Effective oral delivery of insulin in animal models using vitamin B12-coated dextran nanoparticles
Effective oral delivery of insulin in animal models using vitamin B12-coated dextran nanoparticles
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DOI：
10.1016/j.jconrel.2007.05.019
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发表时间：
2007-09-26
影响因子：
10.8
通讯作者：
Jain, Sanjay K.
中科院分区：
文献类型：
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作者：
Chalasani, Kishore B.;Russell-Jones, Gregory J.;Jain, Sanjay K.
维生素B12载体系统用于口服递送缀合肽/蛋白质和增强纳米颗粒（NPs）转运的潜在效用已被证明。本研究旨在优化使用不同交联水平的VB 12-NPs缀合物的有效性，与不同的VB 12-涂层连接，并在动物模型中进行评估，以研究有效的胰岛素载体。通过氨基甲酸酯和酯/酰胺键在5 '羟基核糖和c-丙酰胺位点合成适合于口服递送的氨基烷基VB 12衍生物，并将其偶联到具有不同交联的琥珀酸修饰的葡聚糖NP上。通过XPS分析确认VB 12结合，并通过HPLC定量（4.0至5.7%w/w的NP）。这些多分散的纳米颗粒结合物显示出更高的尺寸，高胰岛素截留和更快的胰岛素释放，低水平的交联。这些VB 12-NP缀合物（150-300 nm）在STZ糖尿病大鼠中显示出具有双相行为的显著（70-75%血糖降低）和延长（54 h）的抗糖尿病作用。发现具有低水平交联的NP是上级载体，并且与氨基甲酸酯键的VB 12衍生物一起更有效。发现相对于SC胰岛素的药理学利用度为29.4%，其优于酯连接的VB 12的NP缀合物（1.5倍）和相对较高交联的颗粒（I.我弃牌）。此外，NP载体在先天性糖尿病小鼠中显示出类似的口服胰岛素功效（在20小时时减少60%）。在两种动物模型中均发现大量血浆胰岛素（231和197 mu IU/ml）。在两个研究剂量下，载体系统显示出剂量响应。用大量过量的游离VB 12预给药使观察到的活性最小化，表明VB 12介导的摄取占优势。得出的结论是，VB 12-右旋糖酐纳米粒缀合物是口服胰岛素输送治疗糖尿病的可行载体。(C)2007 Elsevier B. V.保留所有权利。
The potential utility of vitamin B12 carrier system for the oral delivery of conjugated peptides/proteins and enhancement of nanoparticles (NPs) transport has been demonstrated. The present study aims to optimize the effectiveness of VB12-NPs conjugates using different levels of cross-linking, linked with different VB12-COatings and evaluates in animal models to investigate an efficient insulin carrier. Amino alkyl VB12 derivatives suitable for oral delivery were synthesized at 5 ' hydoxy ribose and c-propionamide sites via carbamate and ester/amide linkages, and were coupled to succinic acid modified dextran NPs of varied cross-linking. VB12 binding was confirmed by XPS analysis, and was quantified by HPLC (4.0 to 5.7% w/w of NPs). These polydisperse NPs conjugates showed higher size, high insulin entrapment and faster insulin release with low levels of cross-linking. These VB12-NPs conjugates (150-300 nm) showed profound (70-75% blood glucose reductions) and prolonged (54 h) anti-diabetic effects with biphasic behaviour in STZ diabetic rats. NPs with the low levels of cross-linking were found to be superior carriers, and were more effective with VB12 derivatives of carbamate linkage. The pharmacological availability relative to SC insulin was found to be 29.4%, which was superior compared to NPs conjugate of ester linked VB12 (1.5 fold) and relatively higher cross-linked particles (I. I fold). Further, the NPs carrier demonstrated a similar oral insulin efficacy in congenital diabetic mice (60% reduction at 20 h). Significant quantities of plasma insulin were found in both animal models (231 and 197 mu IU/ml). At two investigated doses, the carrier system shows dose response. Pre-dosing with a large excess of free VB12 minimized the observed activity, indicating predominance of VB12 mediated uptake. It is concluded that VB12-dextran NPs conjugate is a viable carrier for peroral insulin delivery to treat diabetics. (C) 2007 Elsevier B.V. All rights reserved.