfer reaction, and were characterized by infrared spectroscopy (FT-IR) and nuclear magnetic resonance hydrogen spectroscopy (1HNMR). The micelles were self-assembled into nano-micelles with special core-shell structure. The CMC, shape and size of the micelles were determined by surface tensiometer, transmission electron microscopy (TEM) and dynamic light scattering laser particle sizer (DLS). The micelles were spherical in different environments. The CMC value of the micelles was 1 by measuring the surface tension. In the range of 20.33-251.19 mg/L, zeta potential showed electronegativity and regular change under different pH conditions. The results of UV-vis and DLS measurements showed that the micelle size depended on pH value and the transition point was about pH=6.4. The results of cytotoxicity measurements showed that the micelles were non-toxic. The results showed that CNTs-g-PMAA could be used in biomedical materials, especially in increasing drug loading. Second, pH-responsive amphiphilic H-type amphiphilic block copolymers. Synthesis, Micellation and Drug Release of Polymer PMAA2-b-HTPBN-b-PMAA2. A novel H-type block copolymer PMAA2-b-HTPBN-b-PMAA2 was synthesized by atom transfer radical polymerization. The structure of the copolymer was obtained by FT-IR and 1H NMR. The copolymers were self-assembled into spherical nanomicelles with CMC values ranging from 366 to 58.0 mg/L, zeta values ranging from - 24 to - 34 mV, and Dh was measured by dynamic light scattering laser particle sizer (DLS). The results were obtained by UV-vis spectrophotometer. Compared with linear polymers with the same molecular weight, H-type micelles have smaller particle size and CMC value, indicating better stability in vivo circulation. We used MTT method to study the cytotoxicity of blank micelles and drug-loaded micelles. The toxicity of blank micelles and drug-loaded micelles was significantly lower than that of free drugs. In vitro drug release behavior in the body environment has been studied, and we have obtained a controllable drug release law, which has a greater release in the lesion site. The release behavior depends on the change of external pH. Therefore, the block polymer can be used as a hydrophobic drug carrier and used in controlled release research.
【學(xué)位授予單位】：陜西師范大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2016
【分類號】：O631;TQ460.4

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相關(guān)期刊論文 前1條

1 趙群;倪沛紅;;pH/溫度響應(yīng)的兩親性嵌段共聚物的研究[J];化學(xué)進(jìn)展;2006年06期

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本文編號：2201826