【摘要】：癌癥是威脅人類(lèi)健康和生存的重大疾病，長(zhǎng)期以來(lái)，廣大科研人員不斷探索和開(kāi)發(fā)各種各樣的治療方法，藥物載體是其中重要的一方面，因?yàn)樗梢杂行У胤乐顾幬锝到猓瑢⑺幬镙斔偷讲∽儏^(qū)域，降低毒副作用，提高治療效果。然而，隨著時(shí)代的發(fā)展，傳統(tǒng)藥物載體逐漸暴露出了一些缺點(diǎn)，如穩(wěn)定性差、生物相容性差、載藥量低、腫瘤靶向富集少、體內(nèi)循環(huán)時(shí)間短等，這些問(wèn)題極大地降低了藥物的生物利用度，增加了患者的痛苦，因此，迫切需要發(fā)展新型藥物載體。當(dāng)前，藥物載體正向著可控化、智能化、綠色化和診療一體化的方向發(fā)展，不斷涌現(xiàn)出了各種具有良好發(fā)展前景的新型載體。有機(jī)-無(wú)機(jī)復(fù)合載體材料就是其中的一種，它綜合了有機(jī)物和無(wú)機(jī)物的特性，具備獨(dú)特的優(yōu)勢(shì)。本文以有機(jī)無(wú)機(jī)復(fù)合材料的一種——硅質(zhì)體作為研究對(duì)象，從有機(jī)-無(wú)機(jī)復(fù)合脂質(zhì)分子設(shè)計(jì)的角度出發(fā)，在藥物載體的結(jié)構(gòu)控制釋放、光控釋放、光動(dòng)力治療，以及光動(dòng)力治療結(jié)合磁共振成像等方面開(kāi)展了系統(tǒng)的研究。 研究了有機(jī)無(wú)機(jī)復(fù)合脂質(zhì)結(jié)構(gòu)對(duì)硅質(zhì)體藥物釋放性能的影響。通過(guò)調(diào)節(jié)脂質(zhì)分子親疏水基團(tuán)的比例，合成了4種不同結(jié)構(gòu)的復(fù)合脂質(zhì)分子，利用溶膠凝膠和自組裝技術(shù)獲得了四種具有不同表層硅酸鹽網(wǎng)絡(luò)致密度的新型硅質(zhì)體，并以親水藥物阿霉素和疏水藥物紫杉醇為代表，成功制備了4種阿霉素硅質(zhì)體和4種紫杉醇硅質(zhì)體。通過(guò)體外藥物釋放行為和細(xì)胞毒性的對(duì)比分析，闡明了載體對(duì)藥物的釋放性能與相應(yīng)復(fù)合脂質(zhì)的結(jié)構(gòu)密切相關(guān)。實(shí)驗(yàn)結(jié)果表明，各載體對(duì)藥物均具有良好的緩釋作用，當(dāng)疏水基團(tuán)相同時(shí)，親水硅烷數(shù)量越多，藥物的釋放速率越慢；當(dāng)親水硅烷相同時(shí)，疏水基團(tuán)越多，對(duì)親水藥物的釋放越快，而對(duì)疏水藥物的釋放則越慢。細(xì)胞實(shí)驗(yàn)結(jié)果表明，各載藥硅質(zhì)體對(duì)細(xì)胞的抑制作用與其藥物釋放行為一致，即載體對(duì)藥物的釋放越快，則相同藥物濃度和相同孵育時(shí)間下對(duì)細(xì)胞的抑制作用也越明顯，充分體現(xiàn)了分子結(jié)構(gòu)的設(shè)計(jì)對(duì)脂質(zhì)雙層滲透性的有效調(diào)控。 開(kāi)展了高度穩(wěn)定靈敏的光響應(yīng)控制釋藥載體材料的研究。通過(guò)有機(jī)合成的方法將光敏感基團(tuán)偶氮苯與復(fù)合脂質(zhì)相結(jié)合，獲得了一種新型的光響應(yīng)有機(jī)無(wú)機(jī)復(fù)合脂質(zhì)分子，進(jìn)而制備了脂質(zhì)雙層富含偶氮苯基團(tuán)的光響應(yīng)囊泡載體。通過(guò)紫外可見(jiàn)吸收光譜研究了囊泡中偶氮苯基團(tuán)光致異構(gòu)的情況，闡明了光致異構(gòu)的影響因素。實(shí)驗(yàn)結(jié)果表明，脂質(zhì)雙層中偶氮苯基團(tuán)與脂質(zhì)雙鏈主要以交替排列的方式分布，在紫外光和可見(jiàn)光輪流照射下，雙層中的偶氮苯能順利地實(shí)現(xiàn)可逆的構(gòu)型異構(gòu)，且其反-順異構(gòu)化比例可達(dá)到33.4%。以染料尼羅紅作為模型藥物，研究了光響應(yīng)載體的光控釋藥性能。研究發(fā)現(xiàn)，在紫外光照下，載體在20min內(nèi)即可釋放48.2%的尼羅紅，表現(xiàn)出靈敏的光響應(yīng)控制釋藥能力。 研制了具有光動(dòng)力治療和熒光診斷功能的硅質(zhì)體。將卟啉基團(tuán)引入復(fù)合脂質(zhì)分子中，合成了含有雙鏈、硅烷頭部、卟啉基團(tuán)的新型復(fù)合脂質(zhì)，制備了相應(yīng)的卟啉硅質(zhì)體光動(dòng)力載體材料，其光敏劑載藥量可高達(dá)33.4%。通過(guò)包載親水性染料鈣黃綠素研究了卟啉硅質(zhì)體的囊泡結(jié)構(gòu)；通過(guò)大量的實(shí)驗(yàn)和討論分析，研究了載體雙層中卟啉基團(tuán)的聚集和排列方式、化學(xué)共價(jià)鍵連卟啉基團(tuán)的重要作用、單線態(tài)氧產(chǎn)生的情況并解釋了其產(chǎn)生機(jī)理，探討載體被細(xì)胞攝取的方式，并通過(guò)細(xì)胞形態(tài)變化和MTT方法研究了光動(dòng)力治療效果，在此基礎(chǔ)上進(jìn)行了初步的動(dòng)物實(shí)驗(yàn)，考察載體在大鼠血液中的循環(huán)動(dòng)力學(xué)。實(shí)驗(yàn)結(jié)果表明，卟啉硅質(zhì)體脂質(zhì)雙層中卟啉基團(tuán)基本不存在聚集情況，其與雙鏈之間主要以交替方式有序排列，在紫外光照射下，載體呈現(xiàn)出明顯的紅色熒光。在重水和細(xì)胞中卟啉硅質(zhì)體均能顯著地產(chǎn)生單線態(tài)氧，且產(chǎn)生效率與濃度和時(shí)間成正比。激光共聚焦顯微鏡圖片清楚地顯示載體以?xún)?nèi)吞方式被腫瘤細(xì)胞攝取，且主要聚集于溶酶體中。載體對(duì)細(xì)胞表現(xiàn)出很低的暗毒性和顯著高的光毒性，且在血液中具有長(zhǎng)循環(huán)的特點(diǎn)，體現(xiàn)了其作為藥物載體的顯著優(yōu)勢(shì)。 構(gòu)建了同時(shí)具有磁共振成像與光動(dòng)力治療功能的診療一體化納米粒子。在前一章合成的基礎(chǔ)上，，將卟啉與金屬錳卟啉衍生物相結(jié)合，制備了一種內(nèi)有雙層卟啉基團(tuán)外有金屬錳卟啉的新型納米粒子，其中脂質(zhì)雙層中的卟啉用于光動(dòng)力治療，外層的錳卟啉用于磁共振成像。研究了該類(lèi)粒子的制備方法、光譜性質(zhì)、單線態(tài)氧產(chǎn)生效率、細(xì)胞攝取實(shí)驗(yàn)，并在此基礎(chǔ)上進(jìn)行體外磁共振成像效果和光動(dòng)力治療效果的檢測(cè)。實(shí)驗(yàn)結(jié)果表明，所制備的納米粒子在透射電鏡下呈現(xiàn)明顯的核殼結(jié)構(gòu)，通過(guò)調(diào)節(jié)5種不同比例的外層錳卟啉，可制備出光動(dòng)力治療和磁共振成像效果可調(diào)節(jié)的納米粒子，隨著鍵連錳卟啉比例的增加，粒子對(duì)水質(zhì)子的縱向馳豫效率加速也越明顯，達(dá)到40.1%以上時(shí)，成像效果達(dá)到最佳。細(xì)胞實(shí)驗(yàn)證實(shí)了該納米粒子能被腫瘤細(xì)胞有效攝取，且對(duì)細(xì)胞具有低暗毒性和高光毒性，最終能同時(shí)滿(mǎn)足成像和光動(dòng)力治療的納米粒子上鍵連錳卟啉的最佳比例是40.1%。
[Abstract]:Cancer is a major disease that threatens the health and survival of human beings. For a long time, the vast majority of researchers have been exploring and developing a variety of treatment methods. Drug carriers are one of the important aspects of it, because it can effectively prevent drug degradation, transport drugs to the lesion area, reduce toxic and side effects and improve the therapeutic effect. However, along with it, it can improve the therapeutic effect. With the development of the times, traditional drug carriers have gradually exposed some shortcomings, such as poor stability, poor biocompatibility, low drug loading, low tumor targeting and short circulation time in the body. These problems greatly reduce the bioavailability of drugs and increase the pain of the patients. Therefore, the development of new drug carriers is urgently needed. Current, drugs The carrier is developing in the direction of controllability, intelligence, green and diagnosis and treatment. A variety of new carriers with good prospects are emerging. Organic inorganic composite carrier is one of them, which combines the characteristics of organic and inorganic materials and has unique advantages. This paper is an organic and inorganic composite material. From the perspective of organic-inorganic compound lipid molecules, the systematic research on the structure control release, light control release, photodynamic therapy, photodynamic therapy combined with magnetic resonance imaging is carried out from the perspective of organic-inorganic compound lipid molecules.
The effect of organic-inorganic compound lipid structure on the drug release performance of siliceous body was studied. By adjusting the proportion of hydrophobic groups of lipid molecules, 4 kinds of composite lipid molecules with different structures were synthesized. By using sol-gel and self-assembly technology, four new types of silicosomes with different surface silicates density were obtained, and the hydrophilic group was hydrophilic. 4 kinds of doxorubicin and 4 taxol silicones were successfully prepared with drug doxorubicin and taxol, a hydrophobic drug paclitaxel. The release performance of the drug and the structure of the corresponding compound lipid were closely related to the drug release behavior and cytotoxicity in vitro. When the hydrophobic group is the same, the more the hydrosilane number is, the more the drug release rate is, the more the hydrophile silane phase, the more hydrophobic groups, the faster the release of hydrophilic drugs, and the slower the release of hydrophobic drugs. The faster the release of the drug, the more obvious the inhibitory effect of the same drug concentration and the same incubation time on the cells, which fully reflects the effective regulation of the molecular structure design on the lipid bilayer permeability.
A highly stable and sensitive light response controlled release carrier material was studied. A novel light responsive organic inorganic compound lipid molecule was obtained by combining the light sensitive group azobenzene with the compound lipid by organic synthesis, and the light response vesicle carrier rich in the azobenzene group in the lipid bilayer was prepared. The photoisomerization of azobenzene group in the vesicles was studied by the external visible absorption spectrum, and the influence factors of photoisomerism were clarified. The experimental results showed that the azobenzene group and the double chain of lipid in the lipid bilayer were mainly distributed in an alternately arranged way. The azobenzene in the double layer could be reversible in the ultraviolet and visible light wheel flow. The structure isomerism, and its inverse isomerization ratio can reach 33.4%. with dye Nile red as a model drug. The photocontrolled release performance of light response carrier is studied. It is found that under ultraviolet light, the carrier can release 48.2% Nile red in 20min, showing the sensitive light response to control the drug release ability.
A siliceous body with the function of photodynamic therapy and fluorescence diagnosis was developed. The porphyrin group was introduced into the compound lipid molecule, and a new compound lipid containing double chain, silane head and porphyrin group was synthesized. The corresponding porphyrin siliceous photodynamic carrier material was prepared. The dosage of the photosensitizer could be as high as 33.4%. by carrying the hydrophilic dye calcium. The vesicle structure of porphyrin siliceous body was studied by yellowish green. Through a large number of experiments and discussions, the aggregation and arrangement of porphyrin groups in the carrier double layer, the important role of the chemical covalent bond group, the production of single wire oxygen and the mechanism of its production were explained. Morphological changes and MTT methods were used to study the effect of photodynamic therapy. On this basis, a preliminary animal experiment was carried out to investigate the circulation kinetics of the carrier in the rat blood. The experimental results showed that the porphyrin group in the porphyrin siliceous lipid bilayer had no aggregation, which was arranged alternately and orderly between the double strands. Under ultraviolet light, the carrier shows a clear red fluorescence. In heavy water and cells, the porphyrin silicates can produce a single state of state oxygen significantly, and the production efficiency is proportional to the concentration and time. The laser confocal microscope picture clearly shows that the carrier is absorbed by the tumor cells and mainly in the lysosome. Cells exhibit low dark toxicity and significant high phototoxicity, and have a long circulation in the blood, reflecting its significant advantages as a drug carrier.
An integrated nanoparticle with magnetic resonance imaging and photodynamic therapy was constructed. On the basis of the previous chapter, porphyrin and manganese porphyrin derivative were combined to prepare a new type of nanoparticle with metal manganese porphyrin with bilayer porphyrin group. The porphyrin in the lipid bilayer was used for photodynamic treatment. Treatment, manganese porphyrin on the outer layer used in magnetic resonance imaging. The preparation methods of such particles, spectral properties, single state oxygen production efficiency, cell uptake experiments, and the detection of the magnetic resonance imaging effect and photodynamic treatment effect in vitro were carried out on this basis. The experimental results showed that the prepared nanoparticles were obvious under transmission electron microscope. The nuclear shell structure can be prepared by adjusting 5 different proportions of the outer manganese porphyrin, which can prepare the nanoparticles with the effect of photodynamic therapy and magnetic resonance imaging. With the increase of the ratio of manganese porphyrins, the acceleration of the longitudinal relaxation efficiency of the particles to the water protons is also more obvious. The imaging results are best at the time of 40.1%. Cell experiments confirmed that The nanoparticles can be effectively absorbed by the tumor cells and have low dark toxicity and high phototoxicity to the cells. The optimal ratio of the nanoparticles to manganese porphyrin at the same time can meet the imaging and photodynamic therapy is 40.1%.
【學(xué)位授予單位】：哈爾濱工業(yè)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2012
【分類(lèi)號(hào)】：R318.08

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