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drugs and the endogenous ligands of the membrane transporters. Consequently, through specific interaction of ligands between the moiety and its transporter, drug candidates can be shuttled across or into the cells and eventually be released from the ligands.

Taking advantages of recent advances in molecular biology and computer modeling, scientists are now starting to design pro-drugs based on the structural requirements of the transporter systems. In general, prodrug strategies involving carrier-mediated pathways have the advantage of high uptake capacity. However, the size of drug conjugates is relatively limited (—1000 Da), probably because larger conjugates fail to be shuttled through the restricted space within the carrier protein. For peptide and protein delivery, carrier-mediated pathways could facilitate pep-tides only up to four amino acids.

Compared to active carriers, receptor-mediated endocytosis (RME) systems have a rather limited uptake capacity, which in some cases is insufficient to elicit pharmacological activities. Yet, because of the endocytic pit formation (up to several hundred nanometers) and the vesicular internalization mechanism, RME pathways are perfectly suited to accommodate large molecular weight peptide and/or protein conjugates. More important, recent success in transport of RME ligand-drug vehicle conjugates (e.g., nanoparticles, liposomes) by way of RME pathways opens new possibilities for macromolecular delivery across biological barriers. First of all, formulating pharmaceuticals in drug vehicle systems compensates the limited capacity of RME systems, resulting in 103- to 106-fold increase in uptake. Second, drug vehicle systems also protect drug molecules from possible enzymaticdegradation in the biological membrane. Furthermore, this type of conjugation avoids direct chemical reaction between drug molecules and ligands, allowing incorporation of drugs with more diverse structural properties.

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