Journal
JOURNAL OF CONTROLLED RELEASE
Volume 117, Issue 3, Pages 403-412Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2006.12.001
Keywords
transferrin; diphtheria toxin; drug carrier; trafficking; targeted cancer therapy
Funding
- NIDDK NIH HHS [R01 DK021739, R01 DK21739] Funding Source: Medline
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Transferrin (To conjugates of CRM107 are currently being tested in clinical trials for treatment of malignant gliomas. However, the rapid cellular recycling of Tf limits its efficiency as a drug carrier. We have developed a mathematical model of the Tf/TfR trafficking cycle and have identified the Tf iron release rate as a previously unreported factor governing the degree of Tf cellular association. The release of iron from Tf is inhibited by replacing the synergistic carbonate anion with oxalate. Trafficking patterns for oxalate Tf and native Tf are compared by measuring their cellular association with HeLa cells. The amount of Tf associated with the cells is an average of 51% greater for oxalate Tf than for native Tf over a two hour period at Tf concentrations of 0.1 nM and 1 nM. Importantly, diphtheria toxin (DT) conjugates of oxalate Tf are more cytotoxic against HeLa cells than conjugates of native Tf. Conjugate IC50 values were determined to be 0.06 nM for the oxalate Tf conjugate vs. 0.22 nM for the native Tf conjugate. Thus, we show that inhibition of Tf iron release improves the efficacy of Tf as a drug carrier through increased association with cells expressing TfR. (c) 2006 Elsevier B.V. All rights reserved.
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