Gemcitabine is a nucleoside analog effective against a number of cancers. However, it has an oral bioavailability of less than 10%, due to its high hydrophilicity and low permeability through the intestinal epithelium. Therefore, the aim of this project was to develop a novel nanoparticulate drug delivery system for the oral delivery of gemcitabine to improve its oral bioavailability. In this study, gemcitabine-loaded β-glucan NPs were fabricated using a film-casting method followed by a freezer-milling technique. As a result, the NPs showed a small particle size of 447.6 ± 14.2 nm, and a high drug entrapment efficiency of 64.3 ± 2.1%. By encapsulating gemcitabine into β-glucan NPs, a sustained drug release profile was obtained, and the anomalous diffusion release mechanism was analyzed, indicating that the drug release was governed by diffusion through the NP matrix as well as matrix erosion. The drug-loaded NPs had a greater ex vivo drug permeation through the porcine intestinal epithelial membrane compared to the plain drug solution. Cytotoxicity studies showed a safety profile of the β-glucan polymers, and the IC50s of drug solution and drug-loaded β-glucan NPs were calculated as 228.8 ± 31.2 ng·mL−1 and 306.1 ± 46.3 ng·mL−1, respectively. Additionally, the LD50 of BALB/c nude mice was determined as 204.17 mg/kg in the acute toxicity studies. Notably, pharmacokinetic studies showed that drug-loaded β-glucan NPs could achieve a 7.4-fold longer T1/2 and a 5.1-fold increase in oral bioavailability compared with plain drug solution. Finally, in vivo pharmacodynamic studies showed the promising capability of gemcitabine-loaded β-glucan NPs to inhibit the 4T1 breast tumor growth, with a 3.04- and 1.74-fold reduction compared to the untreated control and drug solution groups, respectively. In conclusion, the presented freezer-milled β-glucan NP system is a suitable drug delivery method for the oral delivery of gemcitabine and demonstrates a promising potential platform for oral chemotherapy.

中文翻译：

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用于口服药物输送的冷冻研磨 β-葡聚糖纳米颗粒

吉西他滨是一种核苷类似物，可有效对抗多种癌症。然而，由于其高亲水性和低肠上皮渗透性，其口服生物利用度低于 10%。因此，该项目的目的是开发一种新型纳米颗粒药物递送系统，用于吉西他滨的口服递送，以提高其口服生物利用度。在这项研究中，使用薄膜流延法和冷冻研磨技术制备了负载吉西他滨的 β-葡聚糖纳米颗粒。结果，纳米粒子表现出447.6±14.2 nm的小粒径和64.3±2.1%的高药物包封率。通过将吉西他滨封装到β-葡聚糖纳米颗粒中，获得了持续的药物释放曲线，并分析了异常扩散释放机制，表明药物释放是通过纳米颗粒基质扩散和基质侵蚀控制的。与普通药物溶液相比，载药纳米粒子通过猪肠上皮膜具有更大的离体药物渗透性。细胞毒性研究显示了β-葡聚糖聚合物的安全性，药物溶液和载药β-葡聚糖纳米颗粒的IC50分别计算为228.8±31.2ng·mL−1和306.1±46.3ng·mL−1。另外，急性毒性研究测定BALB/c裸鼠的LD50为204.17 mg/kg。值得注意的是，药代动力学研究表明，与普通药物溶液相比，载药β-葡聚糖纳米颗粒的 T1/2 延长了 7.4 倍，口服生物利用度提高了 5.1 倍。最后，体内药效学研究表明，载有吉西他滨的β-葡聚糖纳米粒子具有抑制4T1乳腺肿瘤生长的良好能力，与未处理的对照组和药物溶液组相比，分别抑制了3.04倍和1.74倍。总之，所提出的冷冻研磨β-葡聚糖纳米粒子系统是一种适合口服吉西他滨的药物递送方法，并为口服化疗展示了一个有前途的潜在平台。