温度敏感性生物降解阴道凝胶的合成、性能及其应用研究
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摘要
阴道凝胶作为各种药物的载体在过去几十年中一直是研究热点，其包覆的各种抗艾滋病病毒的药物、避孕药物及阴道杀菌剂等取得的科研成果推动了女性生理、生殖安全的进步及生物医用材料学科的发展。本论文计划合成一种新型的可降解控释材料，即通过先“臂”后“核”法，合成以温敏性聚乙丙交酯-单甲氧基聚乙二醇二元嵌段共聚物(PLGA-mPEG)为臂和以羧基化的多元醇为核的多臂星形温敏性载药材料。这种多臂嵌段共聚物主要有以下特点：温敏性、两亲性、生物相容性、降解性可控、结构上为多臂星形及其水溶胶粘度低。采用溶液共混法将避孕药复方雌、孕激素和吲哚美辛载入高聚物载体，制备的载药系统作为阴道节育喷剂，其在室温时为液相，可以自由流动，在体温时成凝胶状，不能流动。这种喷剂可以制成小剂量包装，在妇女月经完后将一个包装喷入阴道中，在人体体温环境下迅速转变成网状通透凝胶附着于阴道壁上，缓慢、可控制地释放出雌孕激素和吲哚美辛，起到节育作用。同时，在30天左右的时间内，这种附着于阴道上的可降解凝胶缓慢降解完全，在妇女月经时间内不再有雌孕激素释放，直到月经完毕后再次喷入本品。
本论文的主要研究内容与研究结果如下：
1．采用先“臂”后“核”法设计合成了一系列具有不同臂数、PLGA/mPEG嵌段比例、mPEG嵌段长度及丙交酯/乙交酯单元摩尔比例（LA/GA）的星形嵌段共聚物。采用红外光谱、凝胶渗透色谱与核磁共振氢谱分析了这些共聚物的分子结构、分子量及其分布。
2．采用静态流变曲线研究了确定溶胶-凝胶转变过程中各个转变温度的方法；并结合试管倒转法研究了一系列具有不同臂数、PLGA/mPEG嵌段比例、mPEG嵌段长度及LA/GA单元摩尔比例的星形嵌段共聚物浓溶液随温度改变时的溶胶-凝胶转变规律；同时探讨了亲水性添加剂对共聚物溶液溶胶-凝胶转变规律的影响。研究表明，PLGA/mPEG嵌段质量比例是决定星形共聚物是否具有溶胶-凝胶转变性能的最关键因素，其比例应该在2-3之间；mPEG嵌段长度是决定溶胶-凝胶转变温度最重要因素，要求在体温下能发生凝胶化转变一般需要选择的mPEG分子量为550道尔顿，可通过选择mPEG嵌段分子量来“粗调”溶胶-凝胶转变温度；再通过选择PLGA/mPEG嵌段质量比例、臂数与LA/GA摩尔比来“微调”溶胶-凝胶转变温度。
3．采用核磁共振氢谱与电子透射电镜研究了核壳胶束的形成与形态，星形共聚物分子在浓度为1wt%的稀溶液中自组装形成30-50nm的核壳胶束；采用动态光散射进一步分析了胶束粒径及其分布随共聚物稀溶液浓度与温度改变的变化规律，探讨了胶束化与凝胶化机制；利用荧光染料-紫外光谱法分析了共聚物稀溶液临界胶束浓度的变化规律。我们发现临界凝胶浓度（CGC）远远大于临界胶束浓度（CMC），基于此，我们认为星形嵌段共聚物水溶液物理凝胶化过程为：共聚物先自组装形成核壳胶束，然后通过胶束间的互相堆积引起溶胶-凝胶转变，PLGA嵌段间的疏水相互作用是其内在的驱动力。
4．采用称重法、凝胶渗透色谱法及核磁共振氢谱法分析了星形嵌段共聚物凝胶在体外阴道模拟液及SD大鼠颈部皮下在不同降解时间下的质量损失变化、分子量变化与嵌段组成变化；同时比较与分析了体外与体内降解规律的差异。研究发现，对于相同分子量及嵌段组成的星形四臂嵌段共聚物水凝胶， LA/GA摩尔比例越小，其在体外模拟阴道液及SD大鼠体内降解质量损失越大及分子量减小得越快，同时该水凝胶在体内的降解速率快于体外降解速率；通过各组成（EG单元、GA单元与LA单元）的相对质量分数随降解时间的变化规律，将星形共聚物的降解过程分为三个阶段：第一个阶段主要为与mPEG嵌段相连的酯键的水解，第二阶段主要为与mPEG嵌段相连的酯键及PLGA嵌段中GA单元的水解，最后一个阶段主要为PLGA嵌段中LA单元的水解。
5．建立了同时检测三种药物含量（雌激素炔雌醇、孕激素孕二烯酮与消炎药吲哚美辛）的高效液相色谱条件：混合流动相甲醇/水最佳比例为53/47，吲哚美辛（IMC）、孕二烯酮（GSD）及炔雌醇（EE）的淋出时间依次为11.18min，13.11min和15.57min；通过对模拟阴道释放液中药物含量的测试，发现载药星形共聚物凝胶中LA/GA摩尔比值越小，三种药物的累积释放分数越大，说明各药物的释放由降解机制控制。而低药物含量的共聚物凝胶具有更高的IMC、GSD与EE累积释放分数。同时对不同LA/GA摩尔比值和不同载药量的星形共聚物凝胶的各药物累积释放曲线进行Higuchi模型、零级药物释放模型及一级药物释放模型拟合，发现拟合线性关系的好坏顺序仍为：Higuchi模型>零级药物释放模型>一级药物释放模型，说明IMC、GSD与EE的药物释放规律符合Higuchi模型。
6．我们通过四甲基偶氮唑盐微量酶反应比色法（MTT实验）发现，星形嵌段共聚物不具有明显的细胞毒性。另外，尽管星形共聚物凝胶材料注射进SD大鼠体内于早期出现了急性的炎症反应，但后期炎症反应的消除表明温敏性凝胶材料仍然具有良好的生物相容性。另外，我们将载有不同药物剂量的星形共聚物水凝胶喷入SD大鼠阴道后，对比不同时间点与不同剂量下的SD大鼠的各器官宏观性状及微观组织，发现高剂量组下的SD大鼠出现了较严重的子宫水肿、阴道充血、部分肝细胞溶解坏死、肝细胞碎片状坏死及脾脏淋巴细胞增多等现象；中剂量组下的SD大鼠仅出现了子宫充血现象；而低剂量组与对照组（未添加药物的水凝胶）则未发现明显组织病变，表明低药物剂量组的水凝胶可作为女性节育喷剂。
7．通过混合两种各自不具有温敏性星形嵌段共聚物水溶液，惊奇地发现其混合液出现了温敏性。初步研究了该混合凝胶的制备方法、胶束化性能、溶胶-凝胶转变性能、体外降解性能、体外细胞毒性及体内生物相容性。
In the past few decades, vaginal gels as the carriers of various drugs have garneredmuch attention. Vaginal gels encapsulated a variety of anti-HIV drugs, contraceptive drugsand vaginal microbicides were widely investigated to promote the progress of femalephysiology, reproductive safety and the subdiscipline of biomedical materials.
In the present paper, a series of copolymer, multiarm star-shapedpoly(D,L-lactic-co-glycolic acid)-b-methoxy poly(ethylene glycol)(PLGA-mPEG), weresynthesized via the arm-first method using linear PLGA-mPEG diblock as a arm andcarboxylation of polyols as a core. These multiarm block copolymers have the followingcharacteristics, namely, temperature-sensitive nature, amphiphilicity, biocompatibility,controlled degradability, multiarm star-shape on the structure and low viscosity of sol.Ethinyl estradiol (EE), gestodene (GSD) and indomethacin (IMC) were loaded into thecopolymer solutions using mixed method. This drug release system as a vaginal spraycould flow freely at room temperature and could not flow due to formation of gel at bodytemperature. This spray could be made into a small packaging, and after womenmenstruation a packaging was sprayed into the vagina at body temperature. Themesh-shaped gel formed quickly and attached to the vaginal wall. Estrogen, progesteroneand indomethacin in gel slowly released. At the same time, this spray degraded slowly anddrugs were released within about30days in the vagina and were re-sprayed.
The main achievements were summarized as follows:
1. A series of star-shaped block copolymers with various arm numbers,PLGA/mPEG block ratios, mPEG block length and LA/GA mol ratios were synthesizedusing arm-first method. And molecular structure, molecular weight and molecular weightdistribution of these star-shaped block copolymers were analyzed via Fourier transforminfrared spectrometer (FT-IR), gel permeation chromatography (GPC) and1H nuclearmagnetic resonance spectroscopy (1H NMR).
2. The new method, in order to determining sol-gel transition process and transition temperatures, was established using static rheological curves. Combining with theinverting tube method, sol-gel transition behaviours of a series of star-shaped blockcopolymers with different arm numbers, PLGA/mPEG block ratios, mPEG block lengthand LA/GA mol ratios were investigated with changing temperature. Simultaneously,sol-gel transition behaviours of star-shaped block copolymers with adding hydrophilicmPEG homopolymer were also studied. PLGA/mPEG block mass ratio was the mostcritical factor to decide whether star-shaped block copolymers solutions had performanceof the sol-gel transition, and the ratios should be between2and3. The mPEG block lengthwas the most important factor to determine the sol-gel transition temperatures. The mPEGmolecular weight of550daltons was selected in order to gelation of copolymer solution atbody temperature. The sol-gel transition temperatures were coarsely tuned by selecting themolecular weight of mPEG block, and fine tuned by selecting PLGA/mPEG block ratios,arm numbers and LA/GA mol ratios.
3. Formation and morphology of core-shell micelles were investigated via1H NMRand TEM. Star-shaped block copolymers in dilute solution with the concentration of1wt%self-assemble to form core-shell micelles with size of30-50nm. Micelle sizes anddistributions were further investigated using dynamic light scattering (DLS) with changingconcentrations and temperatures of dilute solution. Micellization and gelation mechanismswere subsequently discussed. The critical micelle concentrations (CMC) of copolymers indilute solution were studied via hydrophobic dye-UV spectroscopy method. The resultsshowed the critical gel concentration (CGC) was far greater than the critical micelleconcentration. Based on this, physical gelation process of star-shaped block copolymeraqueous solutions was discussed by us. Copolymer macromolecules in aqueous solutionsself-assembled and formed core-shell micelles, and then accumulated each other betweenthe micelles to cause the sol-gel transition. The hydrophobic interaction of PLGA blockwas considered as intrinsic driving force.
4. With degradation time increased, changes in weight loss, molecular weight andcomposite of blocks of star-shaped copolymer hydrogels incubated in simulated vaginalfluid solution (SVF) in vitro and injected in neck of SD rats in vivo were investigated via weight method, GPC and1H NMR. At the same time, the differences between in vitrodegradation and in vivo degradation were compared. Weight and molecular weight ofstar-shaped copolymer hydrogels incubated in simulated vaginal fluid solution (SVF) invitro and injected in neck of SD rats in vivo decreased with decreasing LA/GA mol ratiosof star-shaped copolymer with the same molecular weight and block composite.Meanwhile, in vivo degradation rate of the hydrogel was quicker than in vitro degradation.The relative weight fractions of EG, GA and LA units were calculated using NMRend-group analysis with degradation time increased. Subsequently, degradation process ofstar-shaped copolymers in hydrogels was divided into three stages. In the first stage, esterbonds connected with the mPEG block were hydrolyzed mainly. In the second stage, esterbonds connected with the mPEG block and GA units of PLGA blocks were hydrolyzedmainly. In the last stage, ester bonds in LA units of PLGA blocks were hydrolyzed mainly.
5. High performance liquid chromatography (HPLC) conditions simultaneouslydetecting drug content of ethinyl estradiol, gestodene and indomethacin were determined.Namely, optimal volume ratio of methanol and water as mixed mobile phase of HPLC was53/47, the retention time of indomethacin (IMC), gestodene (GSD) and ethinyl estradiol(EE) were11.18min,13.11min and15.57min, respectively. By examining three drugcontents of SVF solutions, cumulative release fraction of three drugs became bigger withdecreasing LA/GA mol ratios of copolymers, indicating that release of these drugs werecontrolled by degradation mechanism. By means of fitting of cumulative release curves ofstar-shaped copolymer hydrogels with various LA/GA mol ratios and drug-loadingcontents using Higuchi model, zero-order release model and first-order release model,good or bad order of the linear fitting relationship was as follows: Higuchi model>zero-order release model> first-order release model, indicating that drug releases of IMC,GSD and EE were suitable to Higuchi model.
6. The star-shaped copolymers were basically biocompatible with low cellcytotoxicity due to high cell viability at all culture concentration and time by an MTTassay. Even though an acute inflammatory response occurred at the surrounding injectedsite of SD rats in early stage, the inflammatory response disappeared at late stage indicating that star-shaped copolymer hydrogels had a good biocompatibility. In addition,after spraying hydrogels with various drug dosages into vagina of SD rats, macroscopiccharacters and microstructure of organs were observed at various dosage groups andsprayed time. As to high dosage group, severe uterine edema, vaginal hyperemia, partiallysis necrosis of the liver cell, piecemeal necrosis of hepatocytes, and increasing spleenlymphocyte were found in SD rats. As to middle dosage group, uterine hyperemia was justobserved. As to low dosage group and control group, no significant pathological changeswere found. As a result, hydrogels loaded drugs with low dosage group is suitable to applyin female birth control spray.
7. Interestingly, temperature-sensitivity of mixed copolymer aqueous solution wasfound using simply mixing two star-shaped copolymer solutions withouttemperature-sensitive property at different mixing ratios. Preparation method of the mixedgels, the performance of the micellization, sol-gel transition properties, in vitrodegradation, in vitro cytotoxicity and in vivo biocompatibility were preliminary studied.
本论文的主要研究内容与研究结果如下：
1．采用先“臂”后“核”法设计合成了一系列具有不同臂数、PLGA/mPEG嵌段比例、mPEG嵌段长度及丙交酯/乙交酯单元摩尔比例（LA/GA）的星形嵌段共聚物。采用红外光谱、凝胶渗透色谱与核磁共振氢谱分析了这些共聚物的分子结构、分子量及其分布。
2．采用静态流变曲线研究了确定溶胶-凝胶转变过程中各个转变温度的方法；并结合试管倒转法研究了一系列具有不同臂数、PLGA/mPEG嵌段比例、mPEG嵌段长度及LA/GA单元摩尔比例的星形嵌段共聚物浓溶液随温度改变时的溶胶-凝胶转变规律；同时探讨了亲水性添加剂对共聚物溶液溶胶-凝胶转变规律的影响。研究表明，PLGA/mPEG嵌段质量比例是决定星形共聚物是否具有溶胶-凝胶转变性能的最关键因素，其比例应该在2-3之间；mPEG嵌段长度是决定溶胶-凝胶转变温度最重要因素，要求在体温下能发生凝胶化转变一般需要选择的mPEG分子量为550道尔顿，可通过选择mPEG嵌段分子量来“粗调”溶胶-凝胶转变温度；再通过选择PLGA/mPEG嵌段质量比例、臂数与LA/GA摩尔比来“微调”溶胶-凝胶转变温度。
3．采用核磁共振氢谱与电子透射电镜研究了核壳胶束的形成与形态，星形共聚物分子在浓度为1wt%的稀溶液中自组装形成30-50nm的核壳胶束；采用动态光散射进一步分析了胶束粒径及其分布随共聚物稀溶液浓度与温度改变的变化规律，探讨了胶束化与凝胶化机制；利用荧光染料-紫外光谱法分析了共聚物稀溶液临界胶束浓度的变化规律。我们发现临界凝胶浓度（CGC）远远大于临界胶束浓度（CMC），基于此，我们认为星形嵌段共聚物水溶液物理凝胶化过程为：共聚物先自组装形成核壳胶束，然后通过胶束间的互相堆积引起溶胶-凝胶转变，PLGA嵌段间的疏水相互作用是其内在的驱动力。
4．采用称重法、凝胶渗透色谱法及核磁共振氢谱法分析了星形嵌段共聚物凝胶在体外阴道模拟液及SD大鼠颈部皮下在不同降解时间下的质量损失变化、分子量变化与嵌段组成变化；同时比较与分析了体外与体内降解规律的差异。研究发现，对于相同分子量及嵌段组成的星形四臂嵌段共聚物水凝胶， LA/GA摩尔比例越小，其在体外模拟阴道液及SD大鼠体内降解质量损失越大及分子量减小得越快，同时该水凝胶在体内的降解速率快于体外降解速率；通过各组成（EG单元、GA单元与LA单元）的相对质量分数随降解时间的变化规律，将星形共聚物的降解过程分为三个阶段：第一个阶段主要为与mPEG嵌段相连的酯键的水解，第二阶段主要为与mPEG嵌段相连的酯键及PLGA嵌段中GA单元的水解，最后一个阶段主要为PLGA嵌段中LA单元的水解。
5．建立了同时检测三种药物含量（雌激素炔雌醇、孕激素孕二烯酮与消炎药吲哚美辛）的高效液相色谱条件：混合流动相甲醇/水最佳比例为53/47，吲哚美辛（IMC）、孕二烯酮（GSD）及炔雌醇（EE）的淋出时间依次为11.18min，13.11min和15.57min；通过对模拟阴道释放液中药物含量的测试，发现载药星形共聚物凝胶中LA/GA摩尔比值越小，三种药物的累积释放分数越大，说明各药物的释放由降解机制控制。而低药物含量的共聚物凝胶具有更高的IMC、GSD与EE累积释放分数。同时对不同LA/GA摩尔比值和不同载药量的星形共聚物凝胶的各药物累积释放曲线进行Higuchi模型、零级药物释放模型及一级药物释放模型拟合，发现拟合线性关系的好坏顺序仍为：Higuchi模型>零级药物释放模型>一级药物释放模型，说明IMC、GSD与EE的药物释放规律符合Higuchi模型。
6．我们通过四甲基偶氮唑盐微量酶反应比色法（MTT实验）发现，星形嵌段共聚物不具有明显的细胞毒性。另外，尽管星形共聚物凝胶材料注射进SD大鼠体内于早期出现了急性的炎症反应，但后期炎症反应的消除表明温敏性凝胶材料仍然具有良好的生物相容性。另外，我们将载有不同药物剂量的星形共聚物水凝胶喷入SD大鼠阴道后，对比不同时间点与不同剂量下的SD大鼠的各器官宏观性状及微观组织，发现高剂量组下的SD大鼠出现了较严重的子宫水肿、阴道充血、部分肝细胞溶解坏死、肝细胞碎片状坏死及脾脏淋巴细胞增多等现象；中剂量组下的SD大鼠仅出现了子宫充血现象；而低剂量组与对照组（未添加药物的水凝胶）则未发现明显组织病变，表明低药物剂量组的水凝胶可作为女性节育喷剂。
7．通过混合两种各自不具有温敏性星形嵌段共聚物水溶液，惊奇地发现其混合液出现了温敏性。初步研究了该混合凝胶的制备方法、胶束化性能、溶胶-凝胶转变性能、体外降解性能、体外细胞毒性及体内生物相容性。
In the past few decades, vaginal gels as the carriers of various drugs have garneredmuch attention. Vaginal gels encapsulated a variety of anti-HIV drugs, contraceptive drugsand vaginal microbicides were widely investigated to promote the progress of femalephysiology, reproductive safety and the subdiscipline of biomedical materials.
In the present paper, a series of copolymer, multiarm star-shapedpoly(D,L-lactic-co-glycolic acid)-b-methoxy poly(ethylene glycol)(PLGA-mPEG), weresynthesized via the arm-first method using linear PLGA-mPEG diblock as a arm andcarboxylation of polyols as a core. These multiarm block copolymers have the followingcharacteristics, namely, temperature-sensitive nature, amphiphilicity, biocompatibility,controlled degradability, multiarm star-shape on the structure and low viscosity of sol.Ethinyl estradiol (EE), gestodene (GSD) and indomethacin (IMC) were loaded into thecopolymer solutions using mixed method. This drug release system as a vaginal spraycould flow freely at room temperature and could not flow due to formation of gel at bodytemperature. This spray could be made into a small packaging, and after womenmenstruation a packaging was sprayed into the vagina at body temperature. Themesh-shaped gel formed quickly and attached to the vaginal wall. Estrogen, progesteroneand indomethacin in gel slowly released. At the same time, this spray degraded slowly anddrugs were released within about30days in the vagina and were re-sprayed.
The main achievements were summarized as follows:
1. A series of star-shaped block copolymers with various arm numbers,PLGA/mPEG block ratios, mPEG block length and LA/GA mol ratios were synthesizedusing arm-first method. And molecular structure, molecular weight and molecular weightdistribution of these star-shaped block copolymers were analyzed via Fourier transforminfrared spectrometer (FT-IR), gel permeation chromatography (GPC) and1H nuclearmagnetic resonance spectroscopy (1H NMR).
2. The new method, in order to determining sol-gel transition process and transition temperatures, was established using static rheological curves. Combining with theinverting tube method, sol-gel transition behaviours of a series of star-shaped blockcopolymers with different arm numbers, PLGA/mPEG block ratios, mPEG block lengthand LA/GA mol ratios were investigated with changing temperature. Simultaneously,sol-gel transition behaviours of star-shaped block copolymers with adding hydrophilicmPEG homopolymer were also studied. PLGA/mPEG block mass ratio was the mostcritical factor to decide whether star-shaped block copolymers solutions had performanceof the sol-gel transition, and the ratios should be between2and3. The mPEG block lengthwas the most important factor to determine the sol-gel transition temperatures. The mPEGmolecular weight of550daltons was selected in order to gelation of copolymer solution atbody temperature. The sol-gel transition temperatures were coarsely tuned by selecting themolecular weight of mPEG block, and fine tuned by selecting PLGA/mPEG block ratios,arm numbers and LA/GA mol ratios.
3. Formation and morphology of core-shell micelles were investigated via1H NMRand TEM. Star-shaped block copolymers in dilute solution with the concentration of1wt%self-assemble to form core-shell micelles with size of30-50nm. Micelle sizes anddistributions were further investigated using dynamic light scattering (DLS) with changingconcentrations and temperatures of dilute solution. Micellization and gelation mechanismswere subsequently discussed. The critical micelle concentrations (CMC) of copolymers indilute solution were studied via hydrophobic dye-UV spectroscopy method. The resultsshowed the critical gel concentration (CGC) was far greater than the critical micelleconcentration. Based on this, physical gelation process of star-shaped block copolymeraqueous solutions was discussed by us. Copolymer macromolecules in aqueous solutionsself-assembled and formed core-shell micelles, and then accumulated each other betweenthe micelles to cause the sol-gel transition. The hydrophobic interaction of PLGA blockwas considered as intrinsic driving force.
4. With degradation time increased, changes in weight loss, molecular weight andcomposite of blocks of star-shaped copolymer hydrogels incubated in simulated vaginalfluid solution (SVF) in vitro and injected in neck of SD rats in vivo were investigated via weight method, GPC and1H NMR. At the same time, the differences between in vitrodegradation and in vivo degradation were compared. Weight and molecular weight ofstar-shaped copolymer hydrogels incubated in simulated vaginal fluid solution (SVF) invitro and injected in neck of SD rats in vivo decreased with decreasing LA/GA mol ratiosof star-shaped copolymer with the same molecular weight and block composite.Meanwhile, in vivo degradation rate of the hydrogel was quicker than in vitro degradation.The relative weight fractions of EG, GA and LA units were calculated using NMRend-group analysis with degradation time increased. Subsequently, degradation process ofstar-shaped copolymers in hydrogels was divided into three stages. In the first stage, esterbonds connected with the mPEG block were hydrolyzed mainly. In the second stage, esterbonds connected with the mPEG block and GA units of PLGA blocks were hydrolyzedmainly. In the last stage, ester bonds in LA units of PLGA blocks were hydrolyzed mainly.
5. High performance liquid chromatography (HPLC) conditions simultaneouslydetecting drug content of ethinyl estradiol, gestodene and indomethacin were determined.Namely, optimal volume ratio of methanol and water as mixed mobile phase of HPLC was53/47, the retention time of indomethacin (IMC), gestodene (GSD) and ethinyl estradiol(EE) were11.18min,13.11min and15.57min, respectively. By examining three drugcontents of SVF solutions, cumulative release fraction of three drugs became bigger withdecreasing LA/GA mol ratios of copolymers, indicating that release of these drugs werecontrolled by degradation mechanism. By means of fitting of cumulative release curves ofstar-shaped copolymer hydrogels with various LA/GA mol ratios and drug-loadingcontents using Higuchi model, zero-order release model and first-order release model,good or bad order of the linear fitting relationship was as follows: Higuchi model>zero-order release model> first-order release model, indicating that drug releases of IMC,GSD and EE were suitable to Higuchi model.
6. The star-shaped copolymers were basically biocompatible with low cellcytotoxicity due to high cell viability at all culture concentration and time by an MTTassay. Even though an acute inflammatory response occurred at the surrounding injectedsite of SD rats in early stage, the inflammatory response disappeared at late stage indicating that star-shaped copolymer hydrogels had a good biocompatibility. In addition,after spraying hydrogels with various drug dosages into vagina of SD rats, macroscopiccharacters and microstructure of organs were observed at various dosage groups andsprayed time. As to high dosage group, severe uterine edema, vaginal hyperemia, partiallysis necrosis of the liver cell, piecemeal necrosis of hepatocytes, and increasing spleenlymphocyte were found in SD rats. As to middle dosage group, uterine hyperemia was justobserved. As to low dosage group and control group, no significant pathological changeswere found. As a result, hydrogels loaded drugs with low dosage group is suitable to applyin female birth control spray.
7. Interestingly, temperature-sensitivity of mixed copolymer aqueous solution wasfound using simply mixing two star-shaped copolymer solutions withouttemperature-sensitive property at different mixing ratios. Preparation method of the mixedgels, the performance of the micellization, sol-gel transition properties, in vitrodegradation, in vitro cytotoxicity and in vivo biocompatibility were preliminary studied.
引文
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