Transcellular delivery of an insulin-transferrin conjugate in enterocyte-like Caco-2 cells

Journal of Pharmaceutical Sciences
D Shah, W C Shen

Abstract

Insulin, acylated with dimethylmaleic anhydride, was conjugated to transferrin (Tf) via a disulfide linkage. The molar insulin: Tf ratio in the conjugate was 3:1. The insulin-Tf conjugate (insulin-Tf) was tested for the transport of insulin across enterocyte-like Caco-2 cell monolayers by the process of transferrin receptor (TfR)-mediated transcytosis. The uptake of insulin-Tf in Caco-2 cells was TfR-mediated but no insulin receptor-mediated. Transport studies showed that insulin-Tf transport was 5- to 15-fold higher than free insulin transport across Caco-2 cells in both apical-to-basal and basal-to-apical directions. Brefeldin A (BFA), an agent that we have previously shown to cause an increase in TfR transcytosis, further enhanced the transport of the conjugated insulin three-fold in both directions; thus, a combination of the conjugate and BFA can cause a net 45-fold increase in the apical-to-basolateral transport of insulin across Caco-2 cell monolayers. The transported conjugate was intact as indicated by elution on a Sephadex G-50 column. Insulin in the transcytosed conjugate, unlike the original dimethylmaleyl insulin, was capable of binding to anti-insulin antibodies, indicating that free amino groups of insulin were r...Continue Reading

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