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Importance Of Receptor-mediated Endocytosis In Peptide Delivery And Targeting: Kinetic Aspects

H. Sato, Y. Sugiyama, A. Tsuji, I. Horikoshi
Published 1996 · Biology

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Abstract Receptor-mediated endocytosis (RME) is a general mechanism by which eukaryotic cells internalize peptide hormones, growth factors, cytokines, plasma glycoproteins, lysosomal enzymes, toxins and viruses concomitantly with their receptors on the cell surface. Receptor-mediated drug targeting is considered to show promise as a drug delivery system (DDS). The success of RME-utilizing drug targeting is dependent not only on the in vitro efficacy but on the in vivo behavior of the drug-polypeptide complex. In fact, there has not been much progress from the “natural” targeting of glycoproteins and LDL to hepatocytes or macrophage lineages, due to unfavorable effects on the pharmacokinetics and pharmacodynamics (PK/PD) of polypeptides. In this review, we considered the kinetic modelling of polypeptide RME in isolated or cultured cells in vitro, in perfused organs and in the whole body. Typical RME analyses are described to estimate the rate constants for polypeptide-receptor internalization, the degradation of internalized polypeptide and receptor externalization, based upon the “receptor recycling” model. The kinetic RME analysis enables not only the non-linear clearance and distribution in the liver to be predicted, but also the surface-bound and internalized polypeptide in the target cell, which is important for the intracellular efficacy of drug-polypeptide complex. In particular, the kinetics of down-regulation and subsequent recovery of surface receptors were precisely elucidated, because if the receptors are once down-regulated, the next dosage should be given only after the surface receptors are restored. The therapeutic efficacy/toxicity of a drug-carrier conjugate should be assessed from its microscopic pharmacology based on the RME mechanisms, in conjunction with macroscopic pharmacokinetic modelling.
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