Quantitative Aspects of Intracellularly-Targeted Drug Delivery

Abstract

Many pharmacological agents act intracellularly, need to be endocytosed, and reach the site of action in specific organelle to exert their action. The cell’s interior is highly compartmentalized, and complexity of the cellular endocytosis and trafficking pathways (1,2) leads to suboptimal magnitude and duration of pharmacological effects at the organelle of interest, as well as to non-specific effects due to exposure of additional organelles to the drug. Thus, attaining efficient and selective pharmacological effects for intracellularly acting drugs requires development of specialized drug delivery systems (DDS) that should be targeted to specific organelle and deliver the drug in a controlled fashion (3,4). For this purpose, particle or vesicle (liposome)-basedDDS can be used, and intracellular targeting can be achieved by decorating the drug or the DDS with organelle-specific targeting moieties. This approach relies on recognition of these moieties by the endogenous intracellular trafficking mechanisms andpreferential delivery of the drug or theDDS into specific organelle (3,4). Feasibility of targeted delivery of drugs and model compounds into individual organelles has been assessed in several studies (summarized in Table I). However, the quantitative aspects of this targeting, in terms of targeting efficiency and kinetics of drug delivery to the specific intracellular organelles, are not yet clear and should be intensively studied in order to pave the way to the clinical application of the intracellularly targeted DDSs. This commentary analyzes the existing approaches for intracellular drug targeting, their efficiency and limitations. For an introduction to intracellular drug delivery, the reader is referred to several excellent recent reviews (3,5). Delivery of DNA and RNA molecules is not in the scope of this commentary and will be mentioned only briefly.