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Article

A Star-Shaped Copolymer with Tetra-Hydroxy-Phenylporphyrin Core and Four PNIPAM-b-PMAGA Arms for Targeted Photodynamic Therapy

by
Changling Liu
1,†,
Yirong Wang
2,†,
Siyu Wang
2,
Pengcheng Xu
2,
Renning Liu
2,
Dandan Han
2,* and
Yen Wei
3,*
1
School of Materials Science and Engineering, Jilin Institute of Chemical Technology, Jilin City 132022, China
2
College of Biology and Food Engineering, Jilin Institute of Chemical Technology, Jilin City 132022, China
3
Department of Chemistry, The Tsinghua Center for Frontier Polymer Research, Tsinghua University, Beijing 100084, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Polymers 2023, 15(3), 509; https://doi.org/10.3390/polym15030509
Submission received: 25 November 2022 / Revised: 13 January 2023 / Accepted: 16 January 2023 / Published: 18 January 2023
(This article belongs to the Special Issue Self-Assembly of Polymers: Towards Multiscale Functional Materials for Bioapplications)
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Versions Notes

Abstract

:
The novel thermosensitive star-shaped tetra-hydroxy-phenylporphyrin-cored (THPP) double hydrophilic poly(N-isopropylacrylamide)-b-poly(methylacrylamide glucose) block copolymers (THPP-(PNIPAM-b-PMAGA)4) were synthesized via the reversible addition-fragmentation chain transfer (RAFT) polymerization. Notably, the low critical solution temperatures (LCSTs) of THPP-(PNIPAM-b-PMAGA)4 were above normal body temperature (37 °C) which depended on the hydrophilic PMAGA contents of copolymers. When the temperature was higher than the LCST of the copolymer, the copolymer could be neutralized into micelles in aqueous and could be coated with antitumor drugs and released around tumor cells. The MTT study indicated that THPP-(PNIPAM-b-PMAGA)4 had a low toxicity to L929 and HeLa cells in the absence of light. However, THPP-(PNIPAM-b-PMAGA)4 showed a high toxicity with HeLa cells under light irradiation which could be used as a potential photosensitizer for photodynamic therapy (PDT). In addition, THPP-(PNIPAM-b-PMAGA)4 showed specific a recognition function with Concanavalin A (Con A) to achieve active targeted drug delivery. This work provides a new approach for the development of tumor targeting and chemotherapy/PDT.

1. Introduction

Porphyrins and their derivatives have attracted extensive attention in the field of designing and synthesizing novel functional materials. However, most of porphyrin’s derivatives were hydrophobic, non-selective, and self-quenching [1,2,3,4,5,6,7,8,9,10,11,12,13,14]. Up to the present, water-soluble porphyrins without charge were not easy to obtain, and almost all had ionic structure [15]. In recent years, many studies have addressed the above shortcomings by modifying porphyrins in liposomes, nanoparticles, and polymers [16,17,18,19,20,21,22,23,24]. Frechet et al. synthesized a functional porphyrin-cored polymeric shell using Ring Opening Polymerization (ROP) of 3-caprolactone (CL) or L-lactic (L-LA) [25]. Holder and Cornelissen et al. reported a series of star polymers with porphyrin cores by Atom Transfer Radical Polymerization (ATRP). Among these, the modified porphyrins by hydrophilic polymers could effectively improve the solubility of porphyrin [26,27,28]. The hydrophilic compounds could be coupled with porphyrin to a PDT-like hyaluronic acid, chondroitin sulfate, pluronic F127, and polyethylenimine [29,30]. Nicosia et al. combined the bactericidal and photothermal properties of AgNPs with the characteristics of PEGylated porphyrins [31]. Among porphyrin polymers, Poly (N-isopropylacrylamide) (PNIPAM) based on polymer-porphyrin has attracted a great deal of attention due to the temperature responsiveness of PNIPAM. Xu et al. [32] prepared amphiphilic PNIPAM-b-PTPPC6MA block copolymers containing porphyrin. Our group has also successfully synthesized a series of porphyrin-based PNIPAM for photodynamic therapy [33,34]. These porphyrin-modified thermosensitive polymers can self-assemble into micelles which could be used as PDT agents and drug carriers [35,36,37]. However, none of them had the ability to recognize the active targeting of malignant tissue. Glycosylation can offer the possibility of specific interactions with lectin-type receptors that are overexpressed in specific malignant tissues. D-glucosamine (GA) has good hydrophilicity, biocompatibility, and biodegradation and also has an excellent cell penetrating ability, immunomodulatory properties, and a strong tumor cell killing ability [38]. Until now, Dong et al. synthesized a serial of hydrophilic chains composed of some glycopolymers which provided a specific sugar-protein recognition processes [39]. Dai et al. prepared a biomimetic poly (3-caprolactone)-bglycopolymer block copolymers with porphyrin, but also provided a very specific recognition with Concanavalin A (Con A) [40].
We have previously synthesized several polymers with PNIPAM and porphyrin that self-assemble into micelles in organic solvents. Here, our research group designed and synthesized star-shaped double hydrophilic THPP-(PNIPAM-b-PMAGA)4 containing a free tetra-hydroxy-phenylporphyrin core and four poly (N-isopropylacrylamide)-b- poly (methacrylamide Glucose) (PNIPAM-b-PMAGA) arms via RAFT polymerization. Moreover, the reaction process is shown Scheme 1. This compound did not require an organic solvent and can form micelles directly in water.
When the temperature was higher than LCST, the PNIPAM segment of THPP-(PNIPAM-b-PMAGA)4 changed from hydrophilic to hydrophobic, while the PMAGA segment remained hydrophilic and soluble, resulting in the formation of micelles in the aqueous solution of THPP-(PNIPAM-b-PMAGA)4. By adjusting the LCST of the copolymer, the hydrophilic PNIPAM chain segment became hydrophobic and released drugs in the tumor tissue. Consequently, it provided not only a specific sugar recognition and temperature-targeting block copolymer, but also a potential porphyrin-cored star-shaped PNIPAM-b-PMAGA copolymers for combination chemotherapy/PDT strategies.

2. Materials and Methods

2.1. Materials

N-isopropylacrylamide (NIPAM) was purchased from Aldrich (Sigma-Aldrich Trading Co, Ltd, Shanghai, China) and recrystallized to remove the polymer inhibitor. The monomer methacrylamide glucose was synthesized according to the literature [41]. S-1-Dodecyl-S′-(α, α′-dimethyl-α″-acetic acid) trithiocarbonate (DMP) as chain transfer agent of RAFT was synthesized according to the literature [42,43]. All other chemicals were purchased from Aldrich with analytical grade and used directly.

2.2. Characterization

The structures of the products were characterized by Fourier Transform infrared (FT-IR) spectra recorded on Shimadzu-8400S (Shimadzu Corporation, Tokyo, Japan)infrared spectrometer, nuclear magnetism resonance spectroscopy (NMR) which recorded on Bruker Avance 400 MHz spectrometer(Bruker, Schlieren, Switzerland), and gel permeation chromatography (GPC) which was measured by Waters e2695(Waters, Milford, MA, USA). The thermal response of the copolymer was measured by shimadu-1240 UV–visible spectrophotometer with an external temperature controller. The dynamic light scattering (DLS) of 2 mg·mL−1 THPP-(PNIPAM-b-PMAGA)4 was measured on a Malvern Nano S particle analyzer (Malvern Panalytical Ltd, Malvern, UK) in the temperature range of 25 °C to 45 °C. The CMC of polymer was determined by fluorescence spectrophotometer [44].

2.3. The Synthesis of THPP-(PNIPAM-b-PMAGA)4 Copolymers

THPP-(PNIPAM-b-PMAGA)4 containing porphyrin core, PNIPAM, and PMAGA were synthesized by RAFT. The tetra-hydroxy-phenylporphyrin was synthesized according to the literature [45]. Firstly, THPP-(DMP)4 was synthesized by esterification of THPP core with chain transfer agent catalyzed by DCC and DMAP. Subsequently, the THPP-(PNIPAM)4 was synthesized by RAFT polymerization.
In short, a certain amount of THPP-(DMP)4 was added into DMF (2 mL) solution of 226 mg NIPAM and stirred to deoxygenate. Then, 3.3 mg AIBN was added into oil bath at 70 °C for 24 h. The product was concentrated and precipitated in ice ether and dried under vacuum. Mn,GPC = 10,500, Mw/Mn = 1.15. FTIR: 1640 (νC = O), 1540 (δC-N-H) [Figure 1]. 1HNMR (400 MHz, CDCl3), δ ppm: 8.8–8.2 (porphyrin-H), 6.26 (t,-NH), 4.0 (m,-NCH) [Figure 2c].
D- (+) -glucosamine hydrochloride (5.00 g, 28 mmol) and potassium carbonate (4.2 g, 30 mmol) were added to 125 mL of methanol and cooled to −15 °C. The methylacrylyl chloride (3.12 g, 30 mmol) drop by drop to the reactor and the reaction was performed at −15 °C for 30 min. The reaction was continued at 25 °C for 3 h. After the reaction, the filtrate was filtered and spun to the suspension. The suspension was purified by silica gel column chromatography (the VCH2Cl2:VCH3OH = 4:1) and the white solid was obtained. FT-IR (KBr, cm−1): 1664 cm−1(ν-CONH), 1542 cm−1(ν-N-H), 2937 cm−1, 2862 cm−1 (ν-C-H) [Figure 1]. 1H NMR (400 MHz, D2O) δ 5.6 (s, 1H, -NH), 5.4 (s, 2H, =CH2), 3.2 (s, 4H, -OH), 3.88–3.43 (s, 5H, -CH-OH), 1.76 (s, 3H, -CH3) [Figure 2a].
THPP-(PNIPAM-b-PMAGA)4 were prepared via RAFT using THPP-(PNIPAM)4 as chain transfer agent. THPP-(PNIPAM)4 of 1.05 g, MAGA of 0.49 g, and AIBN of 3.3 mg were dissolved in 5 mL of DMF and the reaction was performed at 65 °C for 12 h after stirring and deoxygenation. Polymer products were dialysed in water using dialysis bags (MWCO, 12,000) at 6-h intervals for two days and freeze-dried for storage. Mn,GPC = 30,200, Mw/Mn = 1.3. FT-IR (KBr, cm−1): 1643 cm−1(ν-CONH), 1525 cm−1(ν-N-H), 3392 cm−1(ν-O-H) [Figure 1]. 1H NMR (400 MHz, D2O): δ 7.3 (s, -NH-C (CH3)2), 8.35 (s, -NH-MAGA), 4.0 (m, -NCH), 3.4 (s, -SCH2), 3.0–5.0 ppm (m, MAGA-CH), 1.03 (m, -CH2CH3) [Figure 2c].

2.4. The Preparation of THPP-(PNIPAM-b-PMAGA)4 Micelles

Using pyrene as a fluorescent probe, a certain amount of pyrene was added into acetone solvent, and 0.1 mL pyrene-acetone solution was added into 10 mL volumetric bottles respectively [46]. The acetone solvent was volatilized at room temperature. Then 10 mL of polymer aqueous solution with different concentrations were added to above volumetric bottles, and the final concentration of pyrene reached 2 × 10−6 mol/L. The emission spectrum of the copolymer in the range of 340~600 nm was measured at an excitation wavelength of 335 nm. The CMC was taken as the cross-point when extrapolating the intensity ratio I383/I372 at low-and high-concentration regions.

2.5. Singlet Oxygen Generation

In this study, the 1O2 quantum yield was determined by mixing 1,3-diphenylisobenzofuran (DPBF) with THPP-(PNIPAM-b-PMAGA)4, the DPBF decay at 410 nm was measured by UV–visible spectrophotometer and monitored every 1 min.
The ΦΔ was calculated according to Equation (1):
Φ Δ = Φ Δ S t d R I a b s S t d R S t d I a b s
Among them, Φ Δ S t d is 0.62 of the 1O2 quantum yield for TPP. The DPBF photobleaching rates of copolymers and TPP are R and RStd, respectively, while I a b s and I a b s S t d are their photoabsorption rates.

2.6. Cell Biology Experiment of THPP-(PNIPAM-b-PMAGA)4 Micelles

The toxicity of THPP-(PNIPAM-b-PMAGA)4 micelles to different cells was determined by methylthiazoltetrazole (MTT) method without light irradiation. Fetal bovine serum (FBS, 10% (v)), penicillin (100 units mL−1), and streptomycin (100 μg·mL−1) were added to all cells by adding amino acid and glucose medium to the 96-well flat plate.
At 37 °C, the cells were incubated for 48 h, washed with PBS 3 times, incubated for 6 h, added 20 μL MTT solution containing micelle solution of different concentrations for 4 h, and then returned to the incubator. Carefully, the MTT solution was taken out, 200 μL DMSO was added and gently stirred for 10 min and the formazan product was extracted. Absorbance at 492 nm was read with an enzyme-linked immunosorbent assay (ELISA) microplate reader (Bio-Rad). According to Formula (2), cell viability (%) can be calculated.
Cell viability (%) = (Asample/Acontrol) × 100%
At the same time, the phototoxicity of THPP-(PNIPAM-b-PMAGA)4 micelles on cells were measured by red light irradiation at 670 nm for 5 min according to the above method.
HeLa cells were cultured in 96-well plates containing 2 mL medium for 24 h with a cell density of 1 × 106 cells per well. The cells were then treated with samples for a certain period of time and washed with phosphate buffered saline (PBS). Finally, the expected precipitation was analyzed by BD FACS Calibur flow cytometry. The data were analyzed by FlowJo software.

2.7. Lectin Recognition

The Con A lectin recognition behavior of the sugar-containing copolymer solution was determined by UV–VIS method at 360 nm. In addition, the concentration of Con A was set as 0.5 mg·mL−1, and different concentrations of aggregate solution were added to the Con A solution.

3. Results and Discussion

3.1. Analysis of Copolymers Architecture

The architecture of the THPP-(PNIPAM-b-PMAGA)4 was authenticated by FTIR spectra and 1HNMR. Figure S1 shows O-H absorbance and N-H tensile vibration in THPP at 3430 cm−1 and 3350 cm−1, respectively. From Figure 2a, the chemical shift of 9.96, 8.65, and −2.86 ppm were the characteristic signals of THPP’s hydroxyl group, benzene ring, and amino group (Figure S1 and Figure 2a). The absorbance at 1760 cm−1 was ascribed to the ester group of THPP-(DMP)4 (Figure S2). In Figure S3, 1HNMR spectra of THPP-(DMP)4 showed that (δ~3.4) and (δ~0.98) were assigned to the proton of -CH2S and -CH3. The FTIR and 1HNMR spectra of Methylacrylamide glucose (MAGA) are shown in Figure 1 and Figure 2a. The peak at 2937 cm−1 was the methyl antisymmetric stretching vibration peak, 2920 cm−1 and 2955 cm−1 were the methylene C-H stretching vibration peak, the peaks at 1664 cm−1 and 1542 cm−1 were vested in the stretching vibration peak of the carbon oxygen double bond on MAGA, which were the characteristic absorption peaks of amide I band and the characteristic absorption peaks of N-H bending vibration coupling with C-N stretching vibration in CONH, namely the amide II band (Figure 1). In Figure 2b, two peaks at about 1.6 ppm, 5.5 ppm, and 5.7 ppm were attributed to protons of the methyl group attached to the double bond, and the MAGA double bond and N-H, respectively. The target product MAGA was successfully characterized by FTIR and 1HNMR.
The FTIR spectrum of THPP-(PNIPAM-b-PMAGA)4 was shown in Figure 1. The absorption peaks of the amide I and II bands in PNIPAM were at 1643 cm−1 and 1552 cm−1, respectively. After copolymerization with MAGA, the presence of a large number of hydroxyl groups in the glucose molecule resulted in a broad and strong hydroxyl absorption peak near 3320 cm−1. From the 1HNMR of Figure 2c, the acylamino groups and methenyl adjacent to acylamino of PNIPAM were located at 6.0–7.0 ppm and 4.0 ppm. In Figure 2d, the new signal at 3.0–5.0 ppm was corresponding to protons in PMGA. Figure S4 shows the GPC curve of the polymer. The polymerization data of THPP-(PNIPAM)4 and THPP-(PNIPAM-b-PMAGA)4 is shown in Table 1. All the above test results confirmed that THPP-(PNIPAM-b-PMAGA)4 copolymers were synthesized successfully [47,48].

3.2. Photophysical Properties of THPP-(PNIPAM-b-PMAGA)4

Figure 3a showed the ultraviolet absorption spectra of THPP and THPP-(PNIPAM-b-PMAGA)4 in methanol solution. THPP-(PNIPAM-b-PMAGA)4 and THPP both had B-band absorption peaks at about 420 nm and four weak Q-band absorption peaks at 500–700 nm. However, THPP-(PNIPAM-b-PMAGA)4 had a red shift which was caused by the narrowing of the band gap due to the long polymer chain and the easy excitation of electrons.
Fluorescence emission spectra of THPP and THPP-(PNIPAM-b-PMAGA)4 were illustrated in Figure 3b. At the excitation wavelength of 380 nm, the maximum emission peak was around 650 nm, but the charge-transfer effect of THPP-(PNIPAM-b-PMAGA)4 was reduced due to the presence of long polymer chains, and therefore, the emission band was enhanced and potentially split [49,50].

3.3. Thermosensitive Behavior of THPP-(PNIPAM-b-PMAGA)4

Figure 4a shows the LCST curve of THPP-(PNIPAM-b-PMAGA)4 copolymers in aqueous solution. The LCST of copolymer THPP-(PNIPAM-b-PMAGA)4 with the introduction of hydrophilic MAGA segment was higher than that of THPP-PNIPAM4 [51,52] (Table 2). The LCST increased with the increase in hydrophilic MAGA segments. Figure 3c,d shows the dynamic radius and distribution of THPP-(PNIPAM-b-PMAGA)4 micelles at 35 °C and 45 °C.
It was shown that the particle size of a THPP-(PNIPAM-b-PMAGA)4 micelle was 43.6 nm when the temperature was 35 °C, but the particle size increased to 181.6 nm when the temperature was increased to 45 °C in Figure 4. The results revealed that when the temperature was higher than the LCST of the copolymer, the PNIPAM segment changed from hydrophilic to hydrophobic and the completed collapse of hydrogen bonds led to an increase in the particle size of the formed micelles.

3.4. CMC of THPP-(PNIPAM-b-PMAGA)4

The CMC of THPP-(PNIPAM-b-PMAGA)4 are shown in Figure 4b. With the increasing of THPP-(PNIPAM-b-PMAGA)4 concentration, the ratio of I383/I372 remained unchanged, but it increased sharply when the copolymer concentration gradually increased to a certain value. It indicated that hydrophobic pyrene accumulates to the micelle core, which was a sign of micelle formation. The CMC value of THPP-(PNIPAM-b-PMAGA)4 copolymer increased from 0.0005 mg·mL−1 to 0.0025 mg·mL−1 with the increasing of the hydrophilic PMAGA segment. It was confirmed that the polymer micelle might be formed with the increase in the length of hydrophobic block.

3.5. Singlet Oxygen Quantum Yields of THPP-(PNIPAM-b-PMAGA)4

The absorbance intensity of DPBF and the THPP-(PNIPAM-b-PMAGA)4 mixture in DMF determined by a UV–UV spectrophotometer is shown in Figure 5. The ΦΔ of THPP-(PNIPAM-b-PMAGA)4 was estimated from Equation (1). The ΦΔ of THPP-(PNIPAM-b-PMAGA)4 with different molecular weights in DMF were 0.41 and 0.37, respectively. In conclusion, THPP-(PNIPAM-b-PMAGA)4 might be a promising reagent for PDT.

3.6. Dark Cytotoxicity and Phototoxicity of THPP-(PNIPAM-b-PMAGA)4

Figure 6a shows the dark-cytotoxicity of THPP, THPP-(PNIPAM-b-PMAGA)4 to normal cell L929 and human cervical cancer cell HeLa measured by the MTT method at different concentrations (from 0 to 0.25 mg·mL−1). The results confirmed that even if the concentration of the compound reached 0.25 mg·mL−1 under non-illuminated conditions, L929 cells and HeLa cells still had a high survival rate and the results indicated that these two compounds had no obvious dark toxicity.
PDT was evaluated by investigating the cytotoxicity of porphyrin derivate at varying concentrations (0 to 0.25 mg·mL−1) against L929 cells and HeLa cells under red light irradiation (Figure 6b). The results revealed that THPP and THPP-(PNIPAM-b-PMAGA)4 have very low phototoxicity to L929 cells. However, for the phototoxicity of HeLa cells, the THPP-(PNIPAM-b-PMAGA)4 was higher than THPP which may be due to π–π stacking and the poor water solubility of THPP. All the decreasing effects of PDT were in aqueous solution to trigger quenching. Figure 6c shows that the toxicity of paclitaxel-coated THPP-(PNIPAM-b-PMAGA)4 micelles to HeLa cells under light was higher than that of uncoated micelles, which might be due to the death of HeLa cells caused by the release of paclitaxel.

3.7. Cellular Uptake of THPP-(PNIPAM-b-PMAGA)4 Micelles

The cellular uptake behavior of THPP-(PNIPAM-b-PMAGA)4 could be detected by flow cytometry. The cellular internalization of THPP-(PNIPAM-b-PMAGA)4 micelles in HeLa cells for 4 h and 12 h was shown in Figure 6d. The fluorescence intensity of HeLa cells with THPP-(PNIPAM-b-PMAGA)4 micelles produced a greater shift compared with untreated cell, this indicated mostly THPP-(PNIPAM-b-PMAGA)4 micelles had been internalized. The results showed that the fluorescence intensity after 12 h treatment was significantly stronger than that after 4 h treatment. This indicated that HeLa cells had an obvious time-dependent engulfment of THPP-(PNIPAM-b-PMAGA)4 micelles and could be better engulfed by tumor cells.

3.8. Recognition Properties of Star-Shaped THPP-(PNIPAM-b-PMAGA)4 Copolymers

The mutual sugar-protein recognition and specific binding in the living body was of great significance for drug discovery and biomaterial application. Con A could specifically recognize that D-glucopyranoside contains free 3-, 4-, and 6-hydroxyl groups which usually combine with sugar copolymers form Con A cross-linked aggregation. Therefore, the interaction between Con A and THPP-(PNIPAM-b-PMAGA)4 was studied in an aqueous solution at room temperature. It was found that the turbidity of THPP-(PNIPAM-b-PMAGA)4 samples increased slightly with the increase in copolymer concentration and there was no precipitation in the solution. It indicated that THPP-(PNIPAM-b-PMAGA)4 copolymer may combine with Con A to form aggregates. There were no significant changes of Con A aggregation in aqueous which was measured by UV–vis solution turbidity (Figure 7). The specific binding of THPP-(PNIPAM-b-PMAGA)4 copolymer to ConA in aqueous solution indicated that the sugar copolymer with the core of porphyrin could be used for targeted drug delivery.

3.9. Exploration of Paclitaxel Release In Vitro

The sustained-release behavior of THPP-(PNIPAM-b-PMAGA)4 micelles was evaluated using paclitaxel as the model drug. The encapsulation rate (EE) of the copolymer was about 42.7% by HPLC.The results indicated that the copolymer with a star structure was suitable for drug encapsulation. The two-phase release curves in free paclitaxel and paclitaxel-loaded nanoparticles buffer solutions were observed (Figure 8). It could be found that micelles release of paclitaxel was significantly slower than the free paclitaxel release, followed by a sustained and slower release over a prolonged period of time (72 h, 85.9%). Therefore, the continuous release of paclitaxel-coated nano-micelles could improve its bioavailability and induce cancer cell death to achieve better therapeutic effect.

4. Conclusions

The star-shaped double hydrophilic THPP-(PNIPAM-b-PMAGA)4 with thermo-sensitivity was synthesized by RAFT using porphyrin-cored as a chain transfer agent. The LCST of THPP-(PNIPAM-b-PMAGA)4 increased with the increasing of the hydrophilic chain segment PMAGA and which could self-assemble into micelles in an aqueous above 37 °C. In vitro experiments of THPP-(PNIPAM-b-PMAGA)4 showed good biocompatibility and high phototoxicity to HeLa which might be a potential application prospect. In addition, these THPP-(PNIPAM-b-PMAGA)4 copolymers had a stable Con A aggregation in aqueous solution, so it had a specific ability to recognize Con A. In addition, these block copolymers could be used as nanoscale photosensitizers to further encapsulate hydrophobic paclitaxel.

Supplementary Materials

The following supporting information could be downloaded at: https://www.mdpi.com/article/10.3390/polym15030509/s1, Figure S1: FTIR spectra of THPP; Figure S2: FTIR spectrum of THPP-(DMP)4; Figure S3: 1HNMR spectrum of THPP-(DMP)4; Figure S4: GPC traces of THPP-(PNIPAM)4 and THPP-(PNIPAM-b-PMAGA)4.

Author Contributions

C.L. performed the experiments, analyzed the data, and wrote the original draft. Y.W. (Yirong Wang) and D.H. reviewed and edited the paper. Y.W. (Yen Wei) and S.W. checked and revised the paper. P.X. and R.L. were responsible for project administration. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (21788102), Science & Technology Nova Program of Jilin Province (20200301051RQ), Natural Science Foundation of Jilin Province (20170101211JC), Youth Foundation of Jilin Science and Technology (20190104194), and the Science Foundation of Jilin Institute of chemical Technology (2018019). The authors acknowledge the assistance of JLICT Center of Analysis Characterization and Analysis.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in [insert article or supplementary material here].

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

NIPAMN-isopropylacrylamide;
DMPS-1-Dodecyl-S′-(α, α′-dimethyl-α″-acetic acid) trithiocarbonate;
RAFTreversible addition-fragmentation chain transfer;
FT-IRFourier Transform infrared;
NMRnuclear magnetism resonance spectroscopy;
GPCgel permeation chromatography;
DLSdynamic light scattering.

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Polymers 15 00509 sch001 550
Scheme 1. Schematic diagram of PDT mechanism and synthesis of THPP-(PNIPAM-b-PMAGA)4-1(Mn = 18,700)/paclitaxel.
Scheme 1. Schematic diagram of PDT mechanism and synthesis of THPP-(PNIPAM-b-PMAGA)4-1(Mn = 18,700)/paclitaxel.
Polymers 15 00509 sch001
Polymers 15 00509 g001 550
Figure 1. FTIR spectra of MAGA, THPP-(PNIPAM)4 and THPP-(PNIPAM-b-P MA GA)4.
Figure 1. FTIR spectra of MAGA, THPP-(PNIPAM)4 and THPP-(PNIPAM-b-P MA GA)4.
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Polymers 15 00509 g002 550
Figure 2. (a) 1HNMR spectrum of THPP in DMSO; (b) 1HNMR spectra of MAGA in D2O; (c) 1HNMR spectra of THPP-(PNIPAM)4 in CDCl3; (d) 1HNMR spectra of THPP-(PNIPAM-b-PMAGA)4 in CDCl3.
Figure 2. (a) 1HNMR spectrum of THPP in DMSO; (b) 1HNMR spectra of MAGA in D2O; (c) 1HNMR spectra of THPP-(PNIPAM)4 in CDCl3; (d) 1HNMR spectra of THPP-(PNIPAM-b-PMAGA)4 in CDCl3.
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Polymers 15 00509 g003 550
Figure 3. (a) UV–Vis spectra of free THPP and THPP-(PNIPAM-b-PMAGA)4 in CH3OH solution; (b) emission spectra of free THPP and THPP-(PNIPAM-b-PMAGA)4 in CH3OH solution (0.125 mg mL−1).
Figure 3. (a) UV–Vis spectra of free THPP and THPP-(PNIPAM-b-PMAGA)4 in CH3OH solution; (b) emission spectra of free THPP and THPP-(PNIPAM-b-PMAGA)4 in CH3OH solution (0.125 mg mL−1).
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Polymers 15 00509 g004 550
Figure 4. (a,b) Temperature dependence of optical transmittance at wavelength of 500 nm obtained for aqueous solutions and Plot of the I383/I372 ratio against log C of THPP-PNIPAM4 and THPP-(PNIPAM-b-PMAGA)4−1; (c) Average size of THPP-(PNIPAM-b-PMAGA)4 micelles at 35 °C; (d) Average size of THPP-(PNIPAM-b-PMAGA)4 micelles 45 °C (the concentration of copolymer was 1 mg·mL−1).
Figure 4. (a,b) Temperature dependence of optical transmittance at wavelength of 500 nm obtained for aqueous solutions and Plot of the I383/I372 ratio against log C of THPP-PNIPAM4 and THPP-(PNIPAM-b-PMAGA)4−1; (c) Average size of THPP-(PNIPAM-b-PMAGA)4 micelles at 35 °C; (d) Average size of THPP-(PNIPAM-b-PMAGA)4 micelles 45 °C (the concentration of copolymer was 1 mg·mL−1).
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Polymers 15 00509 g005 550
Figure 5. UV–vis spectra for the determination of singlet oxygen generation quantum yield of THPP-(PNIPAM-b-PMAGA)4 in DMF use DPBF as quencher (λ = 410 nm).
Figure 5. UV–vis spectra for the determination of singlet oxygen generation quantum yield of THPP-(PNIPAM-b-PMAGA)4 in DMF use DPBF as quencher (λ = 410 nm).
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Polymers 15 00509 g006 550
Figure 6. Viability of L929 cells and HeLa cells determined by the MTT assay after treatment of THPP and THPP-(PNIPAM-b-PMAGA)4 micelles: (a) dark toxicity; (b) phototoxicity; (c) Viability of HeLa cells determined by the MTT assay after treatment of THPP-(PNIPAM-b-PMAGA)4 and THPP-(PNIPAM-b-PMAGA)4/paclitaxel micelles; (d) Flow cytometric demonstration of HeLa cells after incubation with control (dark green line), THPP for 4 h (brown line), THPP-(PNIPAM-b-PMAGA)4 for 12 h (green line).
Figure 6. Viability of L929 cells and HeLa cells determined by the MTT assay after treatment of THPP and THPP-(PNIPAM-b-PMAGA)4 micelles: (a) dark toxicity; (b) phototoxicity; (c) Viability of HeLa cells determined by the MTT assay after treatment of THPP-(PNIPAM-b-PMAGA)4 and THPP-(PNIPAM-b-PMAGA)4/paclitaxel micelles; (d) Flow cytometric demonstration of HeLa cells after incubation with control (dark green line), THPP for 4 h (brown line), THPP-(PNIPAM-b-PMAGA)4 for 12 h (green line).
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Polymers 15 00509 g007 550
Figure 7. The interactions of Con A (0.5 mg·mL−1) with THPP-(PNIPAM-b-PMAGA)4 at different concentration.
Figure 7. The interactions of Con A (0.5 mg·mL−1) with THPP-(PNIPAM-b-PMAGA)4 at different concentration.
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Polymers 15 00509 g008 550
Figure 8. Cumulative release curve of the free paclitaxel and the THPP-(PNIPAM-b-PMAGA)4/paclitaxel in PBS.
Figure 8. Cumulative release curve of the free paclitaxel and the THPP-(PNIPAM-b-PMAGA)4/paclitaxel in PBS.
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Table
Table 1. Polymerization data of THPP-(PNIPAM)4 and THPP-(PNIPAM-b-PMA GA)4.
Table 1. Polymerization data of THPP-(PNIPAM)4 and THPP-(PNIPAM-b-PMA GA)4.
Polymer[M]0/[CTA]0Time (h)Mn,GPC aMw/Mn a
THPP-(PNIPAM)4501210,5001.15
THPP-(PNIPAM-b-PMAGA)4-1201218,7001.19
THPP-(PNIPAM-b-PMAGA)4-2301222,6001.21
a Determined by GPC using THF as eluent relative to polystyrene standards. [M]0/[CTA]0: the molar ratio of monomer to chain transfer agent. Mn,GPC a: numerical average molecular weight. Mw/Mn a: molecular weight distribution index.
Table
Table 2. Characterization of THPP-(PNIPAM-b-PMAGA)4.
Table 2. Characterization of THPP-(PNIPAM-b-PMAGA)4.
PolymerLCSTDh aCMC b (mg/mL)ΦΔ
THPP-PNIPAM431.5——————
THPP-(PNIPAM-b-PMAGA)4-139.9156.20.00050.41
THPP-(PNIPAM-b-PMAGA)4-241.9181.60.00250.37
a Determined by DLS. b CMC was determined by a fluorescence spectroscopic method using pyrene as the fluorescent probe.
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MDPI and ACS Style

Liu, C.; Wang, Y.; Wang, S.; Xu, P.; Liu, R.; Han, D.; Wei, Y. A Star-Shaped Copolymer with Tetra-Hydroxy-Phenylporphyrin Core and Four PNIPAM-b-PMAGA Arms for Targeted Photodynamic Therapy. Polymers 2023, 15, 509. https://doi.org/10.3390/polym15030509

AMA Style

Liu C, Wang Y, Wang S, Xu P, Liu R, Han D, Wei Y. A Star-Shaped Copolymer with Tetra-Hydroxy-Phenylporphyrin Core and Four PNIPAM-b-PMAGA Arms for Targeted Photodynamic Therapy. Polymers. 2023; 15(3):509. https://doi.org/10.3390/polym15030509

Chicago/Turabian Style

Liu, Changling, Yirong Wang, Siyu Wang, Pengcheng Xu, Renning Liu, Dandan Han, and Yen Wei. 2023. "A Star-Shaped Copolymer with Tetra-Hydroxy-Phenylporphyrin Core and Four PNIPAM-b-PMAGA Arms for Targeted Photodynamic Therapy" Polymers 15, no. 3: 509. https://doi.org/10.3390/polym15030509

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