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論文摘要，已經(jīng)google翻譯，請高人幫忙修改潤色，不勝感激
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中文摘要： 本文的實驗?zāi)康模海?）考察影響非靶向性聚乳酸（PLA）載藥納米粒制備的工藝因素，并對處方進(jìn)行工藝優(yōu)化，制備出粒徑較小、載藥率和包封率較高的PLA載藥納米粒；（2）探索不同反應(yīng)條件對肺靶向配體分子葉酸（FA）和透明質(zhì)酸（HA）偶聯(lián)量的影響，確定配體分子的最佳偶聯(lián)工藝；（3）通過模擬體內(nèi)環(huán)境考察不同因素對納米粒釋藥性能的影響，分析釋藥機(jī)理并建立合適的釋藥模型，為藥物在體內(nèi)的藥效學(xué)研究奠定基礎(chǔ)。采用的實驗方法：（1）采用復(fù)乳法（W/O/W）和乳化溶劑揮發(fā)法（O/W）分別制備奧沙利鉑PLA納米粒、吉西他濱PLA納米粒和紫杉醇PLA納米粒，對兩種制備方法中影響納米粒粒徑和載藥率的因素進(jìn)行單因素考察，篩選出較好的水平設(shè)計正交實驗，優(yōu)化得到最佳制備工藝。通過透射電子顯微鏡（TEM）和Zeta電位及激光粒度分析儀對納米粒形貌和粒徑進(jìn)行表征；（2）過酰胺化反應(yīng)分別將FA和HA偶聯(lián)到PLA載藥納米粒表面，考察不同反應(yīng)條件對配體偶聯(lián)量的影響并找出最佳偶聯(lián)工藝。紅外光譜（IR）表征配體偶聯(lián)情況，Zeta電位及激光粒度分析儀和掃描電子顯微鏡（SEM）對偶聯(lián)配體后的納米粒粒徑和形貌進(jìn)行表征；（3）考察不同PH值（PH=4.3、PH=5.6和PH=7.4）、不同載藥率（9.53%、17.48%和26.37%）以及偶聯(lián)配體對納米粒釋藥性能的影響，并模擬人體內(nèi)部環(huán)境進(jìn)行釋藥行為的研究，分析每個階段的釋藥機(jī)理，擬合五種常見藥物模型的曲線方程并選擇最佳釋藥模型。實驗結(jié)果：（1）通過單因素考察和正交試驗設(shè)計確定了制備三種載藥納米粒的最佳制備工藝，在最佳制備條件下制得的載藥納米粒載藥率和包封率分別為26.9%，66.5%；27.4%，67.2%和30.3%，73.6%。納米粒表面光滑圓整、分散性好，平均粒徑分別為110nm、117nm和125nm，且粒徑分布范圍較窄；（2）用紅外光譜（IR）表征納米粒表面分子基團(tuán)的變化，表明FA和HA分別通過酰胺鍵作用成功的偶聯(lián)到了納米粒表面。確定了FA和HA的最佳偶聯(lián)工藝，在最佳偶聯(lián)反應(yīng)條件下FA和HA的偶聯(lián)量分別為0.0237×10-3mol/g和0.0178×10-6mol/g。粒徑分析表明FA偶聯(lián)前后納米粒粒徑基本無變化，HA（Mr=300000）偶聯(lián)后粒徑由122.2nm增長到131.3nm，表明大分子量的HA對粒徑變化影響較大。通過放大不同倍數(shù)的SEM照片可看出配體偶聯(lián)后納米粒分布均勻，分散性較好；（3）納米粒釋藥速率和累積釋藥量順序為PH=4.3＞PH=5.6＞PH=7.4，且在一定PH范圍內(nèi)酸性越強釋藥速率和累計釋放量越高，高載藥率納米粒在相同環(huán)境下的釋藥速率高于中、低載藥率納米粒，F(xiàn)A偶聯(lián)后對納米粒釋藥性能基本無影響，大分子的HA偶聯(lián)到納米粒表面后釋藥速率明顯降低。靶向PLA載藥納米粒模擬體內(nèi)環(huán)境釋藥表現(xiàn)出良好的緩釋效果，擬合的FA/HA-PLA載藥納米粒的釋藥模型分別為InIn(1/(1-Q))=0.04633Int-1.03562和1-Q1/3=-0.01368t+1.04726。 google翻譯： The purpose of this experiment: (1) examine the impact on non-target polylactic acid (PLA) drug-loaded nanoparticles preparation of process factors, and prescription process optimization, the preparation of a smaller particle size, drug loading and encapsulation efficiency. high PLA drug-loaded nanoparticles; (2) to explore different reaction conditions for lung targeting ligand folic acid (FA) and the amount of hyaluronic acid (HA) coupling to determine the optimal coupling of the ligand molecule process; (3) examine the impact of different factors on the drug release properties of nanoparticles by simulating the in vivo environment, analysis of the release mechanism and the establishment of appropriate release model, to lay the foundation for the drug in vivo pharmacodynamic studies. Experimental methods: (1) double emulsion (W / O / W) emulsion solvent evaporation method (O / W) Preparation of of oxaliplatin PLA nanoparticles, the gemcitabine PLA nanoparticles and paclitaxel PLA nanoparticles, two preparation methods of nanoparticles particle size and drug loading rate single factor study, filter out the good level orthogonal experiments to optimize the best preparation process. By transmission electron microscopy (TEM) and Zeta potential and laser particle size analyzer nanoparticle morphology and particle size characterization; (2) Over amidation reaction of the FA and HA coupling to the surface of the PLA drug-loaded nanoparticles investigated The reaction conditions on the amount of ligand coupled and find out the best coupling process. Infrared spectroscopy (IR) characterization of ligand coupling, zeta potential and laser particle size analyzer and scanning electron microscope (SEM) coupled ligand nanoparticle size and morphology were characterized; (3) study at different pH values ( pH = 4.3 and pH = 5.6 and pH = 7.4), different drug loading rate (9.53%, 17.48% and 26.37%, respectively), and the of coupling ligands on the drug release properties of nanoparticles and simulate the body's internal environment release behavior research, analysis of each stage of the release mechanism, fitting the curve equation model of five common drugs and select the best drug delivery model. Results: (1) single factor and orthogonal design to determine optimal preparation prepared three kinds of drug-loaded nanoparticles, drug loading and encapsulation efficiency obtained in the best preparation conditions of drug-loaded nanoparticles were 26.9%, 66.5%; 27.4%, 67.2% and 30.3%, 73.6%, respectively. Nanoparticle surface is smooth and round, good dispersion, the average particle size of 110nm, 117nm and 125 nm, and the particle size distribution is narrow; (2) changes in the nanoparticle surface molecular groups characterized by infrared spectroscopy (IR), indicating that the HA and FA were successful through the amide key role of coupling to the surface of the nanoparticles. The FA and HA coupling process, under the reaction conditions in the top coupling a coupling amount of FA and HA were 0.0237 × 10-3mol / g and 0.0178 × 10 6 mol / g. The particle size analysis showed that the nanoparticles before and after the FA coupled particle size did not change the basic HA (Mr = 300000) the coupled particle size growth from 122.2nm to 131.3nm, indicating that the high molecular weight HA greater impact on particle size change. As can be seen by SEM photographs zoom multiples ligand coupled nanoparticle distribution, good dispersion; (3) nanoparticles release rate and the cumulative amount of drug release order for pH = 4.3 pH = 5.6> pH = 7.4, and the stronger the acidity within a certain pH range higher release rate and cumulative release, high drug loading nanoparticles release rate is higher than in the same environment in low drug loading nanoparticles FA coupling basically no effect on the drug release properties of nanoparticles, macromolecular HA coupled to the surface of the nanoparticles, drug release rate was significantly lower. Exhibit good release effect targeting PLA drug-loaded nanoparticles simulated environment in vivo release fitting FA / HA-PLA model the release of the drug-loaded nanoparticles were ININ (1 / (1-Q)) = 0.04633 Int-1.03562 and 1-Q1 / 3 =-0.01368t +1.04726-. |
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