Drug Targeting Organ-Specific Strategies

8 1 Drug Targeting: Basic Concepts and Novel Advances
1.3 Intracellular Routing of Drug–Carrier Complex
Targeting of therapeutics, whether they are chemical entities, peptides, proteins or nucleic
acid polymeric substances, relies on the release of the drug from the carrier and subsequent
access to the molecular target. Advances in the understanding of membrane structure, functions
and properties of the various cellular organelles is the basis for directing the pharmacologically
active components to the correct cellular compartments [39].
1.3.1 Passive Versus Active Drug Targeting
In drug targeting, two types of strategies can be distinguished: passive targeting and active
targeting. In the case of passive targeting, the carrier–drug complex is often delivered to
macrophages and other cells of the monocyte-phagocytic system.This leads to gradual degradation
of the carrier and (slow) release of the liberated drug from the cells either into the
blood circulation or into the tissue environment. By size exclusion, extravasation of the carrier–drug
complex can be limited, thereby preventing the drug from being distributed to nontarget
sites.As a consequence, toxicity can be reduced.Active targeting should lead to a higher
therapeutic concentration of the drug at the site of action.This can be accomplished by cell
specific delivery of the drug. In the ideal case, the dose of the drug can be reduced and sideeffects
can be diminished. The majority, if not all, active drug targeting strategies exploit receptor-based
drug targeting principles, in which receptor-specific ligands attached to the carrier–drug
complex or directly to the drug itself deliver the drug to the target cell of choice.
Depending on the subsequent routing of the receptor complex, the drug will arrive in a specific
compartment in the target cell.
1.3.2 Lysosomes as a Cellular Target Compartment
Ligands that are taken up via endocytosis or phagocytosis, are often transferred to lysosomes
for degradation. Many drug targeting strategies exploit the decrease in pH and/or the presence
of lysosomal enzymes for drug release from the carrier molecules (see Chapter 11 for a
detailed discussion of acid and enzyme sensitive drug-carrier linkers). Only in the case of
lysosomal infections and some metabolic disorders is the lysosome a relevant target compartment.
Furthermore, lysosomal routing provides a pathway for presentation of peptides in
major histocompatibility complexes (MHC) class I or II in macrophages or other antigen
presenting cells.
In most other cases, the lysosomes are a transit compartment en route to the cytoplasm. In
case the targeted agent is lysosomally unstable (e.g. DNA) this compartment should be
avoided.