Chen Guanyu, Liu Yi, Svirskis Darren, Li Hongyu, Ying Man, Lu Weiyue, Wen Jingyuan
School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China.
School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, 95 Park Road, Grafton, Auckland 1142, New Zealand.
Pharmaceutics. 2024 Apr 16;16(4):546. doi: 10.3390/pharmaceutics16040546.
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 IC of drug solution and drug-loaded β-glucan NPs were calculated as 228.8 ± 31.2 ng·mL and 306.1 ± 46.3 ng·mL, respectively. Additionally, the LD 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 T 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.
吉西他滨是一种对多种癌症有效的核苷类似物。然而，由于其高度亲水性和通过肠上皮的低渗透性，其口服生物利用度低于10%。因此，本项目的目的是开发一种新型纳米颗粒药物递送系统，用于口服递送吉西他滨，以提高其口服生物利用度。在本研究中，采用流延法结合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，纳米颗粒显示出447.6±14.2nm的小粒径和64.3±2.1%的高药物包封率。通过将吉西他滨包封到β-葡聚糖纳米颗粒中，获得了持续的药物释放曲线，并分析了反常扩散释放机制，表明药物释放受通过纳米颗粒基质的扩散以及基质侵蚀的控制。与普通药物溶液相比，载药纳米颗粒通过猪肠上皮膜的体外药物渗透更大。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IC分别计算为228.8±31.2ng·mL和306.1±46.3ng·mL。此外，在急性毒性研究中，BALB/c裸鼠的LD测定为204.17mg/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T可延长7.4倍，口服生物利用度提高5.1倍。最后，体内药效学研究表明，负载吉西他滨的β-葡聚糖纳米颗粒具有抑制4T1乳腺肿瘤生长的潜力，与未治疗的对照组和药物溶液组相比，分别降低了3.04倍和1.74倍。总之，所提出的冷冻研磨β-葡聚糖纳米颗粒系统是一种适合口服递送吉西他滨的药物递送方法，并展示了一个有前景的口服化疗潜在平台。
