淫羊藿苷壳聚糖/明胶微球的制备及其体外释放研究

本试验以壳聚糖、明胶为载药基质,以中药淫羊藿苷为模拟药物,通过乳化交联的方法制备淫羊藿苷/壳聚糖/明胶微球。考察微球的理化特性,建立持续流动释放系统,检测了微球的体外释放特性和影响因素。微球的理化特性受工艺条件如搅拌速度、乳化剂用量、交联剂用量等因素影响。微球的体外释放速率与微球的粒径、交联度负相关,与载药量正相关。试验结果表明,壳聚糖、明胶可作为缓释微球的载体基质,微球制备工艺简单稳定,微球的释放速率可控,淫羊藿苷/壳聚糖/明胶微球是一种良好的药物释放体系。     

含5-氟尿嘧啶的羧甲基纤维素钠/聚(N-异丙基丙烯酰胺)半互穿网络水凝胶的药物释放性能

以5-氟尿嘧啶(5-FU)为模型药物,对羧甲基纤维素钠/聚(N-异丙基丙烯酰胺)半互穿网络水凝胶(CMC/PNIPA semi-IPN)的药物释放性能进行了研究。结果表明:在37℃、pH=7.4时,药物的释放速率以及释放量都随着凝胶中羧甲基纤维素钠含量的增加而增大。在25℃时,pH对药物释放速率的影响较小;而在37℃时,药物释放速率受pH的影响较大。该凝胶体系用做5-FU的口服释放载体具有较佳的释放性能。     

双重载药多层海藻酸盐-壳聚糖缓释微球的制备及体外释放

采用滴注法将海藻酸钠与钙离子交联,制成负载血管内皮生长因子(VEGF)的藻酸钙核心球,利用层层自组装技术在核心球的表面依次包覆壳聚糖、海藻酸和壳聚糖,壳聚糖中负载万古霉素(VAN),形成多药载药缓控体系.采用正交实验考察海藻酸钠浓度、钙离子浓度及壳聚糖浓度对VEGF和VAN的药物包封率和载药量的影响,优化了制备工艺.采用扫描电子显微镜观察多层微球的表面、截面形貌及粒径,采用傅里叶变换红外光谱检测海藻酸盐与壳聚糖的自组装情况,分别采用酶联免疫吸附(ELISA)双抗体夹心法和紫外分光光度法检测VEGF和VAN的包封率、载药量及体外释放情况.结果表明,海藻酸钠最优浓度为0.04g/mL,氯化钙最优浓度为0.15g/mL,壳聚糖最优浓度为0.01g/mL.微球光滑圆整,均质实心,直径900~1100μm,VEGF的包封率达61.31%,VAN的包封率为3.48%.体外释放实验结果表明,VEGF缓释时间为15.5d,并出现2个释放高峰;VAN缓释时间为4.5d,释药情况平稳持续,无明显突释.双重载药多层包覆微球兼具控制感染和促进血管生成两种潜能,有望应用于组织工程骨的基础研究和临床实践.     

壳聚糖-g-聚甲基丙烯酸凝胶粒的制备及其药物释放行为

以壳聚糖和甲基丙烯酸为原料,硝酸铈铵为引发剂,合成了不同接枝率的壳聚糖-g-聚甲基丙烯酸(CS-g-PMAA),用FTIR、1H NMR和元素分析表征了产物的结构,以柠檬酸三钠和戊二醛为交联剂制备了具有核壳结构的CS-g-PMAA载药体系。 用UV/Vis检测了CS-g-PMAA粒子对模型药物的释放行为。 结果表明,CS-g-PMAA接枝率为12.21%时药物释放速率最慢,其在pH=1.8介质中药物累积释放量(11 h)为44.18%,而壳聚糖粒子的累积释放量高达65.24%,即接枝改性壳聚糖粒子对药物的缓慢控制释放性能较好; CS-g-PMAA粒子的释药行为还依赖于介质的pH值和盐浓度,在低pH值和低盐浓度下,药物释放速率较快;酶环境下由于载体材料的降解使药物释放速率加快。 分析了不同条件下CS-g-PMAA载药粒子中药物的释放机理。     

温敏性聚膦腈及其在药物释放体系中的应用

温敏性聚合物能通过感知温度而实现环境响应,作为药剂可依靠对此类信号的自反馈响应而释放药物或中止释放,极大地增强了释药的持续性和专一性,从而提高了药物的药效和安全性.温敏性聚膦腈是一类新型的温敏材料,它具有良好的生物可降解性质,优良的生物相容性.因此,温敏性聚膦腈作为药物载体用于药物释放体系具有很好的应用前景,近年来备受关注.本文对聚膦腈的温敏性质、生物降解性质进行了评述,并探讨了LCST的影响因素,以及在药物释放体系的应用进展.     

温敏性PCL-PEG-PCL水凝胶的合成、表征及蛋白药物释放

考察了温敏性PCL-PEG-PCL水凝胶中聚乙二醇(PEG)及聚己内酯(PCL)不同嵌段组成对其溶胶-凝胶相转变温度以及亲水性药物(牛血清白蛋白, BSA)释放速率的影响. 采用开环聚合法, 以辛酸亚锡为催化剂、PEG1500/PEG1000为引发剂, 与己内酯单体发生开环共聚, 合成了一系列具有不同PEG和PCL嵌段长度的PCL-PEG-PCL型三嵌段共聚物. 通过核磁共振氢谱及凝胶渗透色谱对其组成、结构及分子量进行了表征. 共聚物的溶胶-凝胶相变温度由翻转试管法测定. 利用透射电镜、核磁共振氢谱及荧光探针技术证实了该材料在水溶液中胶束的形成. 以BSA为模型蛋白药物, 制备载药水凝胶, 利用microBCA法测定药物在释放介质中的浓度, 研究其体外释放行为. 实验结果表明, 共聚物的溶胶-凝胶相变温度与PCL及PEG嵌段长度紧密相关, 即在给定共聚物浓度情况下, 固定PEG嵌段长度而增加PCL嵌段长度, 会导致相变温度降低; 而固定PCL嵌段长度而增加PEG嵌段长度, 其相变温度相应升高. 水凝胶中蛋白药物的释放速率与疏水的PCL嵌段长度无关, 而与亲水的PEG嵌段长度密切相关, 即PEG嵌段越长, 蛋白药物释放越快.     

基于天然高分子基元的阻隔层对磁性载药聚乳酸微球的控释作用

利用层层组装技术构建了基于天然高分子壳聚糖和海藻酸钠的阻隔层, 并研究了该阻隔层对磁性载药聚乳酸微球的药物释放作用. 实验结果表明, 阻隔层能够有效抑制模型药物的突释, 具有延缓药物释放的效果. 具有阻隔层的磁性载药体系具有药物释放平缓和生物相容性高等特点, 是理想的磁靶向载药体系.     

盐溶液调控海藻酸钙微球中的自由羧酸根及其对阿霉素的装载和释放行为研究

采用膜乳化-凝胶化法制备了粒径窄分布的海藻酸钙微球.用不同浓度的氯化钠溶液处理微球来调控微球中的自由羧酸根的含量.用原子吸收光谱和红外光谱表征了微球中钙、钠离子以及化学基团的变化,证明盐处理后海藻酸钙微球内发生了钠离子置换钙离子的过程,海藻酸中的羧酸根由螯合态转变为自由态.用盐处理后的微球吸附带正电荷的小分子抗癌药物阿霉素的能力大大提高,其中用浓度1.8%的氯化钠溶液处理后的微球载药量达到1310μg/mg,是未处理微球的10倍.负载药物的微球具有pH敏感的释放行为,在pH5.5的PBS溶液中的释放速率和释放量显著大于在pH 7.4的PBS溶液中.     

5-氟尿嘧啶分子表面印迹微球MIP-PSSS/CPVA的制备及其体外结肠定位释药特性研究

以对苯乙烯磺酸钠(SSS)为功能单体, 以N,N'-亚甲基双丙烯酰胺(MBA)为交联剂, 采用铈盐-羟基氧化还原引发体系, 在交联聚乙烯醇(CPVA)微球表面实施了5-氟尿嘧啶(5-FU)分子的表面印迹, 在微球CPVA表面形成印迹聚合物(MIP)层, 即制备了5-FU分子印迹微球MIP-PSSS/CPVA. 采用红外光谱(FTIR)和扫描电子显微镜(SEM)法, 对印迹微球进行了表征. 重点考察分析了印迹微球对5-氟尿嘧啶(5-FU)的结合(载药)性能与结合机理, 考察探索了载药微球在不同pH介质中的释放行为. 实验结果表明, 基于本体系特殊的羟基-铈盐表面引发体系, 可有效地实现5-FU分子的表面印迹, 在微球CPVA表面形成分布有大量5-FU分子印迹空穴的聚合物层. 在酸性介质中, 受强静电相互作用的驱动, 印迹微球MIP-PSSS/CPVA对5-FU分子表现出很强的结合能力, 结合容量达110 mg/g, 可实现有效载药. 载药微球的释药行为既具有强烈的pH依赖性, 又具有时滞性: 在模拟胃液中(pH＝1), 基本不释药; 在模拟小肠液中(pH＝6.8), 释药量很小; 在模拟结肠液中(pH＝7.4), 则发生突释, 表现出高效的结肠定位释放行为.     

主链含己烷雌酚的聚酸酐的合成及其降解性能研究

聚酸酐是一类新型的药物控制释放载体材料,具有良好的生物相容性和表面溶蚀性能^[1].聚酸酐的降解和药物释放速率可通过改变单体结构、共聚物的组成和主链上的酸酐键密度实现.后者主要是把降解速率不同的酯键、酰(亚)胺键和磷酸酯键引入主链上.     

Controlled release of 5-fluorouracil or mitomycin-c from polymer matrix: Preparation by radiation polymerization and in vivo evaluation of the anticancer drug/polymer composites

Polymer tablets containing anticancer drugs such as 5-fluorouracil (5-FU) and mitomycin-C (MMC) have been prepared to evaluate the drug-release characteristics in vitro and the effect on local control of mouse solid tumors in vivo. Radiation-induced polymerization of hydrophilic monomers (2-hydroxyethyl methacrylate and related monomers) at low temperature (-80°C) was performed to immobilize 5-FU or MMC in the polymer matrix. The drug was dispersed as microcrystallines within the polymer matrix. The rate of drug release in vitro in buffer solution (pH7.0, 37°C) increased with increase in hydrophilicity of polymer matrix. Appropriate amount of crosslinks within the polymer matrix, as formed by ethylene glycol dimethacrylate (2G) added in the polymerization system, was effective to control the rate of drug release. The drug release became faster upon the addition of increasing amount of water in the radiation-induced polymerization. The tablet consisting of drug/polymer was buried surgically near solid tumors of striate muscle sarcoma (S180) transplanted to Kunming mice and the therapeutic effect of slow releasing drugs was evaluated in vivo by reference to intraperitoneal (i.p.) injection of the corresponding drugs. The slow releasing drugs led to high chemotherapeutic gain for local control of solid tumors with remarkable reduction of toxic side effect of the drugs.     

Chondroitin/polypyrrole nanocomposite hydrogels for the accurate release of 5-fluorouracil by electrical stimulation

The development of electro-stimulated drug release devices is an innovative approach to attain the drug delivery in accurate doses at target sites in a programmed manner. In this work, novel electroactive nanocomposite hydrogels were prepared by encapsulating green-synthesized polypyrrole (PPy) colloids within chondroitin sulfate (CS) networks during the self-crosslinking of CS via N-ethyl-N′-(3-dimethylaminopropyl) carbodiimide chemistry. The structural and morphological properties of CS/PPy hydrogels were studied by Fourier-transformed infrared spectroscopy, scanning electron microscopy, and swelling kinetic measurements. The chemotherapeutic agent 5-fluorouracil (5-FU) was loaded into CS/PPy samples by hydrogel swelling method, or alternatively, by pre-incubating the drug in polymer mixture before crosslinking. Different electrical stimulations can be used to switch ON and accurately tune the 5-FU delivery from GG/PPy hydrogels. A single pulse potential of 5 V switched on the drug delivery up to 90% from nanocomposite hydrogel, in contrast to the low 5-FU amount released in a passive form (< 20%). PPy electroactive behavior played a determining role as the main driving force in 5-FU release activation. Cytotoxicity of hydrogels with and without 5-FU was examined in normal and cancer cells. Considering the high cytotoxicity of 5-FU, the ON/OFF 5-FU release patterns evidenced the potential of CS/PPy hydrogels for electrically controlled drug delivery in implantable or transdermal drug release devices.     

Anticancer drug release from poly(N-isopropylacrylamide/itaconic acid) copolymeric hydrogels

The drug uptake and release of anticancer drug from N-isopropylacrylamide/itaconic acid copolymeric hydrogels containing 0–3 mol% of itaconic acid irradiated at 48 kGy have been investigated. 5-Fluorouracil (5-FU) is used as a model anticancer drug. The effect of 5-FU solution on swelling characteristics of PNIPAAm and P(NIPAAm/IA) copolymeric hydrogels have also been studied. The percent swelling, equilibrium swelling, equilibrium water/5-FU content and diffusion constant values are evaluated for poly(N-isopropylacrylamide) (PNIPAAm) and poly(N-isopropylacrylamide/itaconic) (P(NIPAAm/IA)) hydrogels at 130 ppm of 5-FU solution at room temperature. Diffusion of 5-FU solution into the hydrogels has been found to be the non-Fickian type. Finally, the kinetics of drug release from the hydrogels are examined.     

表面预处理对镁铝水滑石结构性质和缓释性能影响

以Mg-Al-NO3水滑石(LDHs)为载体,将5-氟尿嘧啶(5-FU)通过离子交换法插入其层间,得5-FU/LDHs缓释材料。并对水滑石表面进行弱酸预处理改性,利用XRD、FTIR、TG-DSC、SEM和零电荷点(pHPZC)等表征手段,考察酸预处理对水滑石表面化学性质及微观结构的影响。结果表明,5-FU/LDHs的层间距从0.858 nm扩大到1.064 nm,层间5-FU2阴离子与主体层板通过氢键与静电作用,以呈一定角度单层交替排列于层间。酸预处理的水滑石粒径变小,层板正电荷密度增大。5-FU的释放机理是物理扩散、离子交换和药物溶解等协同作用,酸预处理可提高水滑石的缓释性能和稳定性。     

表面预处理对镁铝水滑石结构性质和缓释性能影响

以Mg-Al-NO₃水滑石（LDHs）为载体,将5-氟尿嘧啶（5-FU）通过离子交换法插入其层间,得5-FU/LDHs缓释材料。并对水滑石表面进行弱酸预处理改性,利用XRD、FTIR、TG-DSC、SEM和零电荷点（pHPZC）等表征手段,考察酸预处理对水滑石表面化学性质及微观结构的影响。结果表明,5-FU/LDHs的层间距从0.858nm扩大到1.064nm,层间5-FU₂阴离子与主体层板通过氢键与静电作用,以呈一定角度单层交替排列于层间。酸预处理的水滑石粒径变小,层板正电荷密度增大。5-FU的释放机理是物理扩散、离子交换和药物溶解等协同作用,酸预处理可提高水滑石的缓释性能和稳定性。     

同载基因和药物的超微载体粒子的制备及体外评价

以聚乳酸_乙醇酸共聚物 (PLGA)和自行制备的O_羧甲基壳聚糖 (O_CMC)为原料 ,以 5_氟尿嘧啶 (5 Fu)为抗癌药物模型 ,以反义EGFR(表皮生长因子受体 )为基因药物模型 ,构建与评价了同载抗癌药物与基因的复合功能纳米药物载体系统。同载超微粒子的平均粒径为 2 5 8 7nm ,粒径分布指数为 0 14 2 ,粒子表面 ξ电位为 - 10 6 7eV。同载超微粒子在PBS中的释药行为研究表明 :超微粒子中 5_FU和基因均具有零级缓慢释放特性。体外肿瘤细胞存活率实验和免疫组化实验均证实同载超微粒子能高效抑制TJ90 5人脑胶质瘤细胞的增殖。最后用荧光共聚焦显微镜动态监测了超微粒子进入瘤细胞的转染过程 ,发现粒子可在不同时间内进入细胞浆和细胞核。     

Thermoresponsive N-vinyl caprolactam grafted sodium alginate hydrogel beads for the controlled release of an anticancer drug

A series of thermoresponsive sodium alginate-g-poly(vinyl caprolactam) (NaAlg-g-PNVCL) beads were prepared as drug delivery matrices of 5-flurouracil (5-FU) crosslinked by glutaraldehyde (GA) in the hydrochloric acid catalyst. Graft copolymers of sodium alginate with vinyl caprolactam were synthesized using azobisisobutyronitrile as an initiator, and characterized by Fourier infrared spectroscopy, differential scanning calrimetry and X-ray diffraction for analysis of the amorphous nature drug in the beads, and by scanning electron microscopy for the spherical nature of the beads. Preparation condition of the beads was optimized by considering the percentage of encapsulation efficiency, swelling behavior of beads and their release data. Effects of variables such as GA concentration, drug/polymer ratio and catalyst concentration on the release of 5-FU were carried out at two different temperatures (25 and 37 °C) in simulated intestinal fluid for 12 h. It was observed that, drug release from the beads decreased with increasing drug/polymer (d/p) ratio, extent of crosslinking agent and catalyst concentration. The swelling degree of graft copolymer beads was found to be increased with decreasing of environmental temperature. In vitro release studies were performed at 25 and 37 °C for 12 h, and showed that thermoresponsive graft copolymer beads had higher drug release behavior at 25 °C than that at 37 °C, following Fickian diffusion transport mechanism with slight deviation.     

功能化纳米粒子作为药物载体的研究

将合成的含有羧基侧基官能团的己内酯类聚合物, 用溶剂挥发与超声乳化相结合的方法制备成表面可供修饰的纳米粒子. 利用扫描电镜(SEM)研究了纳米粒子在水溶液中的形态. 使用5-氟脲嘧啶(5-FU)作为模型药物制备了载药纳米粒子, 利用紫外分光光度计法、差示扫描量热法(DSC)、X射线衍射法(XRD)研究了纳米粒子的载药及释放性能. 研究表明, 载药纳米粒子可以控制5-FU的释放速率. 释放时间可持续至96 h 以上, 符合Higuchi 动力学方程.     

聚乳酸包载5-氟尿嘧啶靶向超微粒子对人胃癌转移瘤的靶向性和控制释放研究

使用w／o／w复乳法制备聚乳酸载5-氟尿嘧啶超微粒子,使用透射电镜、激光粒度仪和紫外分光光度计对超微粒子进行表征,并考察其体外释药性质。将^99mTc标记的连有VEGF121单克隆抗体的超微粒子通过尾静脉注射到SCID裸鼠体内,观察它对胃癌转移瘤的靶向效果和治疗效果。结果显示超微粒子成圆球形,平均粒径为195.2nm,多分散系数为0.148,靶向载药超微粒子的载药率为8．23％,包封率为24．71％。聚乳酸载5-Fu超微粒子在PBS缓冲溶液中具有较好的控释效果,累积释放量Q与时间平方根t^1/2基本呈线性关系．尾静脉注射靶向超微粒子两小时以后可看到大部分超微粒子集中到肿瘤部位。在所有的实验组中,含5-Fu靶向载药超微粒子组的疗效最好,说明本靶向载药超微粒子具有抑制肿瘤的血管生成并在肿瘤组织释放化疗药物抑制肿瘤生长的双重作用。     

Development of biodegradable co-poly( -lactic/glycolic acid) microspheres for the controlled release of 5-FU by the spray drying method

The water-soluble anti-cancer drug, 5-fluorouracil (5-fluoro-2,4-pyrimidinedione) (5-FU) is encapsulated into biodegradable co-poly ( -lactic/glycolic acid) (PLGA) using the spray drying method for the development of long-lasting controlled release systems. In this study, the effects of both polymeric composition and technological parameters on release profiles of 5-FU were investigated. The degradation of various microspheres was also investigated. The mixture of dichloromethane/chloroform/methanol (1:1:2 v/v) instead of dichloromethane/chloroform (1:1 v/v) resulted in the modification of morphology, while the physical structure of the microsphere varied from a porous PLGA microsphere to a dense PLGA microsphere. The results show that the average diameter was 2 μm and the anti-cancer drug loading of microspheres approached approximately 8% (w/w). In addition, the lactide/glycolide ratio of the polymer is an important parameter for controlling the release profile of the entrapped anticancer drug. Our results indicate that the mixture solvent using the spray drying method was more efficient than emulsification solvent diffusion.