本文選題：羧甲基-β-環(huán)糊精 + Fe_3O_4磁性納米顆粒　； 參考：《山東大學(xué)》2017年博士論文

【摘要】：近年來,半導(dǎo)體量子點(diǎn)獨(dú)特的尺寸依賴光學(xué)性質(zhì),在熒光標(biāo)記、生物傳感、太陽(yáng)能電池等領(lǐng)域具有廣泛的應(yīng)用前景。然而,將量子點(diǎn)與磁性納米顆粒復(fù)合制備的多功能藥物載體,普遍存在載藥量不高,穩(wěn)定性不好及熒光猝滅等問題,因而限制了其更廣泛的應(yīng)用。同時(shí),基于量子點(diǎn)的熒光性能已發(fā)展了多種熒光探針用于金屬離子檢測(cè),然而由于選擇性和檢測(cè)靈敏度不高,如何實(shí)現(xiàn)對(duì)目標(biāo)分析物的高選擇性分析測(cè)定仍是目前具有挑戰(zhàn)性的課題。本論文深入研究量子點(diǎn)的表面修飾及功能化,進(jìn)一步實(shí)現(xiàn)量子點(diǎn)與其它納米材料的組裝與復(fù)合,從而獲得更有實(shí)用價(jià)值的量子點(diǎn)材料。制備復(fù)合納米藥物載體的關(guān)鍵技術(shù)在于選擇一個(gè)良好的介質(zhì)能夠同時(shí)穩(wěn)定磁性材料和量子點(diǎn)。殼聚糖及其衍生物具有良好的穩(wěn)定性和緩釋性能,作為表面修飾穩(wěn)定材料和藥物載體方面具有明顯優(yōu)勢(shì)。因此,本論文首先利用聚合物(CM-β-CD或CMCS)對(duì)磁性顆粒進(jìn)行表面修飾,其修飾層不僅可以提高藥物的負(fù)載量,降低對(duì)量子點(diǎn)熒光性能的影響,其表面豐富的功能基團(tuán)有利于與量子點(diǎn)的有效結(jié)合。其次,聚合物改性的磁性納米顆粒與量子點(diǎn),經(jīng)化學(xué)鍵合法共同包埋于殼聚糖基體中,得到穩(wěn)定的復(fù)合納米藥物載體。同時(shí),基于量子的熒光特性及電催化性能,經(jīng)特異性表面配體分子修飾,通過采用ZnSe量子點(diǎn)溶液,ZnSe-XG納米復(fù)合物及CS/ZnSe生物膜,三種策略構(gòu)建用于金屬離子檢測(cè)的電化學(xué)傳感器及熒光傳感器,實(shí)現(xiàn)對(duì)金屬離子的高選擇性分析測(cè)定。主要內(nèi)容歸納如下:(1)基于殼聚糖基體制備磁性復(fù)合納米藥物載體(CS-CDpoly-MNPs),利用羧甲基-β-環(huán)糊精修飾磁性納米顆粒,其疏水空腔結(jié)構(gòu),經(jīng)疏水包合作用對(duì)微溶性抗癌藥物(5-Fu)具有優(yōu)越的承載能力。藥物載體的形貌和性能受制備過程中交聯(lián)劑用量、交聯(lián)時(shí)間及CS/5-Fu/CM-β-CD質(zhì)量比等因素的影響。磁性納米顆粒表面CM-β-CD的最大接枝量為6.5 wt%,復(fù)合納米藥物載體具有良好的磁性能(43.8 emu/g)和藥物負(fù)載能力(44.7 ±1.8%)。(2)基于殼聚糖基體制備磁性熒光復(fù)合納米藥物載體(DCMFNPs),利用殼聚糖(CS)、羧甲基殼聚糖(CMCS)修飾的Fe304和谷胱甘肽(GSH)穩(wěn)定的CdSe@ZnSQDs表面豐富的氨基基團(tuán),以戊二醛為交聯(lián)劑,通過醛基與氨基的共價(jià)交聯(lián)反應(yīng)制備出具有良好磁性能和熒光性能的DCMFNPs,其化學(xué)鍵合作用結(jié)合不同組分明顯提高了藥物載體的穩(wěn)定性。磁性納米顆粒表面羧甲基殼聚糖(CMCS)的修飾作用有效降低了對(duì)量子點(diǎn)熒光性能的影響。DOX的累積釋放主要涉及殼聚糖的溶脹行為和不同組分之間的靜電作用力。體外細(xì)胞實(shí)驗(yàn)研究表明:CMFNPs具有低的細(xì)胞毒性和良好的生物相容性,且具有良好的成像功能。隨孵育時(shí)間的延長(zhǎng),腫瘤細(xì)胞對(duì)藥物載體的攝入量明顯增加。(3)制備以羧甲基殼聚糖(CMCS)為基體的復(fù)合納米材料載藥體系,利用CMCS表面豐富的氨基和羧基基團(tuán),將量子點(diǎn)、CMCS修飾的Fe3O4及葉酸酸通過共價(jià)酰胺結(jié)合有效包埋在羧甲基殼聚糖基體中。與物理相互作用(如靜電作用力)相比,各成分之間的共價(jià)鍵合作用有利于藥物載體在生理環(huán)境中的穩(wěn)定性。磁性熒光復(fù)合納米藥物載體(DOX-CLM)具有良好磁響應(yīng)性和熒光性能,其藥物釋放具有pH依賴性可控釋放。體外細(xì)胞實(shí)驗(yàn)研究表明,復(fù)合納米顆粒具有良好的生物相容性,腫瘤細(xì)胞對(duì)藥物載體的攝入主要是特異性受體介導(dǎo)的內(nèi)吞機(jī)制。細(xì)胞凋亡數(shù)據(jù)表明,隨孵育時(shí)間延長(zhǎng),細(xì)胞的早期凋亡和晚期凋亡的比例明顯增加。(4)基于谷胱甘肽(GSH)修飾的ZnSe量子點(diǎn)的熒光猝滅法,開發(fā)一種檢測(cè)銅離子的方法,并成功用于環(huán)境樣品中銅離子的測(cè)定。與其它文獻(xiàn)報(bào)道的量子點(diǎn)熒光探針相比,顯示出優(yōu)異的檢測(cè)限和選擇性,這主要?dú)w因于Cu(Ⅱ)加入導(dǎo)致量子點(diǎn)表面配體分子的剝離及量子點(diǎn)的表面狀態(tài)的改變;同時(shí),谷胱甘肽與Cu2+離子之間的電荷轉(zhuǎn)移,還原后的Cu+可與GSH形成多種模式的配合物,進(jìn)一步誘導(dǎo)量子點(diǎn)熒光的有效猝滅。在最佳條件下,此熒光探針對(duì)Cu2+的檢出限為2×10-10 mol/L。同時(shí),外來離子在Cu2+離子檢測(cè)中顯示出低的干擾響應(yīng)。此外,ZnSe量子點(diǎn)不變的吸收峰和衰減的熒光壽命分析證實(shí),此猝滅過程為動(dòng)態(tài)猝滅過程。(5)研發(fā)一種ZnSe-XG納米復(fù)合物作為電極修飾材料,并基于該修飾電極構(gòu)建了用于Cd(Ⅱ)選擇性檢測(cè)的電化學(xué)傳感器。與單獨(dú)的ZnSeQDs相比,由于ZnSe和XG之間的氫鍵和絡(luò)合作用,ZnSe-XG電極膜的檢測(cè)穩(wěn)定性和對(duì)Cd(Ⅱ)離子的吸附能力具有顯著優(yōu)勢(shì)。ZnSe-XG納米復(fù)合物及多壁碳納米管(MWCNT)的引入均為電子轉(zhuǎn)移提供了有利途徑,且對(duì)Cd(Ⅱ)的檢測(cè)顯示出更優(yōu)良的電催化活性。修飾電極對(duì)Cd(Ⅱ)檢測(cè)的線性范圍為0.336-5.6 mg/L,并且顯示出高的靈敏度22.257μA·mg-1·L-1 和低的檢測(cè)限6.11 μg/L。修飾電極對(duì)Cd(Ⅱ)的催化氧化過程證明是表面吸附控制,其飽和吸附量為3.45×10-9mol/cm2。該修飾電極顯示出良好的檢測(cè)靈敏度、選擇性、再現(xiàn)性和長(zhǎng)期穩(wěn)定性,可以作為金屬離子電化學(xué)檢測(cè)的理想電極材料。(6)基于量子點(diǎn)溶液和量子點(diǎn)生物膜的熒光猝滅開發(fā)兩種靈敏的熒光傳感器用于檢測(cè)Cd(Ⅱ)和Cu(Ⅱ)離子。量子點(diǎn)生物膜(CS/ZnSe)的熒光傳感器有望應(yīng)用于便攜式感測(cè)裝置的開發(fā)。隨著金屬離子濃度的增加,量子點(diǎn)的光致發(fā)光強(qiáng)度成比例地減小,并且熒光猝滅程度與金屬離子濃度的關(guān)系可通過Stern-Volmer方程進(jìn)行線性擬合。同時(shí),基于黃原膠(XG)和ZnSe量子點(diǎn)(ZnSe-XG)納米復(fù)合物構(gòu)建可對(duì)兩種金屬離子實(shí)現(xiàn)單獨(dú)和同步檢測(cè)的電化學(xué)傳感器。在最佳實(shí)驗(yàn)條件下,其峰值電流與金屬離子的濃度具有良好的線性關(guān)系,并且對(duì)于Cd(Ⅱ)和Cu(Ⅱ)的檢測(cè)限分別為6.1和0.074 μg/L。三種測(cè)定方法均對(duì)Cu2+比Cd2+具有更高的檢測(cè)靈敏性和更低的檢測(cè)限。對(duì)基于量子點(diǎn)的熒光傳感器與電化學(xué)傳感器的性能進(jìn)行系統(tǒng)比較,結(jié)果表明,電化學(xué)傳感器在重復(fù)性、靈敏度、選擇性和檢測(cè)限(LOD)方面具有顯著優(yōu)勢(shì)。
[Abstract]:In recent years, semiconductor quantum dots have a wide range of applications in the fields of fluorescence labeling, biosensing, solar cells and other fields. However, the multifunctional drug carriers, which are prepared by the combination of quantum dots and magnetic nanoparticles, have a wide range of problems such as low drug loading, poor stability and fluorescence quenching. At the same time, based on the fluorescence properties of quantum dots, a variety of fluorescent probes have been developed for metal ion detection. However, because of the low selectivity and detection sensitivity, it is still a challenging task to realize the high selective analysis of the target analytes. This paper is a thorough study of the surface of quantum dots. The key technology for the preparation of a compound nanoscale drug carrier is to select a good medium to stabilize the magnetic material and the quantum dots. The chitosan and its derivatives have good stability. As a surface modified stable material and drug carrier, it has obvious advantages. Therefore, the surface modification of magnetic particles is first used in this paper (CM- beta -CD or CMCS). The modified layer can not only improve the load of the drug, but also reduce the effect of the fluorescence of the quantum dots. Secondly, the polymer modified magnetic nanoparticles and quantum dots are embedded in the chitosan matrix by the chemical bond method to obtain a stable compound nanoscale drug carrier. At the same time, based on the quantum fluorescence and electrocatalytic properties, the ZnSe quantum dots are used by the specific surface ligand molecular modification. Solutions, ZnSe-XG nanocomposites and CS/ZnSe biofilms, three strategies to construct electrochemical sensors and fluorescence sensors for metal ion detection, to achieve high selectivity and determination of metal ions. The main contents are as follows: (1) the preparation of magnetic compound nanoscale drug carrier (CS-CDpoly-MNPs) based on chitosan matrix and using carboxymethyl - Beta cyclodextrin modified magnetic nanoparticles, the hydrophobic cavity structure, the hydrophobic inclusion effect of the micro soluble anticancer drug (5-Fu) has superior bearing capacity. The morphology and properties of the drug carrier are affected by factors such as the amount of crosslinking agent, the crosslinking time and the mass ratio of CS/5-Fu/CM- beta -CD in the preparation process. Most of the CM- beta -CD on the surface of magnetic nanoparticles The large grafting amount is 6.5 wt%, and the composite nanoscale drug carrier has good magnetic properties (43.8 emu/g) and drug loading capacity (44.7 + 1.8%). (2) magnetic fluorescent composite nanomaterials (DCMFNPs) based on chitosan matrix, Fe304 and glutathione (GSH) modified CdSe@ZnSQDs surface modified by chitosan (CS), carboxymethyl chitosan (CMCS) The rich amino group, with glutaraldehyde as the crosslinking agent, was prepared by the covalent crosslinking reaction of aldehyde group and amino group, and the DCMFNPs with good magnetic energy and fluorescence properties was prepared. The chemical bonding combined with different components obviously improved the stability of the drug carrier. The modification effect of carboxymethyl chitosan (CMCS) on the surface of magnetic nanoparticles was effectively reduced. The effect of.DOX on the fluorescence properties of quantum dots is mainly related to the swelling behavior of chitosan and the electrostatic force between different components. In vitro cell experiments show that CMFNPs has low cytotoxicity and good biocompatibility, and has good imaging function. With the prolongation of incubation time, the tumor cells are drug The intake of the carrier is significantly increased. (3) the preparation of a compound nanomaterial carrier system based on Carboxymethyl Chitosan (CMCS), using the rich amino and carboxyl groups on the surface of CMCS, can be effectively embedded in the carboxymethyl chitosan matrix by binding the quantum dots, CMCS modified Fe3O4 and folic acid through covalent amides. In contrast, the covalent bond between the components is beneficial to the stability of the drug carrier in the physiological environment. The magnetic fluorescent composite nano drug carrier (DOX-CLM) has good magnetic responsiveness and fluorescence properties, and the release of the drug has a pH dependent controlled release. Biocompatibility, the intake of tumor cells to drug carriers is mainly specific receptor mediated endocytosis. Apoptosis data show that the proportion of early apoptosis and late apoptosis increased significantly with incubation time. (4) a kind of copper ion detection was developed based on the fluorescence quenching method of glutathione (GSH) modified ZnSe quantum dots. The method has been successfully used for the determination of copper ions in environmental samples. Compared with other reported quantum dots, the detection limits and selectivity are excellent, which is attributed to the Cu (II) addition leading to the dissection of the ligand molecules on the surface of the quantum dots and the change of the surface state of the quantum dots; at the same time, between glutathione and Cu2+ ions The charge transfer, the reduced Cu+ can form a variety of mode complexes with GSH, and further induce the effective quenching of the quantum dots fluorescence. Under the optimum conditions, the detection limit of the fluorescence probe to Cu2+ is 2 x 10-10 mol/L., and the external ions show low interference response in the Cu2+ ion detection. In addition, the constant absorption peaks of ZnSe quantum dots and the same absorption peaks are found. The decay of the fluorescence lifetime analysis confirms that the quenching process is a dynamic quenching process. (5) a ZnSe-XG nanocomposite is developed as an electrode modifier, and an electrochemical sensor for selective detection of Cd (II) is constructed based on the modified electrode. Compared with the single ZnSeQDs, the hydrogen bond and complexation between ZnSe and XG, ZnSe-XG electricity The detection stability of the polar membrane and the adsorption capacity of Cd (II) ions have significant advantages. The introduction of.ZnSe-XG nanocomposites and multi walled carbon nanotubes (MWCNT) provides a favorable way for electron transfer, and shows better electrocatalytic activity for the detection of Cd (II). The linear range of the modified electrode for Cd (II) detection is 0.336-5.6 mg/L, and The high sensitivity of 22.257 A. Mg-1. L-1 and low detection limit 6.11 mu g/L. modified electrode for Cd (II) was proved to be a surface adsorption control. The saturated adsorption capacity was 3.45 * 10-9mol/cm2., and the modified electrode showed good detection sensitivity, selectivity, reproducibility and long-term stability, which could be used as metal ions. Ideal electrode materials for electrochemical detection. (6) based on the fluorescence quenching of quantum dots solution and quantum dot biomembrane, two sensitive fluorescent sensors are used to detect Cd (II) and Cu (II) ions. The fluorescence sensors of the quantum dot biomembrane (CS/ZnSe) are expected to be applied to the development of portable sensing devices. The photoluminescence intensity of the subpoints is reduced proportionately, and the relationship between the fluorescence quenching degree and the concentration of metal ions can be linearly fitted by the Stern-Volmer equation. At the same time, the electrochemical sensors based on the xanthan gum (XG) and ZnSe quantum dots (ZnSe-XG) nanocomposites can be constructed to detect two kinds of metal ions separately and synchronously. Under good experimental conditions, the peak current has a good linear relationship with the concentration of metal ions, and the detection limits for Cd (II) and Cu (II) are 6.1 and 0.074 micron g/L. respectively, which have higher detection sensitivity and lower detection limit for Cu2+ than Cd2+. The results show that electrochemical sensors have significant advantages in repeatability, sensitivity, selectivity and detection limit (LOD).

【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：TQ460.1;O657.3
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本文編號(hào)：1889624