Nanopreparations for mitochondria targeting drug delivery system: Current strategies and future prospective

Abstract

Mitochondria are a novel and promising therapeutic target for diagnosis, treatment and prevention of a lot of human diseases such as cancer, metabolic diseases and neurodegenerative disease. Owing to the mitochondrial special bilayer structure and highly negative potential nature, therapeutic molecules have multiple difficulties in reaching mitochondria. To overcome multiple barriers for targeting mitochondria, the researchers developed various pharmaceutical preparations such as liposomes, polymeric nanoparticles and inorganic nanoparticles modified by mitochondriotropic moieties like dequalinium (DQA), triphenylphosphonium (TPP), mitochondrial penetrating peptides (MPPs) and mitochondrial protein import machinery that allow specific targeting. The targeted formulations exhibited enhanced pharmacological effect and better therapeutic effect than their untargeted counterpart both in vitro and in vivo. Nanocarriers may be used for bio-therapeutic delivery into specific mitochondria that possess a great potential treatment of mitochondria related diseases.

Keywords: Cancer; DQAsomes; Diabetes; Liposomes; Mitochondria-targeting; Nanoparticles.

Graphical abstract

Fig. 1

Mitochondrial four parts: the outer mitochondrial membrane (OMM), the inner mitochondrial membrane (IMM), the intermembrane space (IMS) and the matrix. And the electron transport chain contains five proteins: complex I (NADH dehydrogenase), complex II (succinate dehydrogenase), complex III (cytochrome bc₁), complex IV (cytochrome c oxidase), and complex V (ATP synthase).

Fig. 2

The five main mitochondria targeting strategies: lipophilic cations such as TPP (A), DQA and DQAsomes (B), mitochondrial penetrating peptides like SS-31 (C), a special liposomes named MITO-Porter (D), and mitochondrial protein import machinery (E).

Fig. 3

The schematic of DQAsomes. Lipophilic drugs are encapsulated between two hydrophobic chains while the hydrophilic drugs are wrapped in the core of DQAsomes.

Fig. 4

The chemical structure of Szeto–Schiller (SS) peptide.

Fig. 5

The mitochondrial targeting mechanism of MITO-Porter: cells internalized MITO-Porter through micropinocytosis, then it escaped from macropinosomes and bound to mitochondria via electrostatic interactions with R8. The membrane fusion was helped by sphingomyelin or phosphatidic acid which is fusogenic lipids with mitochondrial membrane and the cargos released to intra-mitochondrial compartment. Redrawn based on reference .