Molecular Vehicles for Mitochondrial Chemical Biology and Drug Delivery

Abstract

The mitochondria within human cells play a major role in a variety of critical processes involved in cell survival and death. An understanding of mitochondrial involvement in various human diseases has generated an appreciable amount of interest in exploring this organelle as a potential drug target. As a result, a number of strategies to probe and combat mitochondria-associated diseases have emerged. Access to mitochondria-specific delivery vectors has allowed the study of biological processes within this intracellular compartment with a heightened level of specificity. In this review, we summarize the features of existing delivery vectors developed for targeting probes and therapeutics to this highly impermeable organelle. We also discuss the major applications of mitochondrial targeting of bioactive molecules, which include the detection and treatment of oxidative damage, combating bacterial infections, and the development of new therapeutic approaches for cancer. Future directions include the assessment of the therapeutic benefit achieved by mitochondrial targeting for treatment of disease in vivo. In addition, the availability of mitochondria-specific chemical probes will allow the elucidation of the details of biological processes that occur within this cellular compartment.

Insight into nanoparticle cellular uptake and intracellular targeting

“…Mitochondrial dysfunction has been implicated for a number diseases, including cancer, neurodegenerative and neuromuscular diseases, obesity, and diabetes, and has been recognized for hosting vital therapeutic targets [174–178]. A synergy of highly dense inner membrane (abundant in saturated phospholipids) and high membrane potential (negative inside) compared to the plasma membrane results in a highly controlled transportation across the mitochondrial membranes [179,180]. Because of the highly selective and impermeable nature of the mitochondrial membrane, targeting and delivering therapeutic agents to mitochondria has been a formidable challenge.…”

Endolysosomal targeting of a clinical chlorin photosensitiser for light-triggered delivery of nano-sized medicines

“…17 demonstrated enhanced PDT efficacy using a nucleus-directed linear peptide conjugated with chlorin e 6. Cell-penetrating peptides (CPPs) have been widely investigated as delivery systems for targeted drug delivery 18–20 . CPPs typically consist of 8–30 amino acid residues and can translocate diverse molecular cargoes across biological membranes and transport, either covalently or non-covalently attached, which would otherwise be poorly internalised.…”

Cell-Penetrating, Guanidinium-Rich Oligophosphoesters: Effective and Versatile Molecular Transporters for Drug and Probe Delivery

“…Work by Kelley and co-workers demonstrated that amphipathic guanidinium-rich oligopeptides accumulated in the mitochondria due to increased hydrophobic interactions with the inner mitochondrial membrane, and delocalization of charge by a mixed amphipathic scaffold which aligns with the structure of the HexPhos oligomers. 65 This localization could be exploited in future work by delivering chemotherapeutic agents directly to the mitochondria for increased efficacy, 66 but does not preclude cytosolic delivery and release of free drug/probe (such as through a reducible disulfide) as transporters would still spend ample time in the cytosol for release to occur.…”