A Photoactive Oligo(p-phenylene vinylene) Functionalized with

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A Photoactive Oligo(p-phenylene vinylene) Functionalized with Phospholipid Units for Control and Visualization of Delivery into Living Cells Yanyan Chen, Lingyun Zhou, Jianwu Wang, Xiaoyan Liu, Huan Lu, Libing Liu, Fengting Lv, and Shu Wang ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b07847 • Publication Date (Web): 06 Jul 2018 Downloaded from http://pubs.acs.org on July 10, 2018

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ACS Applied Materials & Interfaces

A Photoactive Oligo(p-phenylene vinylene) Functionalized with Phospholipid Units for Control and Visualization of Delivery into Living Cells Yanyan Chen,a,b Lingyun Zhou,a,b Jianwu Wang,a,b Xiaoyan Liu,c Huan Lu,a Libing Liu,a* Fengting Lv,a and Shu Wanga,b* a

Beijing National Laboratory for Molecular Sciences, Key Laboratory of Organic Solids, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China

b

College of Chemistry, University of Chinese Academy of Sciences, Beijing 100049, P. R. China c

School of Physics, Shandong University, Jinan 250100, P. R. China Email: [email protected]; [email protected]

Keywords: conjugated molecular materials, oligo (p-phenylene vinylene) derivative, phospholipid, controllable delivery, fluorescent imaging

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Abstract: To take advantage of the excellent optical properties of conjugated polymers (CPs) or conjugated oligomers (COs) for biological applications, there is still a requirement to find new ways to deliver these conjugated molecular materials into cells in a facile, controllable and noninvasive manner. Herein, a photoactive oligo(p-phenylene vinylene) (OPV) derivative was covalently attached with phospholipid units (OPV-lipid) to enhance its dispersion in water and facilitate its internalization by cells. OPV-lipid could be delivered into either cell membrane or cytoplasm controllably through the assistance of liposomes with different formulas. It could also act as fluorescent probe for cell imaging and visualization of the delivery process. This work shows a good potential for delivering functional conjugated molecular materials into cells in a controllable way.

Cell membrane plays a dominant role in the regulation of cellular biological processes, including signal transduction, metabolism and apoptosis.1-3 Since the cell membrane acts as a selectively semi-permeable barrier, many functional molecules and drugs are blocked outside the cell, limiting their applications in cell sensing, drug delivery and tumor therapy.4-6 To overcome this challenge, many carriers have been developed to assist functional materials and drugs to be delivered into cells.7-9 Among these carriers, liposome that is mainly composed of lipids has made great contributions to deliver drugs, siRNA and proteins into cells with high efficiency, low cytotoxicity and good biocompatibility.10-12 Meanwhile, by altering the species and proportions of lipids in liposome, the internalization and intracellular tracking pathway of liposome could be manipulated.13-16 Thus, liposome has become a promising carrier for delivering various cargoes into specific intracellular segments. Conjugated polymers (CPs) and conjugated oligomers (COs) have attracted extensive interests in 2


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the fields of sensor, imaging and biomedicine due to their excellent optical properties, such as unique light harvesting ability, high fluorescence quantum yield and photosensitization ability.17-19 Especially, conjugated oligomers are favored in biology and biomedical applications because of their defined structures and compositions.20-24 However, the rigid conjugated backbones of COs were accountable to their poor water solubility and inevitably restricted their biological application. To solve this problem, two main traditional ways have been intensively studied, including grafting hydrophilic side chains and preparing conjugated polymer/oligomer nanoparticles.18, 19, 25 However, there is still a requirement to find new ways to deliver conjugated materials into cells in a facile, efficient and noninvasive manner. It is well known that phospholipid-like molecules could efficiently anchor onto cell membrane through hydrophobic interactions between the hydrophobic tails and the cellular lipid bilayer. 26-29 Attaching lipid molecules onto COs will offer them good dispersibility in water and biocompatibility, thus providing a possible strategy to deliver them into cells. In this work, an oligo(p-phenylene vinylene) (OPV) derivative

functionalized with

phospholipid moieties (OPV-lipid) was designed and synthesized by conjugating OPV with a palmitoyl lysophosphatidylcholine derivative. Since OPV-lipid could incorporate into liposome conveniently through the insertion of lipophilic tails into the lipid layer of liposomes, commercial lipids were hybridized with OPV-lipid to generate two different types of liposomes, and their interactions with living cells were studied. This work provides a promising platform for controllably delivering conjugated materials into cells as well as visualizing the delivery process. OPV-lipid was prepared from commercial available materials through the procedure displayed in Scheme 1a. Finally, a neutral oligo p-phenylene vinylene) (OPV) derivative functionalized with azide group (OPV-N3) was covalently attached to alkyne-modified phospholipid through “click” 3



reaction to afford OPV-lipid. The OPV-lipid was characterized by NMR spectroscopy and high-resolution mass spectrometry (HR-MS) (see characterization data in Supporting Information), and its optimizing structure was calculated by Gaussian 09 program (Scheme 1b). OPV-lipid exhibits absorption and emission maxima at 410 nm and 528 nm in aqueous solution, respectively. Its absolute fluorescence quantum yield was measured to be 0.4 % in water and 66.4 % in THF. Due to the fact that amphipathic molecules could self-assemble into various structures in solvents with diverse concentrations or polarities,30 transmission electron microscopy (TEM) technique was firstly employed to study the aggregation behaviors of OPV-lipid in water at different concentrations. As shown in Figure 1a, nanoparticles were formed at the lower concentration (5 µM), and the individual nanoparticles clustered together when the concentration of OPV-lipid reached up to 20 µM (Figure 1b). Subsequently, the rod-like structure appeared at the higher concentration (300 µM) (Figure 1c) and the fiber-like structure gradually emerged after increasing the concentration up to 600 µM (Figure 1d). TEM images revealed that amphiphilic OPV-lipid could form diverse aggregates at different concentrations. To further understand the amphiphilic property of OPV-lipid, fluorescence emission spectra of OPV-lipid in THF-H2O mixtures with different volume ratios were monitored. The aggregation of OPV-lipid in water would result in fluorescence self-quenching through intermolecular interactions.30 As shown in Figure 1e and 1f, the emission intensity of OPV-lipid enhanced gradually with the increase of THF volume fraction from 0 to 70 % and reached the maximum at 80 %. Afterwards the emission intensity decreased significantly with adding THF continuously to 100 %. Moreover, the emission maximum of OPV-lipid at 522 nm in water gradually red shifted to 548 nm when the THF ratio changed from 0 to 50 % (v/v). When the THF/H2O ratios were higher than 40/60 (v/v), the emission maximum slowly blue shifted to 529 nm. These results disclosed that two kinds of aggregations formed. When 4


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THF content was lower, the aggregate was tight and governed by intermolecular π-π stacking and hydrophobic interactions, leading to lower emission intensity. The interchain interactions were broken after adding THF to OPV-lipid aqueous solution, resulting in increased emission. The maximum emission at 80% THF represented a complete destruction of the former aggregate of OPV-lipid. When the volume ratio of THF was higher than 80%, a new loose aggregate spontaneously formed through electrostatic interactions of charged head groups of OPV-lipid. These results, consisting with TEM images, confirmed that OPV-lipid could form various aggregation structures depending on its concentration and the solvent polarity. Both TEM and fluorescence experiments indicated that OPV-lipid exhibited amphipathic characteristic due to the pendant natural lipid moiety, which provided a possibility to interact and disperse in lipid bilayer structure.

Scheme 1.

(a) Synthetic route of OPV-lipid. (b) Optimized structure of OPV-lipid molecule at the

B3LYP/6-311g (d, p)/IEF-PCM (water) theoretical level. Red: O; gray: H; black: C; blue: N; and green: P.

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Figure 1. TEM images of OPV-lipid in H2O at various concentrations: (a) 5 µM; (b) 20 µM; (c) 300 µM; (d) 600 µM. (e) Fluorescence emission spectra of OPV-lipid in THF-H2O mixture with different volume ratios. (f) The maximum emission peak and corresponding intensity as a function of THF-H2O volume ratios. [OPV-lipid] = 100 µM, λex = 405 nm.

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Both endocytic (OPEL) and fusogenic liposomes (OPFL) containing OPV-lipid were prepared via a thin-film hydration method followed by extrusion through polycarbonate membrane with a pore size of 200 nm.12 To be specific, OPV-lipid was incorporated into POPC, DOTAP and cholesterol at a molar ratio of 5:85:3:7 (Figure 2a, 2b) to form OPEL that could enter cells mainly through an endocytosis process. Similarly, OPV-lipid was mixed with DOPE, POPC, DOTAP and cholesterol at a molar ratio of 5:30:60:3:2 (Figure 2e) to form OPFL that could be internalized by cells via fusion with cell membrane. Dynamic light scattering (DLS) measurement displayed that the average hydrodynamic diameter was 194.5 ± 3.4 nm for OPEL and 198.5 ± 2.8 nm for OPFL (Figure 2c, 2f). TEM images (Figure 2d, 2g) exhibited that both the two liposomes formed vesicle structures.

Figure 2. (a) The structures of the lipids that constitute liposomes. The formulas of OPEL (b) and OPFL (e) DLS analysis and TEM images of OPEL (c, d) and OPFL (f, g) extruded through 200 nm polycarbonate membrane.

Various endocytotic inhibiting conditions, including low-temperature (4 ºC), dynasore, nystatin, 7



sucrose and chlorpromazine (CPZ) were applied to study the internalization mechanism of OPV-lipid by MCF-7 cells.22 For experiment group, MCF-7 cells pretreated for 1 h under different inhibiting conditions were continuously incubated with OPV-lipid (20 µM) for another 6 h. Confocal laser scanning microscope (CLSM) images were collected and analyzed. As illustrated in Figure 3, almost no fluorescence signal was observed in OPV-lipid channel at 4 ºC, probably because energy-depended endocytosis was suppressed at low temperature. Similar result was obtained for dynasore group. Since dynasore could inhibit the activity of dynamin and block the clathrin-mediated endocytosis, it was expected that clathrin played a dominant role in the uptake of OPV-lipid into cells. For sucrose and CPZ groups, the uptake of OPV-lipid into MCF-7 cells was respectively inhibited by 72% and 48%, which indicated that clathrin participated the endocytosis process of OPV-lipid because both sucrose and CPZ were inhibitors of clathrin. While for MCF-7 cells treated with nystatin, a 36% decrease of fluorescence intensity relative to the control group illuminated that caveolae had a little effect on the endocytosis process of OPV-lipid. Thus, OPV-lipid was mainly internalized by MCF-7 cells through a clathrin-mediated, energy-dependent endocytosis pathway.

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Figure 3. CLSM images and related normalized intensities of inhibitor-treated MCF-7 cells incubated with OPV-lipid for 6 hours. The endocytosis inhibition conditions including low-temperature (4 ºC), dynasore, nystatin, sucrose and chlorpromazine (CPZ). The excitation wavelength was 405 nm and the fluorescence images were collected the signals from 425-475 nm. [OPV-lipid] = 20 µM.

CLSM technique was employed to investigate the cellular distribution of OPV-lipid. In these experiments, MCF-7 cells were respectively treated with OPV-lipid, OPEL and OPFL for 6 h, 12 h, 24 h and 36 h. As shown in Figure 4, the CLSM images of OPV-lipid group were nearly consistent with those of the OPEL group. For short incubation time (6 h or 12 h), OPV-lipid was mainly spread in the cell cytoplasm and only a little amount was distributed on cell membrane. When incubation time was prolonged to 24 h and 36 h, more OPV-lipid redistributed onto cell membrane while it mainly remained in the cytoplasm. For OPFL group, almost all of OPV-lipid was stably anchored on cell membrane after 6 h and then internalized into cytoplasm gradually after 12 h. Consequently, OPV-lipid distributed in both cell membrane and cytoplasm, and almost same cellular distribution was obtained for all the three groups when incubation time was above 24 h. 9



Figure 4. CLSM images of MCF-7 cells incubated with OPV-lipid, OPEL and OPFL for 6 h, 12 h, 24 h and 36 h. The excitation wavelength was 405 nm and the fluorescence images were collected the signals from 425-475 nm. [OPV-lipid] = 20 µM, [OPEL] = 20 µg/mL, [OPFL] = 20 µg/mL.

Upon colocalizing with organelle-specific dyes, the precisely cellular location of OPV-lipid was successfully traced. As shown in Figure 5a, the fluorescence of OPV-lipid overlayed with all the organelle-specific dyes to some degree. Combining with the line series analysis of CLSM images, OPV-lipid colocalized quite well with the dyes staining lysosomes and cell membrane but relatively less with those dyes of endoplasmic reticula, Golgi apparatuses and mitochondria (Figure 5b). Similar results were observed for OPEL and OPFL group (Figure S2, S3). These results suggested that the final distribution of OPV-lipid was independent of the entrance way into cells at the 10


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beginning. OPV-lipid mainly located in the lysosome of MCF-7 cells, while also dispersed in cell membrane, endoplasmic reticula, Golgi apparatuses and mitochondria at the same time.

Figure 5. (a) Colocalizing with various organelle-specific dyes after treated MCF-7 cells with OPV-lipid for 24 h, including endoplasmic reticulum (ER Tracker), Golgi apparatus (Golgi Tracker), lysosomes (Lyso Tracker), mitochondria (Mito Tracker) and cell membrane (DiD). (b) Line series analysis of OPV-lipid with the dyes mentioned above. The colors are false colors, of which green represents OPV-lipid and blue means organelle-specific dyes. The excitation wavelength was 405 11



nm and the fluorescence images were collected the signals from 425-475 nm. [OPV-lipid] = 20 µM.

Since cell membrane is fluid and participates cell metabolism constantly, a portion of its lipid bilayer enter cytoplasm via the invagination during endocytosis process and then the phospholipid returns to cellular organelles and cell surface as recycling cell-building materials.15 All of our experiment results revealed that OPV-lipid, governed by its lipid-like structure, underwent approximately metabolic pathway with natural phospholipids of MCF-7 cells (Scheme 2). OPV-lipid itself was endocytosed into cells and mainly distributed in the cytoplasm while some anchored on cell membrane. OPEL group shared similar metabolic pathway with OPV-lipid group. For OPFL group, OPV-lipid was spread on cell membrane entirely in a short time owing to membrane fusion process between OPFL and cells. It was noted that OPFL was spread in both cytoplasm and cell membrane after a long-time incubation. Thus, we could manipulate the uptake ways of OPV-lipid into cells as well as its cellular distributions. These phenomena demonstrated that OPV-lipid could be endocytosed into cells because of its lipid-mimic nature, meanwhile, it also could be delivered into cells controllably with the assistance of liposomes with different formulas. Thus, OPV-lipid could act as a fluorescent probe for cell imaging and visualization of its delivery process.

Scheme 2. The mechanism of OPV-lipid, OPEL and OPFL internalized by cells and their metabolic pathways (1, 2, 3).

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In summary, a photoactive oligo(p-phenylene vinylene) functionalized with phospholipid units was designed and synthesized, in which choline unit acted as hydrophilic heads while long alkyl chains and OPV backbone as hydrophobic tails. OPV-lipid could insert into lipid bilayer of MCF-7 cells without interfering cell physiology and share similar metabolic pathway of native phospholipid. OPV-lipid could be delivered into cells controllably with the assistance of liposomes with different formulas. The uptake ways of OPV-lipid into cells and its cellular distributions were successfully manipulated. Due to good optical characteristic, OPV-lipid could also act as fluorescent probe for cell imaging and visualization of its delivery process. Benefiting from good biocompatibility, facile operation and controllable cell uptake process, the liposome-assisted delivery strategy shows good potential in the delivery of various functional molecular systems, which provides a powerful tool 13



for biological and biomedical applications.

ASSOCIATED CONTENT Supporting Information. Detailed experimental procedures and additional Figures S1−S3. The Supporting Information is available free of charge via the Internet at http://pubs.acs.org/.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. *E-mail: [email protected]. Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT The authors are grateful to the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16020804, XDB12030300) and the National Natural Science Foundation of China (Nos. 21473220, 21661132006, 21473221).

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SYNOPSIS TOC

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A Photoactive Oligo(p-phenylene vinylene) Functionalized with

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