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

https://doi.org/10.1016/j.apsb.2018.05.006Get rights and content
Under a Creative Commons license
open access

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.

Graphical abstract

Mitochondria-targeted anticancer, antioxidant, and sensing agents can selectively accumulate in the mitochondria, where their modes of action occur. In most cases, lipophilic molecules intercalate into the mitochondrial membrane through lipophilic affinity and further move through the matrix owing to the membrane potential difference.

fx1
  1. Download : Download high-res image (341KB)
  2. Download : Download full-size image

Abbreviations

4-AT
4-amino-TEMPO
Aβ
beta amyloid
AD
Alzheimer׳s disease
AIE
aggregation-induced emission
Arg
arginine
ATP
adenosine triphosphate
BODIPY
boron-dipyrromethene
CAT
catalase
C-dots
carbon dots
CoA
coenzyme A
COX
cytochrome c oxidase
CZBI
carbazole and benzo[e]indolium
DDS
drug delivery system
DEPMPO
5-(diethylphosphono)-5-methyl-1-pyrroline N-oxide
DIPPMPO
5-(diisopropoxyphosphoryl)-5-methyl-1-pyrroline-N-oxide
Dmt
dimethyltyrosine
DQA
dequalinium
EPR
enhanced permeability and retention
F16
(E)-4-(1H-indol-3-ylvinyl)-N-methylpyridinium iodide
5-FU
5-Fluorouracil
(Fx
r)3, (l-cyclohexyl alanine-d-arginine)3
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
MitoChlor
TPP-chlorambucil
MitoE
TPP-vitamin E
MitoLA
TPP-lipoic acid
MitoQ
TPP-ubiquinone
mitoTEMPO
(2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium)
MitoVES
TPP-vitamin E succinate
MLS
mitochondria localization sequences
MPO
myeloperoxidase
MPP
mitochondria-penetrating peptides
mtCbl
(Fx,r)3-chlorambucil
mtDNA
mitochondrial DNA
mtPt
mitochondria-targeting (Fx,r)3-platinum(II)
nDNA
nuclear DNA
Nit
nitrooxy
NitDOX
nitrooxy-DOX
OMM
outer mitochondrial membrane
OXPHOS
oxidative phosphorylation
PD
Parkinson׳s disease
PDT
photodynamic therapy
PET
photoinduced electron transfer
Phe
phenylalanine
PS
photosensitizer
PTPC
permeability transition pore complex
RNS
reactive nitrogen species
ROS
reactive oxygen species
SkQ1
Skulachev ion-quinone
SOD
superoxide dismutase
SS peptide
Szeto-Schiller peptides
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
αTOS
alpha-tocopheryl succinate.

KEY WORDS

Anticancer agents
Antioxidants
Direct conjugation
Mitochondria-targeting
Sensing agents

Cited by (0)

Peer review under responsibility of Institute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association

These authors made equal contributions to this work.