Transduction of adenovirus vectors modified with cell-penetrating peptides.
Adenovirus vectors (Advs) are widely used for basic and clinical research because of their high transduction efficiency. However, they are poorly transduced into cells lacking the primary adenovirus receptor, the coxsackievirus and adenovirus receptor (CAR). Here, we generated Adv conjugated with cell-penetrating peptides (CPPs), such as Tat, octaarginine (R8) or proline-rich (Pro) peptides, and compared the transduction properties of these constructs. We constructed the Advs conjugated to the CPPs (CPP-Adv) by chemical conjugation. The CPP-conjugated Advs created with optimal modification ratios led to gene expression 1-2log orders higher than unmodified Adv in CAR-negative cells. Tat-Adv and R8-Adv were taken up into the cells mainly through macropinocytosis, independently of the CAR. In addition, the cellular uptake of Tat-Adv was highly dependent on heparan sulfate on the cell surface, whereas that of R8-Adv was dependent on chondroitin sulfate B. These data suggest that the use of CPP-Advs with different cellular uptake pathways might create new methods for the delivery of Adv. The results obtained in this research encourage the use of CPP-peptide-modified Advs as an attractive tool for transducing cells and as useful platform vectors for gene therapy and basic research.
Eto
Yusuke
Y
Department of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Yamadaoka, Suita, Osaka 565-0871, Japan.
Yoshioka
Yasuo
Y
Asavatanabodee
Ratima
R
Kida
Shinya
S
Maeda
Mitsuko
M
Mukai
Yohei
Y
Mizuguchi
Hiroyuki
H
Kawasaki
Koichi
K
Okada
Naoki
N
Nakagawa
Shinsaku
S
D000256:Adenoviridae / Q000737:chemistry* / Q000235:genetics*; D002460:Cell Line; D005822:Genetic Vectors / Q000737:chemistry* / Q000235:genetics*; D006801:Humans; D010455:Peptides / Q000737:chemistry*; D014161:Transduction, Genetic / Q000379:methods*
D010455:Peptides