Improving photophysical properties and hydrophily of conjugated polymers simultaneously by side-chain modification for near-infrared cell imaging

doi:10.21203/rs.3.rs-4400662/v1

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Improving photophysical properties and hydrophily of conjugated polymers simultaneously by side-chain modification for near-infrared cell imaging

https://doi.org/10.21203/rs.3.rs-4400662/v1

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published 09 Aug, 2024

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Conjugated polymers (CPs)-based near-infrared phototheranostics are receiving increasing attention due to their high molar extinction coefficient, wide emission wavelength, easy preparation and excellent biocompatibility. Herein, several new conjugated polymers with D₂-D₁-A structures were easily prepared through one-pot coupling using triphenylamine as well as thiophenes as electron donors and benzothiadiazole as electron acceptors. Interesting, their optical performance and power conversion efficiency could be tuned by side chains on thiophenes (D₁). The introduction of ethane-1,2-diylbis(oxy) into D₁ as side chain significantly improves fluorescence imaging brightness, photothermal conversion efficiency and hydrophilicity, and extends emission wavelength, which are beneficial for phototheranostic. The side chain modification provides new opportunity to design efficient phototheranostics without construction new fluorescent skeletons.

Conjugated polymers

side-chain modification

near-infrared

cell imaging

photothermal materials

Cancer has one of the highest morbidity and mortality rates around the world.¹ Traditional radiotherapy, chemotherapy and surgery have been unable to meet the current clinical demand for cancer treatment owing to their serious side effects and multi-drug resistance.² Phototheranostics, harnessing photon energy to output fluorescence, acoustic signals, reactive oxygen species and/or hyperthermia, has emerged as an enticing solution to cancer by dint of the integrated superiorities of light prompted non-invasiveness and real-time monitoring as well as in situ manipulative treatment.^3–5 The near-infrared (NIR) region(λ = 650–1400 nm) exhibits relatively low levels of absorption, scattering, and autofluorescence background in biological tissues. Consequently, near-infrared light can penetrate deeper into biological tissues, allowing for effective deep tissue imaging.⁶ Up to now, NIR fluorescence imaging-guided photothermal therapy (PTT) with the integrated diagnosis and treatment, could enable the detection and observation of biologically relevant analytes at the molecular level, which is very important in preclinical studies.^7–10

Currently, a variety of inorganic nanomaterials, such as carbon nanotubes,¹¹ quantum dots,^12–14 and rare earth nanoparticles,^15–17 have been widely explored for NIR fluorescence imaging. Compared to inorganic probes, conjugated polymers are very convenient to allow for various molecular designs and have an excellent biocompatibility.¹⁸ Furthermore, conjugated polymers have strong light absorption capacity, excellent photothermal stability and high photothermal conversion efficiency.^19,20 A variety of conjugated polymers were developed for NIR fluorescence imaging and PTT.^21,22 Although significant progress has been made, the means of regulating photophysical properties are limited and mainly focus on modulating the D-A effect,²³ adjusting the length of π conjugation²⁴ and controlling intermolecular π-π stacking interactions.²⁵ In addition, these conjugated polymers often require encapsulation or the introduction of additional hydrophilic groups to form water-dispersible nanoparticles for probes.^26–28 Therefore, developing suitable strategies to improve the PTT efficacy, brightness and hydrophily of conjugated polymers has been the tireless pursuit of researchers.²⁹

Herein, we present a side chain strategy to improve photophysical properties and hydrophily of conjugated polymers simultaneously. To extend the π conjugation length in the structure, three thiophenes with different side chain groups were introduced to as the first donor (D₁), while triphenyl amine served as the second donor (D₂), and benzothiadiazole (BT)^30,31 acted as the acceptor (Fig. 1). On one hand, the steric hindrance of different side groups on D₁ weakened interchain and intrachain interactions in the polymerization state. On the other hand, thiophene with enhanced electronic donor capacity and a rigid conjugated backbone optimized the D-A interaction. Generally, all the three nano-organic conjugated polymers (NCPs) emitted light in the near-infrared region. Notably, the introduction of ethane-1,2-diylbis(oxy) into D₁ as side chain significantly improved fluorescence imaging brightness, photothermal conversion efficiency and extended emission wavelength, which were beneficial for phototheranostic. Furthermore, it also enhanced hydrophilicity, which eliminated the need for encapsulation or functionalization. To the best of our knowledge, this is the first study reporting bioimaging application of pure conjugated nano-organic polymers without conventional encapsulation in the near-infrared region. We found that pTOB bearing ethane-1,2-diylbis(oxy) side chain exhibited the longest emission wavelength (824 nm), superior hydrophilicity, good photothermal conversion efficiency (29.25%) and the highest quantum yield (3.87%) among three polymers. These results show side chain modification can be used as an alternative means to design promising phototheranostics.

2.1 Materials

N, N-dimethylacetamide (DMAc), mesitylene, tetrahydrofuran (THF), 1,4-Dioxane, methanol, toluene, ethyl acetate and concentrated hydrochloric acid were purchased from Chengdu Forest Science and Technology Development Co., ltd. (Chengdu, China). Tris (4-bromophenyl) amine (TBA-Br₃), 4, 7-Dibromo-2, 1, 3-Benzothiadiazole (BT-Br₂), 2-Thiopheneboronic acid, 3, 4-Ethylenedioxythiophene (EDOT), 3-Hexylthiophene, pivalic acid, Pd (PPh₃)₄, Pd (OAc)₂ and anhydrous K₂CO₃ were obtained from the Adamas Reagent Co., ltd. (Shanghai, China). Tricyclohexylphosphonium tetrafluoroborate (PCy₃⋅HBF₄) was obtained from the Aladdin Chemistry Co. ltd. (Shanghai, China). Cesium Pivalate was obtained from the Leyan Co., ltd. (Shanghai, China). All chemicals were analytical grade (AR) and used as received without further puri-fication. Water used in all the experiments was ultrapure water. The MCF-7 cell lines were received from Beijing Bei Na Biotechnology Co., Ltd. The CCK-8 assay kits were acquired from Invigentech Co., Ltd (America).

2.2 Synthesis of pTB

First, in a Schlenk tube, tris (4-bromophenyl) amine (0.96 g, 2.0 mmol), 2-Thiopheneboronic acid (1.5 g, 12 mmol), Pd (PPh₃)₄ (0.10 g, 0.090 mmol) and anhydrous K₂CO₃ (2.1 g, 15 mmol) were dissolved in 1,4-Dioxane (30 mL). And then, the mixture was stirred at 120 ℃ for 8 h under N₂ atmosphere. When the reaction was completed, the mixture was then washed with water and saturated NaCl solution, respectively. The organic layer was separated and dried over anhydrous Na₂SO₄. After evaporation of the solvent, the crude product was obtained as brown oily. The final product, Tris(4-(thiophen-2-yl) phenyl) amine (TTBA), was obtained as yellow solid (720 mg, 73.0%) after purifying with column chromatography (petroleum ether / dichloromethane,12: 1 = v: v). ¹H NMR (400 MHz, DMSO): δ = 7.63 (d, J = 8.7 Hz, 6H, Ar), 7.50 (m, 6H, Ar), 7.44 (m, 6H, Ar), 7.09 (m, 3H, Ar). Second, in a Schlenk tube, DMAc (2 mL) was added to a mixture of TTBA (0.15 g, 0.30 mmol), BT-Br₂ (0.13 g, 0.45 mmol), Pd (OAc)₂ (0.0044 g, 0.020 mmol), PCy₃·HBF₄ (0.015 g, 0.040mmol), Cesium Pivalate (0.35 g, 1.5 mmol). After nitrogen replacement and protection, the mixture was stirred at 120°C in an oil bath for 72 h. The reaction was cooled to room temperature and then diluted with ethanol. The powder was collected by filtration and washed with 2 M HCl solution, water and THF. Then it was transferred into 2 M HCl solution and stirred overnight. The solid was filtered again and washed with 2 M HCl solution, water, THF, toluene and ethyl acetate, respectively. Subsequently, it was subjected to Soxhlet extraction with methanol and THF sequentially for 24 h with each solvent. A black-red solid was obtained after dried at 80°C in vacuum overnight with 96% isolated yield.

2.3 Synthesis of pTRB

In a Schlenk tube, DMAc (2 mL) was added to a mixture of TBA-Br₃ (0.096 g, 0.20 mmol), 3-Hexylthiophene (0.36 mL, 1.2 mmol), BT-Br₂ (0.88 g, 0.30 mmol), Pd (OAc)₂ (0.035 g, 0.16 mmol), PCy₃·HBF₄ (0.12 g, 0.32 mmol) and Cesium Pivalate (0.13 g, 0.53 mmol). After nitrogen replacement and protection, the mixture was stirred at 120°C in an oil bath for 72 h. The purification method was similar to above, and a black-gray solid was obtained after dried at 80°C in vacuum overnight with 98% isolated yield.

2.4 Synthesis of pTOB

In a Schlenk tube, DMAc (2 mL) was added to a mixture of TBA-Br₃ (0.096 g, 0.20 mmol), EDOT (0.13 mL, 1.2 mmol), BT-Br₂ (0.088 g, 0.30 mmol), Pd (OAc)₂ (0.035 g, 0.16 mmol), PCy₃·HBF₄ (0.12 g, 0.32 mmol) and Cesium Pivalate (0.13 g, 0.53 mmol). After nitrogen replacement and protection, the mixture was stirred at 120°C in an oil bath for 72 h. The purification method was similar to above, and a black-purple solid was obtained after dried at 80°C in vacuum overnight with 87% isolated yield.

2.5 Tumor cell cytotoxicity test

MCF-7 cells were grown in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum (FBS) at 37°C in 5% CO₂.

The viability of pTOB were evaluated through cell counting kit-8 (CCK-8) assay. MCF-7 cells were seeded in 96-well flat-bottomed plates at 6 × 10³ cells per well and incubated at 37 ℃ in a 5% CO₂ incubator for 24 h and then incubated with pTOB with different concentrations (0, 0.5, 1, 2, 5, 10, 15, 20, 30, 40 µg mL^-1) for 24 h. We use DMEM medium to prepare pTOB solutions at different concentrations. After that, the cells were rinsed with PBS 3 times and incubated with PBS (90 µL) and CCK-8 (10 µL) for 2 h at 37°C. The fluorescence analysis was using a microplate reader (TECAN, SPARK 10M) at the wavelength of 450 nm. The viability of cell growth was calculated using (Relative vitality% = (experimental Group OD Value - Background OD Value) / (Control Group OD Value Mean - Background OD Value) ×100). The background OD value is the absorbance of only CCK-8 reagent and medium.

2.6 Cell imaging

MCF-7 cells were grown in DMEM supplemented with 10% fetal bovine serum (FBS) at 37°C in 5% CO₂. The sample was diluted to 5 µg mL^-1 using complete medium. The experimental group was divided into 2 groups: Control group and 5 µg mL^-1 sample group. The sample was incubated with 5 µg mL^-1 pTOB for 1 h. The control was added equal amount PBS. MCF-7 cells were inoculated into confocal dishes at concentration of 8×10⁴ cells per well and cultivated in a constant temperature incubator at 37°C, 5% CO₂ overnight. Excite the sample with a 599 nm laser and collect images in a 700–900 nm window.

2.7 Statistical analysis

All results were presented as Mean ± S.D. for three independent experiments. Statistical analysis was performed using Graphpad Prism 6 software. ANOVA was used to compare multiple groups and statistical significance was determined with probability values of *p < 0.05, **p < 0.01 compared to control.

3.1 Synthesis and Characterization

All the three conjugated polymers were prepared by direct C–H arylation reaction. pTRB and pTOB were obtained in 98% and 87% yields respectively by one-pot direct coupling. While pTB was prepared by two steps with 96% yield. Apart from having different side chains on thiophen, the three compounds shared the same structural characteristics (Fig. 2a).

To confirm the chemical structure of the obtained NCPs pTB, pTRB and pTOB, Fourier-transform infrared (FT-IR) spectroscopy, solid-state ¹³C-NMR and X-ray photoelectron spectra (XPS) were applied. The FT-IR spectras were shown in Fig. 2b, for three polymers, the characteristic absorption of ν (C = N) at 1596 cm^-1 and ν (C-S-C) at 1496 cm^-1 in BT and thiophene rings were observed, respectively. The peaks at 690–840 cm^-1 were ascribed to the aromatic sp² C–H bend absorption frequencies in triphenylamine. The intense peak in 1062 cm^-1 was corresponding to ν (C-O-C) in EDOT in pTOB. The attenuation or disappear of the C-Br band around 1108 cm^-1 and 580 cm^-1 of NCPs illustrated the high degree of polymerization. The XPS survey scan of three NCPs indicated the presence of C, N, O, S (Fig. 2c) in polymers.³² The O peaks in pTB and pTRB are oxygen in the air.

Three NCPs were further corroborated by ¹³C-CP/MAS NMR (Fig. S2). pTRB, pTB and pTOB exhibited chemical shifts at 10–160 ppm, the chemical shifts at 158 − 138 ppm were corresponding to C-N and C-O (C_a, C_h, C_f and C_k of pTOB, C_a and C_k of pTB, C_a and C_q of pTRB). The chemical shifts of remaining carbons on the aromatic ring appeared at 120–140 ppm. (C_b−c, C_j and C_l of pTOB, C_b−j of pTB, C_b−f and C_m−p of pTRB). The low-field signal at 117 and 114 ppm was attributed to C-S (C_e and C_i), while the strong signal peak at 65 ppm and was ascribed to C-O (C_g) in EDOT of pTOB. The peak at 25–35 ppm and 14 ppm were attributed to alkyl chains (C_g−l) of pTRB.³³ In summary, the results of FT-IR, solid-state ¹³C-NMR and XPS confirmed the successful synthesis of three polymers.

Fortunately, all three NCPs can be dispersed in aqueous solutions (Fig. S3). The water contact angle for pTRB, pTB and pTOB was 79°, 73°, 68°, respectively, (Fig. 3a) which was less than 90°, confirming that they were hydrophilic NCPs. The hydrophilicity of pTRB was the worst because of alkyl chains. While pTOB had the best hydrophilicity due to the abundance of O in its structure. The average hydrodynamic diameter of pTRB, pTB, pTOB were determined by dynamic light scattering (DLS) (Fig. 3b), showing approximately 206, 324, 116 nm, respectively. The morphologies (Fig. 3c) of pTRB and pTB were confirmed by scanning electron microscopy (SEM), and pTOB was confirmed by transmission electron microscope (TEM). pTRB and pTB were irregularly shaped nanoparticles, and pTOB was spherical particles with different particle sizes.

3.2 Optical Properties

To investigate the substituent effect on the electronic donor structures in the ground state, UV-vis/NIR absorption measurements of NCPs were carried out in diluted solution (150 µg mL^− 1 in water) (Fig. 4a). All three NCPs exhibited a very wide absorption band at 206–1000 nm, and the absorption ability of pTOB was significantly stronger than that of other two NCPs. The molar extinction coefficients on 808 nm of pTRB, pTB and pTOB were 0.878 L g^− 1 cm^− 1, 0.848 L g^− 1 cm^− 1 and 3.43 L g^− 1 cm^− 1, respectively. It could be seen that the introduction of alkyl into pTRB had little effect on the absorbance coefficient, while the addition of ethane-1,2-diylbis(oxy) into D₁ increased the absorbance coefficient by about 4 times, which implied that pTOB had potential photothermal property at 808 nm due to its excellent light-capture ability. Before 708 nm, the absorption of pTB was greater than that of pTRB due to the better hydrophilicity. But the absorption of pTRB exceeded that of pTB after 708 nm because alkyl chain on thiophene lateral group hindered charge transfer between molecular chains, thereby promoting stronger intramolecular charge transfer, resulting in stronger absorption. The fluorescence emission spectrum (Fig. 4: b, c, d) showed that the maximal emission wavelengths of pTRB, pTB and pTOB were 685 nm, 724 nm, 827 nm, respectively. In a comparison of pTB, the fluorescence wavelength of pTOB increased from 724 to 827 nm, which proved that the addition of ethane-1,2-diylbis(oxy) into D₁ could lead to the red shift of NCPs fluorescence wavelength. Surprisingly, the quantum yield of pTOB was enhanced more than 100 times than that of pTB (3.87% vs 0.03%). To sum up, the addition of ethane-1,2-diylbis(oxy) into D₁ could simultaneously improve the absorbance coefficient, make the emission wavelength redshifted and increase the fluorescence brightness, and these good optical properties of pTOB were beneficial for biological imaging. Furthermore, the diffuse reflectance of solid UV absorption (Fig. S4) showed that pTRB had absorption at 220–550 nm, pTB at 200–400 nm and pTOB at 250–600 nm, which were attributed to the π - π* and n - π* transitions of the conjugated aromatic segments. And longer wavelength absorption (pTRB had absorption at 600–800 nm, pTB had absorption at 400–600 nm, pTOB had absorption at 700–800 nm) was due to intramolecular charge transitions between donor groups and acceptor nuclei, which indicated a significant intramolecular charge transfer (ICT) effect within the polymer molecule.³⁴ And their optical band gaps obtained from the Tauc plots were 1.83 eV (pTRB), 1.78 eV (pTB), 1.57 eV (pTOB).

3.3 DFT calculation

In order to further elucidate the structure-activity relationship between structure and optical properties of the three NCPs, we carried out theoretical calculations regarding molecular geometries of NCPs series by using density functional theory (DFT). In the calculation, we calculated only one repeating-unit (D₂-D₁-A) owing to the limit of computation power. As shown in Fig. 5a, all the highest occupied molecular orbital (HOMO) were mainly located on TBA. Due to the strong D-A effect, the distribution of electron clouds in the lowest unoccupied molecular orbital (LUMO) was different. LUMOs of pTRB and pTB were mainly distributed on thiophene groups and BT, while LUMO of pTOB was almost all on BT. It could be seen that there was obvious ICT in all three polymers, but the ICT ability of pTOB was significantly stronger than that of pTRB, pTB. In addition, according to the DFT structure optimization calculation results, as seen clearly (Fig. 5b), the angles between thiophene and benzene ring of triphenylamine were 51.56°, 25.64°and 20.57° for TRB, pTB and pTOB, respectively. Based on the results of our calculations, the intramolecular charge transfer increased along with angle decreasing. For pTRB, the dihedral angle was the largest (51.56°) due to the influence of alkyl chains, resulting that the charge transfer was hindered to a certain extent, further leading it to possess the lowest emission wavelength of 685nm among the three polymers. While pTOB had the longest emission wavelength of 827 nm because of the smallest dihedral angle (20.57°). Ethane-1,2-diylbis(oxy) in pTOB was a strong electron donor and the π-π conjugation between oxygen atoms and thiophene in this structure further increased the electronic density of the entire molecule.³⁵ According to the calculation, the band gap of pTRB (2.587 eV), pTB (2.510 eV) and pTOB (2.492 eV) gradually decreased. Although these values were greater than experimental values, they had the same overall trend (pTRB < pTB < pTOB), which revealed the polymer can effectively extend the π conjugate chain and effectively reduce the band gap value.³⁶

3.4 Tumor cell cytotoxicity test

Good biocompatibility is one of the key characteristics of polymer nanoparticles for application in biomedical fields. Moreover, tumor cell cytotoxicity test is also critical for the application of polymer nanoparticles in the related fields of biological diagnosis and treatment. MCF-7 cells were employed to evaluate the viability of pTOB nanoparticles by CCK-8 testing. Figure 6a showed the cell viability after incubation with varied concentrations of pTOB ranging from 0 to 40 µg mL^− 1, respectively. After incubation for 24 h, MCF-7 cells still exhibited more than 98% cell viability even at very high pTOB concentration of 40 µg mL^− 1. The results based on above discussion suggested that the pTOB had negligible cytotoxicity, which was very important for long-term bioimaging.

3.5 In vitro cell imaging

The pTOB had spherical morphology with uniform particle size and good biocompatibility and water-dispersibility, which was expected to be preferable for bioimaging. The CLSM images of MCF-7 cells were taken under 599 nm irradiation after incubated with 5 µg mL^− 1 pTOB for 1 h. As shown in Fig. 6b, pTOB group had bright near-infrared light while control cells showed negligible fluorescence in the observed channel, implying the feasibility of using pTOB for real time and in situ imaging of biological events.

3.6 Photothermal effect

The NIR absorption properties of the polymers prompted us to evaluate the potential of NIR PTT active materials. When aqueous solutions of pTRB, pTB and pTOB (150 µg mL^− 1) were exposed to an 808 nm laser under 1 W cm^− 2, the maximum temperature change (ΔT_max) of 8.1 ℃, 7.8 ℃ and 24.8 ℃, respectively, were observed after 10 min (Fig. 6c, d). Furthermore, the photothermal stability of pTOB and ICG were evaluated by six continuous off/on cycles of the 808 nm laser (1 W cm^− 2, 20 min in each cycle). As shown in Fig. 5e, the temperature of ICG decreased to half of its initial temperature in the second cycle. In contrast, the pTOB did not exhibit any temperature loss even after six cycles, indicating a photothermal stability far exceeded that of ICG. In order to comprehensively evaluate photothermal properties of pTOB in vitro, temperature variation curve was recorded under 808 nm light activation (Fig. 6f). These data indicated that temperature elevation was proportionally dependent on the molar concentration of NCPs, disclosing the controllability of light-to-heat conversion. The photothermal conversion efficiency of pTOB was calculated to be 29.25% (Fig. 6g), clearly indicating its potential as a promising photothermal agent.

In conclusion, three novel hydrophilic conjugated polymer pTRB, pTB and pTOB with D₂-D₁-A structure were designed and synthesized by simple one-pot method in this study. Their optical performance, power conversion efficiency and hydrophily could be tuned by side chains on thiophenes (D₁). pTOB bearing with ethane-1,2-diylbis(oxy) side chain on D₁ elicited bright deep-red fluorescence with 3.87% QY in solid state. It also exited good photothermal conversion efficiency excited at 808 nm with good photostability. DFT calculations showed that the introduction of ethane-1,2-diylbis(oxy) side chain increased the electronic density of the entire molecule and minimize the angles between thiophene and benzene of triphenylamine, resulting in strong ICT effect. pTOB showed good biocompatibility and had been successfully applied to image in MCF-7 cells. These results showed that side chain modification could be an efficient way to design phototheranostics.

AUTHOR INFORMATION

Corresponding authors

ChuanqinXia-College of Chemistry, Sichuan University, Chengdu 610064, P.R. China;

E-mail: [email protected]

Shanyong Chen-College of Chemistry, Sichuan University, Chengdu 610064, P.R. China;

E-mail: [email protected]

Authors

Min Zhou- College of Chemistry, Sichuan University, Chengdu 610064, P.R. China

Fenglei Wang- College of Chemistry, Sichuan University, Chengdu 610064, P.R. China

Yongdong Jin- College of Chemistry, Sichuan University, Chengdu 610064, P.R. China

Acknowledgements Not applicable.

Funding This work is financially supported by the National Natural Science Foundation of China (Grant Nos. 22176136, U21A20296, 22376149, 22125605), and the Key Research and Development Program of Sichuan Province, China (Project No. 2023YFH0098). We are grateful for the technical support from the Comprehensive Training Platform of the Specialized Laboratory (College of Chemistry, Sichuan University) and Analytical & Testing Center of Sichuan University.

Data Availability The raw data are available from the corresponding author on reasonable request.

Ethical Approval and Consent to Participate Not applicable.

Consent for Publication Not applicable.

Competing Interests The authors have no conflicts of interest to declare that are relevant to the content of this article.

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No competing interests reported.

SupportingInformation.docx
Supporting Information Additional data, including instrumentation, synthetic route, ¹H NMR imaging, calculation of the photothermal conversion efficiency, water contact angle test, solid- state ¹³C-NMR spectra, pictures of scattered situations and UV−vis DR spectra.

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Improving photophysical properties and hydrophily of conjugated polymers simultaneously by side-chain modification for near-infrared cell imaging

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Journal Publication

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Abstract

Figures

1. INTRODUCTION

2. EXPERIMENTAL SECTION

2.1 Materials

2.2 Synthesis of pTB

2.3 Synthesis of pTRB

2.4 Synthesis of pTOB

2.5 Tumor cell cytotoxicity test

2.6 Cell imaging

2.7 Statistical analysis

3. RESULTS AND DISCUSSION

3.1 Synthesis and Characterization

3.2 Optical Properties

3.3 DFT calculation

3.4 Tumor cell cytotoxicity test

3.5 In vitro cell imaging

3.6 Photothermal effect

4. CONCLUSION

Declarations

References

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1