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Lyoprotectant Optimization for the Freeze-Drying of Receptor-Targeted Trojan Horse Liposomes for Plasmid DNA Delivery.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-04-21 , DOI: 10.1021/acs.molpharmaceut.0c00310 Hungyen Lee 1 , Dahai Jiang 1 , William M Pardridge 1
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-04-21 , DOI: 10.1021/acs.molpharmaceut.0c00310 Hungyen Lee 1 , Dahai Jiang 1 , William M Pardridge 1
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Trojan horse liposomes (THLs) are a form of ligand-targeted nanomedicine, where a plasmid DNA is encapsulated in the interior of a 100–150 nm pegylated liposome, and the tips of a fraction of the surface pegylated strands are covalently linked to a receptor-specific monoclonal antibody (MAb) via a thio-ether linkage. The goal of this work was to develop a lyophilization methodology that enables retention of the structure and function of the THLs following the freeze-drying/hydration process. THL fusion and leakage of plasmid DNA were observed with several lyoprotectants, including trehalose, hyaluronic acid, γ-cyclodextrin, or sulfobutylether-β-cyclodextrin. However, the use of hydroxypropyl-γ-cyclodextrin, at a 40:1 wt/wt ratio relative to the THL phospholipid, eliminated liposome fusion and produced high retention of encapsulated plasmid DNA and THL-mediated gene expression after lyophilization followed by hydration. The freeze-dried THL cake was amorphous without cavitation, and the diameters and functional properties of the THLs were preserved following hydration of cakes stored for at least six months. Intravenous administration of the hydrated freeze-dried THLs in the Rhesus monkey demonstrated the safety of the formulation. Blood plasmid DNA was measured with a quantitative polymerase chain reaction method, which enabled a pharmacokinetics analysis of the blood clearance of the THL-encapsulated plasmid DNA in the primate. The work shows that optimization of the lyoprotectant enables long-term storage of the MAb-targeted DNA encapsulated liposomes in the freeze-dried state.
中文翻译：
冻干优化的针对受体的特洛伊木马脂质体的冷冻干燥，用于质粒DNA的递送。
特洛伊木马脂质体（THL）是靶向配体的纳米药物的一种形式，其中质粒DNA封装在100–150 nm聚乙二醇脂质体内，一部分聚乙二醇表面链的末端共价连接至受体硫醚键形成特异性单克隆抗体（MAb）。这项工作的目的是开发一种冻干方法，该方法能够在冷冻干燥/水合过程后保留THL的结构和功能。用几种冻干保护剂，包括海藻糖，透明质酸，γ-环糊精或磺丁基醚-β-环糊精，观察到THL融合和质粒DNA的泄漏。但是，以相对于THL磷脂40：1 wt / wt的比例使用羟丙基-γ-环糊精，冻干然后水合后，它消除了脂质体融合并产生了高保留的包封质粒DNA和THL介导的基因表达。冻干的THL饼是无定形的无气穴现象，在将饼储存至少六个月后水合后，THL的直径和功能特性得以保留。在恒河猴中静脉内给予水合的冻干THLs证明了该制剂的安全性。用定量聚合酶链反应法测量血液质粒DNA，该方法能够对灵长类动物中THL包埋的质粒DNA的血液清除率进行药代动力学分析。这项工作表明，冻干保护剂的优化可以使以MAb为靶标的DNA包裹的脂质体在冻干状态下长期保存。
更新日期：2020-04-21
中文翻译：
冻干优化的针对受体的特洛伊木马脂质体的冷冻干燥，用于质粒DNA的递送。
特洛伊木马脂质体（THL）是靶向配体的纳米药物的一种形式，其中质粒DNA封装在100–150 nm聚乙二醇脂质体内，一部分聚乙二醇表面链的末端共价连接至受体硫醚键形成特异性单克隆抗体（MAb）。这项工作的目的是开发一种冻干方法，该方法能够在冷冻干燥/水合过程后保留THL的结构和功能。用几种冻干保护剂，包括海藻糖，透明质酸，γ-环糊精或磺丁基醚-β-环糊精，观察到THL融合和质粒DNA的泄漏。但是，以相对于THL磷脂40：1 wt / wt的比例使用羟丙基-γ-环糊精，冻干然后水合后，它消除了脂质体融合并产生了高保留的包封质粒DNA和THL介导的基因表达。冻干的THL饼是无定形的无气穴现象，在将饼储存至少六个月后水合后，THL的直径和功能特性得以保留。在恒河猴中静脉内给予水合的冻干THLs证明了该制剂的安全性。用定量聚合酶链反应法测量血液质粒DNA，该方法能够对灵长类动物中THL包埋的质粒DNA的血液清除率进行药代动力学分析。这项工作表明，冻干保护剂的优化可以使以MAb为靶标的DNA包裹的脂质体在冻干状态下长期保存。
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