DOI:
10.1039/C4RA01412J
(Paper)
RSC Adv., 2014,
4, 19495-19501
BODIPY-based macromolecular photosensitizer with selective recognition and enhanced anticancer efficiency†
Received
18th February 2014
, Accepted 15th April 2014
First published on 15th April 2014
Abstract
Photodynamic therapy (PDT) is attracting ongoing attention for treatment of cancer as a noninvasive technique. A BODIPY-based macromolecular photosensitizer, p(GEMA-co-BODIPYMA)-2I, with high water solubility, specificity recognition to cancer cells and no dark cytotoxicity was prepared, which achieved enhanced therapeutic efficacy and reduced side-effects. P(GEMA-co-BODIPYMA)-2I generated 1O2 (ΦΔ = 0.79) rapidly in aqueous system and confocal laser scanning microscopy (CLSM) images showed that p(GEMA-co-BODIPYMA)-2I was avidly taken up specifically by cancer cells, however, couldn't be uptaken by normal cells. The novel photosensitizer displayed high photocytotoxicity for cancer cells, but not normal cells. The cell viability of normal cells was over 80% when the concentration was 20 nmol mL−1 under illumination for 10 min and that for cancer cells was 0.4% under the same conditions. Our facile strategy provides a novel avenue for the effective development of photosensitizers for cancer therapy.
Introduction
Cancer is one of the leading causes of death worldwide with limited available therapeutic options. Efficient anticancer treatment methods are critical to achieve a number of beneficial goals ranging from improving health care to the quality of day-to-day life of cancer patients. Current effective strategies to combat this disease include surgical ablation of tumor, radiation therapy, chemotherapy, hyperthermia, gene therapy, photodynamic therapy (PDT), and so on.1–8 PDT, an emerging clinical modality for cancer treatment through the production of cytotoxic reactive oxygen species (ROS), particularly singlet oxygen (1O2), is a noninvasive technique, does not induce resistance, and has inherent dual selectivity that focuses light to confine damage to the targeted region, thus reducing side-effects.9,10 However, owing to the hydrophobic nature and non-specificity of the majority of known photosensitizers, considerable attention has been focused on the development of an optimal photosensitizer formulation with stable aqueous dispersion and site specificity.11 The poorly water-soluble compounds aggregate in aqueous solution easily, resulting in self-quenching of excited-state molecules and reduction in subsequent in 1O2 production. This affects bioavailability unfavorably, limits pharmacologic studies, and leads to poorer therapeutic outcome. Moreover, lack of specificity results in unavoidable damage to normal cells.
To overcome these problems, biocompatible delivery vehicles have been used to improve stabilization and specificity of photosensitizers in aqueous solutions.12–18 However, these fabrication processes usually require sophisticated assembly techniques as well as the assistance of organic solvents, which often result in tedious purification procedures.19 The majority of these drug delivery vehicles face strong limitations, such as poor drug loading and burst release, which may hamper further usage in the clinic and eventual release to the market.20 Some works have involved the use of antibodies or antibody fragments to enhance targeting of photosensitiser. However, it has also been shown that immunoconjugates are distributed and retained in vital organs to unacceptable levels, that is a major obstruction to clinical acceptance.21–23 Since release of the photosensitizer is not a prerequisite for therapeutic action,24 an alternative strategy may be used to prepare a water-soluble macromolecular photosensitizer with higher specificity to enhance the outcome of PDT. In addition, therapeutic agents do not require an extra step for encapsulation, and “encapsulation efficiency” could be simply adjusted by controlling copolymerization.
Based on these considerations, we prepared a novel macromolecular photosensitizer, with the aim of enhancing water solubility and targeting to cancer cells. As expected, selective killing of cancer cells was observed with the novel photosensitizer, while normal cell viability remained essentially unaffected. The novelty of this work lies in the fact that the newly established anticancer macromolecular photosensitizer possesses the ability of selective recognition, leading to killing of cancer cells over normal cells. More importantly, the optimized features are integrated into a single glycopolymer, distinct from the currently designed multifunctional anticancer systems composed of complicated systematic compositions. A BODIPY structure-based molecular was selected as the model photosensitizer molecule and galactose as ligand. BODIPY-based structures have potential as ideal PDT agents, owing to anti-self-oxidation and high light-to-dark toxicity ratios, compared with cyclic tetrapyrroles and phenothiazinium-based structures.25–31 Asialoglycoprotein (ASGP) receptors are present on the surface of mammalian liver parenchymal cells, which can be specifically identified by galactose.32,33 Accordingly, galactose promotes their interactions with the cancer cell surface, and facilitates specific recognition between the photosensitizer and cancer cells. Our findings provide a novel avenue in the application of PDT for cancer therapy.
Experimental
Materials and instruments
Dichloromethane and chlorobenzene were distilled through calcium hydride before used. 2-O-Methacryloyloxyethyl-2,3,4,6-tetra-O-acetyl-β-D-galactopyranoside (AcGEMA) and boron dipyrromethene monomer (BODIPYMA) were synthesized according to the literature.34 BODIPYMA-2I was synthesized according to the literature28 and the description was in the ESI.† 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenylterazolium bromide (MTT) and 4′,6-diamidino-2-phenylindole (DAPI) were purchased from the J&K China Chemical Ltd. (Beijing, China). Other solvents used were of analytical grade without further purification. The semipermeable membrane (molecular weight cutoff, 3500 Da) was purchased from Shanghai Green Bird Science and Technology Co. Ltd. (Shanghai, China). 1H NMR spectra were recorded on a Varian UNITY-plus 400 spectrometer, using TMS as an internal standard. Infrared spectra were recorded on a BIO-RAD FTS 6000 spectrometer. The UV spectrophotometer (UV-2550) of Shimadzu was used to record UV absorption spectrum. The molecular weight of polymer was measured with Gel Permeation Chromatography (Waters 1525). Confocal Laser Scanning Microscope was performed using TCS SP5 of Leica.
Synthesis of the macromolecular photosensitizer
The macromolecular photosensitizer of p(GEMA-co-BODIPYMA)-2I was obtained through the process as Scheme 1. First, synthesis of p(AcGEMA-co-BODIPYMA) was carried out by ATRP using α-bromoisobutyic as initiator, CuBr as catalyst and PMEDTA as amine ligand at 60 °C in chlorobenzene solution (50 wt%) with a constant monomer/initiator/CuBr concentration ratio of 100
:
1
:
1. The resultant mixture was further degassed by bubbling nitrogen for 30 min. Then initiator was introduced into the above solution. The reaction was conducted at 60 °C for predetermined time, and was quenched by ice bath. The catalyst was removed by passing through a neutral alumina column eluted with tetrahydrofuran. Then, the resultant solution was poured into a large excess of ether for the precipitation of polymer, and obtained samples were dried under vacuum. Secondly, in order to introduce the iodine atom into BODIPY molecule, N-iodosuccinimide was used as iodination agent in anhydrous dichloromethane.35,36 The final product was a deep red solid of p(AcGEMA-co-BODIPYMA)-2I.
 |
| Scheme 1 Synthesis of the macromolecular photosensitizer. | |
Finally, the resultant polymer (100 mg) was deacetylated using hydrazine (8 mmol) in DMSO (10 mL) for 24 h at 25 °C under nitrogen.37,38 The reaction was quenched by addition of 1 mL acetone, and the resultant solution was dialyzed against water (3500 Da cutoff) for 3 days, and followed by lyophilization to give the macromolecular photosensitizer-p(GEMA-co-BODIPYMA)-2I.
The generation of singlet oxygen and photostability
To assess whether p(GEMA-co-BODIPYMA)-2I and BODIPYMA-2I had the photoreactivity to generate cytotoxic singlet oxygen (1O2) in aqueous system, a simple test was performed.39,40 P-nitrosodimethylaniline (RNO) and histidine were used as singlet oxygen scavenger. RON does not react directly with 1O2, however, can react with the product formed by the reaction of 1O2 with histidine reducing an absorption loss at 440 nm. A solution of neutral aqueous buffers containing RNO (5 μg mL−1), histidine (100 μg mL−1) and p(GEMA-co-BODIPYMA)-2I and BODIPYMA-2I (20 nmol mL−1) under investigation was prepared, this solution was transferred into a glass cuvette, placed in the spectrophotometer and irradiated under the white light (1.5 mW cm−2, 400–800 nm) at room temperature. The rate of 1O2 production was determined by measuring the decrease of RNO absorbance at 440 nm at fixed time intervals. Irradiation was also carried out on a RNO solution in the absence of photosensitizer (negative control). In the experiment, Rose Bengal (ΦΔ = 0.76) was used as reference.
The photostability of the macromolecular photosensitizer under UV (365 nm) and white light (25 mW cm−2) was measured with UV-vis spectrophotometer.
Cell selectivity of the macromolecular photosensitizer
The liver-targeting of the macromolecular photosensitizer was visualized by CLSM and flow cytometry. A number of 1 × 105 of HepG2 or NIH3T3 cells was seeded on glass bottom culture dishes (12 mm) and incubated for 24 h. Then, the cell culture medium was removed, and 200 μL of the solution of p(GEMA-co-BODIPYMA) (5 nmol mL−1) was added into the dish for further incubation. At the predetermined time (30 min), the cell culture medium was removed and the cells were rinsed three times with PBS and fixed by 200 μL 4% paraformaldehyde in PBS for 10 min. After being washed three times with PBS, the cells were incubated with 200 μL of 10% DAPI solution in PBS for 20 min to stain the cell nucleus, and then removing the solution and being washed with PBS three times. The fluorescence photographs of stained cells were obtained by CLSM argon laser (the maximum excitation and emission wavelength for the polymers were 488 and 506 nm, and maximum excitation and emission wavelength for DAPI were 360 and 488 nm).
Flow cytometry was also used to determined selectivity of the macromolecular photosensitizer on cancer cells. NIH3T3 and HepG2 cells were treated with 5 nmol mL−1 p(GEMA-co-BODIPYMA) for 30 min, then flow cytometry was used to detect the cells.
The cytotoxicity of p(GEMA-co-BODIPYMA)-2I and BODIPYMA-2I
The dark-cytotoxicity and light-cytotoxicity of p(GEMA-co-BODIPYMA)-2I and BODIPYMA-2I were evaluated by MTT assay, HepG2 and NIH3T3 as model cells. The cells were seeded in 96-well plate at a density of 1.0 × 104 cells per well in 100 μL of Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum and incubated for 24 h at 37 °C in 5% CO2. The solution of p(GEMA-co-BODIPYMA)-2I and BODIPYMA-2I was diluted with DMEM to obtain predetermined concentrations (160, 80, 40, 20, 10 and 5 nmol mL−1), respectively. The medium in the well was replaced with the sample solution. Cells were exposed to the solution of p(GEMA-co-BODIPYMA)-2I or BODIPYMA-2I at concentrations 160, 80, 40, 20, and 10 nmol mL−1 for the period of 24 and 48 h without illumination to evaluate the dark-cytotoxicity. While another cells were exposed at concentrations 80, 40, 20, 10 and 5 nmol mL−1 with illumination. These samples were illuminated under white light (400–800 nm, 25 mW cm−2) for 5, 10 or 15 min, then were cultured for another 24 h under dark to evaluate the light-cytotoxicity of p(GEMA-co-BODIPYMA)-2I and BODIPYMA-2I to cells. Then, 20 μL MTT was added into each well incubated for further 4 h. Then the medium was completely removed, and 150 μL dimethylsulfoxide (DMSO) was added to each well to dissolve the formazan crystals. The plate was placed at 37 °C for 10 min, and then the optical density was read on a microplate reader at 490 nm in triplicate. The cells without p(GEMA-co-BODIPYMA)-2I and BODIPYMA-2I were used as a control and their viability was set at 100%. Each sample was tested in five replicates per plate.
Results and discussion
Synthesis of the macromolecular photosensitizer
The galactose-functionalized BODIPY-based macromolecular photosensitizer-p(GEMA-co-BODIPYMA)-2I, showed good water-solubility in physiological condition, the aqueous solution of the photosensitizer was clarified even at 20 mg mL−1. P(GEMA-co-BODIPYMA)-2I displayed maxima at wavelength 535 nm, which was consistent with BODIPYMA-2I (Fig. 1). To obtain the highly water-soluble, multivalent and selective p(GEMA-co-BODIPYMA)-2I, p(AcGEMA-co-BODIPYMA) was synthesized by ATRP copolymerization of AcGEMA and BODIPYMA. P(AcGEMA-co-BODIPYMA) with molecular weight of 31.7 kDa was obtained. Molecular weight of p(AcGEMA-co-BODIPYMA)-2I was 32.6 kDa after iodination as shown Fig. S2.† And BODIPY content in P(GEMA-co-BODIPYMA)-2I was 12.3% (mass ratio), which was determined by UV spectrophotometer.
 |
| Fig. 1 Absorption spectra of polymers and BODIPYMA-2I. For p(GEMA-co-BODIPYMA)-2I, H2O was used as solvent, while CH2Cl2 was the solvent for the other three samples. | |
The results of 1H NMR in Fig. 2 and 3 also show that 6.10 ppm of Ar–H was disappeared after iodination. The result proves that we had introduced iodine atom into the BODIPY molecule. The results of 1H NMR in Fig. 3 and 4 show that 1.5–2.5 ppm of acetyl group for p(GEMA-co-BODIPYMA)-2I almost disappeared. And 3.5–4.5 ppm of p(GEMA-co-BODIPYMA)-2I was still strong respect to p(AcGEMA-co-BODIPYMA)-2I that represented the galactose residues. IR spectra shown as Fig. 5, the peak at 3378 cm−1 was assigned to –OH stretching vibrations, and the peak of p(GEMA-co-BODIPYMA)-2I increased significantly compared with p(AcGEMA-co-BODIPYMA)-2I. The peak at 1750 cm−1 in p(AcGEMA-co-BODIPYMA)-2I was ascribed to C
O stretching vibrations of acetyl. And 1721 cm−1 of p(GEMA-co-BODIPYMA)-2I represented C
O stretching vibrations of methacrylate unit. 1370 cm−1 was belonged to C–H in-plane bending vibrations of –CH3, and the peak at 1228 cm−1 was ascribed to asymmetric stretching vibrations of C–O–C. Comparing p(AcGEMA-co-BODIPYMA)-2I and p(GEMA-co-BODIPYMA)-2I, the two peaks at 1370 cm−1 and 1228 cm−1 for p(GEMA-co-BODIPYMA)-2I were weaken significantly after the deacetylation reaction. According to the results, acetyl groups of p(GEMA-co-BODIPYMA)-2I have been removed completely and the galactose structure was not damaged.
 |
| Fig. 2 1H NMR spectrum of p(AcGEMA-co-BODIPYMA) (CDCl3 as solvent). | |
 |
| Fig. 3 1H NMR spectrum of p(AcGEMA-co-BODIPYMA)-2I (CDCl3 as solvent). | |
 |
| Fig. 4 1H NMR spectrum of p(GEMA-co-BODIPYMA)-2I (D2O). | |
 |
| Fig. 5 FTIR spectra of p(AcGEMA-co-BODIPYMA)-2I (A) and p(GEMA-co-BODIPYMA)-2I (B). | |
The generation of singlet oxygen and photostability
The outstanding ability to generate cytotoxic ROS is a key factor for the application of PDT agents to treat cancer. 1O2 is considered the main species responsible for cell death in PDT. Our results clearly show that p(GEMA-co-BODIPYMA)-2I rapidly generated 1O2 (ΦΔ = 0.79) in aqueous system (Fig. 6). As a control experiment, hydrophobic BODIPYMA-2I could not generate 1O2 under the same condition. BODIPYMA-2I generated 1O2 (ΦΔ = 0.21) when ethanol was used as cosolvent (30%), but the rate was only 26% that recorded with p(GEMA-co-BODIPYMA)-2I. Moreover, BODIPYMA-2I could generate 1O2 in DMSO with 1,3-diphenylisobenzofuran as an 1O2 scavenger (Fig. S3†). Notably, p(GEMA-co-BODIPYMA)-2I showed good dispersibility, while BODIPYMA-2I aggregated in aqueous solution, leading to self-quenching of excited-state molecules and reduction in subsequent 1O2 production. And, doping effect may be enhance the PDT efficacy.41 P(GEMA-co-BODIPYMA)-2I led to a significant increase in efficiency of 1O2 generation, compared to BODIPYMA-2I. The results collectively indicate that p(GEMA-co-BODIPYMA)-2I achieved elevated 1O2 under illumination, leading to improved light cytotoxicity for PDT, and therefore has potential use as a PDT agent for cancer treatment.
 |
| Fig. 6 The decrease of RNO absorption at 440 nm under illumination (400–800 nm, 1.5 mW cm−2) against time in the aqueous system. | |
Photostability of the photosensitizer in PBS is regarded as an important factor for effective PDT.42 The results in Fig. S4† show that the UV absorption of the glycopolymer at 535 nm maintained at 77% under UV irradiated after 8 h and 64% under white light irradiated after 30 min. The BODIPY-based macromolecular photosensitizer show excellent photostability in PBS.
Specific cell binding and imaging
Apart from efficiency in generating 1O2, effective targeting of malignant tissues is a critical factor for improving therapeutic outcomes and decreasing side-effects of PDT agents.43 Specific recognition of p(GEMA-co-BODIPYMA)-2I was confirmed by cellular internalization. The glycopolymer without iodination was used as a fluorescent reagent. Cellular internalization of p(GEMA-co-BODIPYMA)-2I was visualized under a Confocal Laser Scanning Microscope (CLSM). As shown in Fig. 7, the glycopolymer was clearly observed in the cytoplasm of HepG2 cells as green dots, indicating internalization of p(GEMA-co-BODIPYMA)-2I. In contrast, green dots were barely observed in NIH3T3 cells. Previous studies reported by our group showed that BODIPY monomer and BODIPY-based copolymer without galactose do not target HepG2 cells.34 These findings suggest that cellular internalization of p(GEMA-co-BODIPYMA)-2I mainly depends on ASGP receptors, which are over expressed by HepG2 cells, through receptor-mediated endocytosis. P(GEMA-co-BODIPYMA)-2I was avidly taken up by liver tumour cells but not normal cells, confirming targeting to the liver. The same results are also proved by flow cytometry. The results in Fig. S5† show that fluorescence intensity on NIH3T3 cells was just 1% of HepG2 cells. The result was similar to that determined by CLSM images. The significant targeting specificity of p(GEMA-co-BODIPYMA)-2I contributes to its increased bioavailability and reduced side-effects.
 |
| Fig. 7 Confocal laser scanning microscope of HepG2 and NIH3T3 cells incubated with solution of p(GEMA-co-BODIPYMA) (5 nmol mL−1) for 30 min. Blue was the nuclei which were stained with DAPI. | |
The cytotoxicity of p(GEMA-co-BODIPYMA)-2I and BODIPYMA-2I
Low dark toxicity is essential for the effective application of PDT agents in cancer treatment. The viability of HepG2 and NIH3T3 cells incubated with p(GEMA-co-BODIPYMA)-2I was >80% under the dark (Fig. 8). We observed lower viability of cells incubated with BODIPYMA-2I, compared to those incubated with p(GEMA-co-BODIPYMA)-2I. The results indicate that p(GEMA-co-BODIPYMA)-2I had lower dark cytotoxicity, compared with BODIPYMA-2I. The low dark cytotoxicity of p(GEMA-co-BODIPYMA)-2I makes it an ideal PDT agent for cancer treatment.
 |
| Fig. 8 Cell viability of HepG2 and NIH3T3 cells after the treatment with p(GEMA-co-BODIPYMA)-2I (A and C) and BODIPYMA-2I (B and D) under dark. Each sample was carried out five times, and the error bars represented SD. | |
P(GEMA-co-BODIPYMA)-2I enhanced the selective killing of cancer cells. As shown in Fig. 9A, the viability of HepG2 cells was lower than 20% at a p(GEMA-co-BODIPYMA)-2I concentration >20 nmol mL−1 under illumination, and almost all cancer cells were apoptotic at concentrations up to 40 and 80 nmol mL−1. In comparison, the viability of NIH3T3 cells was ∼60%, even at a concentration 80 nmol mL−1 under illumination for 10 min (Fig. 9B). BODIPYMA-2I has adverse properties, compared with p(GEMA-co-BODIPYMA)-2I, such as high light cytotoxicity to NIH3T3 but low light cytotoxicity to HepG2 cells. This may be attributable to the fact that NIH3T3 is more sensitive to 1O2 than HepG2, and BODIPYMA-2I does not specifically target cancer cells. These findings clearly demonstrate that p(GEMA-co-BODIPYMA)-2I has specific cancer cell-targeting photodynamic activity. Our design promoted penetration of the novel PDT agent into liver, and ensured greater efficiency in specific killing of cancer cells. P(GEMA-co-BODIPYMA)-2I displayed low dark cytotoxicity and high light cytotoxicity for cancer cells, supporting its utility as an anticancer agent.
 |
| Fig. 9 Cell viability of HepG2 and NIH3T3 cells after the treatment with p(GEMA-co-BODIPYMA)-2I (A and C) and BODIPYMA-2I (B and D) under illumination. Each sample was carried out five times, and the error bars represented SD. | |
Conclusions
We have synthesized a BODIPY-based, highly water-soluble and target-specific macromolecular photosensitizer, p(GEMA-co-BODIPYMA)-2I, with enhanced anticancer efficiency. P(GEMA-co-BODIPYMA)-2I rapidly generated 1O2 (ΦΔ = 0.79) in aqueous system. The photosensitizer was avidly taken up by cancer cells, but not normal cells. Cell viability analysis further revealed that p(GEMA-co-BODIPYMA)-2I displayed specific light cytotoxicity for cancer cells and no dark cytotoxicity. Accordingly, we conclude that p(GEMA-co-BODIPYMA)-2I has potential application as an anticancer agent. This facile strategy may present a novel avenue for the development of an optimal PDT formulation as effective therapy for cancer.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (no. 21174071), Program for Changjiang Scholars and Innovative Research Team in University of Ministry of Education of China (IRT1257) and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin).
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Footnote |
† Electronic supplementary information (ESI) available: Synthesis of BODIPYMA-2, GPC profiles of polymers and the generation of singlet oxygen of BODIPYMA-2I in DMSO. See DOI: 10.1039/c4ra01412j |
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