title: Synthesis, identification and in vivo studies of tumor-targeting agent peptide doxorubicin (PDOX) to treat peritoneal carcinomatosis of gastric cancer with similar efficacy but reduced toxicity.
abstract: BACKGROUND
  This work aimed to synthesize a cathepsin B (CTSB)-cleavable tumor-targeting prodrug peptide doxorubicin (PDOX) and study the in vivo efficacy and toxicities on an animal model of gastric peritoneal carcinomatosis (PC).
  
  
  METHODS
  PDOX was synthesized using doxorubicin (DOX) attaching to a CTSB-cleavable dipeptide Ac-Phe-Lys and a para-amino-benzyloxycarbonyl (PABC) spacer. PC model was established by injecting VX2 tumor cells into the gastric sub-mucosa of 40 rabbits, which then were randomized into 4 groups: the Control (n = 10) without treatment, the HIPEC (n = 10) receiving cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC), the PDOX (n = 10) and the DOX (n = 10) receiving systemic chemotherapy with PDOX 50.0 mg/kg or DOX 5.0 mg/kg, respectively, after CRS + HIPEC.
  
  
  RESULTS
  The median overall survivals (OS) were 23.0 d (95% CI: 19.9 d - 26.1 d) in the Control, 41.0 d (36.9 d - 45.1 d) in the HIPEC, 65.0 d (44.1 d - 71.9 d) in the PDOX, and 58.0 d (39.6 d - 54.4 d) in the DOX. Compared with the Control, the OS was extended by 70% in the HIPEC (p < 0.001) and further extended by 40% in the DOX (p = 0.029) and by 58% in the PDOX (p = 0.021), and the PC severity was decreased in the HIPEC and further decreased in the PDOX and DOX. Animals receiving DOX treatment showed hematological toxicities with marked reduction of white blood cells and platelets, as well as cardiac toxicities with significant increases in creatine kinase mb isoenzyme, evident myocardium coagulation necrosis, significant nuclear degeneration, peri-nucleus mitochondria deletion, mitochondria-pyknosis, and abnormal intercalated discs. But these toxicities were not evident in the PDOX.
  
  
  CONCLUSIONS
  PDOX is a newly synthesized tumor-targeting prodrug of DOX. Compared with DOX, PDOX has similar efficacy but reduced hematological and cardiac toxicities in treating rabbit model of gastric PC.
authors.forename: Li
authors.initials: L
authors.lastname: Tang
authors.forename: Rui
authors.initials: R
authors.lastname: Duan
authors.forename: Yan-jun
authors.initials: YJ
authors.lastname: Zhong
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Firestone
authors.forename: Ya-ping
authors.initials: YP
authors.lastname: Hong
authors.forename: Ji-guo
authors.initials: JG
authors.lastname: Li
authors.forename: Yan-chao
authors.initials: YC
authors.lastname: Xin
authors.forename: Han-lin
authors.initials: HL
authors.lastname: Wu
authors.affiliation: Department of Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, No 169, Donghu Road, Wuhan 430071, China. liyansd2@163.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000188:drug therapy* / Q000556:secondary; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D008297:Male; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000556:secondary; D011355:Prodrugs / Q000494:pharmacology; D011817:Rabbits; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000473:pathology*
chemical_list: D009842:Oligopeptides; D011355:Prodrugs; C573848:acetyl-phenylalanyl-lysyl-para-aminobenzyloxycarbonyl-adriamycin; D004317:Doxorubicin