Targeted nanocarriers have shown great promise in drug delivery because of optimized drug behavior and improved therapeutic efficacy. How to improve the targeting efficiency of nanocarriers for the maximum possible drug delivery is a critical issue. Here we developed L-carnitine-conjugated nanoparticles targeting the carnitine transporter OCTN2 on enterocytes for improved oral absorption. As a variable, we introduced various lengths of the polyethylene glycol linker (0, 500, 1000, and 2000) between the nanoparticle surface and the ligand (CNP, C5NP, C10NP and C20NP) to improve the ligand flexibility, and consequently for more efficient interaction with the transporter, to enhance the oral delivery of the cargo load into cells. An increased absorption was observed in cellular uptake in vitro and in intestinal perfusion assay in situ when the polyethylene glycol was introduced to link L-carnitine to the nanoparticles; the highest absorption was achieved with C10NP. In contrast, the linker decreased the absorption efficiency in vivo. As the presence or absence of the mucus layer was the primary difference between in vitro/in situ versus in vivo, the presence of this layer was the likely reason for this differential effect. In summary, the size of the polyethylene glycol linker improved the absorption in vitro and in situ, but interfered with the absorption in vivo. Even though this strategy of increasing the ligand flexibility with the variable size of the polyethylene glycol failed to increase oral absorption in vivo, this approach is likely to be useful for enhanced cellular uptake following intravenous administration of the nanocarriers.

中文翻译：

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用于口服紫杉醇的OCTN2靶向纳米颗粒：聚乙二醇接头大小对体外，原位和体内药物递送的不同影响。

由于优化的药物行为和改善的治疗功效，靶向纳米载体在药物递送中显示出巨大的希望。如何提高纳米载体的靶向效率以实现最大可能的药物输送是一个关键问题。在这里，我们开发了针对肠上皮细胞上的肉碱转运蛋白OCTN2的L-肉碱共轭纳米颗粒，以改善口服吸收。作为变量，我们在纳米颗粒表面和配体（CNP，C5NP，C10NP和C20NP）之间引入了各种长度的聚乙二醇接头（0、500、1000和2000），以提高配体的柔性，从而提高了配体的效率。与转运蛋白的相互作用，以增强口服方式将货物装载入细胞。当引入聚乙二醇将L-肉碱与纳米颗粒连接时，在体外细胞吸收和原位肠灌注试验中观察到吸收增加。C10NP达到最高吸收。相反，接头降低了体内吸收效率。由于粘液层的存在与否是体外/原位与体内之间的主要区别，因此该层的存在是产生这种差异作用的可能原因。总之，聚乙二醇接头的大小改善了体外和原位的吸收，但干扰了体内的吸收。即使通过可变大小的聚乙二醇来增加配体柔韧性的这种策略未能提高体内口服吸收，