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Development and in vitro/in vivo evaluation of AcHES-PLGA composite microspheres for protein delivery.

机译：开发用于蛋白质递送的AcHES-PLGA复合微球并进行体外/体内评估。

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摘要

This dissertation focused on development and in vitro/in vivo evaluation of a novel PLGA and starch-based hydrogel composite microsphere delivery system for sustained release of proteins. PLGA acts as an effective barrier and controls biodegradation, thereby providing sustained release characteristics. The hydrogel's propensity for water uptake and its hydrophilic nature offered a friendly microenvironment for proteins.; The composite microspheres were prepared by soaking protein into blank acryloyl hydroxyethyl starch (AcHES) hydrogel microparticles followed by encapsulation into the PLGA matrix. Bovine serum albumin, a common model protein, was selected to develop the fabrication process and scanning electron microscopy showed a PLGA matrix containing many AcHES particles. AcHES 5–10% and 5–10% BSA target load provided high drug encapsulation efficiency. The composite exhibited a favorable profile with a reduced initial burst, higher incremental and more complete release than that from PLGA alone. Enzymatically active proteins, maltase and horseradish peroxidase retained over 70% specific activity after encapsulation, suggesting that sensitive proteins could survive the composite manufacturing process.; To further characterize the composite microsphere system, lysozyme, similar in size to many commercial biopharmaceuticals, was selected to study the in vitro-in vivo correlation (IVIVC). Lysozyme displayed high conformational stability and lack of adsorption to PLGA in acetate and glycine buffers, whereas in PBS, the protein conformational stability was low with a trend toward aggregation and significant protein adsorption was evident. The adsorption resulted in slow and incomplete release in PBS while the release in acetate and glycine buffers was complete within 40 and 70 days, respectively. The in vivo profile qualitatively correlated with in vitro release in glycine buffer, suggesting that protein stability and adsorption are critical factors controlling protein release kinetics and optimization of IVIVC.; Finally, the composite system was adapted to a therapeutic protein, insulin. Insulin integrity was confirmed by SDS-PAGE and MALDI-TOF Mass Spectrometry. An extraction and HPLC analytical method was developed to determine insulin loading. Microspheres with low initial burst batches were achieved by sonication and they exhibited a sustained in vitro release pattern over 28 days. Glucose suppression correlated well with serum insulin levels and animal growth for ten days after single dose microsphere treatment. Multiple dosing based on glucose titration showed sustained suppression of glucose as well as repetitive efficacy and blood insulin levels from each dose. These results indicate that the composite microsphere system can be costumed for a target therapeutic protein and can be engineered to meet desired therapeutic needs.
机译：本文主要研究和开发了一种新型的PLGA和淀粉基水凝胶复合微球递送系统，用于蛋白质的持续释放和体内/体外的评价。 PLGA充当有效的屏障并控制生物降解，从而提供持续释放的特性。水凝胶的吸水倾向及其亲水性为蛋白质提供了友好的微环境。通过将蛋白质浸入空白的丙烯酰基羟乙基淀粉（AcHES）水凝胶微粒中，然后封装到PLGA基质中来制备复合微球。选择牛血清白蛋白（一种常见的模型蛋白）来开发制备过程，扫描电子显微镜显示PLGA基质中含有许多AcHES颗粒。 AcHES 5-10％和5-10％BSA的目标负荷可提供较高的药物封装效率。该复合材料表现出良好的特性，与单独的PLGA相比，具有减少的初始爆裂，更高的增量和更完全的释放。包囊后，具有酶活性的蛋白质，麦芽糖酶和辣根过氧化物酶保留了70％以上的比活性，这表明敏感的蛋白质可以在合成过程中幸存下来。为了进一步表征复合微球系统，选择了与许多商业生物药物类似的溶菌酶，以研究 in vitro-in vivo 相关性（IVIVC）。溶菌酶在乙酸盐和甘氨酸缓冲液中显示出高的构象稳定性和对PLGA的缺乏吸附，而在PBS中，蛋白的构象稳定性低，具有聚集的趋势，并且明显的蛋白吸附是明显的。吸附导致在PBS中缓慢且不完全释放，而在乙酸盐和甘氨酸缓冲液中的释放分别在40和70天内完成。体内的概况与甘氨酸缓冲液中的体外释放在质量上相关，表明蛋白质的稳定性和吸附是控制蛋白质释放动力学和优化IVIVC的关键因素。最终，复合系统适应了治疗性蛋白质胰岛素。通过SDS-PAGE和MALDI-TOF质谱法确认了胰岛素的完整性。开发了一种提取和HPLC分析方法来确定胰岛素负荷。通过超声处理获得的初始爆破批次低的微球，在28天内显示出持续的体外释放模式。单剂量微球治疗后十天内，葡萄糖抑制与血清胰岛素水平和动物生长密切相关。基于葡萄糖滴定的多次给药显示持续抑制葡萄糖以及每个剂量的重复功效和血液胰岛素水平。这些结果表明，复合微球系统可适合目标治疗蛋白，并可进行工程改造以满足所需的治疗需求。

著录项

  • 作者

    Jiang, Ge.;

  • 作者单位

    University of Kentucky.;

  • 授予单位 University of Kentucky.;
  • 学科 Health Sciences Pharmacy.
  • 学位 Ph.D.
  • 年度 2002
  • 页码 156 p.
  • 总页数 156
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药剂学;
  • 关键词

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