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

BackgroundThis 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).MethodsPDOX 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.ResultsThe 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.ConclusionsPDOX 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.

Animal models of colorectal peritoneal metastasis

“…The V×2 cell line is derived from the Shope papilloma virus (family Papovaviridae), an oncogenic DNA virus, transmitted by biting arthropods and causing hyperkeratotic skin lesions resulting in malignant transformation in the rabbit [22]. A 'gastric' peritoneal carcinomatosis model based on the V×2 cell line was proposed by Tang et al [23,24] The authors simulated gastric cancer with early stage PC in New Zealand white rabbits (Oryctolagus cuniculus) by transmural injection of V×2 cells in the stomach. Turner and coworkers succeeded in engrafting human colon cancer cells (LS174T) in cyclosporine treated sheep by subperitoneal injection [25].…”

Combination of Sodium Selenite and Doxorubicin Prodrug Ac-Phe-Lys-PABC-ADM Affects Gastric Cancer Cell Apoptosis in Xenografted Mice

“…The mice were randomly divided into four groups (n = 6 per group) and treated as follows: control (intraperitoneal injection of saline); SS (3 mg/kg SS by gastric lavage [9]); PADM (intraperitoneal injection of 10 mg/kg PADM [10]); and SS+PADM (3 mg/kg SS by gastric lavage + intraperitoneal injection of 10 mg/kg PADM). The volume of administration was 10 mL/kg for intraperitoneal injection and 200 μ L for gastric perfusion.…”

Preclinical In Vivo-Models to Investigate HIPEC; Current Methodologies and Challenges

“…The following pig strains were used: white (38%) [ 58 , 60 , 61 , 83 , 84 ], sus scrofa domesticus (23%) [ 85 , 86 , 87 ], mini (8%) [ 59 ] and pigs without specifying the strain (31%) [ 88 , 89 , 90 ]. New Zealand white rabbit was the only used rabbit strain [ 41 , 42 , 91 ].…”