Targeting to tumor necrotic regions with biotinylated antibody and streptavidin modified liposomes

Tumor Necrosis Treatment (TNT) was developed to target solid tumors using monoclonal antibodies such as the chimeric TNT-3 monoclonal antibody (chTNT-3), which bind to degenerating cells located in necrotic regions of tumors. Since biotinylated chTNT-3 showed shorter circulating time and more uptakes in tumors than unmodified chTNT-3, we designed the two-step pretargeting approach composed of administering biotinylated chTNT-3 and 24 h later administering streptavidin modified liposomes encapsulating doxorubicin (DOX) to deliver DOX to the tumor site. The preservation of immunoreactivity of biotinylated chTNT-3 was confirmed by ELISA. The biological half-life of total DOX in two-step pretargeting approach was longer than that of free DOX but shorter than that of sterically stabilized liposomes in Sprague-Dawley rats. The two-step pretargeting approach regimen displayed good tumor targeting with a gradual process in biodistribution study. At 4 h and 24 h after administering DOX-loaded liposomes a highest DOX level of the two-step pretargeting approach was observed. The best antitumor efficacy was observed 3 days after the second treatment in Balb/c nude mice bearing H460 tumors. These results suggested the two-step pretargeting approach regimen may be a new form for delivering anticancer drugs to tumor necrotic regions. (C) 2007 Elsevier B.V. All rights reserved.