Department of Pharmacy, Uppsala University, SE-751 43 Uppsala, Sweden.
Department of Pharmacy and Pharmaceutical Technology, CIMUS, Universidade de Santiago de Compostela, Santiago de Compostela ES 15782, Spain.
ACS Nano. 2022 Sep 27;16(9):14210-14229. doi: 10.1021/acsnano.2c04330. Epub 2022 Aug 23.
Peptide drugs and biologics provide opportunities for treatments of many diseases. However, due to their poor stability and permeability in the gastrointestinal tract, the oral bioavailability of peptide drugs is negligible. Nanoparticle formulations have been proposed to circumvent these hurdles, but systemic exposure of orally administered peptide drugs has remained elusive. In this study, we investigated the absorption mechanisms of four insulin-loaded arginine-rich nanoparticles displaying differing composition and surface characteristics, developed within the pan-European consortium TRANS-INT. The transport mechanisms and major barriers to nanoparticle permeability were investigated in freshly isolated human jejunal tissue. Cytokine release profiles and standard toxicity markers indicated that the nanoparticles were nontoxic. Three out of four nanoparticles displayed pronounced binding to the mucus layer and did not reach the epithelium. One nanoparticle composed of a mucus inert shell and cell-penetrating octarginine (ENCP), showed significant uptake by the intestinal epithelium corresponding to 28 ± 9% of the administered nanoparticle dose, as determined by super-resolution microscopy. Only a small fraction of nanoparticles taken up by epithelia went on to be transcytosed via a dynamin-dependent process. studies in intact rat jejunal loops confirmed the results from human tissue regarding mucus binding, epithelial uptake, and negligible insulin bioavailability. In conclusion, while none of the four arginine-rich nanoparticles supported systemic insulin delivery, ENCP displayed a consistently high uptake along the intestinal villi. It is proposed that ENCP should be further investigated for local delivery of therapeutics to the intestinal mucosa.
肽类药物和生物制剂为许多疾病的治疗提供了机会。然而，由于其在胃肠道中的稳定性和通透性差，肽类药物的口服生物利用度可以忽略不计。纳米颗粒制剂被提出用于克服这些障碍，但口服给予的肽类药物的全身暴露仍然难以捉摸。在这项研究中，我们研究了四种载胰岛素的精氨酸丰富的纳米颗粒的吸收机制，这些纳米颗粒具有不同的组成和表面特性，是在泛欧联盟 TRANS-INT 内开发的。在新鲜分离的人空肠组织中研究了纳米颗粒渗透性的转运机制和主要障碍。细胞因子释放谱和标准毒性标志物表明纳米颗粒无毒。四种纳米颗粒中的三种显示出与粘液层的显著结合，并且无法到达上皮细胞。由粘液惰性壳和穿透细胞的八精氨酸（ENCP）组成的一种纳米颗粒显示出对肠上皮的显著摄取，相当于通过超分辨率显微镜确定的给药纳米颗粒剂量的 28±9%。只有一小部分被上皮细胞摄取的纳米颗粒通过依赖于胞质动力蛋白的过程进行转胞吞作用。在完整的大鼠空肠环中进行的研究证实了人组织中关于粘液结合、上皮摄取和可忽略不计的胰岛素生物利用度的结果。总之，虽然这四种精氨酸丰富的纳米颗粒都不支持系统胰岛素输送，但 ENCP 沿肠绒毛显示出一致的高摄取。因此，建议进一步研究 ENCP 用于将治疗剂局部递送到肠黏膜。
