Khafagy El-Sayed, Kamei Noriyasu, Nielsen Ebbe Juel Bech, Nishio Reiji, Takeda-Morishita Mariko
Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan; Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.
Eur J Pharm Biopharm. 2013 Nov;85(3 Pt A):736-43. doi: 10.1016/j.ejpb.2013.09.014. Epub 2013 Sep 21.
Recently, cell-penetrating peptides (CPPs) based vehicles have been developed for the delivery of different payloads in animals. Our studies have shown that nasal absorption of insulin and other therapeutic peptides and proteins can be improved significantly by co-administration of the CPP penetratin. Successful development of suitable CPP-based delivery systems, however, will depend not only on the efficiency of CPPs to transport therapeutic agents across the biological barriers of the nasal cavity, but also on the risk of adverse effects such as toxicity and undesired immunogenicity, especially in chronic therapy. In this study, we investigated the bioavailability (BA) of insulin and the adverse effects on the nasal mucosa in rats following a long-term dosing regimen of L-penetratin and the novel penetratin analogue "PenetraMax." Following nasal delivery, a significantly higher BA for insulin (almost 100% relative to subcutaneous (s.c.) injections) was observed for PenetraMax in comparison with the parent penetratin peptide after chronic administrations in rats. Importantly, there was negligible biomarker leakage in nasal lavage fluid and the integrity of the nasal epithelium remained unaffected when PenetraMax was used in long-term multiple administrations. In addition, no significant difference in the release of inflammatory and immunogenicity mediators in plasma was observed after nasal administration of PenetraMax with or without insulin solution. In conclusion, PenetraMax, a novel CPP candidate, can open a new avenue in clinical trials for noninvasive nasal insulin delivery.
最近，基于细胞穿透肽（CPPs）的载体已被开发用于在动物体内递送不同的有效载荷。我们的研究表明，通过共同施用CPP穿膜肽，胰岛素以及其他治疗性肽和蛋白质的鼻腔吸收可得到显著改善。然而，成功开发合适的基于CPP的递送系统不仅取决于CPPs将治疗剂转运穿过鼻腔生物屏障的效率，还取决于诸如毒性和不良免疫原性等不良反应的风险，尤其是在长期治疗中。在本研究中，我们研究了在大鼠长期给药L-穿膜肽和新型穿膜肽类似物“PenetraMax”后，胰岛素的生物利用度（BA）以及对鼻黏膜的不良反应。在大鼠长期给药后，经鼻腔给药后，与母体穿膜肽相比，PenetraMax的胰岛素BA显著更高（相对于皮下（s.c.）注射几乎为100%）。重要的是，当长期多次使用PenetraMax时，鼻灌洗液中的生物标志物泄漏可忽略不计，并且鼻上皮的完整性未受影响。此外，在给予PenetraMax（无论有无胰岛素溶液）鼻腔给药后，血浆中炎症和免疫原性介质的释放未观察到显著差异。总之，新型CPP候选物PenetraMax可为非侵入性鼻腔胰岛素递送的临床试验开辟一条新途径。
