Highly efficient delivery of p16 antitumor peptide into aggressive leukemia/lymphoma cells using a novel transporter system.
Molecular targeting of hematopoietic malignancies has been generally hindered by technological obstacles to gene delivery in the neoplastic cells. The development of peptide delivery systems based on protein transduction domains has recently gained attention as a means of potentially overcoming these impediments. Here, we present a novel peptide transporter system that increases the efficiency of peptide delivery more than 10 times compared with the previous methods. The transporter, Wr-T, has an enlarged hydrophobic pocket consisting of triple tryptophan-rich domains fused with nine d-enantiomer polyarginines (r9) via Gly-Pro-Gly spacer, which serves to augment delivery of a cargo peptide. Wr-T-mediated transport of p16(INK4a) functional peptide dramatically inhibits growth of highly aggressive leukemia/lymphomas by up to 80% through restoration of p16 function. The Wr-T system thus represents a highly effective approach to cargo peptide delivery with the potential for substantially developing p16 peptide-based therapy for hematopoietic malignancies.
Kondo
Eisaku
E
Department of Pathology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan. ekondo@md.okayama-u.ac.jp
Seto
Masao
M
Yoshikawa
Kazuhiro
K
Yoshino
Tadashi
T
D000818:Animals; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D016503:Drug Delivery Systems; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007938:Leukemia / Q000378:metabolism* / Q000473:pathology; D008223:Lymphoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010446:Peptide Fragments / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D021381:Protein Transport / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D019941:Cyclin-Dependent Kinase Inhibitor p16; D010446:Peptide Fragments; D012333:RNA, Messenger