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Facile synthesis of a triazine-based porous organic polymer containing thiophene units for effective loading and releasing of temozolomide

  • Di Hao , Dong-Yue Wang , Bin Dong EMAIL logo , Sun-Chang Xi and Guan Jiang EMAIL logo
Published/Copyright: August 10, 2022
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Abstract

Suzuki cross-coupling reaction was employed to easily obtain a triazine-based porous organic polymer (2,4,6-tris(5-bromothiophene-2-yl)-1,3,5-triazine [TBrTh]–1,3,5-benzene-triyltriboronic acid pinacol ester [BTBPE]–covalent triazine framework [CTF]) containing thiophene units. The chemical structure of TBrTh–BTBPE–CTF was revealed by solid-state 13C NMR, Fourier-transform infrared, and X-ray photoelectron spectroscopy. TBrTh–BTBPE–CTF with an amorphous structure exhibited excellent thermal stability and intrinsic porosity (373 m2·g−1 of Brunauer–Emmett–Teller surface area). Consequently, temozolomide (TMZ) was used as an oral alkylating agent in melanoma treatment to explore the drug loading and releasing behavior of TBrTh–BTBPE–CTF as a result of the low cytotoxicity of thiophene-based polymers. The successful loading of TMZ within the polymeric structure was suggested by thermogravimetric analysis and N2 sorption isotherms. The release experiments were performed in phosphate-buffered saline at pH values of 5.5 and 7.4, exhibiting good controlled-release properties. These results suggest that the current porous organic polymer is expected to be a drug carrier for the delivery and release of TMZ.

1 Introduction

Porous organic polymers (POPs) emerge as an important type of porous materials formed by the integration of organic building blocks via strong covalent bonds (1,2). Due to wide synthetic diversity and rational design, various types of POPs have been reported, including covalent triazine frameworks (CTFs) (3,4), covalent organic frameworks (COFs) (5,6), porous aromatic frameworks (PAFs) (7), conjugated microporous polymers (CMPs) (8), and so on. The advantages of low density, high porosity, tunable pore size, and ease of modification endow POPs with great performance in various fields, such as gas storage and separation, optoelectronic devices, catalysis, and biomedicines. In the absence of toxic metal ions, POPs have exhibited great potential in drug delivery (9,10). It has been reported that not only three-dimensional polyimide COFs but also two-dimensional imine-linked COFs have high loading efficacy for drugs, e.g., ibuprofen (IBU), captopril, caffeine, and 5-fluorouracil (11,12). An imine-linked, triazine-based COF (TTI-COF) was reported to deliver quercetin based on C–H–π and H-bond interactions (13). Porphyrin-based CTFs were also used to deliver IBU, in which the interaction between the acid group of IBU and the triazine ring of CTFs has a positive effect on drug loading and controlled release (14). A pH-sensitive CTF and an imine-linked fluorescent COF were designed for drug loading and responsive doxorubicin release (15,16). The rational design of building units can make more POPs suitable for drug delivery.

Melanoma is a highly malignant skin tumor that develops from melanocytes, and its incidence continues to rise (17). Many chemotherapeutic drugs, such as temozolomide (TMZ), dacarbazine, fotemustine, and paclitaxel, have been employed in melanoma treatment (18,19). Among them, TMZ is an oral alkylating agent that can be used for treating central nervous system malignancies (20,21,22). Similar to other chemotherapeutic drugs, the efficacy of TMZ is limited by some defects, such as nonspecific targeting, uncontrollable drug release, and rapid elimination. Several studies have been reported to enhance the targeting capacity of TMZ, as well as its stability, sensitivity, and overall efficacy against melanoma (23,24). However, there is no report on the use of POPs as smart carriers for TMZ.

Thiophene is a common heterocyclic ring found in many bioactive compounds, and meanwhile, polythiophenes with conjugated structures have shown tremendous biological applications (25,26). In this work, a triazine-based POP containing thiophene units (2,4,6-tris(5-bromothiophene-2-yl)-1,3,5-triazine [TBrTh]–1,3,5-benzene-triyltriboronic acid pinacol ester [BTBPE]–CTF) was facilely synthesized using one-pot Suzuki coupling (Scheme 1). The structure and properties of TBrTh–BTBPE–CTF were investigated in detail by various techniques. With intrinsic porosity, big specific surface area, and high stability, the drug loading and releasing studies of TBrTh–BTBPE–CTF were performed by using TMZ as a model drug. In TBrTh–BTBPE–CTF, the triazine ring and its linked thiophene unit are planar. With the aid of π−π stacking derived from the highly conjugated structure and abundant nitrogen sites in triazine rings, the as-synthesized POP exhibited good drug loading and releasing behavior.

Scheme 1 
               Synthetic route of TBrTh–BTBPE–CTF by Suzuki cross-coupling reaction of TBrTh and BTBPE together with the loading and releasing of the drug TMZ.
Scheme 1

Synthetic route of TBrTh–BTBPE–CTF by Suzuki cross-coupling reaction of TBrTh and BTBPE together with the loading and releasing of the drug TMZ.

2 Materials and methods

2.1 Chemicals

TBrTh was synthesized according to the literature procedure (27), and its chemical structure was confirmed by 1H and 13C NMR spectra (Figure A1 in Appendix). BTBPE, tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4), TMZ, 5-aminoimidazole-4-carboxamide (AIC), and phosphate-buffered saline (PBS) were received from Aladdin. Potassium carbonate (K2CO3), N,N-dimethylformamide (DMF), tetrahydrofuran (THF), and hexane were purchased from Shanghai Titan Scientific Co. Ltd. All the reagents were used as received. Water was doubly deionized.

2.2 Characterization

A solid-state cross-polarization/magic angle spinning (CP/MAS) 13C NMR spectrum was recorded on a 400 MHz Bruker AVANCE III spectrometer. Fourier-transform infrared (FTIR) spectra were recorded on a Nicolet iS50 spectrometer with the conventional KBr plate method. Elemental analysis was carried out on an Elementar Vario EL Cube analyzer. X-ray photoelectron spectroscopy (XPS) spectrum was collected on the Thermo Fisher ESCALAB 250Xi instrument. Powder X-ray diffraction (PXRD) pattern was recorded on a Bruker D8 Advance multipurpose diffractometer operated at a voltage of 45 kV and a current of 30 mA. The thermogravimetric analysis (TGA) was examined using a Netzsch STA 449 F5 analyzer at a heating rate of 10°C·min−1 under a nitrogen atmosphere. The TMZ loading amount was calculated based on the two-step loss of weight in the TGA profile of CTF–TMZ. Field emission scanning electron microscopy (FE-SEM) and energy dispersive X-ray (EDX) spectroscopy images were conducted on a Tescan MIRA3 LMH instrument. The microstructure was detected by high-resolution transmission electron microscopy (TEM, FEI Tecnai G2 60-300) with hexane as the dispersing solvent. Quantachrome Autosorb-iQ analyzer was used for nitrogen adsorption–desorption isotherms at 77 K after the samples were degassed at 100°C for 12 h. UV-visible (UV-Vis) absorption spectra were performed with a TU-1901 UV-Vis spectrophotometer.

2.3 Synthesis of TBrTh–BTBPE–CTF

TBrTh (0.62 g, 1.09 mmol), BTBPE (0.50 g, 1.09 mmol), K2CO3 (1.36 g, 9.83 mmol), Pd(PPh3)4 (22 mg, 0.019 mmol), and DMF (30 mL) were added to a round-bottom flask filled with N2. After bubbling with N2 for 30 min, the mixture was heated to 150°C for 48 h with vigorous stirring. The obtained yellow precipitate was then filtered and washed with H2O and THF. The Soxhlet extraction with THF was carried out for 48 h for further purification. Finally, the pure yellow polymer named TBrTh–BTBPE–CTF was obtained after being dried under a vacuum at 100°C for 12 h (yield: 95%). Anal. Calcd for (C11H7NS) n : C, 71.32; H, 3.81; N, 7.56; and S, 17.31. Found: C, 69.38; H, 3.43; N, 7.20; and S, 16.75.

2.4 Drug loading and releasing

TMZ was employed for drug loading and releasing studies. The drug-loaded sample was prepared by immersing solvent-free TBrTh–BTBPE–CTF (50 mg) in TMZ hexane solution (20 mL, 0.02 mol·L−1) under stirring for 10 h. After that, the TMZ-loaded sample (named CTF–TMZ) was separated from the solution by filtration, washed with hexane, and finally dried under vacuum at room temperature.

The releasing behavior of TMZ from CTF–TMZ was studied at 37°C under two pH conditions (5.5 and 7.4; PBS). Briefly, CTF–TMZ (10 mg) was dipped in PBS (20 mL) in a vial at 37°C. At predetermined time intervals, the dissolution medium (3 mL) was taken out, centrifuged, and measured by UV-Vis spectrophotometry to determine the drug concentration according to the calibration curve. Meanwhile, 3 mL of fresh PBS was added to maintain the overall volume. The releasing experiments were continued until no TMZ was detectable in the withdrawn PBS. The experiments were repeated three times.

3 Results and discussion

3.1 Synthesis and determination of the composition of TBrTh–BTBPE–CTF

The monomer containing thiophene units (TBrTh) was synthesized according to the published procedure and then reacted with BTBPE via Suzuki cross-coupling reaction to obtain the polymeric material (named TBrTh–BTBPE–CTF, Scheme 1). The solid-state CP/MAS 13C NMR spectroscopy revealed the chemical structure of TBrTh–BTBPE–CTF at the molecular level (Figure 1a). The characteristic signal at 166.7 ppm can be assigned to the carbon atoms in triazine rings (28,29,30). The signals at 141.8 and 124.1 ppm correspond to the phenyl carbons, and those around 157.4, 149.5, and 132.6 ppm correspond to the carbon atoms in thiophene rings (30,31,32). The successful polymerization was also indicated by FTIR spectroscopy (Figure 1b). In the FTIR spectrum of TBrTh–BTBPE–CTF, the peaks belonging to the triazine rings appeared at 1,413 and 1,512 cm–1 (33,34), while there was no peak in the C–Br band of TBrTh (500 cm–1) and the CH3 band of BTBPE (2,982 cm–1) (35,36,37), implying the phenyl–phenyl coupling with the consumption of functional groups in the monomers TBrTh and BTBPE.

Figure 1 
                  (a) Solid-state CP/MAS 13C NMR spectrum of TBrTh–BTBPE–CTF. (b) FTIR spectra of TBrTh–BTBPE–CTF along with the monomers (TBrTh and BTBPE).
Figure 1

(a) Solid-state CP/MAS 13C NMR spectrum of TBrTh–BTBPE–CTF. (b) FTIR spectra of TBrTh–BTBPE–CTF along with the monomers (TBrTh and BTBPE).

The contents of the elements C, H, N, and S in TBrTh–BTBPE–CTF were determined by elemental analysis (69.38, 3.43, 7.20, and 16.75, respectively), in agreement with the theoretical values (71.32, 3.81, 7.56, and 17.31, respectively). The chemical states of the elements in TBrTh–BTBPE–CTF were revealed by XPS (Figure 2). The XPS survey spectrum demonstrated the existence of C, N, and S elements. The deconvolution of C 1s XPS spectrum resulted in three peaks at binding energies of 286.7, 284.9, and 284.6 eV, corresponding to the carbon atoms in triazine, thiophene, and phenyl rings, respectively (32,38,39). Both the deconvoluted N 1s and S 2p spectra showed one signal peak, which can be assigned to the triazine (398.7 eV) and thiophene units (163.9 eV), respectively (39,40). All these pieces of evidence demonstrate that the Suzuki cross-coupling reaction is effective for constructing the polymeric material.

Figure 2 
                  (a) XPS survey, (b) C 1s, (c) N 1s, and (d) S 2p spectra of TBrTh–BTBPE–CTF.
Figure 2

(a) XPS survey, (b) C 1s, (c) N 1s, and (d) S 2p spectra of TBrTh–BTBPE–CTF.

3.2 Structural and property characterization of TBrTh–BTBPE–CTF

The PXRD pattern of the as-prepared TBrTh–BTBPE–CTF showed one broad peak at 2θ of 25.6° (Figure 3a), suggesting a generally amorphous structure. TBrTh–BTBPE–CTF was insoluble in water as well as in common organic solvents (e.g., hexane, THF, acetone, methanol, and DMF). Meanwhile, the high thermal stability of TBrTh–BTBPE–CTF was revealed by TGA, with the most drastic decomposition around 600°C (Figure 3b).

Figure 3 
                  (a) PXRD pattern of TBrTh–BTBPE–CTF. (b) TGA profiles of TBrTh–BTBPE–CTF and CTF–TMZ measured under a nitrogen atmosphere.
Figure 3

(a) PXRD pattern of TBrTh–BTBPE–CTF. (b) TGA profiles of TBrTh–BTBPE–CTF and CTF–TMZ measured under a nitrogen atmosphere.

FE-SEM image revealed an aggregated particle morphology of TBrTh–BTBPE–CTF (Figure 4a). The homogeneous distribution of carbon, nitrogen, and sulfur throughout the sample was demonstrated by EDX elemental mapping images (Figure A2). The nano-size morphology with alternately dark and bright microstructures was detected by TEM (Figure 5a).

Figure 4 
                  SEM images of (a) TBrTh–BTBPE–CTF and (b) CTF–TMZ.
Figure 4

SEM images of (a) TBrTh–BTBPE–CTF and (b) CTF–TMZ.

Figure 5 
                  TEM images of (a) TBrTh–BTBPE–CTF and (b) CTF–TMZ.
Figure 5

TEM images of (a) TBrTh–BTBPE–CTF and (b) CTF–TMZ.

The porosity of TBrTh–BTBPE–CTF was characterized by N2 adsorption–desorption analysis at 77 K. As shown in Figure 6a, the N2 capacity displayed a sharp increase at relatively low pressure (P/P 0 < 0.01), implying the existence of plentiful micropores. Meanwhile, a steep rise at relatively high pressure (P/P 0 > 0.9) suggested a mesoporous structure (29,41). The total pore volume was found to be 0.59 cm3·g–1 at P/P 0 = 0.99. The pore size distribution (PSD) was analyzed by the non-local density functional theory (NLDFT) method. The corresponding PSD plot exhibited two peaks at 1.8 and 2.9 nm, also suggesting the micro/mesoporous structures (Figure 6b). The Brunauer–Emmett–Teller (BET) surface area was calculated to be 373 m2·g–1 (Figure A3a). The permanent porosity together with the excellent stability as mentioned earlier makes TBrTh–BTBPE–CTF a potential carrier in drug delivery.

Figure 6 
                  (a) Nitrogen sorption isotherms measured at 77 K and (b) the PSD plot fitting by NLDFT to the sorption data of TBrTh–BTBPE–CTF.
Figure 6

(a) Nitrogen sorption isotherms measured at 77 K and (b) the PSD plot fitting by NLDFT to the sorption data of TBrTh–BTBPE–CTF.

3.3 Synthesis and characterization of CTF–TMZ

TMZ was chosen as a model drug for drug loading and releasing studies of TBrTh–BTBPE–CTF (Scheme 1). The CTF–TMZ was obtained by immersing solvent-free TBrTh–BTBPE–CTF in a TMZ hexane solution. The TGA profile of CTF–TMZ exhibited a two-step loss of weight (Figure 3b). Similar phenomena have been observed in other drug-loaded samples (11,12). A weight loss occurred at a low temperature as a result of the loaded TMZ. When compared with TMZ itself (Figure A4), the decomposition temperature of TMZ in CTF–TMZ was relatively higher because TMZ was loaded into the CTF’s structure. The other at high temperatures similar to that of TBrTh–BTBPE–CTF itself was derived from the decomposition of the polymeric framework. The TMZ loading amount of CTF–TMZ was calculated to be about 13 wt% based on the two onset temperatures (dashed lines shown in Figure 3b). The morphology and microstructure of CTF–TMZ were similar to those of TBrTh–BTBPE–CTF as observed by SEM and TEM (Figures 4b and 5b). Similarly, N2 sorption isotherms at 77 K revealed a combination of type-I and -IV sorption isotherms of CTF–TMZ (Figure 7a). The BET surface area was calculated to be 216 m2·g−1 (Figure A3b), which is smaller than that of TBrTh–BTBPE–CTF. In addition, CTF–TMZ exhibited a decrease in total pore volume (0.37 cm3·g−1) and pore size (1.5 and 2.7 nm, Figure 7b). All these changes in the porosity support the effective TMZ loading into the polymeric framework as well as the structural integrity of the CTF after the drug loading. Due to the intensely conjugated structure of the CTF and the amino groups existing in TMZ, it is speculated that both π–π and hydrogen bonding interactions afford the effective TMZ loading, although no valuable information was obtained from the FTIR spectrum.

Figure 7 
                  (a) Nitrogen sorption isotherms measured at 77 K and (b) the PSD plot fitting by NLDFT to the sorption data of CTF–TMZ.
Figure 7

(a) Nitrogen sorption isotherms measured at 77 K and (b) the PSD plot fitting by NLDFT to the sorption data of CTF–TMZ.

3.4 Drug-releasing behavior of CTF–TMZ

The releasing behavior of TMZ from CTF–TMZ was investigated in PBS (pH of 5.5 and 7.4) at 37°C. The drug-releasing behavior was monitored through the UV-Vis spectrophotometric analysis. As mentioned in the previously published reports, TMZ spontaneously undergoes degradation into an active metabolite (monomethyl triazeno imidazole carboxamide) and then AIC in aqueous solutions. Some reports have focused on the degradation mechanism and the detection of these compounds (42,43). Based on the published reports, the UV-Vis spectrophotometer was employed for the quantification of TMZ and AIC in our experiments. The drug quantification was determined according to the calibration curves of both TMZ and AIC (absorbance wavelengths of 328 and 266 nm, respectively; Figure A5) (43,44). The time-dependent TMZ releasing profiles of CTF–TMZ are shown in Figure 8. Under two different pH conditions, most of the loaded TMZ was released around 12 h and the cumulative releasing amount can reach up to 90% of the initial loading. The effect of pH on the releasing rate was not evident. However, the relatively high releasing rate under acidic conditions may result from the weakened hydrogen bonding interaction when compared with that in neutral conditions (15,16), which enhances the drug release. The good releasing performance should result from the permanent porous structure of the CTF and the physical adsorption between the CTF and TMZ. All these results imply that the current porous material can serve as a drug carrier for the delivery and release of TMZ.

Figure 8 
                  Time-dependent TMZ releasing profiles of CTF–TMZ at pH values of 5.5 and 7.4.
Figure 8

Time-dependent TMZ releasing profiles of CTF–TMZ at pH values of 5.5 and 7.4.

4 Conclusions

In summary, an amorphous triazine-based POP (TBrTh–BTBPE–CTF) containing both triazine and thiophene units was facilely synthesized by Suzuki cross-coupling reaction. On account of the permanent porosity and excellent stability, TBrTh–BTBPE–CTF was explored as a drug carrier with TMZ as a model drug. The TMZ-loaded polymer (CTF–TMZ) was confirmed by TGA and N2 sorption isotherms. The physical adsorption should be responsible for the effective TMZ loading into the polymeric framework (the loading amount of 13 wt%) based on both π–π stacking and hydrogen bonding interactions originating from the highly conjugated structure and nitrogen-rich triazine rings, respectively. Furthermore, CTF–TMZ exhibited sustained releasing behavior under neutral and acidic conditions. The good drug loading and releasing behaviors suggest the potential application of the current POP in drug loading and releasing.

  1. Funding information: The authors gratefully acknowledge financial support from the Fundamental Research Funds for the Central Universities (2018QNA17) and the Open Sharing Fund for the Large-scale Instruments and Equipments of China University of Mining and Technology (DYGX-2021-048).

  2. Author contributions: Di Hao: writing – original draft, methodology, formal analysis; Dong-Yue Wang: methodology, formal analysis; Bin Dong: writing – review and editing, project administration; Sun-Chang Xi: formal analysis; Guan Jiang: writing – review and editing, resources.

  3. Conflict of interest: The authors state no conflict of interest.

  4. Data availability statement: The raw data required to reproduce these findings are accessible upon request to the corresponding author.

Appendix

Figure A1 
                  (a) 1H NMR and (b) 13C NMR spectra of TBrTh in CDCl3. 1H NMR (δ, ppm): 8.03 (d, J = 4.0 Hz, 3H) and 7.23 (d, J = 4.0 Hz, 3H). 13C NMR (δ, ppm): 166.76, 142.17, 132.03, 131.67, and 120.79.
Figure A1

(a) 1H NMR and (b) 13C NMR spectra of TBrTh in CDCl3. 1H NMR (δ, ppm): 8.03 (d, J = 4.0 Hz, 3H) and 7.23 (d, J = 4.0 Hz, 3H). 13C NMR (δ, ppm): 166.76, 142.17, 132.03, 131.67, and 120.79.

Figure A2 
                  EDX elemental mapping images of (a) carbon, (b) nitrogen, and (c) S elements for TBrTh–BTBPE–CTF.
Figure A2

EDX elemental mapping images of (a) carbon, (b) nitrogen, and (c) S elements for TBrTh–BTBPE–CTF.

Figure A3 
                  BET linear plots of (a) TBrTh–BTBPE–CTF and (b) CTF–TMZ.
Figure A3

BET linear plots of (a) TBrTh–BTBPE–CTF and (b) CTF–TMZ.

Figure A4 
                  The TGA profile of TMZ (heating rate: 10°C · min−1). When compared with TMZ itself, the decomposition temperature of TMZ in CTF–TMZ was relatively higher because TMZ was loaded in the CTF’s structure.
Figure A4

The TGA profile of TMZ (heating rate: 10°C · min−1). When compared with TMZ itself, the decomposition temperature of TMZ in CTF–TMZ was relatively higher because TMZ was loaded in the CTF’s structure.

Figure A5 
                  The calibration curves of TMZ and its degradation product (AIC). The aqueous solutions of both TMZ and AIC were freshly prepared. At pH values of 5.5 and 7.4, respectively, the slope for TMZ was 11.162 and 9.958 (a and b), whereas the slope for AIC was 11.238 and 11.846 (c and d), respectively.
Figure A5

The calibration curves of TMZ and its degradation product (AIC). The aqueous solutions of both TMZ and AIC were freshly prepared. At pH values of 5.5 and 7.4, respectively, the slope for TMZ was 11.162 and 9.958 (a and b), whereas the slope for AIC was 11.238 and 11.846 (c and d), respectively.

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Received: 2022-03-10
Revised: 2022-07-06
Accepted: 2022-07-08
Published Online: 2022-08-10

© 2022 Di Hao et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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