Organelle targeting: third level of drug targeting

Abstract

Drug discovery and drug delivery are two main aspects for treatment of a variety of disorders. However, the real bottleneck associated with systemic drug administration is the lack of target-specific affinity toward a pathological site, resulting in systemic toxicity and innumerable other side effects as well as higher dosage requirement for efficacy. An attractive strategy to increase the therapeutic index of a drug is to specifically deliver the therapeutic molecule in its active form, not only into target tissue, nor even to target cells, but more importantly, into the targeted organelle, ie, to its intracellular therapeutic active site. This would ensure improved efficacy and minimize toxicity. Cancer chemotherapy today faces the major challenge of delivering chemotherapeutic drugs exclusively to tumor cells, while sparing normal proliferating cells. Nanoparticles play a crucial role by acting as a vehicle for delivery of drugs to target sites inside tumor cells. In this review, we spotlight active and passive targeting, followed by discussion of the importance of targeting to specific cell organelles and the potential role of cell-penetrating peptides. Finally, the discussion will address the strategies for drug/DNA targeting to lysosomes, mitochondria, nuclei and Golgi/endoplasmic reticulum.

Keywords: cancer chemotherapy; cell penetrating peptides; intracellular drug delivery; therapeutic index.

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.