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Letter Cite This: ACS Macro Lett. 2018, 7, 70−74

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Simple and Green Strategy for the Synthesis of “Pathogen-Mimetic” Glycoadjuvant@AuNPs by Combination of Photoinduced RAFT and Bioinspired Dopamine Chemistry Ming Wen, Mengjie Liu, Wentao Xue, Kai Yang, Gaojian Chen,* and Weidong Zhang* Center for Soft Condensed Matter Physics and Interdisciplinary Research, Soochow University, Suzhou 215006, People’s Republic of China State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, Soochow University, Suzhou 215123, People’s Republic of China S Supporting Information *

ABSTRACT: Innate immune responses recognizing pathogen associated molecular patterns (PAMPs) play a crucial role in adaptive immunity. Toll-like receptors (TLRs) and C-type lectin receptors (CLRs) contribute to antigen capture, uptake, presentation and activation of immune responses. In this contribution, metal-free reversible addition−fragmentation chain transfer (RAFT) polymerization of N-3,4-dihydroxybenzenethyl methacrylamide (DMA) and 2(methacrylamido) glucopyranose (MAG) under sunlight irradiation using 2-cyanoprop-2-yl-α-dithionaphthalate (CPDN) as iniferter agent, can be employed to fabricate the multivalent glycopolymer containing bioresponsive sugar group and multifunctional catechol functionalities. The polymerization behavior is investigated and it presents controlled features. Moreover, bioinspired dopamine chemistry can be successfully utilized to form in situ glycopolymercoated gold nanoparticles (AuNPs) without the need of additional reducing reagent, design “pathogen-mimetic” glycoadjuvant recognized by both CLRs and TLRs. The synthetic glycoadjuvant is found to enhance the adjuvant activity as “infected signals” in vitro.

Vaccine adjuvants can induce robust innate and adaptive immunity and potentiate antigen-specific immune responses.1−3 Compared with traditional adjuvants such as alum and mineral oil, unmethylated CpG adjuvants based on pathogen-associated molecular patterns (PAMPs), a type of Toll-like receptor 9 agonist, can mimic natural infections as “danger signals”, activate professional antigen-presenting cells (APCs), such as dendritic cells (DCs) and macrophages, and elicit desired immune responses through recognition of patternrecognition receptors (PRRs) on APCs.1−3 CpG adjuvant can trigger an APC maturation program, such as up-regulation of MHC and costimulatory molecules, expression of proinflammatory cytokines for inducing antigen-specific cytotoxic T lymphocytes (CTLs) response.4−6 However, their clinical uses as vaccine adjuvants are limited primarily due to lack of the specific uptake by APCs and accumulation in the lymph nodes.7 Recently, we found that carbohydrate-functionalized adjuvants (Dextran-CpG conjugate) markedly increased the uptake by APC and retention in the lymph nodes and enhanced CD8+ T cell responses, leading to improved therapeutic antitumor immunity in vivo.8 In fact, carbohydrate-based materials acting as important ligands for interacting with receptors on cell surfaces play an important role in specific lectin/carbohydrate biological processes such as cell−cell recognition and communication.9,10 Pathogen recognition by C-type lectin receptors (CLRs) expressed by DCs is important not only for © XXXX American Chemical Society

antigen presentation, but also for the induction of appropriate adaptive immune responses.11 In addition, synthetic polymers with pendent carbohydrate moieties called “glycopolymers” possess good binding ability toward proteins, which are able to interact with lectins in a similar manner to natural glycoproteins.12−16 Indeed, CLR-binding carbohydrates are potential therapeutic reagents for cancer immunotherapy.17,18 However, few reports have been conducted for designing specific CLRs- and TLRs-targeted glycopolymer-based adjuvant. Polydopamine and dopamine derivatives inspired by the adhesive proteins secreted by marine mussels have been used to functionalize a wide array of material because molecules bearing catechols are easily converted into highly reactive quinones, which can further react with functional group, including thiols and amines via Michael type addition or Schiff base formation.19,20 For example, conjugation of DNA to polydopamine-coated substrates can be afforded through simple immersion.21 However, the well-controlled catechol-containing copolymers with predetermined chemical compositions is the most challenging work. Generally, postpolymerization modReceived: October 26, 2017 Accepted: December 17, 2017

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DOI: 10.1021/acsmacrolett.7b00837 ACS Macro Lett. 2018, 7, 70−74

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ACS Macro Letters

inhibition cannot be avoided at relatively high temperatures (Table 1). Although SET-RAFT technique opened up a new

ification and protected monomer strategies have been employed to avoid the anticipated side reactions.22,23 We have successfully developed the ambient temperature single electron transfer and reversible addition−fragmentation (SETRAFT) method to prepare the well-defined dopaminecontaining copolymers, which shows excellent tolerance to catechol groups.24 Moreover, based on this technique, wellcontrolled glycopolymers bearing pendant catechols used as versatile platforms for the further design of sugar-targeted nanoparticles and surfaces, has been exploited for cellular uptake and photodynamic therapy in vivo.14,25 It is noted that the interaction between catechol groups and residual transition metal catalysts is regarded as contamination for biomaterials application.26 Indeed, copper(II) complexes could potentially act as effective oxidants to accelerate the oxidation of catechol groups.27 To overcome the challenge of metal contamination in SETRAFT polymerization, the photoinduced, metal-free RAFT polymerization are developed.28−30 Recently, our group has also developed the sunlight-induced RAFT polymerization using typical RAFT agent as initiator and mediator at room temperature,31 which is a good choice for preparing the designed catechol-containing polymers. To develop “pathogenmimetic” glycoadjuvant that can exhibit high affinity and selectivity toward pattern-recognition receptors, helping to augment the immune response in the absence of infection, we synthesized well-controlled glycopolymers carrying pendent catechol moieties via RAFT copolymerization without photocatalyst (metal catalyst) and initiator at ambient temperature (Scheme 1A). Then, using the versatile reactivity and redox

Table 1. Copolymerization of DMA and MAG in DMSO Using Different Techniques entry

method

temp (°C)

time (h)

conv (%)

Mn(GPC) (g/mol)

Mw/Mn

1a 2b 3c 4d 5e

ATRP RAFT NMP SET-RAFT photo-RAFT

80 80 80 25 25

24 24 24 6 20

12.2 30.4 18.0 40.5 54.8

12300 16200

1.36 1.28

a1

[DMA]0/[MAG]0/[EBBr]0/[CuBr]0/[PMDETA]0 = 50:250:1:1:1. [DMA]0/[MAG]0/[CPDN]0/[AIBN]0 = 50:250:1:0.2. c3[DMA]0/ [MAG]0/[TEMPO]0/[BPO]0 = 50:250:1:1. d4[DMA]0/[MAG]0/ [EBBr] 0 : [CPDN] 0 /[Cu(0)] 0/[PMDETA]0 = 150:750:1:3:1:1. e5 [DMA]0/[MAG]0/[CPDN]0 = 50:250:1. b2

avenue to effectively control the copolymerization of dopamine-containing monomer, and no significant radical coupling side reactions are observed,24 the application is limited in the field of biomedical materials due to the specific chelation with residual copper(II) ions (Cu2+). Visually, the white glycopolymers powder obtained by SET-RAFT polymerization of DMA and MAG (Figures S1 and S2), turned dark brown in closed centrifuge tube for only 5 days due to the reduction of Cu2+ ions (Figure S3), could not be dissolved in common solvents, such as DMF, THF, or water. To avoid the interference from residual Cu2+ ions, the sunlight-photolyzed, metal-free RAFT polymerization are employed to prepare the stable catechol-containing glycopolymers (entry 5 in Table 1). Excellent control over molecular weight and a low molecular weight distribution were observed. Moreover, control experiment (Figure S3) indicated the oxidation of catechol-containing glycopolymers prepared by photoinduced RAFT polymerization could be ignored. The typical simulated sunlight-induced RAFT copolymerizations of DMA and MAG were investigated systematically at ambient temperature with CPDN as initiator, chain transfer agent, and termination agent. To investigate the behavior of polymerization, the 1H NMR spectra were employed to observe the polymerization by monitoring the consumption of monomer (Figure S4). As shown in Figure 1A, a linear increase in ln([M]0/[M]) with exposure time was observed, implying the copolymerization was a first-order kinetics with respect to the monomer and with a constant number of active species at the polymerization. It is noted that a significant induction period of about 2 h was often observed, which could be attributed to the time for establishing the equilibrium between in situ activated radicals and CPDN31 or the inhibition of catechol-containing monomer.24 Moreover, monomer conversion increased linearly with exposure time during the intermittent irradiations periods, and almost remained unchanged in the absence of light as demonstrated in Figure 1B, indicating sunlight-photolyzed RAFT process can be temporally manipulated by on/off controls. The NMR results (Figure 1C) revealed that sugar and dopamine are successfully integrated into one polymer as verified with representative chemical shifts at 4.9−5.6 and 6.5−7.0 ppm. In addition, based on the corresponding integration values of i and j. g. h, the apparent number-average molecular weight of PDMA 9-co-PMAG43 (Mn(NMR) = 12900 g/mol) was calculated. The composition

Scheme 1. (A) Fabrication of Glycopolymer by Metal-Free, Sunlight-Induced RAFT; (B) Synthesis of “PathogenMimetic” Glycoadjuvant@AuNPs by Combination of Photoinduced RAFT and Bioinspired Dopamine Chemistry

ability of the bioinspired catechol group, glycoadjuvant@Au nanoparticles capable of mimicking the multivalent binding activity and “danger signals” can be realized (Scheme 1B) in aqueous conditions. In addition, TLR assay indicates glycoadjuvant nanoparticles can potentiate its immunostimulatory activity in vitro. Dopamine and its derivatives, acting as antioxidant agents, have high activities in free radical scavenging.32 For instance, tert-butylcatechol is largely employed as a polymerization inhibitor. Therefore, traditional controlled radical copolymerization (CRP) cannot obtain well-defined, mussel-inspired polymers bearing pendant catechols, because side reactions and 71

DOI: 10.1021/acsmacrolett.7b00837 ACS Macro Lett. 2018, 7, 70−74

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Figure 2. (A) UV−visible absorption spectra. (B) Dynamic light scattering of glycopolymer-coated AuNPs. (C) Typical XPS spectra of glycopolymer and glycopolymer-coated AuNPs. (D) TEM image of glycopolymer-coated AuNPs.

Figure 1. (A) Kinetic plot of copolymerization of DMA and MAG in DMSO solution at 25 °C. (B) ON/OFF controls for the sunlightactivated RAFT copolymerization. (C) Typical 1H NMR spectrum of glycopolymer, PDMA9-co-PMAG43 in D2O. (Mn(GPC) = 9200 g/mol, Mn(NMR) = 12900 g/mol, Mw/Mn = 1.18). (D) GPC curve of glycopolymer for the AuNPs (PDMA9-co-PMAG43).

AuNPs prepared by this strategy was quite stable. Besides, further evidence could be obtained from the X-ray photoelectron spectroscopy (XPS) spectra (Figure 2C). When the glycopolymer was introduced to solution of HAuCl4, the signals at 83.92 and 87.62 eV corresponding to the Au0 signal appeared, implying the successful synthesis and stabilization of gold nanoparticles using glycopolymer bearing catechols as reducing agents. Meanwhile, strong C 1s and N 1s signals were found, proving the presence of carbohydrate on the surface of obtained glycoparticles. All of the above results demonstrated that glycopolymer bearing catechols provide a green strategy for preparing carbohydrate-functionalized AuNPs. Herein, glycopolymer (PDMA9-co-PMAG43) bearing catechols was utilized to reduce not only Au3+ giving rise to carbohydrate-functionalized AuNPs, but also to react or bind with thiol-terminal CpG capable of designing the glycoadjuvant@AuNPs. The formation of glycoadjuvant@AuNPs was confirmed by inhibition of CpG migration in gel electrophoresis (Figure S6). Moreover, the zeta potential (Figure S7) and UV−vis absorption spectra (Figure S8) denoted CpG conjugation was successfully achieved. Then, the adjuvant activity of glycoadjuvant@AuNPs was assessed. RawBlue cells are derived from murine Raw 264.7 macrophages, which can express a wide variety of pattern recognition receptors. Upon TLR or Dectin-1 (C-type lectin, which is the major receptor on macrophages) stimulation, RawBlue cells express a secreted embryonic alkaline phosphatase (SEAP), which is easily qualitatively detectable using QUANTI-Blue as detection medium. Interestingly, glycopolymer-coated AuNPs can activate RAW-Blue cells (Figure 3), the possible reason is mainly attributed to the fact that the aggregated NPs can enhance the specific ligand−lectin (Dectin-1) binding abilities.35,36 Comparable to unmodified CpG, glycoadjuvant@AuNPs induced high levels of SEAP, indicating that glycopolymer-modifited CpG adjuvant can improve the CpG’s immune stimulatory activity. To mimic immunogenic properties of natural pathogens, photoactivated RAFT polymerization capable of fabricating precise glycopolymer for interacting with C-type lectin receptors on APC, and bioinspired catecholic chemistry possessing the reducing and remodified abilities to conjugate

of DMA and MAG is close to the feed ratio. On the other hand, the GPC curve exhibiting sharp peak, confirmed a narrow molecular weight distribution of obtained polymer (Mw/Mn = 1.18) with no significant side reactions (Figure 1D). Moreover, an unsymmetrical peak with a tail toward the low molecular weight was observed, which might be attributed to strong interactions between dopamine-containing copolymer and GPC column. These results strongly suggest that this metalfree RAFT copolymerization of DMA and MAG can be activated and deactivated by sunlight, enables control over the molecular weight and molecular weight distributions, and tolerates catechol and sugar groups. It is well-known that self-polymerization of dopamine at basic conditions is attributed to successive oxidation of catechol, leading to the reducing activity and chelating ability offered by the abundant catechol groups,33 and versatile reactivity generated by highly reactive quinones.34 Here, the glycopolymers (PDMA9-co-PMAG43) bearing catechols employing as strong reducing agents should exhibit versatile the reducing activity and chelating ability to modify the glycopolymers. The time evolution of the absorption spectra indicated the catechol groups were easly oxidized in the absence of basic conditions, resulting in the corresponding glycopolymers bearing quinone groups (Figure S5). This reactivity makes this polymer unique and versatile for adjusting properties. On the other hand, in light of the chelating ability of catechols, glycopolymer-coated gold nanoparticles (glycopolymer@AuNPs) were also obtained in situ by reduction of Au3+ without the need of any other reducing reagent such as NaBH4, citrate, and ascorbate. The UV−vis absorption spectra showed a maximum peak at about 540 nm attributed to the surface plasmon resonance band (SPR) of the gold nanoparticles (Figure 2A). Moreover, the band shifted toward lower wavelength as the quantity of glycopolymers was increased. Furthermore, there was an increase in the hydrodynamic diameter of the particles following the addition of glycopolymers, indicating successful immobilization of glycopolymers onto the gold surface (Figure 2B). From the TEM image (Figure 2D), the nonaggregation of nanoparticles further confirmed that glycopolymer-coated 72

DOI: 10.1021/acsmacrolett.7b00837 ACS Macro Lett. 2018, 7, 70−74

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Figure 3. (A) Illustration of SEAP levels expressed by RAWBlue cells; (B) Immunostimulatory activities of glycopolymer-coated AuNPs, glycoadjuvant@Au, and free CpG in RawBlue cells. Data show the mean values ± SEM.

CpG adjuvant for “infected signals”, were for the first time successfully integrated to design the “pathogen-mimetic” glycoadjuvant@AuNPs. In addition, glycoadjuvant@AuNPs can potentiate the adjuvant activity in vitro. We believe our approach paves the way for the design and synthesis of the glycoadjuvant to augment the immune cell activation.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmacrolett.7b00837. Experimental details and supporting figures (PDF).

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Gaojian Chen: 0000-0002-5877-3159 Weidong Zhang: 0000-0002-6837-3060 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank the Natural Science Foundation of Jiangsu Province (No. BK20171208) and the National Natural Science Foundation of China (No. 21774084) for financial support.

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REFERENCES

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DOI: 10.1021/acsmacrolett.7b00837 ACS Macro Lett. 2018, 7, 70−74