Selective inhibition of ErbB2-overexpressing breast cancer in vivo by a novel TAT-based ErbB2-targeting signal transducers and activators of transcription 3-blocking peptide.
ErbB2 is an excellent target for cancer therapies. Unfortunately, the outcome of current therapies for ErbB2-positive breast cancers remains unsatisfying due to resistance and side effects. New therapies for ErbB2-overexpressing breast cancers continue to be in great need. Peptide therapy using cell-penetrating peptides (CPP) as peptide carriers is promising because the internalization is highly efficient, and the cargoes delivered can be bioactive. However, the major obstacle in using these powerful CPPs for therapy is their lack of specificity. Here, we sought to develop a peptide carrier that could introduce therapeutics specifically to ErbB2-overexpressing breast cancer cells. By modifying the HIV TAT-derived CPP and conjugating anti-HER-2/neu peptide mimetic (AHNP), we developed the peptide carrier (P3-AHNP) that specifically targeted ErbB2-overexpressing breast cancer cells in vitro and in vivo. A signal transducers and activators of transcription 3 (STAT3)-inhibiting peptide conjugated to this peptide carrier (P3-AHNP-STAT3BP) was delivered more efficiently into ErbB2-overexpressing than ErbB2 low-expressing cancer cells in vitro and successfully decreased STAT3 binding to STAT3-interacting DNA sequence. P3-AHNP-STAT3BP inhibited cell growth in vitro, with ErbB2-overexpressing 435.eB breast cancer cells being more sensitive to the treatment than the ErbB2 low-expressing MDA-MB-435 cells. Compared with ErbB2 low-expressing MDA-MB-435 xenografts, i.p. injected P3-AHNP-STAT3BP preferentially accumulated in 435.eB xenografts, which led to more reduction of proliferation and increased apoptosis and targeted inhibition of tumor growth. This novel peptide delivery system provided a sound basis for the future development of safe and effective new-generation therapeutics to cancer-specific molecular targets.
Departments of Surgical Oncology and Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Ming
M
Tan
Keng-Hsueh
KH
Lan
Jun
J
Yao
Chien-Hsing
CH
Lu
Menghong
M
Sun
Christopher L
CL
Neal
Jing
J
Lu
Dihua
D
Yu
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D016503:Drug Delivery Systems; D005260:Female; D015696:Gene Products, tat / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D010446:Peptide Fragments / Q000493:pharmacokinetics / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D015696:Gene Products, tat; D018796:Immunoconjugates; D010446:Peptide Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C404542:anti-HER2-neu peptide mimic, 1.5 kDa