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Subcellular targeting strategies for drug design and delivery
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Journal Article
Subcellular targeting strategies for drug design and delivery
2010
Overview
Key Points
Although great efforts have been made to address the bioavailability and tissue targeting of drugs, little is known about drug delivery to specific subcellular compartments that harbour the drug target. As cells constantly traffic their contents to these compartments, cell biology principles could be effectively used for drug targeting.
For a drug to reach particular subcellular compartments, the drug has to be modified to include the appropriate signal to target it to the subcellular site, without compromising its functional moiety.
Protein modifications or lipid conjugations that direct a drug to targets in the plasma membrane have been shown to increase drug efficacy. These modifications reduce the dimensionality of these otherwise soluble drugs, thereby leading to an increase in effective drug concentration.
Cells internalize various small molecules, nutrients and pathogens and sort them to specific intracellular compartments. Drug conjugation to either the nutrient moieties or part of the pathogens that carry the targeting signal are some of the strategies used to target specific organelles.
In addition to membrane-bound organelles, the cytosol could also be targeted by specific modifications. Cell-penetrating peptides from viruses, viral particles, bacterial toxins, liposomes and nanoparticles are various means to target the cytosol. Targeting the cytosol is also a method for reaching the nuclear compartment.
Specific targeting of drugs to subcellular compartments is still in the early stages of development but shows promise. Issues such as drug stability in intracellular compartments and tissue-specific targeting are still to be addressed.
Although considerable efforts have been made to deliver drugs to particular tissues, little is known about targeting drugs to specific cellular compartments. By examining the fundamental principles of membrane trafficking and subcellular organization, the authors outline strategies to increase drug concentrations specifically in the relevant subcellular locations.
Many drug targets are localized to particular subcellular compartments, yet current drug design strategies are focused on bioavailability and tissue targeting and rarely address drug delivery to specific intracellular compartments. Insights into how the cell traffics its constituents to these different cellular locations could improve drug design. In this Review, we explore the fundamentals of membrane trafficking and subcellular organization, as well as strategies used by pathogens to appropriate these mechanisms and the implications for drug design and delivery.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
