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Mitochondrion targeting peptide-modified magnetic graphene oxide delivering mitoxantrone for impairment of tumor mitochondrial functions
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Hangqi Zhua, Bing Zhangb, c, Nali Zhua, Mingchun Lia, *, Qilin Yua, *
Chinese Chemical Letters | 2021, 32(3) : 1220 - 1223
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Chinese Chemical Letters | 2021, 32(3): 1220-1223
• Communication •
Mitochondrion targeting peptide-modified magnetic graphene oxide delivering mitoxantrone for impairment of tumor mitochondrial functions
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Hangqi Zhua, Bing Zhangb, c, Nali Zhua, Mingchun Lia, *, Qilin Yua, *
Affiliations
  • a Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin 300071, China
  • b College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
  • c Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China
Published: 2021-03-15 doi: 10.1016/j.cclet.2020.09.003
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In this study, we prepared mitochondrion targeting peptide-grafted magnetic graphene oxide (GO) nanocarriers for efficient impairment of the tumor mitochondria. The two-dimensional GOMNP-MitP nanosheets were synthesized by grafting magnetic γ-Fe2O3 to the surface of GO, followed by covalent modification of mitochondrion targeting peptide (MitP). GOMNP-MitP exhibited the high capacity of loading the anticancer drug mitoxantrone (MTX), and preferentially targeted the tumor mitochondria. With the aid of alternating magnetic field (AMF), the MTX-loading GOMNP-MitP released MTX to the mitochondria, severely impairing mitochondrial functions, including attenuation of ATP production, decrease in mitochondrial membrane potential (MMP), and further leading to activation of apoptosis. This study realized high-efficient mitochondrion-targeting drug delivery for anticancer therapy by two-dimensional nanoplatforms.

Magnetic graphene oxide  /  Nanocarrier  /  Mitochondrion-targeting peptide  /  Mitoxantrone  /  Cancer therapy
Hangqi Zhu, Bing Zhang, Nali Zhu, Mingchun Li, Qilin Yu. Mitochondrion targeting peptide-modified magnetic graphene oxide delivering mitoxantrone for impairment of tumor mitochondrial functions[J]. Chinese Chemical Letters, 2021 , 32 (3) : 1220 -1223 . DOI: 10.1016/j.cclet.2020.09.003
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The mitochondria are one of the main organelles in the eukaryotic cells, functioning in energy production, carbohydrate metabolism, and regulation of signal transduction [1, 2]. In tumor cells, the mitochondria are closely associated with cell survival in apoptosis-inducing factors, supply of high-level ATPs, and promotion of invasion and metastasis [3, 4]. Owing to the great significance to tumor survival and malignant progression of cancers, this organelle is becoming a significant anticancer target to induce mitochondrial dysfunction, followed by energy depletion and apoptosis activation of tumor cells [5, 6]. As the development of nanotechnology, some drug-delivery, photodynamic, or photothermal nanoplatforms that target this organelle have been developed to damage it for enhancing the outcome of anticancer therapies [7-10].
Magnetic graphene oxides (GO), i.e., GO grafted by magnetic nanoparticles (e.g., Fe3O4 nanoparticles, γ-Fe2O3 nanoparticles), are promising two-dimensional nanoplatforms in anticancer therapies [11-14]. These nanoplatforms exhibited good biocompatibility, high photothermal/magnetothermal property, and multifunctionality of magnetic targeting and magnetic resonance imaging [15, 16]. In recent years, they have been developed as nanocarriers of anticancer drugs (e.g., doxorubicin, cisplatin, 5-fluorouracil, etc.) or photothermal agents to kill tumor cells [17-22]. However, their applications in mitochondrion-targeting anticancer therapies remain to be further investigated.
In this study, we designed a mitochondrion-targeting drug-delivery nanoplatform for cancer therapy, i.e., the mitochondrion-targeting peptide-grafted and magnetic γ-Fe2O3 nanoparticle-grafted GO (Scheme 1). Drug-loading and drug-releasing assays was performed to investigate the potential of this nanocomposites as drug carriers using mitoxantrone (MTX), a clinical anticancer drug inducing DNA damage in tumor cells [23]. Confocal microscopy observation and mitochondrion function assays were further performed to explore the mitochondrion-targeting/damaging capacity of the MTX-loading nanocarriers with the aid of alternating magnetic field (AMF).
The initial GO nanosheets were firstly synthesized by the modified Hummer's method [24, 25]. To endow the magnetic property of two-dimensional GO nanosheets, FeCl3·6H2O and hexamethylenetetramine were used to deposit γ-Fe2O3 nanoparticles on the surface of GO, obtaining GOMNP [11]. The magnetic GO was further grafted by MitP by the EDC/NHS reaction [26], obtaining GOMNP-MitP. SEM observation and EDS mapping analysis showed that both kinds of nanomaterials had abundant nanoparticles on the surfaces, and showed equal distribution of N, S, O, and Fe elements (Figs. 1a and b). As compared to GOMNP that exposed obvious nanoparticles on the surfaces, GOMNP-MitP had a coating layer on the surface of the nanosheets (Fig. 1a). TEM observation further revealed that both GOMNP and GOMNP-MitP had nanosheet morphology, with the nanosheet sizes of 200–400nm, and with abundantγ-Fe2O3 nanoparticles (10–25nm) on the surface of the nanosheets (Fig. 1c). FT-IR analysis revealed the presence of –NH–CO–(1680nm) and -NH2 (1340nm) in GOMNP-MitP, confirming successful MitP grafting on GOMNP (Fig. 1d). Magnetization curves showed that the magnetic GOs had the maximum magnetization value of 50~55emu/g, with no obvious hysteresis loop (Fig. 1e), validating their superparamagnetic property. Moreover, under the AMF treatment, both of the GOs exhibited similar temperature curve (from 23 ℃ to ~50 ℃ after 10min of AMF treatment, Fig. 1f), indicating their excellent AMF-responsive properties.
The drug-loading and drug-releasing capacities of the GO nanocomposites were evaluated by using the important anticancer drug MTX. After 24h of co-incubation of the GOs with MTX, GOMNP-MitP exhibited higher MTX-loading capacity than GOMNP (19% versus 11%, Fig. 2a). This result indicated that MitP grafting might improve the loading capacity of the nanocomposites, which may be attributed to the drug-retaining effect of the peptide on the nanosheets.
AMF is an important stimulus leading to drug release from magnetic nanocarriers [27, 28]. While both GOMNP-MitP and GOMNP did not obviously release MTX in the absence of AMF, both kinds of GOs rapidly released MTX in 30min and then the release slowly reached to stability (Fig. 2b). Interestingly, GOMNP-MitP released higher percent of MTX than GOMNP (34% versus 21% at 30 min, and 38% versus 25% at 60min, Fig. 2b). Therefore, MitP grafting also enhanced the MTX-releasing capacity under AMF stimulus, which may be related to higher MTX levels in GOMNP-MitP than in GOMNP.
Due to the presence of MitP on the surface of GOMNP-MitP, we hypothesized that it might target the mitochondria. Localization of the nanosheets was observed by confocal microscopy. It is worth noting that the FITC-tagged GOMNP nanosheets had random intracellular distribution and did not co-localize with the mitochondria (Fig. 3, top). In contrast, GOMNP-MitP preferentially distributed at the mitochondria in the tumor cells (Fig. 3, down). This result revealed that grafting of MitP rendered the GO nanosheets specifically targeting the mitochondria.
Owing to the mitochondrion-targeting capacity of GOMNP-MitP, the nanosheets might deliver MTX to the mitochondria for further impairing this organelle. The effect of the MTX-loading nanosheets on mitochondrial function-related indicators, including intracellular ATP levels and mitochondrial membrane potential (MMP), was evaluated. Under no AMF treatment, both the MTX-loading GOs and free MTX only led to slight decrease in intracellular ATP levels (Fig. 4a). However, under the AMF treatment, the MTX-loading GOMNP-MitP showed much more severe impact on ATP levels as compared to MTX-loading GOMNP or free MTX (Fig. 4a). Similarly, MMP assays revealed that the MTX-loading GOMNP-MitP led to the most severe reduction of MMP under AMF treatment (Fig. 4b), indicating that the mitochondrial functions were severely impaired by MTX-loading GOMNP-MitP with the aid of AMF.
Mitochondrial damage may lead to release of mitochondrial cytochrome C (Cyt C) to the cytosol, followed by activation of caspase-3 and apoptosis [29, 30]. Western blotting assays revealed that MTX-loading GOMNP-MitP with the aid of AMF led to the highest Cyt C release from the mitochondria to the cytosol and up-regulation of activated caspase-3 levels (Figs. 4c and d). These results indicated that the MTX-loading GOMNP-MitP caused most severe mitochondrial damage and further activation of the apoptotic pathway under AMF treatment.
Mitochondrial damage is frequently associated with impairment of cell viability and apoptosis-related cell death [31, 32]. As expected, while MTX-loading GOMNP and free MTX only led to slight decrease in cell viability and increase in apoptotic cells, MTX-loading GOMNP rendered drastic decrease in cell viability to < 20%, and remarkable increase in apoptotic cells (> 80%) (Figs. 4e and f) under AMF treatment. Moreover, under the same MTX concentrations (5.5mg/L), GOMNP-MitP+MTX also had higher impact on cell viability than GOMNP+MTX and MTX (Fig. S1 in Supporting information), indicating that both the enhancement of drug release and the synergism between GOMNP-MitP and MTX contributed to the high anti-tumor capacity of GOMNP-MitP+MTX. Together, these results revealed that the MTX-loading GOMNP with AMF had the highest capacity of impairing the mitochondrial functions and killing the tumor cells.
In conclusion, we designed a kind of two-dimensional magnetic nanoplatform composed of GO, magnetic nanoparticles and MitP, which served as efficient mitochondrion-targeting nanocarriers of anticancer drugs. The anticancer drug-loading nanocarrier GOMNP-MitP could efficiently target the tumor mitochondria and severely disrupt mitochondrial functions for killing the tumor cells with the aid of AMF. This study provides a promising mitochondrion-targeting two-dimensional nanocarrier for efficient anticancer therapy.
Declaration of competing interest
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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
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This work was supported by National Natural Science Foundation of China (No. 31870139), Natural Science Foundation of Tianjin (No. 19JCZDJC33800), Tianjin Synthetic Biotechnology Innovation Capacity Improvement Project (No. TSBICIP-KJGG-006), and the Fundamental Research for the Central Universities.
Appendix A. Supplementary data
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Supplementary material related to this article can be found, in the online version, at doi: https://doi.org/10.1016/j.cclet.2020.09.003.
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Year 2021 volume 32 Issue 3
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Article Info
doi: 10.1016/j.cclet.2020.09.003
  • Receive Date：2020-05-25
  • Online Date：2026-01-04
  • Published：2021-03-15
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History
  • Received：2020-05-25
  • Revised：2020-08-31
  • Accepted：2020-09-03
Affiliations
    a Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin 300071, China
    b College of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
    c Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China
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表12种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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