Endocytic mechanisms for targeted drug delivery

Abstract

Advances in the delivery of targeted drug systems have evolved to enable highly regulated site specific localization to subcellular organelles. Targeting therapeutics to individual intracellular compartments has resulted in benefits to therapies associated with these unique organelles. Endocytosis, a mechanism common to all cells in the body, internalizes macromolecules and retains them in transport vesicles which traffic along the endolysosomal scaffold. An array of vesicular internalization mechanisms exist, therefore understanding the key players specific to each pathway has allowed researchers to bioengineer macromolecular complexes for highly specialized delivery. Membrane specific receptors most frequently enter the cell through endocytosis following the binding of a high affinity ligand. High affinity ligands interact with membrane receptors, internalize in membrane bound vesicles, and traffic through cells in different manners to allow for accumulation in early endosomal fractions or lysosomally associated fractions. Although most drug delivery complexes aim to avoid lysosomal degradation, more recent studies have shown the clinical utility in directed protein delivery to this environment for the enzymatic release of therapeutics. Targeting nanomedicine complexes to the endolysosomal pathway has serious potential for improving drug delivery for the treatment of lysosomal storage diseases, cancer, and Alzheimer's disease. Although several issues remain for receptor specific targeting, current work is investigating a synthetic receptor approach for high affinity binding of targeted macromolecules.

Figure 1

Caveolae-assisted internalization of Simian Virus 40 (SV40). Caveolae are specialized lipid rafts that allow for SV40 internalization and subsequent intracellular signaling. After binding to major histocompatibility class 1 antigens (MHC 1), SV40 moves along the plasma membrane and concentrates in caveolae structures. MHC 1 is not endocytosed, therefore it is suggested an unidentified receptor is responsible for SV40 high affinity internalization. A signaling transduction cascade is induced upon the phosphorylation of tyrosine residues resulting in the depolymerization of actin fibers and invagination of the membrane. Caveosomes are transported intracellularly along microtubular networks to either be transcytosed to the opposite membrane domain or transported to the endoplasmic reticulum (ER) from which SV40 will travel to the nucleus [31].

Figure 2

Representative fate of clathrin mediated RME of asialoglycoprotein (ASGP) and its receptor (ASGPr) upon endocytosis. After binding of ASGP to its receptor, the receptor-ligand complex is internalized in a clathrin-coated pit that pinches off to become a coated vesicle. The clathrin coat then depolymerizes to triskelions, resulting in an early endosome. This endosome fuses with a sorting vesicle (late endosome). Lowering of pH causes ASGP dissociation from ASGPr. A receptor-rich region buds off to form a separate vesicle that recycles multiple ASGPr back to the plasma membrane. ASGP-containing vesicles ultimately fuse with lysosomes, wherein it is degraded to amino acids and sugar [72].