Oligo(p-phenyleneethynylene) Derivatives for Mitochondria Targeting

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Oligo(p-phenyleneethynylene) Derivatives for Mitochondria Targeting in Living Cells Through Bioorthogonal Reactions Jianwu Wang, Lingyun Zhou, Han Sun, Fengting Lv, Libing Liu, Yuguo Ma, and Shu Wang Chem. Mater., Just Accepted Manuscript • DOI: 10.1021/acs.chemmater.8b02672 • Publication Date (Web): 10 Aug 2018 Downloaded from http://pubs.acs.org on August 11, 2018

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Chemistry of Materials

Oligo(p-phenyleneethynylene) Derivatives for Mitochondria Targeting in Living Cells Through Bioorthogonal Reactions Jianwu Wang,a,b,c Lingyun Zhou,a,c Han Sun,a,b,c Fengting Lv,a,c Libing Liu,a,c Yuguo Ma,b* and Shu Wanga,c* a

Key Laboratory of Organic Solids, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China; bCollege of Chemistry and Molecular Engineering, Peking University, Beijing 100871, P. R. China; cCollege of Chemistry, University of Chinese Academy of Sciences, Beijing 100084, P. R. China

ABSTRACT: In this work, a fluorogenic oligo(p-phenyleneethynylene) modified with tetrazine groups (OPE) is designed to target mitochondria with the help of guiding molecules through intracellular bioorthogonal reactions. The triphenylphosphonium group (TPP, for mitochondria targeting) is covalently linked with trans-cyclooctene to obtain Mito-TCO that enters cells acting as intracellular guiding molecule. Upon OPE uptakes into cells, it undergoes bioorthogonal reaction with Mito-TCO to afford IntraMito to enter mitochondria. Owing to the fluorescence turn-on characteristic of tetrazine ligation products, the mitochondria targeting process can be easily observed under fluorescence microscopy. This work provides an insight into precisely delivering functional materials into specific organelle and regulating the distribution of inherent cellular functional materials through intracellular bioorthogonal reactions.

Cells are well organized machines that are composed of many subcellular structures, where exist precise production and modification networks to regulate these functions and distributions of biomolecules.1,2 Many efforts have been made to reveal and regulate these complex living systems, such as genetically encoded methods,3,4 enzymes mediated reactions,5 and proteins recombinant methods.6 Complementarily to these complicated biological methods, chemists have elaborated a series of bioorthogonal reactions that can decorate biomolecules with fluorescent probes and other functional groups while cause little interference with the inherent systems.7-11 Although intracellular decorations of biomolecules by bioorthogonal reactions were extensively performed, to precisely deliver functional materials into specific subcellular region in living cells using this strategy still remains challenging. Mitochondria is one of the major organelles of eukaryotic cells that participate in the energy production, cell signaling, programmed cell death and many other biological processes.1216 Mitochondria have also been the target for cancer therapy. By attaching mitochondrial-guiding groups, antitumor drugs,17-19 photothermal20 and photodynamic agents21,22 can be transported to mitochondria to obtain enhanced killing effect to cancer cells. In addition to organic modification methods in extracellular solution, the targeting of mitochondria can also be realized under their native cellular circumstances through an intracellular bioorthogonal chemical reporter strategy.23,,24 In these strategies, bioorthogonal reporters were firstly incorporated to the mitochondria, followed by the ligation of fluorescent probes though bioorthogonal chemical reactions to visualize the mitochondria. Beyond the visualization of mitochondria, attaching targeting groups to cellular molecules through intracellular bioorthogonal reactions offer a new

perspective on regulating the distribution of inherent cellular species from cytoplasm to mitochondria, which is supplemented to the inherent cellular machinery.

Scheme 1. (A) Schematic illustration of the mitochondria targeting process of tetrazine-containing conjugated oligomer OPE through intracellular bioorthogonal tetrazine ligation with the guiding molecule Mito-TCO. (B) The tetrazine ligation reactions of OPE in living cells.

Among the multiple bioorthogonal reactions, tetrazine ligation with unmatchable kinetics and good bioorthogonal property has become a regular choice for intracellular reactions.25-28 Moreover, tetrazine ligation

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Scheme 2. Synthetic routes of OPE (A) and Mito-TCO (B). can be utilized to construct two-component targeting systems, where tetrazines or trans-cyclooctenes can be dosed in spatiotemporally-defined manners, thus enhanced the accumulation of imaging or therapy agents in tumor sites.29,30 When linked with fluorophores containing conjugated πelectron systems, the tetrazine groups as the energy acceptors can efficiently quench the fluorescence of the fluorophores via through-bond energy transfer (TBET) processes.31 Upon bioorthogonally reacting with its counterpart dienes, the resulting ligation products exhibit evident fluorescence “turn on” signal, while the unreacted probes have no background signal.31,32 These features make tetrazine ligation unique for high resolution33,34 and washing-free imaging of diverse targets of cells.23 For conventional fluorgenic reactions, the precursors are initially non-fluorescent and cannot be tracked optically in a non-invasive manner, thus the tracking is only possible for the fluorosent product.31-36 Moreover, tetrazine unit was reported to be a good optical trigger, which can undergo photo dissociation to yield nitrogen and nitrile under light irradiation.37,38 Conjugated oligomers are well-known optical functional materials for their delocalized backbones and excellent optical properties.39-41 They are extensively used for biosensing, fluorescent imaging and disease therapy. In this work, an oligo(pphenyleneethynylene) modified with tetrazine groups (OPE) is designed to target mitochondria with the help of guiding molecules through intracellular tetrazine ligation reactions. The linking of tetrazine groups to conjugated oligomer OPE endows it with bioorthogonal reactivity and fluorogenic properties, which make it easier to track their cellular distributions and intracellular reactions.

Scheme 1A illustrates the mitochondria targeting process of conjugated oligomer OPE through intracellular bioorthogonal tetrazine ligation with Mito-TCO. The triphenylphosphine (TPP, for mitochondria targeting) group is covalently linked with transcyclooctene to obtain Mito-TCO that enters cells acting as intracellular guiding molecule. OPE is firstly incubated with cells to enter the cytoplasm, and after which Mito-TCO is added to uptake into cells. Upon Mito-TCO enters cells, it undergoes tetrazine ligation reaction with OPE to afford Intra-Mito to enter mitochondria, and relative tetrazine ligation reaction was shown in Scheme 1B. Owing to the fluorescence turn-on characteristic of tetrazine ligation products, the mitochondria targeting process could be easily observed under fluorescence microscopy. The synthesis route of OPE and Mito-TCO are shown in Scheme 2A and 2B. The targeting ability of TPP group to mitochondria was firstly studied. OPE was covalently modified with TPP groups on the side chains through the amide bond to obtain OPE-Mito (Figure 1A). Initially, a very weak fluorescence could be detected from the aqueous solution of OPE-Mito, resulted from the quenching effect of tetrazine groups via TBET mechanism. We found that, after irradiated by a 355 nm laser, the fluorescence of OPE-Mito increased gradually with the elongation of irradiation time from one to seven minutes (Figure 1B). The increased fluorescence originated from the photo-dissociation of tetrazine groups to 33,34 cyano groups (Figure 1A), as confirmed by high resolution electrospray ionization mass spectra (HR-ESI) where CN-Mito peak emerged after laser irradiation (Figure S1). The maximum absorption peaks of OPE-Mito solution exhibited a slightly blue shift (Figure S2), which was consistent with the reduced conjugation degree of the backbones. In the cell experiments, confocal laser scanning microscopy (CLSM) was utilized to

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Chemistry of Materials characterize the fluorescence recovery ability of OPE-Mito. MCF7 cells incubated with OPE-Mito were exposed to confocal lasers at different wavelengths for 1 min, respectively. As shown in Figure S3, the fluorescence of OPE-Mito was recovered by 405 nm laser, while negligible fluorescence was observed after exposed to laser sources at 488 nm, 559 nm and 635 nm, respectively. Therefore, to avoid the interferential recovery of fluorescence, 635 nm laser was utilized as the source of the bright field to locate the cells in the following cellular experiments. The dynamic process of the fluorescence enhancement was recorded through continuous scan under 405 nm laser. As shown in Figure 1C, the fluorescence intensity of OPE-Mito was enhanced gradually by increasing the scan times of laser, which was opposite to the commercially available fluorescent probes Rhodamine 110 and fluorescein, whose fluorescence intensity decreased greatly with increasing the scan times (Figure 1D, E) due to photobleaching. This showed that OPE-Mito could be traced by fluorescence imaging in living cells.

Figure 1. Laser irradiation enhanced fluorescence of OPE-Mito and the comparison with commercial available dyes. (A) Schematic illustration of reaction of OPE-Mito after the irradiation of laser. (B) Fluorescence spectra of OPE-Mito after irradiated under 355 nm laser for different time. (C-E) Fluorescent intensity and confocal microscopy images of OPE-Mito, Rhodamine 110 and Fluorescein in MCF-7 cells upon continuous scan under confocal laser sources. OPE-Mito was excited at 405 nm, Rhodamine 110 and Fluorescein were both excited at 488 nm. Scale bar: 10 µm.

Figure 2. The colocalization analysis of OPE-Mito (top) and OPE (bottom) with Mito Tracker in MCF-7 cells. OPE-Mito and OPE were irradiated under 405 nm laser for 1 min to “turn on” their fluorescence. Mito Tracker was excited at 635 nm. Scale bar: 10 µm. It is noted that OPE-Mito could stay in mitochondria for long periods of time without being expelled out of cells, confirmed by the remained high Pearson’s coefficient (0.898, 0.862 and 0.876) upon incubation for 12 h, 24 h and 36 h, respectively (Figure S5). Thus, the covalent linkage of TPP imparts OPE the ability to target mitochondria, indicating the ability of TPP group to guide functional molecules into mitochondria. Subsequently, TPP group was covalently linked to TCO to obtain Mito-TCO molecule, which can bioorthogonally react with the tetrazine group of OPE (Scheme 1B). The reaction between OPE and Mito-TCO was firstly investigated in aqueous solution. The fluorescence of OPE reached its maximum intensity within 10 min after the addition of Mito-TCO (Figure 3A). The increased fluorescence resulted from the reaction between tetrazine group on OPE and TCO group on Mito-TCO, where the quenching effect of tetrazine group was eliminated. As shown in Figure 3B, the maximum absorption of OPE displayed a blue shift after the addition of Mito-TCO, which resulted from the break of tetrazine groups to reduce conjugation degree. Moreover, the absorption spectra of OPE demonstrate a shoulder at around 450 nm resulting from the aggregation of OPE in aqueous solution.Upon reacting with MitoTCO, the shoulder peak gradually decreased, which maybe due to the enhanced solubility of OPE in aqueous solution. The reaction between OPE and Mito-TCO was confirmed by HR-ESI mass spectra, where the molecular peak of Intra-Mito was observed (Figure S6A). In the meanwhile, a control molecule Pr-TCO with no mitochondria targeting ability was synthesized as a contrast to Mito-TCO (Scheme S1). The reaction between OPE and Pr-TCO was confirmed by the fluorescence, absorption and the HR-ESI mass spectra (Figure S6B and Figure S7).

Taking advantage of the fluorescence turn-on property after laser irradiation, the mitochondria targeting ability of OPE-Mito was studied through the colocalization with commercial Mito tracker utilizing CLSM. As shown in Figure 2, the OPE-Mito image (blue fluorescence) is well overlapped with that of Mito Tracker (red fluorescence) in MCF-7 cells, where the merged image turned to pink color. In addition, the high Pearson’s coefficient (0.867) from the colocalization analysis indicated that OPE-Mito could very well target the mitochondria of MCF-7 cells (Figure S4). As a contrast, the image of OPE without TPP groups exhibited poor overlap with that of Mito tracker.



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Figure 3. (A) Fluorescent emission spectra and (B) absorption spectra of OPE upon reaction with Mito-TCO in aqueous solution. (C) Confocal microscopy images and statistical fluorescence intensity of OPE in MCF-7 cells upon reaction with Mito-TCO at different reaction time. OPE was excited at 405 nm. Scale bar: 10 µm.

The intracellular reaction of OPE with Mito-TCO was then carried out in living MCF-7 cells. MCF-7 cells were incubated with OPE for 12 h to make sure the successful uptake of OPE into cells. In this case, negligible fluorescence of OPE was observed in MCF-7 cells due to TBET process. Afterwards, guiding molecule Mito-TCO was added into the medium, and the fluorescence of OPE in MCF-7 cells was observed to gradually increase as the extension of incubation time (Figure 3C). The enhanced fluorescence of OPE indicated that the mitochondria guiding group TPP was attached to OPE.

As the fluoresence of OPE can be turned on via laser irradiation or bioorthogonal reaction, the mitochondria targeting of OPE through intra-cellular tetrazine ligation can be investigated by CLSM. As observed from the confocal images in Figure 4A, the OPE (blue fluorescence) exhibited a good overlap with Mito Tracker (red fluorescence) after reacting with Mito-TCO. As a contrast, after reacting with PrTCO, the fluorescence of OPE still had a poor overlap with that of Mito-tracker. Besides, according to the statistics data, the Pearson’s coefficient of OPE with guiding groups was significantly increased by more than 3.6 times in comparison with those of OPE itself and OPE without the guiding groups (Figure 4B). As a result, the mitochondria targeting of OPE was realized through the intracellular tetrazine ligation with the help of guiding molecule Mito-TCO.

Figure 4. (A) Enhanced distribution of OPE in the mitochondria of MCF-7 cells. MCF-7 cells were incubated with OPE for 12 h, and then incubated with Mito-TCO and Pr-TCO for another 12 h. OPE was excited at 405 nm, Mito Tracker was excited at 635 nm. Scale bar: 10 µm. (B) Colocalizaiton statistics of OPE with Mito Tracker in MCF-7 cells before and after reaction with Mito-TCO or Pr-TCO. The Pearson’s coefficients were normalized with OPE as standard.

In summary, we proposed a molecular guiding strategy for mitochondria-targeting delivery of functional molecules through intracellular bioorthogonal reactions. Specifically, we designed and synthesized a tetrazine-containing conjugated oligomer OPE as functional molecule. The TPP group with delocalized positive charge was covalently linked with transcyclooctene to obtain Mito-TCO as the guiding molecule to target mitochondria in cells. Owing to the fluorogenic properties via laser irradiation and bioorthogonal reaction, the intracellular distribution of OPE and the product of tetrazine ligation can be tracked by CLSM. OPE was firstly assimilated to the cytoplasm of the cells. After the intracellular bioorthogonal reaction with Mito-TCO, OPE was covalently attached with the mitochondria targeting group, thus regulating its cellular distribution from cytoplasm to mitochondria. For conventional fluorgenic reactions, the precursors are initially non-fluorescent and cannot be tracked optically in a non-invasive manner, thus the tracking is only


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Chemistry of Materials possible for the fluorosent product. But our OPE/Mito-TCO system could easily solve this issue. The noninvasive tracking of both the "nonfluorescent precursor" and "fluorogenic product" is possible, which provides an alternative contribution to the field. As tetrazine ligation can reserve its high reactivity and bioorthogonality when the two components were applied to biological systems in a spatiotemporallydefined manner, the molecular guiding strategy has the potential to precisely guide various functional materials into targeted region.

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ASSOCIATED CONTENT Supporting Information. Experimental details and additional Figures. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

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Corresponding Author [email protected]; [email protected]

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Author Contributions The manuscript was written through contributions of all authors. / All authors have given approval to the final version of the manuscript.

Funding Sources

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The National Natural Science Foundation of China and the Strategic Priority Research Program of the Chinese Academy of Sciences. (19)

ACKNOWLEDGMENT The authors are grateful to the National Natural Science Foundation of China (Grant Nos. 21533012, 91527306 and 21661132006) and the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No: XDA16020804)

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Oligo(p-phenyleneethynylene) Derivatives for Mitochondria Targeting

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