Biodegradable Polydioxanone Microspheres for Transcatheter Arterial Embolization: Proof of Principle

PurposeTo evaluate feasibility, embolization success, biodegradability, reperfusion, and biocompatibility of biodegradable microspheres (MS) made from polydioxanone (PDO) for transcatheter arterial embolization.Materials and MethodsUnilateral selective renal embolization of a segmental artery was performed in 16 New Zealand White rabbits with PDO-MS (100–150 μm and 90–315 μm). Animals were randomly assigned to different observation periods and underwent control digital subtraction angiography (DSA) and MR imaging immediately (n = 3), 1 week (n = 2), 4 weeks (n = 2), 8 weeks (n = 2), 12 weeks (n = 5), and 16 weeks (n = 2) after embolization. Kidneys were harvested for macroscopic and histologic analysis of embolization success, biodegradability, and biocompatibility.ResultsEmbolization was technically successful in 15 of 16 animals. One animal died of anesthesia-related circulatory failure. The 100–150 μm MS were injected easily through 3-F catheters; the 90–315 μm MS tended to clog with intermittent catheter obstruction. DSA and MR imaging showed successful target embolization in 13 of 15 animals. In 2 animals, the entire kidney was affected owing to catheter clogging, including a reflux of MS while flushing. Control DSA and MR imaging showed increasing vascular reperfusion with time. Macroscopic and histologic analysis revealed necrosis/infarction in areas in which embolization was achieved. MS were extensively degraded after 16 weeks, and overall inflammatory reaction was mild.ConclusionsBiodegradable PDO-MS induced effective embolization of target vessels while demonstrating good biocompatibility. MS increasingly dissolved at 16 weeks, partial reperfusion started at week 1, and complete reperfusion started at week 8, thus offering possible advantages as a temporary embolic agent.     

携载rhBMP-2微球的新型可注射自凝固复合人工骨的制备及特性研究

[目的]制备一种具有良好降解性和成骨活性、可注射的自凝固新型骨修复材料。[方法]制备携载rhBMP-2的聚乳酸与聚乙醇酸共聚物（PLGA）微球，并将其与rhBMP-2／磷酸钙骨水泥（CPC）复合，制备出rhBMP-2／PLGA微球／CPC复合人工骨。探讨了材料的特性，包括形貌、固化时间、抗压强度及反映材料体外降解速度的指标一体外降解液Ca、P浓度变化，测定复合材料rhBMP乏的释药速度及体外诱导MSCs细胞成骨分化的能力。[结果]与单纯CPC-rhBMP-2相比，复合材料的固化时间少量增加，抗压强度下降明显。体外降解速度及体外释药明显提高，释放的rhBMP-2具有骨诱导活性。[结论]rhBMP-2／PLGA微球／磷酸钙骨水泥新型复合人工骨是具有良好应用前景的骨修复材料。     

顺铂聚乳酸微球的药物释放特性及肝动脉栓塞研究

对顺铂聚乳酸微球进行了体外药物释放和家犬肝动脉栓塞研究。该微球粒径范围为50～200μm,平均粒径为115.76±35.94μm,顺铂含量为37.16%(W/W);体外药物释放机制符合Higuchi方程;肝动脉栓塞后8h,肝组织顺铂浓度高达21.55±12.18μg/g,明显高于肝动脉灌注顺铂组:3.16±0.09μg/g(P<0.05);肝动脉栓塞组的顺铂血浓峰值、各取血点浓度及曲线下面积AUC皆低于肝动脉灌注顺铂组。可望达到提高栓塞部位的药物疗效,降低全身毒副反应的作用。     

Influence of Preparation Factors on the Sustained Release of Nifedipine from Eudragit RL/RS Microspheres

用乳剂—溶剂挥发法制备硝苯地平的丙烯酸树脂缓释微球。微球中药物的释放速度随丙烯酸树脂ＥｕｄｒａｇｉｔＲＬ／ＲＳ比率的增加以及制备时搅拌速率的增加而增大，随内相聚合物浓度的增加及微球粒径的增加而减小，释药５０％所需时间与微球粒径呈良好线性。微球的释药速率也随药物含量的增加（从４．２％到１６．７％）而增大，并快于药物结晶的溶解速率，但药物含量达２６．６％时，微球释药速率明显下降并低于药物结晶的溶解速率。用差热分析和Ｘ射线衍射分析证明，药物含量为４．２，９．４和１６．７％的微球中药物完全是以非晶态分散的，而含药２６．６％的微球中有药物结晶存在。不同微球释药低于７０％时，释放方式均符合Ｈｉｇｕｃｈｉ时间平方根方程。     

In vivo induction of CD4+ T cell responses by antigens covalently linked to synthetic microspheres does not require adjuvant

Macrophages, dendritic cells or B lymphocytes have been shownto play a major role in the presentation of soluble antigensto CD4⁺ T cells. In contrast, the capacity of these cells topresent particulate antigens such as bacterial or parasiticantigens to T cells remains controversial. To investigate thisquestion, well defined particulate antigens were prepared bycovalent linkage of proteins or peptides to 1 µm in diametersynthetic microspheres. The T cell immunogenicity of such particulateantigens was analyzed in vitro and in vivo. In vitro, a solubleprotein such as hen egg lysozyme (HEL) coupled to beads stimulateda strong proliferative T cell response of lymph node cells fromHEL-primed mice or of specific T cell hybridomas. HEL coupledto beads was presented to the specific T cell hybridomas bysplenocytes or by peritoneal macrophages, but not by lymphomaB cells. Immunization of mice with several different proteinantigens or with a synthetic peptide covalently linked to beadsinduced strong CD4⁺ T cell responses in the absence of adjuvant.The strong in vivo immunogenicity of proteins coupled to beadsdid not result from a non-specific adjuvant effect of beadssince covalent linkage of the antigen to beads was strictlyrequired to induce T cell responses in the absence of adjuvant.In vivo treatment by carrageenan showed that macrophages arerequired for the in vivo stimulation of T cell responses bythese particulate antigens. Thus, these results demonstratedthe role of phagocytic cells, especially macrophages, for invivo presentation of particulate antigens. These particulateantigens represent an interesting approach for the developmentof new vaccines, and for the in vivo analysis of the role ofvarious antigen presenting cells in T cell activation and differentiation.     

白蛋白微球作为肝靶向给药载体的研究

用均匀设计方法和计算机技术筛选了乳化化学交联法制备白蛋白微球的六个因素,十二个水平。优化出最佳制备工艺,制备了平均粒径0.41～0.47μm的白蛋白微球。将此工艺制备的¹²⁵I-白蛋白微球做动物体内研究,结果表明微球iv后主要浓集在肝脏,可达注入总剂量的68%,此微球在靶组织肝脏的变化规律可用二室模型契合。     

免疫磁性捕获ELISA法检测甘草中甘草蛋白的研究

目的 制备甘草蛋白免疫磁性微球，并建立快速、精确的免疫磁性捕获ELISA法检测甘草蛋白。方法 采用种子聚合法合成聚苯乙烯磁性微球，并以兔抗甘草蛋白IgG抗体致敏，制备特异性捕获甘草特征蛋白的免疫磁性微球。以生物素标记抗体为示踪抗体，结合辣根过氧化物酶标亲和素建立ELISA检测系统，用于甘草药材和含甘草中成药中甘草蛋白的分析。结果 利用该方法对甘草药材和中成药中甘草蛋白抗原检测，检测灵敏度达到10ng／mL。结论 免疫磁性捕获ELISA检测技术方便、快速、准确，为生药的品种鉴定及中成药的质量控制提供一种新方法。     

蜂毒素微球经动脉介入治疗大鼠肝癌的实验研究

目的:观察蜂毒素微球(M-MS)经动脉介入对大鼠肝癌的治疗作用.方法:采用改良的复乳-液中干燥法制备蜂毒素-聚乳酸/羟乙酸微球,建立大鼠移植性肝癌模型并随机分为四组,分别经肝动脉灌注生理盐水(NS,1.5ml/kg)、蜂毒素(Melittin,0.35mg/kg)、空白微球(B-MS,10mg/kg)和蜂毒素-聚乳酸/羟乙酸微球(10mg/kg).比较治疗后各组大鼠的肿瘤生长情况、肿瘤坏死程度和生存时间.结果:与生理盐水组比较,Melittin组、B-MS组肿瘤生长受到明显抑制(P<0.01),肿瘤坏死程度以轻中度为主,但两组动物生存时间均未能明显延长(P>0.05).M-MS组与NS组、Melittin组及B-MS组相比,肿瘤生长抑制显著(P<0.01),肿瘤坏死更广泛、更彻底,且经蜂毒素微球治疗的大鼠生存期显著延长(P<0.01).结论:蜂毒素以药物微球的剂型经肝动脉给药,抗肿瘤效果明显优于单纯的蜂毒素和空白微球.     

曲安奈德PLGA微球对兔上腭部创面瘢痕形成影响的实验研究

目的:探讨曲安奈德PLGA微球对创面瘢痕愈合中瘢痕生成的抑制作用,研究局部应用曲安奈德的最佳给药途径。方法:3组共24只兔的上腭部创面模型,分别应用曲安奈德PLGA微球以及曲安奈德悬浊液,在瘢痕形成不同时间后切取瘢痕标本进行HE、VG染色及酶组织化学染色并电镜观察其组织形态学改变来分析曲安奈德不同给药途径的差异。结果:三组兔上腭创面愈合时间不同,表面颜色、质地不一样。电镜、常规染色以及免疫组织化学染色皆说明曲安奈德PLGA微球有明显的瘢痕抑制作用,且效果高于曲安奈德悬浊液。结论:曲安奈德PLGA微球能抑制瘢痕的增殖过程,使瘢痕组织纤维化过程明显减轻。合并手术一次性给药治疗瘢痕有很好的临床价值。