School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 11031, Taiwan.
Department of Pharmacy, Sebelas Maret University, Surakarta, 57126, Indonesia.
Int J Nanomedicine. 2024 Apr 25;19:3753-3772. doi: 10.2147/IJN.S443610. eCollection 2024.
Gemcitabine (GEM) faces challenges of poor oral bioavailability and extensive first-pass metabolism. Currently, only injectable formulations are available for clinical use. Hence, there is an urgent demand for the development of advanced, efficacious, and user-friendly dosage forms to maintain its status as the primary treatment for pancreatic ductal adenocarcinoma (PDAC). Nanogels (NGs) offer a novel oral drug delivery system, ideal for hydrophilic compounds like GEM. This study aims to develop NGs tailored for GEM delivery, with the goal of enhancing cellular uptake and gastrointestinal permeability for improved administration in PDAC patients.
We developed cross-linked NGs via photopolymerization of methacryloyl for drug delivery of GEM. We reveal characterization, cytotoxicity, and cellular uptake studies in Caco-2 and MIA PaCa-2 cells. In addition, studies of in vitro permeability and pharmacokinetics were carried out to evaluate the bioavailability of the drug.
Our results show NGs, formed via photopolymerization of methacryloyl, had a spherical shape with a size of 233.91±7.75 nm. Gemcitabine-loaded NGs (NGs-GEM) with 5% GelMA exhibited efficient drug loading (particle size: 244.07±19.52 nm). In vitro drug release from NGs-GEM was slower at pH 1.2 than pH 6.8. Cellular uptake studies indicated significantly enhanced uptake in both MIA PaCa-2 and Caco-2 cells. While there was no significant difference in GEM's AUC and Cmax between NGs-GEM and free-GEM groups, NGs-GEM showed markedly lower dFdU content (10.07 hr∙μg/mL) compared to oral free-GEM (19.04 hr∙μg/mL) after oral administration (p<0.01), highlighting NGs' efficacy in impeding rapid drug metabolism and enhancing retention.
In summary, NGs enhance cellular uptake, inhibit rapid metabolic degradation of GEM, and prolong retention after oral administration. These findings suggest NGs-GEM as a promising candidate for clinical use in oral pancreatic cancer therapy.
吉西他滨（GEM）面临口服生物利用度差和广泛首过代谢的挑战。目前，只有注射剂可供临床使用。因此，迫切需要开发先进、有效且用户友好的剂型，以维持其作为胰腺导管腺癌（PDAC）主要治疗药物的地位。纳米凝胶（NGs）为亲水化合物（如 GEM）提供了一种新型的口服药物递送系统。本研究旨在开发用于 GEM 递送的 NGs，目标是增强细胞摄取和胃肠道通透性，以改善 PDAC 患者的给药效果。
我们通过光聚合甲丙烯酸酯制备了用于 GEM 药物递送的交联 NGs。我们揭示了在 Caco-2 和 MIA PaCa-2 细胞中的表征、细胞毒性和细胞摄取研究。此外，还进行了体外渗透性和药代动力学研究，以评估药物的生物利用度。
我们的结果表明，通过光聚合甲丙烯酸酯形成的 NGs 呈球形，粒径为 233.91±7.75nm。载有吉西他滨的 NGs（NGs-GEM）在 5% GelMA 下表现出高效的药物负载（粒径：244.07±19.52nm）。在 pH 1.2 时，NGs-GEM 的体外药物释放速度比 pH 6.8 时慢。细胞摄取研究表明，在 MIA PaCa-2 和 Caco-2 细胞中均显著增强了摄取。虽然 NGs-GEM 组和游离 GEM 组的 AUC 和 Cmax 没有显著差异，但 NGs-GEM 组在口服后（p<0.01）显示出明显较低的 dFdU 含量（10.07hr·μg/mL），而游离 GEM 组为 19.04hr·μg/mL，这表明 NGs 能有效阻止药物的快速代谢和增强保留。
总之，NGs 增强了细胞摄取，抑制了 GEM 的快速代谢降解，并延长了口服后的保留时间。这些发现表明 NGs-GEM 是一种有前途的候选药物，可用于口服胰腺癌治疗的临床应用。
