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Studies of anticancer activity in vivo and in vitro behaviors of liposomes encapsulated iridium(III) complex

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Abstract

Iridium(III) complexes have gained great attention in cancer treatment in recent years. In this paper, we designed and synthesized a new iridium(III) complex [Ir(piq)2(DQTT)](PF6) Ir1 (piq = 1-phenylisoquinoline, DQTT = 12-(1,4-dihydroquinoxalin-6-yl)-4,5,9,14-tetraazabenzo[b]triphenylene). The Ir1-loaded PEGylated liposomes (Lipo-Ir1) were prepared using the ethanol injection method. The anticancer activity of the complex and Lipo-Ir1 against SGC-7901 (human gastric adenocarcinoma), A549 (human lung carcinoma), HeLa (human cervical carcinoma), HepG2 (human hepatocellular carcinoma), BEL-7402 (human hepatocellular carcinoma), and normal NIH3T3 (mouse embryonic fibroblasts) was tested by the MTT method. The complex Ir1 shows moderate or low cytotoxicity against the selected cancer cells, whereas the Lipo-Ir1 exhibits high anticancer activity toward the same cancer cells. The apoptosis induced by Lipo-Ir1 was assayed by flow cytometry and Lipo-Ir1 induced apoptosis through increasing intracellular reactive-oxygen species levels, decreasing mitochondrial membrane potential, further promoting cytochrome c release and causing the increase of level of intracellular Ca2+. Western blot was used to detect the changes in Bcl-2 family protein and PI3K/AKT pathway proteins. The cloning experiments demonstrated that the Lipo-Ir1 can effectively inhibit cell proliferation. In vivo experiments, Lipo-Ir1 inhibited tumor growth in xenograft nude mice, and the percentage of tumor growth inhibition in vivo was 75.70%. Overall, the liposomes Lipo-Ir1 exhibits higher anticancer activity than Ir1 under the same conditions. These results indicated that Lipo-Ir1 may be a valuable resource for cancer therapy.

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Abbreviations

A549:

Human lung carcinoma

AO:

Acridine orange

ATP:

Adenosine triphosphate

BCA:

Bicinchoninic acid

BEL-7402:

Human hepatocellular

bpy:

2,2′-Bipyridine

CCCP:

Carbonylcyanide-m-chlorophenylhydrazone

CHO-HP:

Cholest-5-en-3β-ol

DAPI:

2-(4-Amidinophenyl)-6-indolecarbamidine dihydrochloride

DCHF:

2′,7′-Dichloro-3,6-fluorandiol

DCHF-DA:

2′,7′-Dichlorodihydrofluorescein diacetate

DCF:

Dichlorofluorescein

dmb:

4,4′-Dimethyl-2,2′-bipyridine

dmp:

2,9-Dimethyl-1,10-phenanthroline

DMSO:

Dimethylsulfoxide

DQTT:

12-(1,4-Dihydroquinoxalin-6-yl)-4,5,9,14-tetraazabenzo[b]triphenylene

DSPE-MPEG2000:

1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-(methoxy(polyethylene glycol)-2000)

EDTA:

Ethylene diamine tetraacetic acid

EB:

Ethidium bromide

EE:

Encapsulation efficiency

FBS:

Fetal bovine serum

Fluo-3AM:

Fluo-3-pentaacetoxymethyl ester

HeLa:

Human cervical cancer

HepG-2:

Human hepatocellular carcinoma

HPIP:

2-(4-Hydroxy)phenylimidazo[4,5-f][1,10]phenanthroline

JC-1:

5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetrethylbenzimidalylcarbocyanine iodide

MAPK:

Mitogen-activated protein kinase

MG-63:

Human osteosarcoma

MTT:

3-(4,5-Dimethylthiazole)-2,5-diphenyltetraazolium bromide

NIH3T3:

Mouse embyonic fibroblast

PBS:

Phosphate buffer saline

PDI:

Polydispersity index

PEG:

Polyethylene glycol

phen:

1,10-Phenanthroline

PI:

Propidium iodide

piq:

1-Phenylisoquinoline

ppy:

2-Phenylpyridine

PQBD:

4-(4,5,9,14-Tetraazabenzo[b]triphenylen-2-yl)benzene-1,2-diamine

RBCs:

Red blood cells

ROS:

Reactive oxygen species

RPMI:

Roswell Park Memorial Institute

SGC-7901:

Human gastric adenocarcinoma

TBST:

20 MM Tris–HCl, 150 mM NaCl, 0.05% Tween 20, pH 8.0

Tris:

Tris(hydroxymethylaminomethane)

Tween:

Polyoxyethy-lene monolaurate sorbaitan

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Acknowledgements

This work was supported by the National Nature Science Foundation of China (no. 21877018).

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Authors and Affiliations

  1. School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, People’s Republic of China

    Yiying Gu, Haoyu Wen, Yuanyuan Zhang, Lan Bai, Yi Zhou, Huiwen Zhang, Li Tian, Jing Hao & Yunjun Liu

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  1. Yiying Gu
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Gu, Y., Wen, H., Zhang, Y. et al. Studies of anticancer activity in vivo and in vitro behaviors of liposomes encapsulated iridium(III) complex. J Biol Inorg Chem 26, 109–122 (2021). https://doi.org/10.1007/s00775-020-01841-9

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