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.
Pan
Hong
H
Department of Pharmaceutics, School of Pharmacy, Fudan University, 200032 Shanghai, China.
Han
Limei
L
Chen
Wei
W
Yao
Ming
M
Lu
Weiyue
W
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000378:metabolism; D019921:Biotinylation; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008081:Liposomes / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008954:Models, Biological; D009336:Necrosis; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D019809:Streptavidin / Q000737:chemistry*; D014018:Tissue Distribution; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D008081:Liposomes; D004317:Doxorubicin; D019809:Streptavidin