Improving solubility and chemical stability of natural compounds for medicinal use by incorporation into liposomes
Improving solubility and chemical stability of natural compounds for medicinal use by incorporation into liposomes
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DOI：
10.1016/j.ijpharm.2011.01.056
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发表时间：
2011-09-20
影响因子：
5.8
通讯作者：
Schiffelers, Raymond M.
中科院分区：
文献类型：
--
作者：
Coimbra, Maria;Isacchi, Benedetta;Schiffelers, Raymond M.
天然生物活性化合物因其在包括癌症在内的多种慢性炎症性疾病中的化学预防和治疗潜力而被研究了很长时间。然而，它们的物理化学性质通常导致化学稳定性差和缺乏体内生物利用度。很少有人体临床试验涉及这些化合物的吸收、分布、代谢和排泄与疗效的关系。在这项研究中，我们研究了咖啡酸（衍生物），香芹酚（衍生物），百里酚，紫檀芪（衍生物），和N-（3-氧代-十二烷酰基）-1-高丝氨酸内酯。这些是天然化合物，具有强烈的抗炎特性，来自植物和细菌。然而，这些化合物具有差的水溶性或化学不稳定。为了克服这些限制，我们制备了脂质体制剂。我们的研究结果表明，亲脂性的3-氧代-C-12-高丝氨酸内酯和芪衍生物可以装载到脂质体脂质双层的效率为50- 70%。因此，脂质体溶解这些化合物，允许静脉内施用而不使用溶剂。当化合物不能加载到脂质双层（香芹酚和百里酚）中或在血清白蛋白（3-氧代-C-12-高丝氨酸内酯和蝶芪衍生物）存在下从脂质体中快速提取时，显示化合物衍生为水溶性前药可提高加载效率和包封稳定性。香芹酚和紫檀芪的磷酸盐形式被装载到脂质体的含水内部，并且封装不受血清白蛋白存在的影响。通过脂质体包封改善了白藜芦醇的化学不稳定性，防止了顺反异构化失活。对于咖啡酸，脂质体包封不能防止氧化成各种产物。尽管3-氧代-C-12-高丝氨酸内酯和白藜芦醇的脂质体缔合不稳定，静脉内施用这些化合物在小鼠肿瘤模型中抑制肿瘤生长约70%，表明简单的增溶可以具有重要的治疗益处。(C)2011 Elsevier B. V.保留所有权利。
Natural bioactive compounds have been studied fora long time for their chemopreventive and therapeutic potential in several chronic inflammatory diseases, including cancer. However, their physicochemical properties generally result in poor chemical stability and lack of in vivo bioavailability. Very few human clinical trials have addressed absorption, distribution, metabolism, and excretion of these compounds in relation to efficacy. This limits the use of these valuable natural compounds in the clinic.In this study, we examined caffeic acid (derivatives), carvacrol (derivatives), thymol, pterostilbene (derivatives), and N-(3-oxo-dodecanoyl)-1-homoserine lactone. These are natural compounds with strong anti-inflammatory properties derived from plants and bacteria. However, these compounds have poor water solubility or are chemically unstable. To overcome these limitations we have prepared liposomal formulations. Our results show that lipophilic 3-oxo-C-12-homoserine lactone and stilbene derivatives can be loaded into liposomal lipid bilayer with efficiencies of 50-70%. Thereby, the liposomes solubilize these compounds, allowing intravenous administration without use of solvents. When compounds could not be loaded into the lipid bilayer (carvacrol and thymol) or are rapidly extracted from the liposomes in the presence of serum albumin (3-oxo-C-12-homoserine lactone and pterostilbene derivatives), derivatization of the compound into a water-soluble prodrug was shown to improve loading efficiency and encapsulation stability. The phosphate forms of carvacrol and pterostilbene were loaded into the aqueous interior of the liposomes and encapsulation was unaffected by the presence of serum albumin. Chemical instability of resveratrol was improved by liposome-encapsulation, preventing inactivating cis-trans isomerization. For caffeic acid, liposomal encapsulation did not prevent oxidation into a variety of products. Still, by derivatization into a phenyl ester, the compound could be stably encapsulated without chemical degradation.Despite the instability of liposome-association of 3-oxo-C-12-homoserine lactone and resveratrol, intravenous administration of these compounds inhibited tumor growth for approximately 70% in a murine tumor model, showing that simple solubilization can have important therapeutic benefits. (C) 2011 Elsevier B.V. All rights reserved.