Delivery of drugs and macromolecules to the mitochondria for cancer therapy

Abstract

Mitochondria are organelles that have pivotal functions in producing the energy necessary for life and executing the cell death pathway. Targeting drugs and macromolecules to the mitochondria may provide an effective means of inducing cell death for cancer therapy, and has been actively pursued in the last decade. This review will provide a brief overview of mitochondrial structure and function, how it relates to cancer, and importantly, will discuss different strategies of mitochondrial delivery including delivery using small molecules, peptides, genes encoding proteins and MTSs, and targeting polymers/nanoparticles with payloads to the mitochondria. The advantages and disadvantages for each strategy will be discussed. Specific examples using the latest strategies for mitochondrial targeting will be evaluated, as well as potential opportunities for specific mitochondrial compartment localization, which may lead to improvements in mitochondrial therapeutics. Future perspectives in mitochondrial targeting of drugs and macromolecules will be discussed. Currently this is an under-explored area that is prime for new discoveries in cancer therapeutics.

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

“…Triphenylphosphonium-based modification of molecules facilitating mitochondria targeting is not a totally new concept as abundant literature already exists with regard to the potent biological effects exhibited by small molecules containing TPP + 28,32,33,40–44 . Alkylated triphenylphosphonium cations initially were used as probes to study the mechanism of coupling of the mitochondrial membrane potential with oxidative phosphorylation (OXPHOS) and subsequently were used to determine mitochondrial membrane potential.…”

Three pairs of enantiomers bearing mitochondria‐targeted TPP+ groups as potential anti‐cancer agents

“…There are many approaches to target compounds to mitochondria . TPP (Triphenylphosphonium‐based) modification of molecules facilitating mitochondria targeting is one of them as abundant literature already exists with regard to the potent biological effects exhibited by small molecules containing TPP + . Alkylated TPP + initially were used as probes to study the mechanism of coupling of the mitochondrial membrane potential with oxidative phosphorylation and subsequently were used to determine mitochondrial membrane potential .…”

Improved mitochondrial targeting effect of HPMA copolymer by SS20 peptide mediation and nonendocytosis pathway

“…Expression change of these proteins in various conditions plays a vital role in oncogenesis. 12 Accordingly, drugs designed to target mitochondria are supposed to make superior contributions to cancer therapy. [13][14][15] To achieve efficient mitochondrial targeted delivery, delocalized lipophilic cations (DLC) (eg, triphenylphosphonium and dequalinium), guanidinium-based small molecules and peptides, mitochondrial targeting sequences (MTSs), XJB peptides, and protein transduction domains (PTD) have been bound to small molecules, nanoparticles, and copolymers for mitochondria-specific delivery of therapeutic agents.…”

“…[13][14][15] To achieve efficient mitochondrial targeted delivery, delocalized lipophilic cations (DLC) (eg, triphenylphosphonium and dequalinium), guanidinium-based small molecules and peptides, mitochondrial targeting sequences (MTSs), XJB peptides, and protein transduction domains (PTD) have been bound to small molecules, nanoparticles, and copolymers for mitochondria-specific delivery of therapeutic agents. 12,16,17 However, these modified drug delivery systems are usually sequestrated in endosomes/lysosomes after internalized, which severely affects their mitochondrial targeting efficiency. SS20 peptide (Phe-D-Arg-Phe-Lys-NH 2 ) is a mitochondrial targeting peptide that centers on alternating aromatic and basic amino acids.…”

“…pharmacokinetics study, healthy male BALB/c mice(20-22 g) were randomly divided into two groups (n = 7) and intravenously injected with P-Cy5 and P-Cy5-SS20 (Cy5 equivalent concentration 2.5 mg/ kg). At predetermined time points(1,3,6,12,24, 48, 72, and 96 hours), blood samples (20 μL) were taken from the orbital, and the fluorescence intensity of each sample was measured with a Varioskan Flash (excitation at 642 nm and emission at 662 nm). The blood pharmacokinetic parameters were analyzed using a noncompartmental model with PK Solver software.…”