Genetically engineering transferrin to improve its in vitro ability to deliver cytotoxins.
作者： Dennis J. Yoon , David S.H. Chu , Christopher W. Ng , Edward A. Pham , Anne B. Mason
DOI: 10.1016/J.JCONREL.2008.10.006
关键词:
摘要: We previously demonstrated that decreasing the iron release rate of transferrin (Tf), by replacing synergistic anion carbonate with oxalate, increases its in vitro drug carrier efficacy HeLa cells. In current work, utility this strategy has been further explored generating two Tf mutants, K206E/R632A and K206E/K534A Tf, exhibiting different degrees inhibition. The intracellular trafficking behavior these mutants assessed measuring their association Compared to native cellular increased 126 250%, respectively. Surface plasmon resonance studies clearly indicate increase is due a decrease not differences binding affinity receptor (TfR). Diphtheria toxin (DT) conjugates showed significantly cytotoxicity against cells IC50 values 1.00 pM 0.93 pM, respectively, compared value 1.73 for conjugate. Besides validating our inhibiting release, provide proof-of-principle site-directed mutagenesis offers an alternative method improving Tf.
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