One-month subchronic toxicity study of cell-penetrating peptides for insulin nasal delivery in rats.
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.
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.
El-Sayed
el-S
Khafagy
Noriyasu
N
Kamei
Ebbe Juel Bech
EJ
Nielsen
Reiji
R
Nishio
Mariko
M
Takeda-Morishita
D000281:Administration, Intranasal; D000818:Animals; D001682:Biological Availability; D002352:Carrier Proteins / Q000737:chemistry* / Q000633:toxicity; D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000633:toxicity; D004337:Drug Carriers / Q000737:chemistry / Q000633:toxicity; D016503:Drug Delivery Systems; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D007328:Insulin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D008297:Male; D009297:Nasal Mucosa / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D059550:Toxicity Tests, Subchronic
D002352:Carrier Proteins; D057846:Cell-Penetrating Peptides; D004337:Drug Carriers; D007004:Hypoglycemic Agents; D007328:Insulin; C414409:penetratin
Cell-penetrating peptide; Insulin; Long-term administration; Nasal delivery; Penetratin; Toxicity