Organelle targeting: third level of drug targeting

Figures & data

Table 1 Types of endocytosis

Endocytosis type	Vesicle size	Shown by	Mechanism of internalization	Intracellular fate	Ref
Phagocytosis	>0.5 μm	Neutrophils Macrophages	Receptor-induced rearrangement in actin cytoskeleton leading to internalization of particle	Lysosomal fusion to form phagolysosome, followed by degradation	21
Macropinocytosis	0.5 μm–5 μm	Epithelial cells Neutrophils Fibroblasts Macrophages	Growth factor triggers plasma membrane ruffling, followed by sealing of aperture to form macropinosomes	Leakage from macropinosomes, released into cytoplasm	126,127
Clathrin-mediated endocytosis	100 nm–150 nm	All cells	Ligand binds to cell surface receptor, which recruits clathrin to cell membrane. Cluster of clathrin invaginates forms a vesicle which engulfs the particle	Cargo fuses with lysosome. Clathrin and receptors are recycled back to plasma membrane	128–130
Caveolae-mediated endocytosis	50 nm–60 nm	Caveolin-1 expressing cells or muscle cells that have caveolin-3	Caveosomes (via caveolin protein) form on the membrane, which is mediated by small hydrophobic microdomains rich in cholesterol and glycosphingolipids	No pH drop in endosomes. The vesicle is sorted to smooth ER or Golgi body	131
Clathrin and caveolin-independent endocytosis	60 nm		Tyrosine kinase and cholesterol-dependent endocytic pathway	It delivers cargo/virus via nonendosomal, cytosolic organelles to ER	132

Abbreviations: ER, endoplasmic reticulum; Ref, reference number.

Figure 1 Four major types of endocytosis.

Notes: The figure depicts phagocytosis, which is the engulfment of large particles/macro-organisms; macropinocytosis, which is the nonspecific uptake of particles/solute; clathrin-mediated endocytosis, which forms the major part of receptor mediated endocytosis; and caveolae-mediated endocytosis, demonstrated by cells expressing caveolin protein. Except for caveolae-mediated endocytosis, all pathways result in fusion with the lysosome.
Abbreviation: H⁺, hydrogen ion.

Figure 2 Intracellular drug delivery by various strategies to cytoplasm, nucleus, mitochondria, or lysosome and the targeting moieties to these organelles.

Abbreviations: CPP, cell-penetrating peptide; siRNA, small interfering RNA; shRNA, small hairpin RNA; RNA, ribonucleic acid.

Figure 3 Diseases associated with specific cell-organelles.

Abbreviations: CDG, congenital disorders of glycosylation; ED, Emery–Dreifuss; ERSDs, endoplasmic reticulum storage diseases; LSD, lysosomal storage disease.

Figure 4 Current approaches being used for successful mitochondrial specific delivery.

Notes: (A) Mitochondrial affinity bearing DQAsomes formed by single chain bolaamphiphiles. Right side shows DQAsomes and DNA forming complexes, DQAplexes, that transport DNA specifically to mitochondria. (B) TPP-mediated delivery of cargo is based on membrane potential created by high negative potential of the mitochondrial inner membrane, thus attachment of TPP to small molecules delivers them initially to the cytoplasm and subsequently to mitochondria. (C) Mitochondrial targeting sequences (MTS) when covalently cross-linked to large molecules like peptide nucleic acids (PNA) or oligodeoxynucleotides (ODN) can be delivered to mitochondria. When the MTS gene is fused with a gene of interest, MTS-fused protein is expressed in the cytosol and delivers the protein to mitochondria. (D) Macromolecules conjugated to the protein transduction domain (PTD) have been found to accumulate in mitochondria due to an unknown mechanism. PTD is known to bypass the classical protein import pathway and accumulate in cytosol.
Abbreviations: ATP, adenosine triphosphate; TOM/TIM, translocse of the outermembrane/translocase of the innermembrane; DQA, dequalinium; DQAsomes, dequalinium based liposome-like vesicles.