本文選題：介孔硅納米粒子 + 層層自組裝��； 參考：《東華大學(xué)》2015年博士論文

【摘要】：納米科技的飛速發(fā)展極大推動(dòng)納米材料在生物醫(yī)學(xué)中的應(yīng)用。探尋高效、快捷的技術(shù)對(duì)納米材料進(jìn)行表面功能化修飾是推進(jìn)納米科技在生物醫(yī)學(xué)等領(lǐng)域發(fā)揮應(yīng)用的關(guān)鍵。在納米醫(yī)學(xué)領(lǐng)域中,開發(fā)出高效、穩(wěn)定和安全的功能化納米材料對(duì)癌癥的治療具有重要意義。針對(duì)癌癥的治療,構(gòu)建具有“智能”響應(yīng)性的藥物控釋體系和先進(jìn)功能性的納米材料,不僅能為抗癌藥物運(yùn)輸系統(tǒng)的改善提供新的思路,而且為癌癥治療檢測(cè)新模式的開展提供參考依據(jù)。為增強(qiáng)介孔硅納米粒子(MSNs)、金納米棒(Au NRs)以及二硫化鉬(MoS2)等熱點(diǎn)材料的生物安全性、提高載體藥物控釋的精度、提升材料的生物利用度、豐富材料的修飾手段并加強(qiáng)對(duì)癌細(xì)胞的殺傷效果,本博士論文以形態(tài)粒徑可控?zé)o機(jī)納米粒子的制備為起點(diǎn),有機(jī)/無(wú)機(jī)功能化的設(shè)計(jì)為主線,良好的生物相容性為基準(zhǔn),高效抗癌納米器件的構(gòu)建為目標(biāo),開展一系列的研究工作。概括地講,研究工作分為兩個(gè)部分:第一部分以MSNs作為基底材料,著眼于p H響應(yīng)性控釋載體的設(shè)計(jì)和制備;第二部分以熱點(diǎn)材料Mo S2和Au NRs為主體材料,分別構(gòu)建出新型的光熱劑和多功能納米診療劑。詳述如下:(1)基于“ph響應(yīng)性控釋載體”的設(shè)計(jì)理念,以msns為基底,選用合成高分子聚電解質(zhì)聚烯丙基胺鹽酸鹽(pah)和聚苯乙烯磺酸鈉(pss),采用層層(lbl)自組裝方法對(duì)msns進(jìn)行表面功能化修飾,并將阿霉素鹽酸鹽(dox)選作模型藥物分子,制備出ph響應(yīng)性藥物控釋體系。該工作首次考察自組裝層數(shù)對(duì)藥物緩釋、細(xì)胞毒性和血液相容性的影響,并對(duì)載體的控釋性能和生物安全性進(jìn)行系統(tǒng)研究。聚電解質(zhì)層(pah/pss)n的厚度與自組裝層數(shù)2n呈指數(shù)關(guān)系。(pah/pss)n-msns具有良好的細(xì)胞相容性,不會(huì)引起溶血、血小板聚集,也不會(huì)激活凝血通路。ph值調(diào)控dox釋放,藥物釋放速率隨ph的降低而增加。癌細(xì)胞對(duì)dox@(pah/pss)4-msns的攝取能力明顯強(qiáng)于正常細(xì)胞,該載藥體系能有效抑制癌細(xì)胞生長(zhǎng)。dox@(pah/pss)4-msns可以實(shí)現(xiàn)dox緩慢持續(xù)釋放,從而延長(zhǎng)dox在癌細(xì)胞的細(xì)胞核中的富集時(shí)間。動(dòng)物體內(nèi)分布實(shí)驗(yàn)表明,與純dox相比,dox@(pah/pss)4-msns不僅可以維持穩(wěn)定生物體的血藥濃度,還可以減少藥物在主要器官,特別是心臟部位的富集。(2)病理切片組織學(xué)檢測(cè)中,雖然dox@(pah/pss)4-msns未引起明顯的組織學(xué)損傷,但在脾臟和肺部中有出血或充血現(xiàn)象,分析可能原因是粒子在器官中發(fā)生聚集而引起的。粒子團(tuán)聚勢(shì)必會(huì)影響長(zhǎng)期的生物安全性。在臨床藥物輸送的應(yīng)用中,載體材料需盡可能具備優(yōu)異的生物相容性和生物可降解性,從而最大限度減小載體的有害副作用�？紤]到除合成高分子聚電解質(zhì)之外,天然聚電解質(zhì)具有生物相容性好、來(lái)源豐富、降解產(chǎn)物對(duì)生物體無(wú)毒害以及能賦予載體新的功能基團(tuán)等優(yōu)點(diǎn)。我們繼續(xù)沿用lbl自組裝技術(shù),msns作為基底,以天然大分子聚電解質(zhì)殼聚糖(chi)和藻酸鈉(alg)作為調(diào)控“開關(guān)”,構(gòu)筑一套具有良好分散性、穩(wěn)定性的ph響應(yīng)性納米控釋體系。通過(guò)改進(jìn)msns的制備工藝,并將組裝層數(shù)控制在4層,成功地制備出具有“核殼”結(jié)構(gòu)的(alg/chi)2-msns。該體系中粒子的平均粒徑為167nm,具有良好的分散性和穩(wěn)定性。ph調(diào)控dox釋放,在低ph值體系中的藥物釋放速率要明顯快于高ph值體系。體外細(xì)胞吞噬實(shí)驗(yàn)的結(jié)果表明,dox@(alg/chi)2-msns可以在癌細(xì)胞內(nèi)持續(xù)釋放dox,延長(zhǎng)dox在細(xì)胞核富集時(shí)間,保持長(zhǎng)期有效的治療。藥代動(dòng)力學(xué)實(shí)驗(yàn)表明,與純dox相比,dox@(alg/chi)2-msns在小鼠體內(nèi)血液清除速率慢并且血液循環(huán)周期長(zhǎng),將dox的半衰期由64.8h延長(zhǎng)至262.5h。該工作的意義不僅證明載藥體系具有良好生物相容性的同時(shí),進(jìn)一步提升癌細(xì)胞對(duì)載藥體系的攝取效率,而且載藥體系中氨基和羧基等基團(tuán)的引入,能為構(gòu)筑多功能以及多重響應(yīng)性載體(如靶向性或熱敏性)的設(shè)計(jì)奠定基礎(chǔ)。(3)基于“高效光熱劑”的設(shè)計(jì)理念,針對(duì)目前光熱劑mos2二維單層納米片制備過(guò)程繁瑣、片層厚度和尺寸難于控制等弊端,采用水熱法,結(jié)合巰基化學(xué),首次制備出形狀和粒徑可控,并具有膠體穩(wěn)定性、良好生物相容性以及較高光熱轉(zhuǎn)換效率的新型光熱劑——mos2-peg納米花。mos2-peg納米花能有效地將nir808nm的光能轉(zhuǎn)換成熱能,光熱轉(zhuǎn)換效率約為27.6%。該光熱劑具有較強(qiáng)的光熱殺傷效果,對(duì)癌細(xì)胞的細(xì)胞膜、溶酶體以及細(xì)胞骨架造成不可逆的殺傷,具備用于腫瘤的光熱治療的潛力。(4)基于“多功能高效光熱劑”的設(shè)計(jì)理念,采用種子生長(zhǎng)法制備金納米棒(Au NRs),通過(guò)氧化聚合法成功地在Au NRs表面均勻包覆聚吡咯(PPY)層,不需要外加鐵(Fe)源,原位對(duì)PPY外表面進(jìn)行超順磁氧化鐵(Fe3O4)修飾,首次制備出多功能診療劑Au/PPY@Fe3O4復(fù)合納米粒。Au/PPY@Fe3O4復(fù)合納米粒子不僅展現(xiàn)出較強(qiáng)的磁性和較高的NIR吸收特性,而且能用于磁共振(MR)和X射線計(jì)算機(jī)斷層掃描(CT)成像。Au/PPY@Fe3O4復(fù)合納米粒子能有效地將NIR 808 nm的光能轉(zhuǎn)換熱能,光熱轉(zhuǎn)換效率約為23.9%。功率密度為2 W/cm2的NIR 808 nm激光照射10 min后,濃度為1.4mg/mL的Au/PPY@Fe3O4分散液溫度升高35℃。體外細(xì)胞實(shí)驗(yàn)表明Au/PPY@Fe3O4復(fù)合納米粒子具有良好生物相容性的同時(shí),可以對(duì)癌細(xì)胞進(jìn)行有效的光熱殺傷。該工作為實(shí)現(xiàn)MR/CT成像監(jiān)控的光熱治療提供可能性。綜上,本論文分別對(duì)MSNs藥物控釋載體和功能性納米光熱劑在藥物pH響應(yīng)釋放和癌癥的光熱治療方面的應(yīng)用展開了研究。期望以上研究工作能有力推進(jìn)基于MSNs、Au NRs和MoS2等納米材料在納米醫(yī)學(xué)上的應(yīng)用,同時(shí)為癌癥的治療提供新的動(dòng)力。
[Abstract]:The rapid development of nanotechnology has greatly promoted the application of nanomaterials in biomedicine. To explore the surface functional modification of nanomaterials by efficient and fast technology is the key to promote the application of nanotechnology in biomedicine and other fields. In the field of nanomedicine, the development of functional nanomaterials with high efficiency, stability and safety The treatment of cancer is of great significance. For the treatment of cancer, the construction of a "intelligent" responsive drug release system and advanced functional nanomaterials can not only provide a new way of thinking for the improvement of the anti-cancer drug transport system, but also provide a reference for the development of a new mode of cancer treatment and detection. The biosafety of MSNs, Au NRs, and molybdenum disulfide (MoS2), improves the precision of the drug controlled release of the carrier, improves the bioavailability of the material, enriches the modification methods of the material and strengthens the killing effect on the cancer cells. The design of inorganic functionalization as the main line, good biocompatibility as the benchmark, the construction of high efficient anti-cancer nanodevices as the target and a series of research work. In general, the research work is divided into two parts: the first part is based on MSNs as the base material, and focuses on the design and preparation of the P H responsive controlled-release carrier; the second part is a hot spot. Materials Mo S2 and Au NRs are the main materials, and the new photothermal and multifunctional nano diagnosis and treatment agents are constructed respectively. The following are as follows: (1) based on the design concept of "pH responsive controlled-release carrier", using MSNs as the base, synthetic polymer polyelectrolytes polyallyl amine hydrochloride (PAH) and polystyrene sulfonate (PSS) are selected, and layer (LBL) self-assembly is adopted. Methods the surface functional modification of MSNs was performed, and adriamycin hydrochloride (DOX) was selected as a model drug molecule, and the pH responsive drug controlled release system was prepared. This work was the first time to investigate the effects of the number of self assembly layers on drug release, cytotoxicity and blood compatibility, and systematically study the controlled release performance and biological safety of the carrier. The thickness of pah/pss n is exponentially related to the number of self assembled layers 2n. (pah/pss) n-msns has good cytocompatibility, does not cause hemolysis, platelet aggregation, nor activates the.Ph value of the coagulation pathway to regulate the release of DOX, and the rate of drug release increases with the decrease of pH. The ability of cancerous cell to dox@ (pah/pss) 4-msns is obviously stronger than that of normal. Cells, the drug delivery system can effectively inhibit the growth of cancer cells.Dox@ (pah/pss) 4-msns to achieve slow and sustained release of DOX, thus prolonging the accumulation time of DOX in the cell nucleus of cancer cells. In vivo distribution experiments in animals showed that dox@ (pah/pss) 4-msns, compared with pure DOX, could not only maintain the blood concentration of stable organisms, but also reduce drugs. The enrichment of the main organs, especially the site of the heart. (2) in histological examination, although dox@ (pah/pss) 4-msns does not cause obvious histological damage, there is bleeding or congestion in the spleen and lungs. The analysis may be caused by the aggregation of particles in the organs. In the application of clinical drug delivery, the carrier materials need to have excellent biocompatibility and biodegradability as far as possible, so as to minimize the harmful side effects of the carrier. We continue to use the LbL self-assembly technology, MSNs as the substrate, and use the natural macromolecule polyelectrolyte chitosan (chi) and sodium alginate (ALG) as the regulation "switch" to construct a set of pH responsive nano controlled release system with good dispersibility and stability. By improving the preparation of MSNs Art, and control the number of assembly layers on the 4 layer, successfully prepared (alg/chi) 2-msns. with a "nuclear shell" structure, the average particle size of the particle is 167nm, with good dispersion and stability,.Ph regulates DOX release. The release rate of the drug in the low pH value system is faster than the high pH value system. The results of the cell phagocytosis experiment in vitro The results showed that dox@ (alg/chi) 2-msns could release DOX continuously in the cancer cells, prolong the accumulation time of DOX in the nucleus and maintain long-term effective treatment. Pharmacokinetics experiments show that the blood clearance rate of dox@ (alg/chi) 2-msns in mice is slow and the blood circulation cycle is longer in mice compared with pure dox, and the half-life of DOX is extended from 64.8h to 262.5h.. The significance of the work is not only to prove that the drug system has good biocompatibility, but also to further enhance the uptake efficiency of cancer cells to the drug delivery system, and the introduction of amino and carboxyl groups in the drug carrying system can provide a basis for the design of multifunction and multiple responsiveness carriers (such as targeting or thermal sensitivities). (3) The design idea of the effective photothermal agent, in view of the tedious process of the preparation of the two dimensional single layer nanoscale of the current photothermal agent MoS2, the thickness and size of the lamellar layer is difficult to control. By using the hydrothermal method and the sulfhydryl chemistry, a new type of light with a controllable shape and particle size and a colloid stability, good biocompatibility and high photothermal conversion efficiency is made for the first time. Heat agent - mos2-peg nanoscale.Mos2-peg nanoscale can effectively convert the light energy of nir808nm into heat energy. The efficiency of photothermal conversion is about 27.6%., which has a strong photothermal killing effect, an irreversible killing on the cell membrane, lysosome and cytoskeleton of cancer cells, and has the potential of photothermal treatment for cancer. (4) In the design concept of "multi-function and high efficiency photothermal agent", gold nanorods (Au NRs) were prepared by seed growth method, and the polypyrrole (PPY) layer was successfully coated on the surface of Au NRs by oxidation polymerization. The superparamagnetic iron oxide (Fe3O4) modification was performed on the external surface of PPY without additional iron (Fe) source, and the multifunction diagnosis agent Au/PPY@Fe was prepared for the first time. 3O4 composite nanoparticles.Au/PPY@Fe3O4 composite nanoparticles not only exhibit strong magnetic properties and higher NIR absorption properties, but also can be used for magnetic resonance (MR) and X ray computed tomography (CT) imaging.Au/PPY@Fe3O4 composite nanoparticles can effectively transfer the energy of NIR 808 nm to heat energy, and the photothermal conversion efficiency is about 23.9%. power density. After 2 W/cm2 NIR 808 nm laser irradiated for 10 min, the temperature of Au/PPY@Fe3O4 dispersing solution with a concentration of 1.4mg/mL increased 35 C. In vitro cell experiment showed that the Au/PPY@Fe3O4 composite nanoparticles had good biocompatibility and effective photothermal killing on cancer cells. This work provided the photothermal treatment for the realization of MR/CT imaging monitoring. To sum up, we have studied the application of MSNs drug controlled-release carrier and functional nano photothermal agent in the response release of drug pH and the photothermal treatment of cancer. The above research work is expected to promote the application of nanomaterials based on MSNs, Au NRs and MoS2 and to provide new treatment for cancer. Power.
【學(xué)位授予單位】：東華大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：TB383.1;TQ460.1
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本文編號(hào)：1997191