Bladder tumor-targeted delivery of pro-apoptotic peptide for cancer therapy.
The overall prognosis of conventional chemotherapy for the treatment of bladder cancer is poor and reduction of its systemic side effects remains an unsolved issue. Targeted therapy for bladder cancer could improve therapeutic efficacy and reduce side effects. This study investigated a hybrid peptide (named Bld-1-KLA) composed of the CSNRDARRC peptide (Bld-1), which binds to bladder tumor cells, and the d-KLAKLAKKLAKLAK (KLA) peptide, which disrupts mitochondrial membrane and induces apoptotic cell death, as a bladder cancer-targeted therapeutic agent. Bld-1-KLA selectively bound to HT1376 bladder tumor cells and efficiently internalized into the cells but not to other types of tumor and normal cell lines. Bld-1-KLA exerted cytotoxic effects selectively to HT1376 cells (LC50=41.5μM), but not to other types of cells. Pretreatment of cells with Bld-1 inhibited the binding and cytotoxicity by Bld-1-KLA in HT1376 cells. It induced apoptosis of bladder tumor cells, while Bld-1 or KLA alone showed much lesser effect on apoptosis, and was co-localized in mitochondria. Bld-1-KLA was stable up to 24h in serum. In vivo fluorescence imaging showed that homing of Bld-1-KLA in the tumor in HT1376 tumor-bearing nude mice was greater than that of the control peptide-KLA after intravenous injection. Treatment of tumor-bearing mice with Bld-1-KLA, compared to the control peptide-KLA, induced apoptosis of tumor cells and inhibited tumor growth more efficiently. No significant side effects on body weight and the liver and myeloid function were observed in mice treated with Bld-1-KLA. These results suggest that Bld-1-KLA is a promising therapeutic agent for targeted therapy of bladder cancer.
Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; CMRI, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
Hyun-Kyung
HK
Jung
Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; CMRI, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
Soyoun
S
Kim
Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; CMRI, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
Rang-Woon
RW
Park
BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
Jae-Yong
JY
Park
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea; KU-KIST School, Korea University, Seoul, Republic of Korea.
In-San
IS
Kim
Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; CMRI, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. Electronic address: leebh@knu.ac.kr.
Byungheon
B
Lee
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010455:Peptides / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D000970:Antineoplastic Agents; D010455:Peptides
Bladder tumor; Peptide; Pro-apoptotic peptide; Targeted therapy