PMID- 34116136
OWN - NLM
STAT- MEDLINE
DCOM- 20210811
LR  - 20210811
IS  - 1873-4995 (Electronic)
IS  - 0168-3659 (Linking)
VI  - 335
DP  - 2021 Jul 10
TI  - Usefulness of cell-penetrating peptides and penetration accelerating sequence for 
      nose-to-brain delivery of glucagon-like peptide-2.
PG  - 575-583
LID - S0168-3659(21)00294-7 [pii]
LID - 10.1016/j.jconrel.2021.06.007 [doi]
AB  - Neuropeptides are expected as therapeutic drug candidates for central nervous 
      system (CNS) disorders. Intracerebroventricular (i.c.v.) administration of 
      glucagon-like peptide-2 (GLP-2) has an antidepressant-like effect not only in 
      depression model mice but also in treatment-resistant depression model mice. 
      However, because i.c.v. administration is very invasive, research is progressing 
      on brain delivery using intranasal administration as a non-invasive method. After 
      intranasal administration of the drug, there are two routes to the brain. That of 
      direct delivery from the paracellular route of olfactory epithelium to the brain 
      via the olfactory bulb has been studied, and that of systemic absorption via the 
      paracellular route of respiratory epithelium has been put to practical use. The 
      high degree of vascularization and permeability of the nasal mucosa enables drug 
      delivery via the paracellular route that leads to systemic delivery. Therefore, 
      suppressing systemic absorption may increase drug delivery to brain, so we 
      focused on the transcellular route. We created a GLP-2 derivative by adding 
      cell-penetrating peptides (CPP) and penetration accelerating sequences (PAS), 
      which are reported to provide efficient intracellular uptake, to GLP-2. However, 
      to deliver GLP-2 by the transcellular route, GLP-2 must not only be taken up into 
      cells but also move out of the cells. We investigated in vitro and in vivo 
      function of PAS-CPP-GLP-2 to enable the translocation of GLP-2 directly from the 
      nose to the brain. Derivatization of PAS-CPP-GLP-2 prevented its degradation. In 
      the evaluation of intracellular dynamics, PAS-CPP-GLP-2 enhanced cellular uptake 
      by macropinocytosis with CPP and promoted escape from endosomal vesicles by PAS. 
      This study also showed that PAS-CPP-GLP-2 can move out of cells. Furthermore, 
      only this PAS-CPP-GLP-2 showed an antidepression-like effect within 20 min of 
      intranasal administration. Intranasal administered PAS-CPP-GLP-2 surprisingly 
      showed the effect at the same dose with i.c.v. administration, but intravenous 
      administered PAS-CPP-GLP-2 did not show the effect. These results suggested that 
      PAS-CPP-GLP-2 can be efficiently delivered from the nose to the CNS and show a 
      pharmacological effect, demonstrating the usefulness of PAS and CPP for 
      nose-to-brain delivery of GLP-2.
CI  - Copyright (c) 2021 Elsevier B.V. All rights reserved.
FAU - Akita, Tomomi
AU  - Akita T
AD  - Department of Pharmaceutics and Drug Delivery, Faculty of Pharmaceutical 
      Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, 
      Japan.
FAU - Kimura, Ryosuke
AU  - Kimura R
AD  - Department of Pharmaceutics and Drug Delivery, Faculty of Pharmaceutical 
      Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, 
      Japan.
FAU - Akaguma, Saki
AU  - Akaguma S
AD  - Department of Pharmaceutics and Drug Delivery, Faculty of Pharmaceutical 
      Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, 
      Japan.
FAU - Nagai, Mio
AU  - Nagai M
AD  - Department of Pharmaceutics and Drug Delivery, Faculty of Pharmaceutical 
      Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, 
      Japan.
FAU - Nakao, Yusuke
AU  - Nakao Y
AD  - Department of Pharmaceutics and Drug Delivery, Faculty of Pharmaceutical 
      Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, 
      Japan.
FAU - Tsugane, Mamiko
AU  - Tsugane M
AD  - Department of Precision Mechanics, Faculty of Science and Engineering, Chuo 
      University, 1-13-27 Kasuga, Bunkyo-ku, Tokyo 112-8551, Japan.
FAU - Suzuki, Hiroaki
AU  - Suzuki H
AD  - Department of Precision Mechanics, Faculty of Science and Engineering, Chuo 
      University, 1-13-27 Kasuga, Bunkyo-ku, Tokyo 112-8551, Japan.
FAU - Oka, Jun-Ichiro
AU  - Oka JI
AD  - Department of Pharmaceutics and Drug Delivery, Faculty of Pharmaceutical 
      Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, 
      Japan.
FAU - Yamashita, Chikamasa
AU  - Yamashita C
AD  - Department of Pharmaceutics and Drug Delivery, Faculty of Pharmaceutical 
      Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, 
      Japan. Electronic address: chikamasa_yamashita@rs.tus.ac.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210609
PL  - Netherlands
TA  - J Control Release
JT  - Journal of controlled release : official journal of the Controlled Release 
      Society
JID - 8607908
RN  - 0 (Cell-Penetrating Peptides)
RN  - 0 (Glucagon-Like Peptide 2)
SB  - IM
MH  - Administration, Intranasal
MH  - Animals
MH  - Brain
MH  - *Cell-Penetrating Peptides
MH  - Drug Delivery Systems
MH  - Glucagon-Like Peptide 2
MH  - Mice
MH  - Nasal Mucosa
OTO - NOTNLM
OT  - Antidepressant-like effect
OT  - Cell-penetrating peptide
OT  - Glucagon-like peptide-2
OT  - Intracellular dynamics
OT  - Nose-to-brain
OT  - Penetration accelerating sequence
EDAT- 2021/06/12 06:00
MHDA- 2021/08/12 06:00
CRDT- 2021/06/11 20:13
PHST- 2021/03/01 00:00 [received]
PHST- 2021/06/02 00:00 [revised]
PHST- 2021/06/06 00:00 [accepted]
PHST- 2021/06/12 06:00 [pubmed]
PHST- 2021/08/12 06:00 [medline]
PHST- 2021/06/11 20:13 [entrez]
AID - S0168-3659(21)00294-7 [pii]
AID - 10.1016/j.jconrel.2021.06.007 [doi]
PST - ppublish
SO  - J Control Release. 2021 Jul 10;335:575-583. doi: 10.1016/j.jconrel.2021.06.007. 
      Epub 2021 Jun 9.