Mitochondria-targeting drug conjugates for cytotoxic, anti-oxidizing and sensing purposes: current strategies and future perspectives

Abstract

Mitochondrial targeting is a promising approach for solving current issues in clinical application of chemotherapy and diagnosis of several disorders. Here, we discuss direct conjugation of mitochondrial-targeting moieties to anticancer drugs, antioxidants and sensor molecules. Among them, the most widely applied mitochondrial targeting moiety is triphenylphosphonium (TPP), which is a delocalized cationic lipid that readily accumulates and penetrates through the mitochondrial membrane due to the highly negative mitochondrial membrane potential. Other moieties, including short peptides, dequalinium, guanidine, rhodamine, and F16, are also known to be promising mitochondrial targeting agents. Direct conjugation of mitochondrial targeting moieties to anticancer drugs, antioxidants and sensors results in increased cytotoxicity, anti-oxidizing activity and sensing activity, respectively, compared with their non-targeting counterparts, especially in drug-resistant cells. Although many mitochondria-targeted anticancer drug conjugates have been investigated in vitro and in vivo, further clinical studies are still needed. On the other hand, several mitochondria-targeting antioxidants have been analyzed in clinical phases I, II and III trials, and one conjugate has been approved for treating eye disease in Russia. There are numerous ongoing studies of mitochondria-targeted sensors.

Keywords: (Fx, r)3, (l-cyclohexyl alanine-d-arginine)3; 4-AT, 4-amino-TEMPO; 5-FU, 5-Fluorouracil; AD, Alzheimer׳s disease; AIE, aggregation-induced emission; ATP, adenosine triphosphate; Anticancer agents; Antioxidants; Arg, arginine; Aβ, beta amyloid; BODIPY, boron-dipyrromethene; C-dots, carbon dots; CAT, catalase; COX, cytochrome c oxidase; CZBI, carbazole and benzo[e]indolium; CoA, coenzyme A; DDS, drug delivery system; DEPMPO, 5-(diethylphosphono)-5-methyl-1-pyrroline N-oxide; DIPPMPO, 5-(diisopropoxyphosphoryl)-5-methyl-1-pyrroline-N-oxide; DQA, dequalinium; Direct conjugation; Dmt, dimethyltyrosine; EPR, enhanced permeability and retention; F16, (E)-4-(1H-indol-3-ylvinyl)-N-methylpyridinium iodide; GPX, glutathione peroxidase; GS, gramicidin S; HTPP, 5-(4-hydroxy-phenyl)-10,15,20-triphenylporphyrin; IMM, inner mitochondrial membrane; IMS, intermembrane space; IOA, imidazole-substituted oleic acid; LA, lipoic acid; LAH2, dihydrolipoic acid; Lys, lysine; MET, mesenchymal-epithelial transition; MLS, mitochondria localization sequences; MPO, myeloperoxidase; MPP, mitochondria-penetrating peptides; MitoChlor, TPP-chlorambucil; MitoE, TPP-vitamin E; MitoLA, TPP-lipoic acid; MitoQ, TPP-ubiquinone; MitoVES, TPP-vitamin E succinate; Mitochondria-targeting; Nit, nitrooxy; NitDOX, nitrooxy-DOX; OMM, outer mitochondrial membrane; OXPHOS, oxidative phosphorylation; PD, Parkinson׳s disease; PDT, photodynamic therapy; PET, photoinduced electron transfer; PS, photosensitizer; PTPC, permeability transition pore complex; Phe, phenylalanine; RNS, reactive nitrogen species; ROS, reactive oxygen species; SOD, superoxide dismutase; SS peptide, Szeto-Schiller peptides; Sensing agents; SkQ1, Skulachev ion-quinone; TEMPOL, 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl; TPEY-TEMPO, [2-(1-oxyl-2,2,6,6-tetramethylpiperidin-4-ylimino)-ethyl]-triphenyl-phosphonium; TPP, triphenylphosphonium; Tyr, tyrosine; VDAC/ANT, voltage-dependent anion channel/adenine nucleotide translocase; VES, vitamin E succinate; XO, xanthine oxidase; mitoTEMPO, (2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium); mtCbl, (Fx,r)3-chlorambucil; mtDNA, mitochondrial DNA; mtPt, mitochondria-targeting (Fx,r)3-platinum(II); nDNA, nuclear DNA; αTOS, alpha-tocopheryl succinate..

Graphical abstract

Figure 1

Historical progress of the development of mitochondrial-targeting drug and antioxidant molecules.

Figure 2

Mitochondrial structure and general functions.

Figure 3

The number of mitochondria-targeting research articles.

Figure 5

Evidence of mitochondrial accumulation of some mitochondrial targeting moieties monitored by a confocal microscopy: (A) Mito-Chlor (TPP–chloroambucil conjugates); adapted with permission from the reference (Copyright © 2013 American Chemical Society); (B) green fluorescence-labeled MitoVES (MitoVES-F) in NeuTL cells; reproduced with permission from the reference (Copyright © 2011 Elsevier Inc.); (C) DQA–DOX conjugates in A549 cells; reproduced with permission from the reference (Copyright © 2015 Springer Nature); (D) (F_x,r)₃–DOX (i.e., MPP–DOX) conjugates; adapted with permission from the reference (Copyright © 2013 American Chemical Society); (E) F16 (green); reproduced with permission from the reference (Copyright © 2002 CELL PRESS); and (F) TPP–porphyrin (red); reproduced with permission from the reference (Copyright © 2009 Elsevier, B.V.). Here, both an anti-Complex I antibody and anti-TPP antisera were used for Mito–Chlor; MitoTracker^® Red was used for MitoVES–F, (F_x,r)₃–DOX and F16; MitoTracker^® Green was used for DQA–DOX and porphyrin conjugates; and TPP–porphyrin was used for rhodamine.

Figure 4

Some common mitochondria-targeting moieties. Red color indicates cationic atoms and dot line indicates conjugation-formable parts with drug molecules.

Figure 6

Some examples of cytotoxic drugs conjugated with the mitochondria-targeting moiety triphenylphosphonium (TPP). Mitochondria-targeting moieties, drugs and linkers are denoted by red, black and blue, respectively. The blue dotted lines indicate connections between a mitochondria-targeting moiety and linker.

Figure 7

Some examples of cytotoxic drugs conjugated with the mitochondria-targeting moiety (F_x,r)₃ and mitochondrial-targeting doxorubicin (DOX) conjugated with various targeting moieties, such as (F_x,r)₃, DQA, nitrooxy (Nit) and 3-phenylsulfonylfuroxan (Fur). Mitochondria-targeting moieties, drugs and linkers are denoted in red, black and blue, respectively.

Figure 8

Some examples of (A) mitochondria-targeting cytotoxic drugs conjugated with the F16 moiety; (B) mitochondria-targeting porphyrin conjugates; and C) cyclic guanidine–geldanamycin conjugates.

Figure 9

(A) The first mitochondria-targeting antioxidant thiobutyltriphenylphosphonium bromide; and (B) mitochondria-targeting ubiquinone derivatives.

Figure 10

Some examples of mitochondria-targeting antioxidants with (A) either pyrrolidine nitroxide or piperidin nitroxide derivatives; and (B) pyrroline nitroxide derivatives.

Figure 11

Some examples of mitochondria-targeting antioxidants with (A) vitamin derivatives; (B) acidic derivatives; and (C) enzyme mimetics.

Figure 12

Mitochondrial-targeting sensor molecules and their activation. (A) Triphenylphosphonium carbon dot conjugate (TPP-C-dots) and its interaction with the peroxinitrite radical; (B) design and sensing mechanism of the probe CZBI for bisulfite anion (HSO₃^–); (C) response mechanism of the mitochondrial-targeted near-infrared fluorescence probe NDMBT for HSO₃^–/SO₃²⁻ sensing; and (D) structure of BiTClO and its reaction mechanism with the hypochlorite anion (ClO^–).