title: PEG-transferrin conjugated TRAIL (TNF-related apoptosis-inducing ligand) for therapeutic tumor targeting.
abstract: Transferrin (Tf) is considered an effective tumor-targeting agent, and PEGylation effectively prolongs in vivo pharmacokinetics by delaying excretion via the renal route. The authors describe the active tumor targeting of long-acting Tf-PEG-TNF-related apoptosis-inducing ligand conjugate (Tf-PEG-TRAIL) for effective cancer therapy. Tf-PEG-TRAIL was prepared using a two-step N-terminal specific PEGylation procedure using different PEGs (Mw: 3.4, 5, 10 kDa). Eventually, only 10 kDa PEG was linked to Tf and TRAIL because TRAIL (66 kDa) and Tf (81 kDa) were too large to link to 3.4 and 5 kDa PEG. The final conjugate Tf-PEG(10K)-TRAIL was successfully purified and characterized by SDS-PAGE, western blotting. To determine the specific binding of Tf-PEG(10K)-TRAIL to Tf receptor, competitive receptor binding assays were performed on K 562 cells. The results obtained demonstrate that the affinity of Tf-PEG(10K)-TRAIL for Tf receptor is similar to that of native Tf. In contrast, PEG(10K)-TRAIL demonstrated no specificity. Biodistribution patterns and antitumor effects were investigated in C57BL6 mice bearing B16F10 murine melanomas and BALB/c athymic mice bearing HCT116. Tumor accumulation of Tf-PEG(10K)-TRAIL was 5.2 fold higher (at 2 h) than TRAIL, because Tf-PEG(10K)-TRAIL has both passive and active tumor targeting ability. Furthermore, the suppression of tumors by Tf-PEG(10K)-TRAIL was 3.6 and 1.5 fold those of TRAIL and PEG(10K)-TRAIL, respectively. These results suggest that Tf-PEG(10K)-TRAIL is a superior pharmacokinetic conjugate that potently targets tumors and that it should be viewed as a potential cancer therapy.
authors: College of Pharmacy, SungKyunKwan University, 300 Chonchon-dong, Jangan-ku, Suwon 440-746, South Korea.
authors: Tae Hyung
authors: TH
authors: Kim
authors: Young Gi
authors: YG
authors: Jo
authors: Hai Hua
authors: HH
authors: Jiang
authors: Sung Mook
authors: SM
authors: Lim
authors: Yu Seok
authors: YS
authors: Youn
authors: Seulki
authors: S
authors: Lee
authors: Xiaoyuan
authors: X
authors: Chen
authors: Youngro
authors: Y
authors: Byun
authors: Kang Choon
authors: KC
authors: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D045325:HCT116 Cells; D006801:Humans; D020014:K562 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D011990:Receptors, Transferrin / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D014168:Transferrin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D011990:Receptors, Transferrin; D053221:TNF-Related Apoptosis-Inducing Ligand; D014168:Transferrin; D011092:Polyethylene Glycols