title: Inhibition of transferrin iron release increases in vitro drug carrier efficacy.
abstract: Transferrin (Tf) 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 IC(50) 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.
authors.affiliation: Department of Bioengineering, University of California, Los Angeles, CA 90095, USA.
authors.forename: Bert J
authors.initials: BJ
authors.lastname: Lao
authors.forename: Wen-Lin P
authors.initials: WL
authors.lastname: Tsai
authors.forename: Foad
authors.initials: F
authors.lastname: Mashayekhi
authors.forename: Edward A
authors.initials: EA
authors.lastname: Pham
authors.forename: Anne B
authors.initials: AB
authors.lastname: Mason
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Kamei
mesh_terms: D000465:Algorithms; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D019540:Area Under Curve; D002254:Carbonates / Q000737:chemistry / Q000378:metabolism; D004167:Diphtheria Toxin / Q000008:administration & dosage / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods*; D006367:HeLa Cells; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008024:Ligands; D015233:Models, Statistical; D010070:Oxalates / Q000737:chemistry; D013778:Tetrazolium Salts; D013844:Thiazoles; D014168:Transferrin / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D002254:Carbonates; D004167:Diphtheria Toxin; D004337:Drug Carriers; D008024:Ligands; D010070:Oxalates; D013778:Tetrazolium Salts; D013844:Thiazoles; D014168:Transferrin; D007501:Iron; C022616:thiazolyl blue