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Preparation of Conjugated Polymer Grafted with H2O2Sensitive Prodrug for Cell Imaging and Tumor Cell Killing Meng Li, Shengliang Li, Hui Chen, Rong Hu, Libing Liu, Fengting Lv, and Shu Wang ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.5b11846 • Publication Date (Web): 29 Dec 2015 Downloaded from http://pubs.acs.org on January 2, 2016

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ACS Applied Materials & Interfaces

Preparation of Conjugated Polymer Grafted with H2O2-Sensitive Prodrug for Cell Imaging and Tumor Cell Killing Meng Li, Shengliang Li, Hui Chen, Rong Hu, Libing Liu*, Fengting Lv, and Shu Wang* Beijing National Laboratory for Molecular Science, Key Laboratory of Organic Solids, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, P. R. China. E-mail: [email protected]; [email protected]

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ABSTRACT: In this work, a new conjugated polymer poly (fluorene-co-phenylene) derivative containing pendent quaternized chlormethine (PFP-Chl) was synthesized by covalent linking small molecular prodrug groups onto conjugated polymer side chains. H2O2-sensitive prodrug with an eightmember-cyclic boronate ester structure could suffer from H2O2-triggered nitrogen mustard release and further DNA cross-linking and alkylation. PFP-Chl combines therapeutic characteristic with excellent optical property of conjugated polymers. It is founded that PFP-Chl could enter into cells by endocytosis to simultaneously exhibit abilities of fluorescent imaging and tumor cell inhibition. KEYWORDS: conjugated polymer, prodrug, cell imaging, tumor cell killing, nitrogen mustard

Conjugated polymers (CPs) with extended π-electron delocalized backbones show excellent photostability and high fluorescence emission, which expand their applications in bio-imaging field. By altering conjugated backbone structures, their absorption and fluorescence emission spectra could be easily modulated and multi-colored bio-imaging would be realized.1-6 Through side-chain modifications, such as the introduction of charged groups and oligo (ethylene glycol) linkers, CPs would exhibit good dispersibility in water and appealing biocompatibility. In addition, for specific and selective interactions with biosystems, a new class of CPs has been developed by embellishing the pendent chains with different kinds of drugs and recognition elements (e.g., phospholipid, oligosaccharide, oligopeptide, and small-molecule ligand).7-11 Based on the precise molecule design, the CPs have widened their applications in tumor therapeutics area. On one hand, upon irradiation, CPs can be promoted to an excited state and sensitize oxygen to generate singlet oxygen (1O2) such that CPs have been exploited as a new type of phtotodynamic therapy photosensitizer.12 On the other hand, the drug-linked polymer may possess excellent cell killing activity mostly due to the enhanced cell endocytosis and the local high concentration of the drug.13


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Many cancer biology researches have elucidated that tumor cells exhibit a higher level of reactive oxygen species (ROS) than normal cells do.14,15 Elevated ROS level is closely related to several pathological processes during the development of cancer, including proliferation, angiogenesis, and metastasis.16-18 Thus the increased oxidative stress has been exploited as a target strategy to selectivity kill tumor cells over normal ones. Recently, quite a few ROS-activated anticancer prodrugs have been well-designed with different ROS-responsive moieties.19-24 In previous works, the H2O2-sensitive arylboronic acids and arylboronates units are the most widely used, partly due to their high sensitivity and specificity towards H2O2 under physiological condition. Cohen and coworkers reported two prodrugs with boronic ester protecting groups linked to the zinc-binding group of matrix metalloproteinase (MMP) inhibitors, and the proinhibitors were verified to be effectively activated by H2O2.25 Kim et al developed a new theranostic prodrug which could be subjected to H2O2-mediated cleavage of boronate ester moiety and concurrent release of anticancer drug and a fluorescent moiety (coumarin), a mouse metastatic lung tumor model was used to evaluate in vivo therapeutic efficacy of the prodrug.26 Peng and co-workers prepared a series of prodrugs of nitrogen mustard whose cytotoxicity could be masked by arylboronate or boronic acid and then be triggered in the presence of H2O2.27 As far as we know, the boronate ester structures used as H2O2-sensitive moiety are mostly fivemembered hetercycles. Here, we synthesized an eight-member-cyclic boronate ester by a transesterification procedure between benzeneboronic acid pinacolate and diethanolamine (DEA). The eight-member-cyclic boronate ester was then linked to poly (fluorene-co-phenylene) derivative to offer PFP-Chl. PFP-Chl combines therapeutic characteristic with excellent optical property of conjugated polymers. The synthetic routes of compound 2, 4, 6, and PFP-Chl are outlined in Scheme 1. Compound 1, 3, 5, 7, and 8 were prepared as previously reported.27-29 Compound 2 and 4 were synthesized by transesterification reactions between compound 1 and 3 with N-methyldiethanolamine, respectively. Compound 6 was obtained by reaction of compound 5 with 4-methylbenzenesulfonyl chloride and further treatment with lithium bromide. PFP-N3 was prepared by Palladium-catalyzed Suzuki coupling 3 Environment ACS Paragon Plus


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polymerization reaction between compound 6 and compound 7, followed by treatment with NaN3. The weight-average molecular weight (Mw) of PFP-N3 is 17960 with a polydispersity index (PDI) of 1.58 based on GPC analysis. PFP-OH was obtained by conversion of azide to amino groups and then addition of bis(2-hydroxyethyl)glycine with NHS and EDCI. Reaction of PFP-OH with compound 8 provided PFP-Chl, whose side chains were partly modified with quaternized chlormethine (Chl). The linking ratio of chlormethine to the polymer side chains is about 10% based on the 1H NMR data (Figure S1). The linking ratio was calculated by comparing the proton number of benzyl in arylboronate with that of benzene ring in conjugated backbones. The photophysical properties of PFP-Chl were studied in water. PFP-Chl showed an absorption maximum at 370 nm and a maximum emission at 420 nm (Figure S2). The fluorescence quantum yield of PFP-Chl was measured in water (QY=44%) with quinine sulfate as the reference.


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Scheme 1. Synthetic route of PFP-Chl.

To confirm the release of chlormethine upon incubation of compound 2 with H2O2, the DNA alkylation and cross-linking was investigated by nondenaturing polyacrylamide gel nucleic acid electrophoresis using a 49-mer DNA duplex. DNA was mixed with varying amounts of compound 2, 4, and H2O2 and then incubated at 37°C for 12 h. As shown in Figure 1a, H2O2 alone had no obvious damage to DNA (lane 2). In the absence of H2O2, compound 2 alone also had no DNA lesion ability (lane 3, 5, and 7), which meant the activity of chlormethine was passivated by arylboronate unit. In the 5 Environment ACS Paragon Plus


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presence of H2O2, efficient DNA damage was observed, and the damage gained with the increase of compound 2 and the corresponding H2O2 concentration. In the control experiments, compound 4 was used with a trimethylamine group in place of chlormethine (Figure 1b). Little DNA cross-linking was observed in all the experimental conditions, which indicated that other by-products of compound 2 after H2O2 treatment (phenol, boric acid, and DEA) had no disruption to DNA structure. A possible mechanism was proposed in Scheme 2 according to the literature28. Since the cytotoxicity of chlormethine strongly depends on the lone-pair electron at the nitrogen atom, the boronic ester protected prodrug is non-toxic due to the electron-withdrawing quaternary ammonium on the nitrogen. Upon H2O2 treatment, compound 2 is firstly oxidized at the carbon-boron bond and then suffers deboronation and chlormethine release. Chlormethine can easily convert to a highly electrophilic aziridinium ring by intramolecular nucleophilic attack (Scheme 2) and it could bind to the nucleophilic groups of the biomolecules, especially N7 nitrogen on the nucleobase guanine, and eventually the DNA alkylation and cross-linking.

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1. DNA 2. DNA + 4 mM H2O2 3. DNA + 0.5 mM 2 4. DNA + 0.5 mM 2 + 1 mM H2O2 5. DNA + 1 mM 2 6. DNA + 1 mM 2 + 2 mM H2O2 7. DNA + 2 mM 2 8. DNA + 2 mM 2 + 4 mM H2O2

1’. DNA 2’. DNA + 4 mM H2O2 3’. DNA + 0.5 mM 4 4’. DNA + 0.5 mM 4 + 1 mM H2O2 5’. DNA + 1 mM 4 6’. DNA + 1 mM 4 + 2 mM H2O2 7’. DNA + 2 mM 4 8’. DNA + 2 mM 4 + 4 mM H2O2

Figure 1. DNA cross-linking formation with compound 2 (a) and compound 4 (b) upon H2O2 treatment. Compound 4 was used as a control.


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Scheme 2. Release of chlormethine by compound 2 upon treatment with H2O2

To verify the coupling of the boronate ester modified prodrug on the polymer side chains and the release of chlormethine after H2O2 treatment, the zeta potentials and size distributions of the polymers in water were tested (Table 1). PFP-N3 was negative charged (-31.0 ± 0.7 mV) due to the oligo (ethylene glycol) side chains which were designed to improve water solubility and avoid nonspecific adsorption of biomolecules. PFP-OH was positive charged (15.4 ± 1.2 mV) which was probably due to the introduction of tertiary amines. The mean size of PFP-OH was 30.1 ± 5.4 nm, which was smaller than PFP-N3 (55.9 ± 1.6 nm). The phenomenon may be related to the more hydrophilic hydroxyl terminal groups. The introduction of quaternary ammonium groups in compound 8 made PFP-Chl more positive (35.5 ± 1.3 mV) than PFP-OH. The mean size of PFP-Chl in water was 27.4 ± 5.9 nm, which was smaller than PFP-OH resulted from the water-soluble charged groups. After incubation of PFP-Chl with H2O2 for 24 hours at 37°C, the zeta potential of PFP-Chl was 24.0 ± 1.2 mV, which was decreased probably due to the destroy of the quaternary ammonium groups after H2O2 oxidation. These results demonstrate that PFP-Chl was able to effectively release chlormethine in H2O2-responsive pattern.

Table 1. Zeta potentials and dynamic light scattering diameters of PFP-N3, PFP-OH, and PFP-Chl. Each value was an average of three measurements. 7 Environment ACS Paragon Plus


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PFP-N3

PFP-OH

PFP-Chl

PFP-Chl treated with H2O2

Zeta Potential (mV)

-31.0 ± 0.7

15.4 ± 1.2

35.5 ± 1.3

22.8 ± 1.6

Size (nm)

55.9 ± 1.6

30.1 ± 5.4

27.4 ± 5.9

—

PFP-Chl was applied for in vitro cell imaging against A549 cells at low concentration (Figure 2). Confocal laser scanning microscopy imaging results showed that PFP-Chl mostly entered into the cytoplasm by endocytosis and located around the perinuclear region. To further confirm their cellular location, a lysosome-located dye (Lyso Tracker Red DND-99) was used for colocalization. The overlapped image of PFP-Chl and lysosome-located dye suggested that PFP-Chl mainly located in the lysosomes of A549 cells. By contrast, PFP-N3 couldn’t enter into cells due to the abundant oligo (ethylene glycol) side chains. The imaging assay also verified the coupling of the boronate ester modified prodrug on the polymer side chains.

Figure 2. Cellular location of PFP-Chl and PFP-N3 in A549 cells. The false colors of PFP and Lyso Tracker are blue and red respectively, the overlay color of blue and red is purple.

The in vitro cytotoxicity of compound 2 and PFP-Chl against two typical tumor cell lines (HeLa and A549 cells) was further evaluated by MTT assay according to the general protocol. As seen in Figure 3, 8 Environment ACS Paragon Plus

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after incubation for 48 h, the cell viability decreased with the concentration increasing. Whereas, compound 4 had no obvious cytotoxicity towards the two types of tumor cells (Figure S3), suggesting that the cell killing ability of compound 2 and PFP-Chl resulted from chlormethine release triggered by the overproduced H2O2 in tumor cells. The experimental results are consistent with the reported research that HeLa cells are more sensitive to nitrogen mustard than A549 cells do30.

Figure 3. Cell viabilities of A549 and HeLa cells after incubation with various concentrations of compound 2 (a) or PFP-Chl (b) for 48 h. In conclusion, we synthesized a new H2O2-sensitive prodrug (compound 2) with an eight-membercyclic boronate ester, which would suffer from H2O2-triggered nitrogen mustard release and further DNA cross-linking and alkylation. The prodrug was covalent linked to poly (fluorene-co-phenylene) derivative and the new polymer PFP-Chl was obtained. The cell imaging and Lyso tracker colocalization assay showed that PFP-Chl could enter into cells by endocytosis. The cell growth inhibition after incubation with compound 2 and PFP-Chl confirmed the release of chlormthine in the intracellular of tumor cells. By virtue of the remarkable optical property of conjugated polymers and the cell growth inhibition of H2O2-sensitive prodrug, PFP-Chl is expected to have potential values in cell imaging and therapeutic area.

ASSOCIATED CONTENT Supporting Information. Detailed experimental procedures, and additional Figures S1∼ S3. This material is available free of charge via the Internet at http://pubs.acs.org/. 9 Environment ACS Paragon Plus


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AUTHOR INFORMATION Corresponding Author *Email: [email protected] (S.W.); [email protected] (L.L.).

ACKNOWLEDGMENTS. The work described in this manuscript was supported by the National Natural Science Foundation of China (Nos. 21473220, 21473221) and the Major Research Plan of China (No. 2013CB932800, 2012CB932600).

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