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-PEG10K-TRAIL was successfully purified and characterized by SDS-PAGE, western blotting. To determine the specific binding of Tf-PEG10K-TRAIL to Tf receptor, competitive receptor binding assays were performed on K 562 cells. The results obtained demonstrate that the affinity of Tf-PEG10K-TRAIL for Tf receptor is similar to that of native Tf. In contrast, PEG10K-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-PEG10K-TRAIL was 5.2 fold higher (at 2 h) than TRAIL, because Tf-PEG10K-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.
Original language | English (US) |
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Pages (from-to) | 422-428 |
Number of pages | 7 |
Journal | Journal of Controlled Release |
Volume | 162 |
Issue number | 2 |
DOIs | |
State | Published - Sep 10 2012 |
Externally published | Yes |
Keywords
- Active tumor targeting
- PEGylation
- Passive tumor targeting
- TRAIL
- Transferrin
ASJC Scopus subject areas
- Pharmaceutical Science