- Intracellularly targeted drug delivery is a promising new approach for enhancing and controlling the drug pharmacological activities. It appears that conjugation of specific targeting residues can affect the intracellular fate of the drug/DDS and result in its preferential accumulation within an organelle of interest. In most cases, cytosolic permeation of the drug/DDS is a pre-requisite for its targeting to the organelle of interest. After arrival to the cytosol, the targeting efficiency of the drug/DDS to the target organelle is apparently affected by the relative kinetics of three major processes, namely drug/DDS cytosolic mobility, degradation rate of the drug/DDS in the cytosol, and rate of drug/DDS uptake by the target organelle. The choice of drug, targeting residues, and formulation type will determine which of these processes will be rate-limiting for the overall targeting efficiency. Currently applied intracellular-targeting delivery approaches have limited efficiency. To develop clinically applicable DDSs, studies that quantitatively assess the mechanisms, barriers, and efficiency of intracellular drug delivery are needed. Mathematical modeling approaches will be of great importance to determine the barriers and limiting factors in intracellular drug delivery. For this purpose, mathematical models of the intracellular drug trafficking mechanisms (i.e., intracellular pharmacokinetics) and the relationship between the drug concentrations in the individual organelles and the pharmacological effects (i.e., intracellular pharmacokinetic-pharmacodynamic models) should be developed. Several such models have been proposed, e.g., for the description of receptor-mediated endocytosis and trafficking (21) and for lysosomal delivery of pharmacological agents (22). Mechanisms of intracellular gene delivery were studied more extensively and were quantified more thoroughly, as compared to small-molecule pharmacological agents, apparently due to somewhat easier quantification of DNA molecules. Subsequently, several mathematical models have been suggested to describe the mechanisms of DNA intracellular traffic and efficiency of nuclear delivery and of the resulting gene expression (23,24). It is expected that intracellularly targeted drug delivery approaches will be the focus of intensive research during the next decade and that efficient and controlled delivery of the drug to specific organelles will be attained using specialized DDSs. For successful clinical application of these DDSs, two levels of targeting are required: targeted uptake by the cells of the specific organ/tissue at the first stage, followed by intracellular targeting within these cells. Most probably, future DDSs will be composed of multiple layers with individual layers responsible for efficient targeting at the whole body and on the cellular levels (25).