本文關(guān)鍵詞：介孔二氧化硅納米材料的制備及在藥物遞送方面的應(yīng)用研究　出處：《湖北中醫(yī)藥大學(xué)》2017年博士論文　論文類(lèi)型：學(xué)位論文

  更多相關(guān)文章： 介孔二氧化硅納米粒 緩釋 遞藥系統(tǒng) 靶向 腫瘤

【摘要】：由于納米材料的獨(dú)特性質(zhì),使其在醫(yī)藥領(lǐng)域尤其是癌癥的治療中起著很重要的作用。介孔二氧化硅納米粒(Mesoporous silica nanoparticles,MSN)是1992年由Stober發(fā)現(xiàn)的無(wú)機(jī)納米材料,是最有前途的藥物載體之一。介孔二氧化硅納米粒的種類(lèi)繁多,可以通過(guò)控制條件制備出不同的型號(hào),如MCM-41、MCM-48、SBA-15等。本課題擬以?xún)煞N不同種類(lèi)的介孔二氧化硅為載體SBA-15和MCM-41,分別裝載3種不同性質(zhì)的藥物,通過(guò)不同的給藥途徑來(lái)研究其在遞藥方面的應(yīng)用。具體研究?jī)?nèi)容如下:(1)通過(guò)水熱合成法制備SBA-15介孔二氧化硅納米粒,建立艾塞那肽體外分析方法,以SBA-15介孔二氧化硅納米粒為載體材料,采用浸漬吸附法制備EXT-SBA-15,并考察其體外釋藥特征;以EXT-Sol為對(duì)照組,研究EXT-SBA-15經(jīng)皮下注射給藥后在大鼠體內(nèi)的藥動(dòng)學(xué)過(guò)程,Exendin-4 ELISA試劑盒測(cè)定不同時(shí)間點(diǎn)大鼠體內(nèi)EXT的含量,計(jì)算藥動(dòng)學(xué)參數(shù),以考察EXT-SBA-15的體內(nèi)釋藥情況;采用糖尿病小鼠為模型動(dòng)物,設(shè)置空白對(duì)照組、模型對(duì)照組、EXT-Sol組、EXT-SBA-15組以及空白SBA-15組,初步考察糖尿病小鼠皮下注射EXT-SBA-15后的降血糖效果。結(jié)果表明,成功制備了EXT-SBA-15納米粒,制備工藝簡(jiǎn)單,載藥量高,體內(nèi)外研究表明EXT-SBA-15能延長(zhǎng)藥物在體內(nèi)滯留時(shí)間,具有明顯緩釋特征和降血糖作用。本研究為SBA-15等介孔硅材料的應(yīng)用和多肽類(lèi)藥物緩釋制劑的研究開(kāi)發(fā)提供了實(shí)驗(yàn)依據(jù)和理論參考。(2)采用共沉淀法制備氨基改性介孔二氧化硅納米粒,靜電吸附載入ATO,PAA酸堿共軛制備PAA-ATO-MSN。采用透射電鏡、掃描電鏡觀察納米粒的形態(tài)結(jié)構(gòu),小角X射線衍射儀考察其介孔結(jié)構(gòu),氮?dú)馕摳絻x測(cè)定其比表面積、孔徑、孔容,紅外光譜儀考察氨基和PAA修飾情況,熱重分析儀測(cè)定PAA接枝率,激光粒度Zeta電位儀測(cè)定粒徑和Zeta電位;高速離心法結(jié)合電感耦合等離子發(fā)射光譜(Inductively coupledplasmaemissionspectrum,icp)測(cè)定其包封率及載藥量;選用不同ph的磷酸鹽緩沖液(phosphatebufferedsaline,pbs)(ph5.0,6.0和7.4)作為釋放介質(zhì),透析袋法考察其在不同ph條件下體外釋藥特性;以smmc-7721細(xì)胞為體外模型,考察空白載體msn、nh2-msn和paa-msn毒性和ato溶液(atosolution,ato-sol),三氧化二砷氨基改性介孔二氧化硅納米粒(arsenictrioxideloadedmesoporoussilicananoparticles,ato-msn)和聚丙烯酸修飾氨基改性介孔二氧化硅納米粒(polyacrylicacidgraftedarsenictrioxideamino-functionedmesoporoussilicananoparticles,paa-ato-msn)的體外腫瘤細(xì)胞抑制率及周期阻滯情況;以ato-sol、ato-msn為對(duì)照組,大鼠尾靜脈注射(intravenousinjection,iv)給藥后,股動(dòng)脈、頸靜脈插管技術(shù)采集血樣,采用電感耦合等離子質(zhì)譜(inductivelycoupledplasmamassspectrometry,icp-ms)測(cè)定血藥濃度計(jì)算藥動(dòng)學(xué)相關(guān)參數(shù),考察其體內(nèi)藥動(dòng)學(xué)行為。以昆明(km)小鼠異位移植肝癌(h22)為藥效模型,設(shè)置空白對(duì)照組、ato-sol組、ato-msn組和paa-ato-msn組考察各制劑抗腫瘤效果。結(jié)果表明成功制備了載三氧化二砷ph響應(yīng)介孔二氧化硅納米粒(paa-ato-msn),其粒徑較小、具有較高的包封率和載藥量,體外釋藥具有明顯的ph響應(yīng)性及緩釋特性,且paa-msn能明顯改善ato在大鼠體內(nèi)的藥動(dòng)學(xué)行為,paa-ato-msn體內(nèi)外抗腫瘤效果均明顯優(yōu)于ato,該載體具有較好的應(yīng)用前景。(3)采用改良的經(jīng)典stober法制備介孔二氧化硅納米粒(msn),通過(guò)熱重分析法、氮?dú)饷撐椒ārd衍射等技術(shù)進(jìn)行表征分析;發(fā)明反復(fù)飽和溶液吸附法制備載入ptx的msn(msn-ptx),然后以msn-ptx為核,采用自組裝和薄膜水化法構(gòu)建核/殼結(jié)構(gòu)的angiopep-2修飾介孔二氧化硅脂質(zhì)囊納米粒(ang-msn-lp-ptx);透析袋法考察體外釋藥特性;mtt法考察空白載體對(duì)hbmec和c6的細(xì)胞毒性,以及載藥納米粒對(duì)c6細(xì)胞的抗腫瘤作用;建立體外bbb模型研究載體對(duì)ptx的跨膜轉(zhuǎn)運(yùn)能力和對(duì)c6細(xì)胞周期的影響。建立荷腦膠質(zhì)瘤大鼠模型,對(duì)腫瘤組織進(jìn)行病理切片觀察腦膠質(zhì)瘤的侵襲情況,考察載藥納米粒對(duì)荷腦膠質(zhì)瘤大鼠治療作用;采用血-腦同步微透析技術(shù),考察載藥納米粒在血液和腦組織中的藥動(dòng)學(xué)特性。結(jié)果表明制備的MSN輪廓圓整光滑,粒徑分布均勻,比表面積大,孔徑均一,性質(zhì)穩(wěn)定;反復(fù)飽和溶液吸附法可有效提高藥物載藥量,解決納米載體載藥量低的問(wèn)題,值得應(yīng)用和借鑒;所構(gòu)建的ANG-MSN-LP載體系統(tǒng),融合了介孔材料和脂質(zhì)材料的優(yōu)點(diǎn),同時(shí)解決二氧化硅易團(tuán)聚、易突釋的問(wèn)題和脂質(zhì)體載藥低、易漏藥的問(wèn)題,是一種安全、可靠、有良好生物相容性的納米粒,經(jīng)Angiopep-2修飾后的二氧化硅脂質(zhì)囊納米�？梢杂行У耐高^(guò)血腦屏障,實(shí)現(xiàn)腦靶向遞藥,其作為一種優(yōu)良的遞藥載體并有望應(yīng)用于腦膠質(zhì)瘤的治療;本論文改進(jìn)的體外BBB模型,將HBMEC和C6腦膠質(zhì)瘤細(xì)胞通過(guò)transwell嵌套共建了雙細(xì)胞模型,體外考察遞藥載體透過(guò)BBB后對(duì)腦膠質(zhì)瘤細(xì)胞的抑制作用,較為逼真模擬遞藥載體在體內(nèi)的運(yùn)行過(guò)程,具有較高的科學(xué)性;血-腦同步微透析技術(shù)研究腦靶向遞藥系統(tǒng)的藥動(dòng)學(xué)特性,能夠同時(shí)和實(shí)時(shí)的測(cè)定腦內(nèi)和血液內(nèi)的游離型藥物的濃度,準(zhǔn)確考察藥物的藥動(dòng)學(xué)特性,具有無(wú)可比擬。
[Abstract]:Due to the unique properties of nano materials, making it especially in the field of medicine plays a very important role in the treatment of cancer. The mesoporous silica nanoparticles (Mesoporous silica nanoparticles, MSN) is inorganic nano materials discovered by Stober in 1992, is the most promising drugs carrier. One of the types of mesoporous silica nanoparticles are by controlling the preparation conditions of different types, such as MCM-41, MCM-48, SBA-15 and so on. This paper intends to two different kinds of mesoporous silica SBA-15 and MCM-41, respectively. The loading of 3 different types of drugs, administered through different ways to study its application in drug delivery. The specific research the contents are as follows: (1) preparation of SBA-15 mesoporous silica nanoparticles by hydrothermal synthesis method, analysis method establishment of exenatide in vitro by SBA-15 mesoporous silica nanoparticles as carrier material, by dipping suction With the preparation of EXT-SBA-15, and investigate its in vitro release characteristics; using EXT-Sol as the control group, EXT-SBA-15 subcutaneous injection after administration in rats in vivo pharmacokinetic process, the content of Exendin-4 ELISA kit for determination of EXT in rats at different time points, the pharmacokinetic parameters were calculated, in order to study the in vivo release of EXT-SBA-15 drug use; diabetic mice as a model animal, set the blank control group, model control group, EXT-Sol group, EXT-SBA-15 group and control group SBA-15, preliminary study of hypoglycemic effect in diabetic mice after subcutaneous injection of EXT-SBA-15. The results show that EXT-SBA-15 nanoparticles were successfully prepared, simple preparation process, high drug loading, in vitro and in vivo research shows that EXT-SBA-15 can prolong the residence time of the drug in the body, has obvious sustained-release characteristics and hypoglycemic effect. The research for the SBA-15 mesoporous silica materials and application of polypeptide drug sustained-release preparation. The experimental and theoretical basis for the development. (2) the preparation of amino modified mesoporous silica nanoparticles coprecipitation method, electrostatic adsorption loading ATO, pH PAA conjugate preparation of PAA-ATO-MSN. by transmission electron microscope observation on the morphology of nanoparticles by scanning electron microscopy, small angle X ray diffraction on the mesoporous structure, nitrogen adsorption determination the specific surface area, pore size, Kong Rong desorption instrument, infrared spectroscopy of amino and PAA modification, determination of the grafting ratio of PAA thermogravimetric analyzer, laser particle and Zeta potential analyzer was used to measure the particle size and Zeta potential; high speed centrifugation combined with inductive coupled plasma atomic emission spectrometry (Inductively coupledplasmaemissionspectrum ICP) to determine the entrapment efficiency and loading dosage; phosphate buffer with different pH (phosphatebufferedsaline, PBS) (ph5.0,6.0 and 7.4) as the release medium, the dialysis bag was used to investigate the pH in different conditions in vitro drug release. ; SMMC-7721 cells in vitro model to study the control vector MSN, nh2-msn and paa-msn toxicity and ATO solution (atosolution, ato-sol), arsenic trioxide amine modified mesoporous silica nanoparticles (arsenictrioxideloadedmesoporoussilicananoparticles, ato-msn) and polyacrylic acid modified amine modified mesoporous silica nanoparticles (polyacrylicacidgraftedarsenictrioxideamino-functionedmesoporoussilicananoparticles, paa-ato-msn) in vitro and the inhibition rate of tumor cell cycle block; ato-sol, ato-msn for the control group, rats were given intravenous injection (intravenousinjection, IV) of femoral artery after administration, jugular vein intubation technique to collect blood samples by inductively coupled plasma mass spectrometry (inductivelycoupledplasmamassspectrometry, ICP-MS) for determination of blood concentration to calculate the pharmacokinetic parameters related, investigate the in vitro and in pharmacokinetic behavior in Kunming (km) mice. Ectopic transplantation for hepatocellular carcinoma (H22) as efficacy model, set the blank control group, ato-sol group, ato-msn group and paa-ato-msn group to investigate the antitumor effect of preparation. The results show that the prepared carrier response of arsenic trioxide pH mesoporous silica nanoparticles (paa-ato-msn), the smaller particle size, high encapsulation efficiency and drug loading, in vitro the drug release has obvious pH response and release characteristics, and paa-msn can significantly improve the ATO pharmacokinetic behavior in rats, paa-ato-msn in vitro and in vivo antitumor effects were better than ATO, the carrier has good application prospects. (3) using a modified classical Stober preparation of mesoporous silica nanoparticles (MSN), by thermogravimetric analysis, nitrogen adsorption, XRD diffraction characterization of the invention; repeated saturated solution adsorption preparation of loaded PTX MSN (msn-ptx), and then to msn-ptx as the core, by self assembling and water film The construction of core / shell structure of angiopep-2 modified mesoporous silica nanoparticles liposome method (ang-msn-lp-ptx); the dialysis bag method to study drug release in vitro; cytotoxic MTT method to study the control vector to HBMEC and C6, and the drug loaded nanoparticles on the anti-tumor effect of C6 cell; effects of transmembrane ability of carrier in vitro the BBB model of PTX and C6 on the cell cycle. To establish the model of glioma bearing rats were invasion of glioma pathological observation of tumor tissue, effects of drug loaded nanoparticles on the therapeutic effect of glioma bearing rats; using synchronous blood brain microdialysis, investigation of drug loaded nanoparticles in the blood and brain tissue pharmacokinetic characteristics. The results show that the MSN circle contour prepared smooth, uniform particle size distribution, large surface area, uniform pore size, stable property; repeated saturated solution adsorption method can effectively improve the drug loading capacity, To solve the problem of low drug loading nanoparticles, it is worthy of application and reference; ANG-MSN-LP vector system constructed by combining the advantages of mesoporous materials and lipid materials, at the same time to solve the problem of silica agglomerate, and liposome easily burst release of drug loaded low leakage of the medicine, is a safe, reliable and compatible the good biological nanoparticles modified by Angiopep-2, silica nanoparticles liposome can penetrate the blood-brain barrier effectively, realize the brain targeting drug delivery, as a kind of excellent drug delivery and is expected to be used for brain glioma treatment; in vitro BBB model this paper improved, HBMEC and C6 in brain glioma the double cell through the cell model and the nested Transwell, in vitro study drug delivery through BBB inhibition of glioma cells, a more realistic simulation of drug delivery in the operation process of the body, with the science high; The blood brain synchronous microdialysis technology can be used to study the pharmacokinetic characteristics of the brain targeting drug delivery system. It can simultaneously determine the concentration of free drugs in the brain and blood simultaneously and accurately, and accurately investigate the pharmacokinetic characteristics of the drug.

【學(xué)位授予單位】：湖北中醫(yī)藥大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R943;TB383.1

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