Mitochondria-targeted rhodamine photosensitizers for tumor fluorescence imaging

doi:10.11949/0438-1157.20231417

Abstract

Abstract:

Two examples of fluorescent dyes RDMID-C and RDMID-N using rhodamine as the parent were designed and synthesized. The results showed that the dyes exhibited low cytotoxicity, good biocompatibility, and the ability to target mitochondria. The fluorescence dyes showed higher co-localization coefficient with commercial mitochondrial dyes in co-localization experiments, and had longer retention time in tumors, which could be used for tumor fluorescence imaging.

Key words: dyestuffs, fluorescence image, biomedical engineering, biological engineering, biotechnology

摘要：

设计合成了两例以罗丹明为母体的荧光染料RDMID-C和RDMID-N。实验结果表明，上述染料分子具有较低的细胞毒性，良好的生物相容性及靶向细胞线粒体的能力。两例荧光染料在细胞器定位实验中与商业化线粒体染料的共定位系数较高，并在小鼠肿瘤中有较长的滞留时间，可以用于肿瘤荧光成像。

关键词: 染料, 荧光成像, 生物医学工程, 生物工程, 生物技术

CLC Number:

TQ 617.3

Shupeng WANG, Jianjun DU, Yao YAO, Jiangli FAN, Xiaojun PENG. Mitochondria-targeted rhodamine photosensitizers for tumor fluorescence imaging[J]. CIESC Journal, 2024, 75(4): 1679-1686.

王书鹏, 杜健军, 姚瑶, 樊江莉, 彭孝军. 线粒体靶向的罗丹明衍生物用于肿瘤荧光成像[J]. 化工学报, 2024, 75(4): 1679-1686.

Figures/Tables 10

Fig.1 Synthetic route of R-1

Fig.2 Synthetic route of RDMID-C

Fig.3 Synthetic route of RDMID-N

Fig.4 Absorption and fluorescence spectra of RDMID-N and RDMID-C in different solvents

Table 1 Photophysical parameters of Rh123， RDMID-C and RDMID-N

染料	λ_max/nm	λ'_max/nm	ε/(10⁵ L/(mol·cm))	Φ_f/%
Rhb	546	568	0.92	69.4
RDMID-C	608	650	0.15	25.2
RDMID-N	636	682	0.81	36.4

Fig.5 Variation of fluorescence emission spectra of RDMID-C and RDMID-N with the change of solution viscosity(water/glycerol system)

Fig.6 Cellular uptake of RDMID-N monitored by confocal imaging

Fig.7 Viabilities of 4T1 cells incubated with RDMID-C and RDMID-N for 24 h

Fig.8 Co-localization of Rhb, RDMID-C, RDMID-N and Mito Tracker Green FM，Lyso Tracker Green DND-26 in MCF-7 cells (λex=490 nm, λem=523 nm)

Fig. 9 In vivo fluorescence images and fluorescence intensities of main organs after injection of RDMID-N for about 4 h

References 34

1	Siegel R L, Wagle N S, Cercek A, et al. Colorectal cancer statistics, 2023[J]. CA: A Cancer Journal for Clinicians, 2023, 73(3): 233-254.
2	Zhu J L, Chen W, Yang L, et al. A self-sustaining near-infrared afterglow chemiluminophore for high-contrast activatable imaging[J]. Angewandte Chemie International Edition, 2024: e202318545.
3	Bai Y L, Hua J, Zhao J J, et al. A silver-induced absorption red-shifted dual-targeted nanodiagnosis-treatment agent for NIR-Ⅱ photoacoustic imaging-guided photothermal and ROS simultaneously enhanced immune checkpoint blockade antitumor therapy[J]. Advanced Science, 2023: 2198-3844.
4	Yang X C, Cheng L L, Zhao Y L, et al. Aggregation-induced emission-active iridium (Ⅲ)-based mitochondria-targeting nanoparticle for two-photon imaging-guided photodynamic therapy[J]. Journal of Colloid and Interface Science, 2024, 659: 320-329.
5	Jin J K, Yuan P C, Yu W, et al. Mitochondria-targeting polymer micelle of dichloroacetate induced pyroptosis to enhance osteosarcoma immunotherapy[J]. ACS Nano, 2022, 16(7): 10327-10340.
6	Fan L, Zan Q, Wang X D, et al. A mitochondria-targeted and viscosity-sensitive near-infrared fluorescent probe for visualization of fatty liver, inflammation and photodynamic cancer therapy[J]. Chemical Engineering Journal, 2022, 449: 137762.
7	Zhao H H, Chen K, Liu M W, et al. A mitochondria-targeted NIR-Ⅱ molecule fluorophore for precise cancer phototheranostics[J]. Journal of Medicinal Chemistry, 2024, 67(1): 467-478.
8	Poor T A, Chandel N S. SnapShot: mitochondrial signaling[J]. Molecular Cell, 2023, 83(6):1012-1012.e1.
9	Lionaki E, Gkikas I, Tavernarakis N. Mitochondrial protein import machinery conveys stress signals to the cytosol and beyond[J]. BioEssays: 2023, 45(3): e2200160.
10	Li Q Y, Lin Y Q, Xu J L, et al. Diet restriction impact on high-fat-diet-induced obesity by regulating mitochondrial cardiolipin biosynthesis and remodeling[J]. Molecules, 2023, 28(11): 4522.
11	Li M Y, Yu Y J, Xue K, et al. Genistein mitigates senescence of bone marrow mesenchymal stem cells via ERR α-mediated mitochondrial biogenesis and mitophagy in ovariectomized rats[J]. Redox Biology, 2023, 61: 102649.
12	Weiser A, Hermant A, Bermont F, et al. The mitochondrial calcium uniporter (MCU) activates mitochondrial respiration and enhances mobility by regulating mitochondrial redox state[J]. Redox Biology, 2023, 64: 102759.
13	Li Y J, Wu R Y, Liu R P, et al. Aurantio-obtusin ameliorates obesity by activating PPAR α-dependent mitochondrial thermogenesis in brown adipose tissues[J]. Acta Pharmacologica Sinca. 2023, 44: 1826-1840.
14	Martínez-Reyes I, Cardona L R, Kong H, et al. Mitochondrial ubiquinol oxidation is necessary for tumour growth[J]. Nature, 2020, 585: 288-292.
15	Mussazhanova Z, Shimamura M, Kurashige T, et al. Causative role for defective expression of mitochondria-eating protein in accumulation of mitochondria in thyroid oncocytic cell tumors[J]. Cancer Science, 2020, 111(8): 2814-2823.
16	Bai R L, Cui J W. Mitochondrial immune regulation and anti-tumor immunotherapy strategies targeting mitochondria[J]. Cancer Letters, 2023, 564: 216223.
17	于富强, 杜健军, 路杨, 等. 血清白蛋白-铜酞菁纳米粒子用于线粒体靶向光疗[J]. 化工学报, 2021, 72(1): 597-608.
	Yu F Q, Du J J, Lu Y, et al. Fabrication of serum albumin-copper phthalocyanine nanoparticles for mitochondria-targeted phototherapy[J]. CIESC Journal, 2021, 72(1): 597-608.
18	Li H D, Wang J Y, Kim H, et al. Activatable near-infrared versatile fluorescent and chemiluminescent dyes based on the dicyanomethylene-4H-pyran scaffold: from design to imaging and theranostics[J]. Angewandte Chemie International Edition, 2024, 63(6): 2311764.
19	Han F P, Abbas Abedi S A, He S, et al. Aryl-modified pentamethyl cyanine dyes at the C2′ position: a tunable platform for activatable photosensitizers[J]. Advanced Science, 2024, 11(7): e2305761.
20	Gu H, Sun W, Du J J, et al. Dual-acceptor engineering of donor‐acceptor type molecules for all-round boosting anti-tumor phototherapy[J]. Smart Molecules, 2023: 2751-4587.
21	Xiong T, Chen Y C, Peng Q, et al. Lipid droplet targeting type Ⅰ photosensitizer for ferroptosis via lipid peroxidation accumulation[J]. Advanced Materials, 2024, 36(4): e2309711.
22	Liu W J, Wu B B, Sun W, et al. Near-infrared Ⅱ fluorescent carbon dots for differential imaging of drug-resistant bacteria and dynamic monitoring of immune system defense against bacterial infection in vivo [J]. Chemical Engineering Journal, 2023, 471: 144530.
23	Zheng J Z, Du J J, Ge H Y, et al. Viscosity-dependent photocatalysis triggers ferroptosis and type-Ⅰ photodynamic therapy to kill drug-resistant tumors[J]. Chemical Engineering Journal, 2022, 449: 136565.
24	Shimolina L E, Izquierdo M A, López-Duarte I, et al. Imaging tumor microscopic viscosity in vivo using molecular rotors[J]. Scientific Reports, 2017, 7: 41097.
25	Inada N, Fukuda N, Hayashi T, et al. Temperature imaging using a cationic linear fluorescent polymeric thermometer and fluorescence lifetime imaging microscopy[J]. Nature Protocols, 2019, 14: 1293-1321.
26	Zeng Y, Ma J W, Zhang S J, et al. Imaging agents in targeting tumor hypoxia[J]. Current Medicinal Chemistry, 2016, 23(17): 1775-1800.
27	Kamya E, Yi S Z, Hussain Z, et al. Donor-acceptor engineering for tailoring highly efficient photosensitizers for image-guided antitumor photodynamic therapy[J]. ACS Macro Letters, 2023, 12(11): 1549-1557.
28	Wang Y P, Li X W, Liu W M, et al. A dual organelle-targeting photosensitizer based on curcumin for enhanced photodynamic therapy[J]. Journal of Materials Chemistry B, 2023, 11(45): 10836-10844.
29	Wen M, Wang X J, Wang T, et al. Acridinium benzoates for ratiometric fluorescence imaging[J]. Chemistry, 2020, 26(15): 3247-3251.
30	Li M L, Long S R, Kang Y, et al. De novo design of phototheranostic sensitizers based on structure-inherent targeting for enhanced cancer ablation[J]. Journal of the American Chemical Society, 2018, 140(46): 15820-15826.
31	Yokomizo S, Henary M, Buabeng E R, et al. Topical pH sensing NIR fluorophores for intraoperative imaging and surgery of disseminated ovarian cancer[J]. Advanced Science, 2022, 9(20): e2201416.
32	Choi H S, Nasr K, Alyabyev S, et al. Synthesis and in vivo fate of zwitterionic near-infrared fluorophores[J]. Angewandte Chemie International Edition, 2011, 50(28): 6258-6263.
33	Owens E A, Lee S, Choi J, et al. NIR fluorescent small molecules for intraoperative imaging[J]. Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology, 2015, 7(6): 828-838.
34	Gregory R. The Guide for Care and use of Laboratory Animals[M]. USA: National Academy of Sciences, 2010.

[1]	Tao SUN, Meili SUN, Ran LU, Yizi YU, Kaifeng WANG, Xiaojun JI. Synthetic biology of yeasts drives green biomanufacturing of succinic acid [J]. CIESC Journal, 2024, 75(4): 1382-1393.
[2]	Wenqi HOU, Yan SUN, Xiaoyan DONG. Basification modification of transthyretin significantly enhances inhibitory effect on amyloid-β protein aggregation [J]. CIESC Journal, 2023, 74(5): 2100-2110.
[3]	Caifeng LI, Xiao WANG, Gangjian LI, Junzhang LIN, Weidong WANG, Qinglin SHU, Yanbin CAO, Meng XIAO. Synergistic relationship between hydrocarbon degrading and emulsifying strain SL-1 and endogenous bacteria during oil displacement [J]. CIESC Journal, 2022, 73(9): 4095-4102.
[4]	Wei LIU, Yan SUN. Research progress on amyloid β-protein aggregation and its regulation [J]. CIESC Journal, 2022, 73(6): 2381-2396.
[5]	Jingnan WANG, Jian PANG, Lei QIN, Chao GUO, Bo LYU, Chun LI, Chao WANG. Breeding and modification strategies of butenyl-spinosyn high-yield strains [J]. CIESC Journal, 2022, 73(2): 566-576.
[6]	Xiaosong HOU, Chenxing LIU, Ailing REN, Bin GUO, Yuanming GUO. Study on purification of toluene waste gas by ultrasonic atomization/surfactants-enhanced absorption coupled with biological scrubbing [J]. CIESC Journal, 2022, 73(10): 4692-4706.
[7]	Wei SONG, Jinhui WANG, Guipeng HU, Xiulai CHEN, Liming LIU, Jing WU. Cascade catalysis for the synthesis of (R)-β-tyrosine [J]. CIESC Journal, 2022, 73(1): 352-361.
[8]	CHEN Tingting, HAN Kaixin, CHEN Cuixue, LING Xueping, SHEN Liang, LU Yinghua. Study of iron-reducing bacteria Shewanellaxiamenensis BC01 under organic solvents stress [J]. CIESC Journal, 2021, 72(7): 3747-3756.
[9]	MAO Jinzhu, XIAO Shuling, YANG Zhichun, WANG Xiaoyu, ZHANG Shi, CHEN Junhong, XIE Jisheng, CHEN Fude, HUANG Zinuo, FENG Tianyu, ZHANG Aihui, FANG Baishan. Application of synthetic biology in pesticides residues detection [J]. CIESC Journal, 2021, 72(5): 2413-2425.
[10]	Nan SU, Yinan WU, Yinyee TAN, Lihua JIN, Chong ZHANG, Aikawa SHIMPEI, Hasunuma TOMOHISA, Kondo AKIHIKO, Xinhui XING. Comparative omics study of Spirulinaplatensis mutants based on ARTP mutagenesis breeding system [J]. CIESC Journal, 2021, 72(12): 6298-6310.
[11]	WANG Kaifeng, WANG Jinpeng, WEI Ping, JI Xiaojun. Metabolic engineering of Yarrowia lipolytica to produce fatty acids and their derivatives [J]. CIESC Journal, 2021, 72(1): 351-365.
[12]	Lei QIN, Jie YU, Xiaoyu NING, Wentao SUN, Chun LI. Synthetic biological system construction and green intelligent biological manufacturing [J]. CIESC Journal, 2020, 71(9): 3979-3994.
[13]	Yan JIANG, Zhe ZHANG. Interaction of VOCs with different hydrophilic properties in biotrickling filters [J]. CIESC Journal, 2020, 71(7): 2973-2982.
[14]	Junkun TAN, Yudong LIU, Shichao GENG, Bing CHEN, Mingwei TONG. Test and numerical simulation of freezing and rewarming performance of vacuum probe [J]. CIESC Journal, 2020, 71(4): 1440-1449.
[15]	Caihong WANG, Jing SUN, Shuxin JI, Yanzi WANG, Wenfang LIU. Immobilization of carbonic anhydrase on polyethylenimine/dopamine co-deposited SiO₂ [J]. CIESC Journal, 2019, 70(5): 1887-1893.