Noncovalent Strategy with Cell-Penetrating Peptides to Facilitate the Brain Delivery of Insulin through the Blood–Brain Barrier

• Published in: Biological & pharmaceutical bulletin 2018/04/01, Vol.41(4), pp.546-554
• Main Authors: Kamei, Noriyasu, Yamaoka, Ai, Fukuyama, Yukiko, Itokazu, Rei, Takeda-Morishita, Mariko
• Format: Article
• Language: English
• Subjects: Animals; Biological Transport; Blood-brain barrier; Brain; Brain - metabolism; brain delivery; Carrier Proteins - administration & dosage; Carrier Proteins - pharmacokinetics; Cell Line, Tumor; Cell Survival - drug effects; cell-penetrating peptide; Cell-Penetrating Peptides - administration & dosage; Cell-Penetrating Peptides - pharmacokinetics; Gene Products, tat - chemistry; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - blood; Hypoglycemic Agents - pharmacokinetics; Insulin; Insulin - administration & dosage; Insulin - blood; Insulin - pharmacokinetics; Intravenous administration; intravenous injection; Male; Membrane permeability; Mice; Microvasculature; octaarginine; Oligopeptides - administration & dosage; Oligopeptides - pharmacokinetics; Peptides; Permeability; Proteins; Rats, Sprague-Dawley; Temperature dependence; Tissue Distribution
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b17-00848

To overcome the difficulty in delivery of biopharmaceuticals such as peptides and proteins to the brain, several approaches combining the ligands and antibodies targeting the blood–brain barrier (BBB) have been tried. However, these are inefficient in terms of their permeability through the BBB and structural modification of bioactive drugs. In the present study, we therefore examined the usefulness of a noncovalent method using the cell-penetrating peptides (CPPs) such as octaarginine (R8) as a suitable brain delivery strategy for biopharmaceuticals. A safety examination using microvascular endothelial model bEnd.3 cells clarified that R8 was the safest among the CPPs tested in this study. The cellular uptake study demonstrated that coincubation with R8 enhanced the uptake of model peptide drug insulin by bEnd.3 cells in a concentration-dependent and a temperature-independent manner. Furthermore, an in vivo study with rats showed that the accumulation of insulin in the deeper region of the brain, i.e., hippocampus, significantly increased after the intravenous coadministration of insulin with D-R8 without altering the insulin disposition in plasma. Thus, the present study provided the first evidence suggesting that the noncovalent method with CPPs is one of the strategic options for brain delivery of biopharmaceuticals via intravenous injection.