Nanoparticles in porous microparticles prepared by supercritical infusion and pressure quench technology for sustained delivery of bevacizumab.
Nanoparticles in porous microparticles prepared by supercritical infusion and pressure quench technology for sustained delivery of bevacizumab.
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DOI：
10.1021/mp400487f
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发表时间：
2013-12-02
影响因子：
4.9
通讯作者：
Kompella UB
中科院分区：
文献类型：
--
作者：
Yandrapu SK;Upadhyay AK;Petrash JM;Kompella UB
多孔微粒中的纳米颗粒（NPinPMP）是一种新型的蛋白质药物缓释系统，采用超临界输注和压力淬灭技术，不将蛋白质暴露于有机溶剂或超声处理。输送系统设计基于超临界二氧化碳（SC CO2）膨胀聚（乳酸-乙醇酸）共聚物（PLGA）基质而非聚乳酸（PLA）基质的能力。该技术应用于贝伐单抗，一种每月一次玻璃体内注射的蛋白质药物，用于治疗湿性年龄相关性黄斑变性。通过将混合物暴露于SC CO2，将贝伐珠单抗包衣的PLA纳米颗粒包封到多孔化PLGA微粒中。在SC CO2暴露后，PLGA微粒的尺寸增加了6.9倍。共聚焦和扫描电子显微镜研究证明了PLGA微粒的膨胀和多孔化以及PLA纳米颗粒在PLGA微粒内的输注。贝伐珠单抗从NPinPMP的体外释放持续4个月。尺寸排阻色谱、荧光光谱、圆二色光谱、SDS-PAGE和ELISA研究表明，释放的贝伐珠单抗保持其单体形式、构象和活性。此外，在大鼠模型中玻璃体内施用溶液或NPinPMP中的Alexa Flour 488缀合的贝伐珠单抗后，使用非侵入性荧光光度法评价贝伐珠单抗从NPinPMP的体内递送。与Alexa-贝伐珠单抗溶液的玻璃体信号在2周时达到基线不同，Alexa-贝伐珠单抗从NPinPMP的释放可以检测到2个月。因此，NPinPMP是一种新型的蛋白质药物缓释系统，以减少在治疗眼后部疾病中的蛋白质注射频率。
Nanoparticles in porous microparticles (NPinPMP), a novel delivery system for sustained delivery of protein drugs, was developed using supercritical infusion and pressure quench technology, which does not expose proteins to organic solvents or sonication. The delivery system design is based on the ability of supercritical carbon dioxide (SC CO2) to expand poly(lactic-co-glycolic) acid (PLGA) matrix but not polylactic acid (PLA) matrix. The technology was applied to bevacizumab, a protein drug administered once a month intravitreally to treat wet age related macular degeneration. Bevacizumab coated PLA nanoparticles were encapsulated into porosifying PLGA microparticles by exposing the mixture to SC CO2. After SC CO2 exposure, the size of PLGA microparticles increased by 6.9 fold. Confocal and scanning electron microscopy studies demonstrated the expansion and porosification of PLGA microparticles and infusion of PLA nanoparticles inside PLGA microparticles. In vitro release of bevacizumab from NPinPMP was sustained for 4 months. Size exclusion chromatography, fluorescence spectroscopy, circular dichroism spectroscopy, SDS-PAGE, and ELISA studies indicated that the released bevacizumab maintained its monomeric form, conformation, and activity. Further, in vivo delivery of bevacizumab from NPinPMP was evaluated using noninvasive fluorophotometry after intravitreal administration of Alexa Flour 488 conjugated bevacizumab in either solution or NPinPMP in a rat model. Unlike the vitreal signal from Alexa-bevacizumab solution, which reached baseline at 2 weeks, release of Alexa-bevacizumab from NPinPMP could be detected for 2 months. Thus, NPinPMP is a novel sustained release system for protein drugs to reduce frequency of protein injections in the therapy of back of the eye diseases.
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