Cell penetrating peptides improve tumor delivery of cargos through neuropilin-1-dependent extravasation

Cell-penetrating peptides (CPPs), also referred to as protein transduction domains (PTDs), can mediate the cellular uptake of a wide range of macromolecules including peptides, proteins, oligonucleotides, and nanoparticles, and thus have received considerable attention as a promising method for drug...

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Bibliographic Details
Published in:Journal of controlled release 2015-03, Vol.201, p.14-21
Main Authors: Kadonosono, Tetsuya, Yamano, Akihiro, Goto, Toshiki, Tsubaki, Takuya, Niibori, Mizuho, Kuchimaru, Takahiro, Kizaka-Kondoh, Shinae
Format: Article
Language:English
Subjects:
Animals
Cell Line
Cell Line, Tumor
Cell-Penetrating Peptides - administration & dosage
Cell-Penetrating Peptides - chemistry
Drug Delivery Systems
Gene Products, tat - administration & dosage
Gene Products, tat - chemistry
Humans
Male
Mice, Inbred BALB C
Neoplasms - metabolism
Neuropilin-1 - metabolism
Oligopeptides - administration & dosage
Protein Structure, Tertiary
Recombinant Fusion Proteins - administration & dosage
Recombinant Fusion Proteins - chemistry
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Summary:Cell-penetrating peptides (CPPs), also referred to as protein transduction domains (PTDs), can mediate the cellular uptake of a wide range of macromolecules including peptides, proteins, oligonucleotides, and nanoparticles, and thus have received considerable attention as a promising method for drug delivery in vivo. Here, we report that CPP/PTDs facilitate the extravasation of fused proteins by binding to neuropilin-1 (NRP1), a vascular endothelial growth factor (VEGF) co-receptor expressed on the surface of endothelial and some tumor cells. In this study, we examined the capacity of the amphipathic and cationic CPP/PTDs, PTD-3 and TAT-PTD, respectively, to bind cells in vitro and accumulate in xenograft tumors in vivo. Notably, these functions were significantly suppressed by pre-treatment with NRP1-neutralizing Ab. Furthermore, co-injection of iRGD, a cyclic peptide known to increase NRP1-dependent vascular permeability, significantly reduced CPP/PTD tumor delivery. This data demonstrates a mechanism by which NRP1 promotes the extravasation of CPP/PTDs that may open new avenues for the development of more efficient CPP/PTD delivery systems.
ISSN:1873-4995
DOI:10.1016/j.jconrel.2015.01.011