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.

Triclosan–lysozyme complex as novel antimicrobial macromolecule: A new potential of lysozyme as phenolic drug-targeting molecule

“…An important property of drug carriers that has particular significance in pharmacy is their ability to increase the solubility of poorly soluble drugs in water and have non-covalent interaction with the drug to facilitate the delivery [14]. We have shown that TCS become completely soluble in water upon complexation with LZ (Fig.…”

“…It has been shown that the type of interaction between protein and phenolic compounds is an important factor in producing effective delivery system. Specifically, it was demonstrated that weak binding affinity of phenolic drug to the carrier molecule is correlated with the effectiveness of drug delivery [14]. Therefore, the effectiveness of phenolic drug-LZ conjugates may be explored by identifying a phenolic antibiotic for LZ that exhibits a less degree of association.…”

Outside the Box—Novel Therapeutic Strategies for Glioblastoma

“…Initially, transferrin receptor was investigated as a potential tumor-targeting mechanism, in combination with mutant DT, as this receptor is expressed on the surface of many types of cancer, including GBM. 12 A mutant DT fused to a molecule of transferrin administered via CED was initially investigated; however, rapid transferrin cycling within the cell limited the duration of toxin exposure reducing potential therapeutic efficacy, 13 Mutant forms of transferrin fused with DT were then investigated in clinical studies; however, this treatment did not increase overall survival when compared with standard therapy. 14 Currently, DT conjugated with a transferrin receptor antibody administered via CED to patients with GBM is being investigated in clinical trials.…”

New drug-targeting strategy from beneath the shell of egg

“…An important property of drug carriers that has particular significance in pharmacy is their ability to increase the solubility of poorly soluble drugs in water and have non-covalent interaction with the drug to facilitate delivery [37]. The insoluble triclosan becomes completely soluble in water on complexation with lysozyme ( Figure 5B), most probably as the phenolic ring is incorporated, non-covalently, into the hydrophobic core underlying the active site cleft of lysozyme, as deduced from fluorescence study.…”

“…Specifically, it has been demonstrated that weak binding affinity of phenolic drug to the carrier molecule is correlated with the effectiveness of drug delivery [37]. Therefore, the effectiveness of phenolic drug-lysozyme conjugates may be explored by identifying a phenolic antibiotic for lysozyme that shows a lesser degree of association.…”