Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan.
Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan; Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Suez Canal University, Ismailia 415-22, Egypt.
Int J Pharm. 2016 Aug 20;510(1):304-10. doi: 10.1016/j.ijpharm.2016.06.054. Epub 2016 Jun 22.
The conjugation of therapeutic proteins to polyethylene glycol (PEG) is known as PEGylation. It improves their retention in the body and reduces the frequency of injections. Development of noninvasive delivery systems for biopharmaceuticals can improve the patients' quality of life. The present study aimed to evaluate the cell-penetrating peptides (CPPs), which act as bioenhancers, for the nasal delivery of protein drug interferon beta (IFN-β) and its PEGylated form (PEG-IFN-β). The ability of CPPs to enhance the nasal mucosal absorption of unmodified IFN-β was assessed in rats. It was shown that only d-amino acid forms of amphipathic CPPs, penetratin and PenetraMax significantly enhanced the nasal absorption of IFN-β. Especially, D-penetratin (up to 2mM) enhanced the absorption of INF-β in a dose-dependent manner. The maximum absolute bioavailability reached 8.26% following in situ nasal coadministration of IFN-β with d-penetratin (2mM). Furthermore, it was found that the coadministration of d-penetratin also facilitated the nasal absorption of PEG-IFN-β, which remained in the circulation for more than 6h. Moreover, the toxicity assessments showed no damage to the epithelial membranes after nasal administration of CPPs including penetratin and PenetraMax. Altogether, this study provides the first evidence that the noncovalent coadministration of PEGylated proteins with CPPs could be a potent strategy for the noninvasive and sustained nasal delivery of therapeutic proteins.
蛋白质与聚乙二醇（PEG）的缀合称为 PEGylation。它可以提高其在体内的保留时间，并减少注射频率。开发用于生物制药的非侵入性递送系统可以提高患者的生活质量。本研究旨在评估细胞穿透肽（CPPs）作为生物增强剂，用于鼻内递送蛋白质药物干扰素β（IFN-β）及其 PEG 化形式（PEG-IFN-β）。在大鼠中评估 CPPs 增强未修饰 IFN-β鼻黏膜吸收的能力。结果表明，只有 D-氨基酸形式的两亲性 CPPs，穿透肽和 PenetraMax 显著增强了 IFN-β的鼻吸收。特别是 D-穿透肽（高达 2mM）以剂量依赖性方式增强了 INF-β的吸收。IFN-β与 D-穿透肽（2mM）原位鼻共给药后，最大绝对生物利用度达到 8.26%。此外，还发现 D-穿透肽的共给药也促进了 PEG-IFN-β的鼻吸收，其在循环中保留时间超过 6 小时。此外，毒性评估表明，鼻内给予穿透肽和 PenetraMax 等 CPP 后，上皮膜没有损伤。总的来说，这项研究首次提供了证据，表明将 PEG 化蛋白与 CPP 进行非共价共给药可能是一种用于非侵入性和持续鼻内递送治疗性蛋白的有效策略。
