Intracellular availability of poorly soluble drugs from lipid nanocapsules
Intracellular availability of poorly soluble drugs from lipid nanocapsules
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DOI：
10.1016/j.ejpb.2019.03.007
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发表时间：
2019-06-01
影响因子：
4.9
通讯作者：
Goepferich, Achim M.
中科院分区：
文献类型：
--
作者：
Bohley, Marilena;Haunberger, Alexandra;Goepferich, Achim M.
脂质纳米胶囊（lnc）由于其体积分布小、生物相容性好和易于制备而被广泛用作药物载体系统。它们对亲脂药物特别有用，以克服限制其功效的物理化学限制，例如在水介质中的低溶解度。这项工作的目的是研究通过LNCs传递的难溶性药物的细胞内可利用性与其体外细胞生物学功效之间的关系。logP(Oct) = 4.3 （Lucangioli et al., 2003）的环孢素A （CsA）和logP(Oct) = 6.2 （Bhardwaj et al., 2013）的伊曲康唑（It）作为模型亲脂化合物，因为它们是治疗新生血管性眼部疾病的极有希望的候选者。由于它们的亲脂性和对LNCs油芯的偏爱，实现了高封装效率。用α v β 3整合素配体（RGD）移植粒径约为50 nm的载药LNCs，以优化人皮肤微血管内皮细胞对LNCs的吸收。尽管RGD-LNCs表现出良好的内化能力，但与游离药物相比，它们在体外对内皮细胞增殖、血管内皮生长因子表达和管形成的抑制作用不足。这种疗效的丧失可能是由于来自LNCs的难溶性药物在细胞内的可利用性可以忽略不计。
Lipid nanocapsules (LNCs) are extensively used as drug carrier systems, due to their small size distribution, biocompatibility and ease of preparation. They are especially useful for lipophilic drugs to overcome physicochemical constraints that limit their efficacy, such as low solubility in aqueous media. The aim of this work was to investigate the relationship between the intracellular availability of poorly soluble drugs delivered via LNCs and their biological efficacy in cells in vitro. Cyclosporin A (CsA) with a logP(Oct) = 4.3 (Lucangioli et al., 2003) and Itraconazole (It) with a logP(Oct) = 6.2 (Bhardwaj et al., 2013) served as model lipophilic compounds, as they are highly promising candidates for the treatment of neovascular ocular diseases. Due to their lipophilic properties and the resulting preference for the oily core of LNCs, high encapsulation efficiencies were achieved. Drug-loaded LNCs with particle sizes around 50 nm were grafted with an alpha v beta 3 integrin ligand (RGD) to optimize cellular uptake by human dermal microvascular endothelial cells. Even though RGD-LNCs showed excellent internalization, they exhibited insufficient inhibitory effects in vitro regarding endothelial cell proliferation, vascular endothelial growth factor expression, and tube formation in contrast to free drugs. This loss of efficacy could be explained by negligible intracellular availability of the poorly soluble drugs from LNCs.