人血清蛋白—無機(jī)納米復(fù)合材料用于金屬抗癌的運(yùn)輸
發(fā)布時間：2018-12-12 13:10
【摘要】：每年全球有上千萬的癌癥新增患者,癌癥已經(jīng)嚴(yán)重威脅著人類的生命健康,在藥物治療中,金屬抗癌藥物有著舉足輕重的作用,順鉑、卡鉑、奧沙利鉑、三氧化二砷等被廣泛用于臨床治療,其他一些金屬藥物比如,NAMI-A、KP1019等釕類抗癌藥物和金類抗癌藥物等進(jìn)入臨床評估。但在臨床治療中表現(xiàn)出的毒副作用、耐藥性以及小分子藥物在體內(nèi)循環(huán)時間短等問題極大限制了其使用。本論文主要研究內(nèi)容有(1)以磷酸鈣納米顆粒和人血清白蛋白為載體運(yùn)輸四價鉑化合物,使得該體系能夠在酸性及還原性環(huán)境中響應(yīng)釋放出順鉑藥物；(2)以人血清白蛋白修飾的上轉(zhuǎn)換納米顆粒為載體運(yùn)輸光敏性的多吡啶釕化合物,該體系具有雙重?zé)晒馓匦?用于細(xì)胞成像,而且能夠通過光照控制釋放抗癌活性藥物；(3)合成軸向為阿司匹林的四價鉑化合物,該化合物能夠在細(xì)胞內(nèi)還原釋放出順鉑和阿司匹林,顯著增加了抗腫瘤活性,而且通過在四價鉑軸向另一端接上膽固醇分子,使得阿司匹林-鉑化合物疏水性增加,能夠有效被高分子納米顆粒負(fù)載。第一章主要是對金屬抗癌藥物及納米運(yùn)輸體系的綜述,主要涉及鉑類、釕類抗癌藥物的發(fā)展、挑戰(zhàn)及其抗癌作用機(jī)理,鉑類、釕類藥物的納米運(yùn)輸體系的發(fā)展及抗癌作用機(jī)理,人血清白蛋白簡介及其用于藥物運(yùn)輸?shù)陌l(fā)展和體內(nèi)抗癌作用機(jī)理。第二章設(shè)計合成了一種四價鉑-HSA/磷酸鈣載藥體系,通過共價鍵把四價鉑化合物結(jié)合到HSA上,再通過共沉淀方法制備出Pt(IV)-HSA-CaP體系,該載藥體系是一種生物兼容性好,能夠?qū)H及氧化還原環(huán)境響應(yīng)的納米運(yùn)輸體系,Pt-HSA/CaP在細(xì)胞外液穩(wěn)定,當(dāng)顆粒被細(xì)胞攝入后,在溶酶體或包涵體酸性環(huán)境中,磷酸鈣降解,釋放出Pt-HSA藥物,四價鉑化合物在細(xì)胞內(nèi)還原劑(AsA)存在下,還原釋放出具有抗癌活性的二價鉑。從實驗結(jié)果可以得到,Pt-HSA只有在還原劑AsA存在下才能和DNA反應(yīng),而磷酸鈣載體保護(hù)四價鉑化合物不會提前被體液中還原劑還原,所以該體系是一種能有效控制藥物釋放的運(yùn)輸體系,從細(xì)胞毒性實驗結(jié)果可以看到,Pt-HSA/CaP體系相比于順鉑,能夠更有效的抑制癌細(xì)胞的生長,而對正常細(xì)胞毒性較弱,而且跟順鉑、Pt-HSA相比,該體系也表現(xiàn)出不同的細(xì)胞周期阻滯,說明在Pt-HSA/CaP中的Pt(Ⅳ)在細(xì)胞內(nèi)有不同細(xì)胞響應(yīng)。在Pt-HSA/CaP體系中,制備材料的試劑都是生物兼容性的,而且制備條件溫和,對磷酸鈣顆粒中的蛋白質(zhì)性質(zhì)影響較小,加上該體系有很高的蛋白質(zhì)負(fù)載量,所以該體系有望用于蛋白質(zhì)藥物運(yùn)輸。第三章合成三種多吡啶釕化合物,通過比較其光敏性及光毒性,選出[Ru(bpy)2(6,6'-dimethyl-2,2'-bipyridine)]Cl2 (Ru-1)化合物作為光敏性釕藥物用于納米藥物運(yùn)輸,通過多空硅、PAA、HSA表面修飾UCNPs,研究不同表面修飾對顆粒穩(wěn)定性及多吡啶釕化合物負(fù)載效率的影響,得到HSA修飾的UCNPs具有優(yōu)異的穩(wěn)定性和負(fù)載效率,通過HSA包覆使得該納米顆粒具有很好的生物相容性、水分散性和穩(wěn)定性,而且通過HSA表面修飾UCNPs獲得一種具有雙重?zé)晒獾募{米載體,該載體在980nm光激發(fā)下,內(nèi)核UCNPs (NaYF4:20 mol% Yb,0.5mo1%Tm)會產(chǎn)生藍(lán)色熒光,而在450nm光激發(fā)下,HSA層產(chǎn)生綠色熒光,這雙重?zé)晒馓匦允沟迷摷{米載體能夠有效用于生物成像,而且提供更多的激發(fā)波長和發(fā)射波長選擇,載體的細(xì)胞攝取能夠同時通過上轉(zhuǎn)換熒光和綠色熒光看到,通過負(fù)載一種光敏性釕化合物Ru-1到載體中,形成Ru-HSA-UCNPs納米顆粒,該納米顆粒具有光誘導(dǎo)的細(xì)胞毒性,在黑暗條件下,Ru-HSA-UCNPs只有很低的細(xì)胞生長抑制效果,但光激發(fā)后細(xì)胞毒性顯著增加。進(jìn)一步分析Ru-1化合物和DNA的反應(yīng),實驗結(jié)果表明,Ru-1化合物和DNA有很低的反應(yīng)活性,但被光激活后,Ru-1化合物轉(zhuǎn)變?yōu)榫哂懈叻磻?yīng)活性的化合物,能夠和DNA反應(yīng),而且和DNA反應(yīng)速率比順鉑快。這種光激活特性使得Ru-HSA-UCNPs有希望用于在腫瘤部位定點控制釋放活性抗腫瘤基團(tuán)。第四章合成了一種新型四價鉑化合物,其軸向是一個阿司匹林分子,該化合物被細(xì)胞攝取后,在細(xì)胞內(nèi)被還原釋放出順鉑和阿司匹林,顯著增加了抗腫瘤活性；為了能夠運(yùn)用高分子載體有效運(yùn)輸阿司匹林-鉑白化合物,設(shè)計合成在其軸向另一端為膽固醇分子的阿司匹林-鉑化合物,使其疏水性增加,能夠被PEG-PLGA等高分子納米顆粒的疏水性內(nèi)核高效負(fù)載。
[Abstract]:Every year, there are tens of millions of newly-added cancer patients in the world, and the cancer has seriously threatened the health of human life. In the treatment of drugs, the metal anti-cancer drugs play a very important role, such as cisplatin, carboplatin, oxaliplatin, arsenic trioxide and the like, and are widely used for clinical treatment. Other metal drugs, such as NMI-A, KP1019, and other anti-cancer drugs and gold-based anti-cancer drugs, will enter the clinical evaluation. but the problems of toxic and side effects, drug resistance and short molecular medicine in the in-vivo circulation time and the like in the clinical treatment are greatly limited. The main contents of this thesis are as follows: (1) the tetravalent platinum compound is transported with calcium phosphate nanoparticles and human serum albumin as a carrier, so that the system can respond to the release of the cisplatin medicament in an acid and a reducing environment; (2) the light-sensitive multiferroic compound is transported by the upconversion nanoparticles modified by human serum albumin as a carrier, the system has double fluorescence characteristics, is used for cell imaging, and can release the anti-cancer active drug through illumination control; (3) synthesizing a tetravalent platinum compound with an axial direction of aspirin, capable of reducing the release of cisplatin and aspirin in the cells, remarkably increasing the anti-tumor activity, and connecting the cholesterol molecules at the other end of the tetravalent platinum, so that the hydrophobic property of the aspirin-platinum compound is increased, and the high-molecular nano-particle load can be effectively absorbed. The first chapter is the review of the metal anti-cancer drug and the nano-transportation system, which mainly deals with the development, challenge and the mechanism of anti-cancer action, the development of the nano-transport system of platinum and the anti-cancer drugs and the mechanism of the anti-cancer action. The introduction of human serum albumin and its application in the development of drug transport and the mechanism of anti-cancer in vivo. in that second chap, a tetravalent platinum-HSA/ calcium phosphate drug delivery system is designed, the tetravalent platinum compound is bound to the HSA by a covalent bond, a Pt (IV)-HSA-CaP system is prepared by a co-precipitation method, The nano-transport system capable of responding to the PH and the oxidation-reduction environment, the Pt-HSA/ CaP is stable in the extracellular fluid, and the Pt-HSA drug and the tetravalent platinum compound are released in the presence of an internal reducing agent (AsA) in the cell when the particles are taken up by the cells, reducing the release of the divalent platinum with anticancer activity. from the experimental results, the Pt-HSA can only react with the DNA in the presence of the reducing agent AsA, and the calcium phosphate carrier protects the tetravalent platinum compound from being reduced in advance by the reducing agent in the body fluid, so the system is a transport system capable of effectively controlling the release of the drug, Compared with the cisplatin, the Pt-HSA/ CaP system can effectively inhibit the growth of the cancer cells compared with the cisplatin-HSA/ CaP system, and the system also shows different cell cycle blocks compared with the cisplatin and the Pt-HSA, The Pt (IV) in the Pt-HSA/ CaP has different cell responses in the cells. In the Pt-HSA/ CaP system, the reagents for preparing the materials are biocompatible, and the preparation conditions are mild, the effect of the protein in the calcium phosphate particles is small, and the system has high protein loading, so the system is expected to be used for protein drug transportation. In the third chapter, three kinds of multiferroic compounds were synthesized. By comparing their photosensitivity and phototoxicity,[Ru (bpy) 2 (6, 6 '-dimetyl-2,2'-biyridine)] Cl2 (Ru-1) compound was used as a photosensitizing agent for the transport of nano-drugs, and the UCNPs were modified by the surface modification of multi-space silicon, PAA and HSA. The effect of different surface modification on the particle stability and the loading efficiency of the multiferrosilicon compound is studied, the obtained HSA-modified UCNPs has excellent stability and loading efficiency, and the nano-particles have good biocompatibility, water dispersibility and stability through the HSA coating, and a nano carrier with double fluorescence is obtained through the HSA surface modification UCNPs, and under the excitation of 980nm light, the core UCNPs (NaYF4: 20 mol% Yb, 0. 5mo1% Tm) can generate blue fluorescence, and the HSA layer generates green fluorescence under the excitation of 450nm light, the dual fluorescence properties enable the nano-carrier to be effectively used for biological imaging and to provide more excitation wavelengths and emission wavelength selection, the cell uptake of the vector can be seen simultaneously by the up-conversion of the fluorescence and the green fluorescence, by loading a photosensitive compound ru-1 into the carrier, The Ru-HSA-UCNPs nanoparticles are formed, and the nano-particles have light-induced cytotoxicity. Under the dark condition, the Ru-HSA-UCNPs only have very low cell growth inhibition effect, but the cytotoxicity of the after-excitation is obviously increased. The reaction of Ru-1 compound and DNA was further analyzed. The results showed that the Ru-1 compound and the DNA had a very low reactivity, but after the photoactivation, the Ru-1 compound was transformed into a compound with a high reactivity, and it was able to react with the DNA, and the reaction rate of the DNA and the DNA was faster than that of the cisplatin. This light-activation characteristic enables the Ru-HSA-UCNPs to be used to control the release of the active anti-tumor group at the site of the tumor. In the fourth chapter, a novel tetravalent platinum compound is synthesized, the axial direction of which is an aspirin molecule, after the compound is taken up by the cells, the cisplatin and the aspirin are released in the cells, and the anti-tumor activity is obviously increased; in ord to be capable of effectively transport aspirin-platinum white compound by using a high-molecular carrier, an aspirin-platinum compound is designed and synthesized at the other end of the aspirin-platinum compound, so that the hydrophobicity of the aspirin-platinum compound is increased, and the high-molecular nano-particle hydrophobic core of the PEG-PLGA can be loaded with high efficiency.
【學(xué)位授予單位】：中國科學(xué)技術(shù)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R730.5
本文編號：2374622
[Abstract]:Every year, there are tens of millions of newly-added cancer patients in the world, and the cancer has seriously threatened the health of human life. In the treatment of drugs, the metal anti-cancer drugs play a very important role, such as cisplatin, carboplatin, oxaliplatin, arsenic trioxide and the like, and are widely used for clinical treatment. Other metal drugs, such as NMI-A, KP1019, and other anti-cancer drugs and gold-based anti-cancer drugs, will enter the clinical evaluation. but the problems of toxic and side effects, drug resistance and short molecular medicine in the in-vivo circulation time and the like in the clinical treatment are greatly limited. The main contents of this thesis are as follows: (1) the tetravalent platinum compound is transported with calcium phosphate nanoparticles and human serum albumin as a carrier, so that the system can respond to the release of the cisplatin medicament in an acid and a reducing environment; (2) the light-sensitive multiferroic compound is transported by the upconversion nanoparticles modified by human serum albumin as a carrier, the system has double fluorescence characteristics, is used for cell imaging, and can release the anti-cancer active drug through illumination control; (3) synthesizing a tetravalent platinum compound with an axial direction of aspirin, capable of reducing the release of cisplatin and aspirin in the cells, remarkably increasing the anti-tumor activity, and connecting the cholesterol molecules at the other end of the tetravalent platinum, so that the hydrophobic property of the aspirin-platinum compound is increased, and the high-molecular nano-particle load can be effectively absorbed. The first chapter is the review of the metal anti-cancer drug and the nano-transportation system, which mainly deals with the development, challenge and the mechanism of anti-cancer action, the development of the nano-transport system of platinum and the anti-cancer drugs and the mechanism of the anti-cancer action. The introduction of human serum albumin and its application in the development of drug transport and the mechanism of anti-cancer in vivo. in that second chap, a tetravalent platinum-HSA/ calcium phosphate drug delivery system is designed, the tetravalent platinum compound is bound to the HSA by a covalent bond, a Pt (IV)-HSA-CaP system is prepared by a co-precipitation method, The nano-transport system capable of responding to the PH and the oxidation-reduction environment, the Pt-HSA/ CaP is stable in the extracellular fluid, and the Pt-HSA drug and the tetravalent platinum compound are released in the presence of an internal reducing agent (AsA) in the cell when the particles are taken up by the cells, reducing the release of the divalent platinum with anticancer activity. from the experimental results, the Pt-HSA can only react with the DNA in the presence of the reducing agent AsA, and the calcium phosphate carrier protects the tetravalent platinum compound from being reduced in advance by the reducing agent in the body fluid, so the system is a transport system capable of effectively controlling the release of the drug, Compared with the cisplatin, the Pt-HSA/ CaP system can effectively inhibit the growth of the cancer cells compared with the cisplatin-HSA/ CaP system, and the system also shows different cell cycle blocks compared with the cisplatin and the Pt-HSA, The Pt (IV) in the Pt-HSA/ CaP has different cell responses in the cells. In the Pt-HSA/ CaP system, the reagents for preparing the materials are biocompatible, and the preparation conditions are mild, the effect of the protein in the calcium phosphate particles is small, and the system has high protein loading, so the system is expected to be used for protein drug transportation. In the third chapter, three kinds of multiferroic compounds were synthesized. By comparing their photosensitivity and phototoxicity,[Ru (bpy) 2 (6, 6 '-dimetyl-2,2'-biyridine)] Cl2 (Ru-1) compound was used as a photosensitizing agent for the transport of nano-drugs, and the UCNPs were modified by the surface modification of multi-space silicon, PAA and HSA. The effect of different surface modification on the particle stability and the loading efficiency of the multiferrosilicon compound is studied, the obtained HSA-modified UCNPs has excellent stability and loading efficiency, and the nano-particles have good biocompatibility, water dispersibility and stability through the HSA coating, and a nano carrier with double fluorescence is obtained through the HSA surface modification UCNPs, and under the excitation of 980nm light, the core UCNPs (NaYF4: 20 mol% Yb, 0. 5mo1% Tm) can generate blue fluorescence, and the HSA layer generates green fluorescence under the excitation of 450nm light, the dual fluorescence properties enable the nano-carrier to be effectively used for biological imaging and to provide more excitation wavelengths and emission wavelength selection, the cell uptake of the vector can be seen simultaneously by the up-conversion of the fluorescence and the green fluorescence, by loading a photosensitive compound ru-1 into the carrier, The Ru-HSA-UCNPs nanoparticles are formed, and the nano-particles have light-induced cytotoxicity. Under the dark condition, the Ru-HSA-UCNPs only have very low cell growth inhibition effect, but the cytotoxicity of the after-excitation is obviously increased. The reaction of Ru-1 compound and DNA was further analyzed. The results showed that the Ru-1 compound and the DNA had a very low reactivity, but after the photoactivation, the Ru-1 compound was transformed into a compound with a high reactivity, and it was able to react with the DNA, and the reaction rate of the DNA and the DNA was faster than that of the cisplatin. This light-activation characteristic enables the Ru-HSA-UCNPs to be used to control the release of the active anti-tumor group at the site of the tumor. In the fourth chapter, a novel tetravalent platinum compound is synthesized, the axial direction of which is an aspirin molecule, after the compound is taken up by the cells, the cisplatin and the aspirin are released in the cells, and the anti-tumor activity is obviously increased; in ord to be capable of effectively transport aspirin-platinum white compound by using a high-molecular carrier, an aspirin-platinum compound is designed and synthesized at the other end of the aspirin-platinum compound, so that the hydrophobicity of the aspirin-platinum compound is increased, and the high-molecular nano-particle hydrophobic core of the PEG-PLGA can be loaded with high efficiency.
【學(xué)位授予單位】：中國科學(xué)技術(shù)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R730.5
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