title: Applicability and Limitations of Cell-Penetrating Peptides in Noncovalent Mucosal Drug or Carrier Delivery Systems.
abstract: Our recent studies show that cell-penetrating peptides (CPPs) have potential to improve the intestinal absorption of peptide and protein drugs safely and effectively when used in the noncovalent drug--CPP approach. To clarify the applicability and limitations of this strategy, the present study examined the effects of cargo size on the absorption-stimulatory effect of CPPs. Different sizes of hydrophilic macromolecular dextran (4.4, 10, and 70 kDa) and polystyrene-based nanoparticles (20, 100, and 200 nm) were chosen as the model cargos in this study. In an in situ rat intestinal absorption study, CPPs (octaarginine, Tat, penetratin, and PenetraMax) increased the intestinal absorption of dextran, and the efficiency varied according to the molecular size of dextran. Among the CPPs, D-penetratin showed an enhancing effect even when coadministered with the largest dextran (70 kDa). By contrast, an in vitro study of Caco-2 cell uptake showed that the ability of CPPs to deliver nanoparticles into epithelial cells was dependent on their particle size and that the relatively poor internalization of 200-nm nanoparticles could be facilitated by coincubation with CPPs. These findings suggest that the intrinsic uptake properties of macromolecules and particulate cargos determine the effectiveness of their intestinal mucosal delivery using the noncovalent CPP method.
authors: Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Hyogo 650-8586, Japan.
authors: Noriyasu
authors: N
authors: Kamei
authors: Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Hyogo 650-8586, Japan; Novo Nordisk A/S, Novo Nordisk Park, DK-2760, Måløv, Denmark; Novozymes A/S, DK-2880 Bagsvaerd, Denmark.
authors: Ebbe Juel
authors: EJ
authors: Bech Nielsen
authors: Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Hyogo 650-8586, Japan.
authors: Takayuki
authors: T
authors: Nakakubo
authors: Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Hyogo 650-8586, Japan.
authors: Yukina
authors: Y
authors: Aoyama
authors: Novo Nordisk A/S, Novo Nordisk Park, DK-2760, Måløv, Denmark.
authors: Ulrik Lytt
authors: UL
authors: Rahbek
authors: Novo Nordisk A/S, Novo Nordisk Park, DK-2760, Måløv, Denmark.
authors: Betty Lomstein
authors: BL
authors: Pedersen
authors: Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Hyogo 650-8586, Japan. Electronic address: mmtakeda@pharm.kobegakuin.ac.jp.
authors: Mariko
authors: M
authors: Takeda-Morishita
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018938:Caco-2 Cells; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism*; D004337:Drug Carriers / Q000008:administration & dosage* / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D057846:Cell-Penetrating Peptides; D004337:Drug Carriers
keywords: absorption enhancer; epithelial delivery/permeability; intestinal absorption; macromolecular drug delivery; nanoparticles; peptide delivery; protein delivery; transmucosal delivery