Abstract The primary purpose of the present study was to design and optimize a solid lipid nanoparticle (SLN) formulation of the poorly water-soluble drug 2-methoxyestradiol (2-ME) to improve its oral bioavailability and prolong the duration of therapeutic drug level. SLN was modified by amphipathic PEG-PCL (PLN) and then encapsulated in pH-sensitive microparticles (MP) by spray drying technology. Several properties of 2-ME PLN-MP were characterized including particle size, drug loading, and drug or PLN release. After oral administration of 2-ME PLN-MP, retention time in mice was evaluated by in vivo imaging technology and the pharmacokinetic parameters in rats were determined by HPLC. The results demonstrated that PEG-PCL modification of 2-ME SLN significantly decreased particle size and delayed drug release without influencing IC50 in 4T1 cells. 2-ME PLN in the microparticles showed significant pH-sensitive release in the simulated gastrointestinal fluid and controlled release in the intestine. The PLN (labelled with IR-780 iodide) prolonged significantly fluorescence duration time compared to the SLN and the prolongation was further enhanced by the PLN-MP formulation. Furthermore, compared with the suspension, the PLN-MP formulation showed a 56.66-fold delay in Tmax, a 10.36-fold extension in MRT and a 140.86-fold increase in the relative bioavailability in the rat. The research work in the paper suggests that the PLN-MP could serve as a practical oral preparation for 2-ME in future cancer therapy.

中文翻译：

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固体脂质纳米粒的 PEG-PCL 修饰和肠道缓释提高 2-甲氧基雌二醇的口服生物利用度

摘要 本研究的主要目的是设计和优化水溶性差的药物 2-甲氧基雌二醇 (2-ME) 的固体脂质纳米颗粒 (SLN) 制剂，以提高其口服生物利用度并延长治疗药物水平的持续时间。SLN 经两亲性 PEG-PCL (PLN) 修饰，然后通过喷雾干燥技术封装在 pH 敏感微粒 (MP) 中。对 2-ME PLN-MP 的几个特性进行了表征，包括粒径、载药量和药物或 PLN 释放。口服2-ME PLN-MP后，通过体内成像技术评估小鼠体内滞留时间，高效液相色谱法测定大鼠体内药代动力学参数。结果表明，2-ME SLN 的 PEG-PCL 修饰显着降低了粒径并延迟了药物释放，而不影响 4T1 细胞中的 IC50。微粒中的 2-ME PLN 在模拟胃肠液中表现出显着的 pH 敏感性释放，并在肠道中控制释放。与 SLN 相比，PLN（用 IR-780 碘化物标记）显着延长了荧光持续时间，PLN-MP 配方进一步增强了这种延长。此外，与悬浮液相比，PLN-MP 制剂显示 Tmax 延迟 56.66 倍，MRT 延长 10.36 倍，大鼠的相对生物利用度增加 140.86 倍。论文中的研究工作表明，PLN-MP 可以在未来的癌症治疗中作为 2-ME 的实用口服制剂。与 SLN 相比，PLN（用 IR-780 碘化物标记）显着延长了荧光持续时间，PLN-MP 配方进一步增强了这种延长。此外，与悬浮液相比，PLN-MP 制剂显示 Tmax 延迟 56.66 倍，MRT 延长 10.36 倍，大鼠的相对生物利用度增加 140.86 倍。论文中的研究工作表明，PLN-MP 可以在未来的癌症治疗中作为 2-ME 的实用口服制剂。与 SLN 相比，PLN（用 IR-780 碘化物标记）显着延长了荧光持续时间，PLN-MP 配方进一步增强了这种延长。此外，与悬浮液相比，PLN-MP 制剂显示 Tmax 延迟 56.66 倍，MRT 延长 10.36 倍，大鼠的相对生物利用度增加 140.86 倍。论文中的研究工作表明，PLN-MP 可以在未来的癌症治疗中作为 2-ME 的实用口服制剂。