Active tumor-targeted delivery of PEG-protein via transferrin-transferrin-receptor system

Transferrin (Tf) holds promise as a drug carrier because of overexpress transferring receptors (TfRs) on the surface of tumor cells. The purpose of this work was to conjugate Tf to PEGylated protein (Tf-PEG-protein) to improve tumor-targeted delivery of PEG-protein. After a model protein, beta-lactoglobulin B (LG), was modified by the heterobifunctional polyethyleneglycol (PEG), Tf was covalently linked to the distal end of the PEG chains on the PEG-LG (PL) conjugate. The purified Tf-PEG-LG (TPL) contained 1.4 of Tf ligand on one LG molecule. The specificity and affinity of TPL to TfR on two kinds of tumor cells (K562 and KB cells) were assessed. The results demonstrated that, TPL can bind specifically to the TfR on the tumor cell surface and the affinity of the conjugate to TfR was similar to that of native Tf. The pharmacokinetics and biodistribution studies in rodents found that TPL exhibited a significantly delayed blood clearance, the longest tumor resident time and the greatest tumor accumulation, as compared with LG and PL. Such design of the Tf conjugate would suggest a promising approach for active tumor targeting of therapeutic proteins or peptides to target cells.