Chiral Polypeptide Thermogels Induce Controlled Inflammatory

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Chiral Polypeptide Thermogels Induce Controlled Inflammatory Response as Potential Immunoadjuvants Yue Wang, Zhongyu Jiang, Weiguo Xu, Yanan Yang, Xiuli Zhuang, Jianxun Ding, and Xuesi Chen ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.9b01872 • Publication Date (Web): 20 Feb 2019 Downloaded from http://pubs.acs.org on February 21, 2019

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ACS Applied Materials & Interfaces

Chiral Polypeptide Thermogels Induce Controlled Inflammatory Response as Potential Immunoadjuvants Yue Wang,†,‡ Zhongyu Jiang,‡,§ Weiguo Xu,‡,§ Yanan Yang,*,† Xiuli Zhuang,‡,§ Jianxun Ding,*,‡,§ and Xuesi Chen‡,§ †Chemical

Engineering Institute, Changchun University of Technology, 2055 Yan'an Street,

Changchun 130012, P. R. China ‡Key

Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese

Academy of Sciences, 5625 Renmin Street, Changchun 130022, P. R. China §Jilin

Biomedical Polymers Engineering Laboratory, 5625 Renmin Street, Changchun 130022, P.

R. China

Corresponding Authors *E-mail: [email protected] (J.D.). *E-mail: [email protected] (Y.Y).

ACS Paragon Plus Environment 1

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KEYWORDS: polypeptide, thermogel, chirality, inflammatory response, immunoadjuvant

ABSTRACT: The in vivo implanted biomaterials are known to induce inflammatory response and recruit immune cells, which could be used as robust adjuvants for immunotherapy. However, the degree of inflammatory response induced by the implanted biomaterials is hard to control. In this work, we reported the application of three kinds of thermogels from the polypeptide methoxy poly(ethylene glycol)−polyalanine (mPEG−PA) with various chiralities to regulate the levels of inflammatory responses in vivo. The mPEG−PLA (EG45LA28) and mPEG−PDA (EG45DA27) thermogels exhibited comparable storage modulus (G′) and loss modulus (G″), both of which were about two times higher than the values of the racemic mPEG−PA (EG45RA) thermogel. The component D-alanine in the polypeptide thermogels led to controlled tissue inflammation after subcutaneous injection, and the content of D-alanine could adjust the level of inflammation. The expression of tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in subcutaneous tissue around the injected thermogel EG45DA27 were 3.62, 1.52, and 4.55 times the levels of those after EG45RA thermogel injection, and 4.52, 7.38, and 7.96 times the levels of those after EG45LA28 injection, respectively. The results indicated that the chiral polypeptide thermogels could induce a controllable inflammatory response in vivo and exhibit great potential as an efficient adjuvant for immunotherapy.


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The biomaterials implanted in vivo usually induce an inflammatory response, which might have severe adverse effects on the human body, thus limiting their applications in the clinic.1-2 However, on the bright side, the inflammation induced by biomaterials is also accompanied by the recruitment and activation of immune cells, such as macrophages, dendritic cells, T lymphocytes, and mast cells.3 As a result, the biomaterials implanted could be employed as a robust adjuvant to improve the efficacies of vaccines and immunotherapy.4-6



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Scheme 1. Polypeptide syntheses and inflammatory response of polypeptide thermogels. (A) Synthetic pathways of polypeptides. (B) Schematic illustration of inflammatory reactions induced by polypeptide thermogels containing alanine with different chiralities. Polypeptide hydrogels have been well developed for application in tissue engineering and drug delivery, benefiting from their excellent biodegradability and biocompatibility.7-9 For the last few years, polypeptide hydrogels have also been used as a potent immunoadjuvant, which could establish an inflammatory microenvironment and promote the immunoreaction.10-12 As a typical example, Yan and coworkers reported the application of an injectable polypeptide hydrogel composed of poly(L-lysine) and N-fluorenylmethoxycarbonyl diphenylalanine (Fmoc-FF) to activate the T lymphocyte and thus inhibit the tumor growth.12 However, no clear strategy has been reported to control the degree of immune response induced by polypeptide hydrogels or other biomaterials up to now. In our opinion, polypeptide hydrogels with controllable inflammatory response may stimulate favorable immune response and demonstrate as a more promising immunoadjuvant for immunomodulation. In this work, we revealed that the content of D-amino acid could adjust the level of inflammation caused by the polypeptide hydrogel in vivo. Three kinds of injectable thermo-responsive hydrogels consisting of polypeptides with different configurations were prepared to regulate the levels of inflammation, as showed in Scheme 1. The matrices of the above

three

thermogels

(mPEG-b-PLAla,

were

EG45LA28),

methoxy methoxy

poly(ethylene poly(ethylene

glycol)-block-poly(L-alanine) glycol)-block-poly(D-alanine)

(mPEG-b-PDAla, EG45DA27), and the equivalent mixture of the above two (EG45RA). The influences of the chirality on the physicochemical properties, gelation behaviors, degradation profiles in vitro and in vivo, as well as inflammatory reactions of the polypeptide thermogels


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were systemically analyzed and compared. Our finding revealed their great potentials as adjustable adjuvants for immunotherapy. EG45LA28, EG45DA27, and mesomeric methoxy poly(ethylene glycol)-block-poly(meso-alanine) (mPEG-b-PmAla, EG45MA25) were synthesized via the ring-opening polymerization (ROP) of L-alanine N-Carboxyanhydrides (L-Ala NCA) or D-alanine N-Carboxyanhydrides (D-Ala NCA) initiated by the amino-terminated mPEG (mPEG-NH2) on the basis of the protocol reported in our previous work.13 The typical proton nuclear magnetic resonance (1H NMR) and Fourier-transform infrared (FT-IR) spectra of Ala NCA monomers with different chiralities were shown in Supplementary Figures S1 and S2, which proved the successful synthesis of Ala NCA. The 1H NMR spectra of EG45LA28, EG45DA27, and EG45MA25 were analyzed to confirm the chemical structures of polypeptides. As shown in Figure 1A, the characteristic peaks at 1.36, 3.40, 3.74, and 4.48 ppm were assigned to the protons of methyl group in alanine, terminal methoxy group in mPEG, mPEG backbone, and methine in the backbone of PAla, respectively, which demonstrated the successful syntheses of the polypeptides. In addition, the FT-IR spectra were collected to verify the chemical structures of polypeptides further. As shown in Figure 1B, the signals at 1660 and 1543 cm−1 attributed to stretching vibration of the amide bond (νC=O) of backbone further validated the chemical structures of polypeptides. As depicted in Table 1, the degrees of polymerization (DPs), calculated by the integration of the proton signals in the 1H NMR spectra, indicated that the length of three kinds of polypeptides was similar. To further confirm, number-average molecular weights (Mn) and polydispersity indexes (PDIs) were obtained from gel permeation chromatography (GPC). The Mns measured by GPC were slightly higher than those obtained from 1H NMR spectra, which could be attributed to the different chemical structures between polypeptides and standard polystyrenes.



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At the same time, the low PDI also implied that the polypeptides obtained had a relatively uniform distribution.

Figure 1. Characterizations of polypeptides. (A) 1H NMR spectra of EG45LA28, EG45DA27, and EG45MA25 in deuterated trifluoroacetic acid (TFA-d). (B) FT-IR spectra of EG45LA28, EG45DA27, EG45MA25, and EG45RA. In order to examine the gelation behaviors of polypeptides, the phase diagrams of EG45LA28, EG45DA27, and EG45RA with the equivalent mixture of the above two were tested using a tube inverting method (Figure 2A). The abovementioned polypeptides were dissolved in phosphate buffered saline (PBS, 0.01 M, pH 7.4) with a concentration of 2.0 − 6.0 wt% and then underwent


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sol−gel transition with the increase of temperature.7 The sol−gel systems with 4.0 wt% polypeptides exhibited the most appropriate critical gelation temperatures between 18 and 27 °C, which were suitable for application in vivo. This screened concentration (4.0 wt%) was used for all further characterizations. Moreover, the changes of thermally induced storage modulus (G′) and loss modulus (G″) of three kinds of polypeptide thermogels were monitored by dynamic mechanical analysis on a Physica MCR 301 Rheometer (Anton Paar, GmbH, Germany). As shown in Figure 2B, G″ was higher than G′ at 5 °C, and then G′ increased and exceeded G″ as the temperature rose, implying the gel formation.14 Higher G′ indicated higher stiffness of hydrogels. The G′ of EG45RA was half of those of EG45LA28 or EG45DA27, because the configuration interaction in EG45RA decreased due to the mixture of chiralities. The morphologies of EG45LA28, EG45DA27, and EG45RA were characterized by scanning electron microscope (SEM). The results revealed various interconnected porous microstructures of polypeptide hydrogels. Table 1. Characterizations of methoxy poly(ethylene glycol)-block- polyalanine with different chiralities. Polypeptide

Abbreviation

DPa

Mn (g mol−1)a

Mn (g mol−1)b

PDI

mPEG-b-PLAla

EG45LA28

28

4000

4500

1.39

mPEG-b-PDAla

EG45DA27

27

3900

4400

1.24

mPEG-b-PMAla

EG45MA25

25

3800

4400

1.32

aDetermined

by 1H NMR. bDetermined by GPC.

To reveal the mechanism of phase transition in response to temperature, the conformation evolutions of hydrogels were characterized by FT-IR spectra and circular dichroism (CD), the diameter changes of polypeptide nanoparticles were investigated by dynamic light scattering



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(DLS), and the signal changes of mPEG segment were monitored by 13C NMR. As depicted in Figure 1B, the peaks at 1627 and 1544 cm−1 illustrated that EG45LA28, EG45DA27, and EG45RA experienced mainly the β-sheet conformation. However, there was no peak at 1627 cm−1 in the spectrum of EG45MA25. The CD spectrum of EG45LA28 indicated the change of secondary structure during sol−gel transition temperature period at a concentration of 50.0 μg mL−1 (Figure 2D). The characteristic peaks, which included a positive Cotton band at 195 nm and a negative Cotton band at 226 nm, were consistent with the signals of β-sheet conformation, and the typical signals became stronger with the escalation of temperature from 20 to 60 °C. EG45DA27 exhibited the opposite peaks because of the reversed chirality, and the typical signals also intensified with the increased temperature. Not surprisingly, EG45RA showed no characteristic peaks due to the racemization between EG45LA28 and EG45DA27. Similarly, EG45MA25 also showed no signals in the CD spectrum (Figures S3), indicating the random coil conformation of mesomeric polypeptides, and the result was consistent with that of FT-IR. More importantly, EG45MA25 did not go through sol−gel transition when the temperature ramped up to 60 °C, indicating that β-sheet was the major inducing factor of phase transition.15 As shown in Supplementary Figure S4, the diameter variations of polypeptide nanoparticles in aqueous solution were tested at a concentration of 5.0 μg mL−1. The hydrodynamic diameter (Dh) of EG45LA28 increased as the temperature rose from 20 to 60 °C. The trends of EG45DA27 and EG45RA were in step with EG45LA28. Besides, the 13C NMR spectrum revealed that the peak of PEG block from EG45LA28 slightly moved from 69.6 to 70.2 ppm with the increase of temperature from 20 to 60 °C, as shown in Supplementary Figure S5, which confirmed the dehydration of PEG groups. The results of EG45DA27 and EG45RA came to the same conclusion. These changes of hydrogels were contributed to the dehydration of PEG and interaction of


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secondary structures among the hydrophobic polypeptides.16 The above results indicated the adjustable physicochemical properties of polypeptides and revealed the sol−gel transformation mechanism of polypeptides in response to temperature.

Figure 2. Performances of polypeptide thermogels. (A) Sol−gel phase diagrams of EG45LA28, EG45DA27, and EG45RA. (B) Changes of G′ and G″ of thermogels versus temperature. (C) SEM images of thermogels. (D) CD spectra of polypeptides with different charities (50.0 μg mL−1) in aqueous solution as a function of temperature. (E) In vitro mass-remaining profiles of thermogels incubated in PBS, PBS with elastase-K or α-chymotrypsin (0.2 mg mL–1). The biodegradability is one of the vital factors for biomedical application of thermogels. The degradation of the polypeptide thermogels was tested in PBS at pH 7.4 with, or without elastase K or α-chymotrypsin for 30 days in vitro.17 As marked in Figure 2E, the thermogels showed a relatively faster degradation in PBS with elastase K or α-chymotrypsin than that in PBS only,



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which could be attributed to the degradation of polypeptides on the surface of thermogels by elastase K or α-chymotrypsin. Moreover, in order to observe the degradation of hydrogels in vivo, images of gel maintenance were recorded at 10 min, and 7, 21, and 28 days, as shown in Supplementary Figure S6. From the images, the solution rapidly gelated in 10 min after injection and degraded gradually with the increase of time. It was obvious that hydrogels degraded at suitable kinetics for application in the biological fields that require long-term treatment.

Figure 3. Histopathological and immunofluorescence assessments of inflammatory response. (A) H&E and immunofluorescence images of adjacent tissues of polypeptide thermogels on day 3.


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The cell nucleus was marked blue by DAPI, and inflammatory cytokine was stained green by FITC. (B) Semi-quantitative analyses of TNF-α, IL-1β, and IL-6. Data are presented as mean ± standard deviation (n = 3; *P < 0.05, **P < 0.01, ***P < 0.001). Furthermore, the biocompatibility of hydrogels was determined by hematoxylin and eosin (H&E) staining (Figure 3A).18 Basically, there was no detectable histopathological damage or inflammatory response in the EG45LA28 group, indicating its excellent biocompatibility. However, the inflammatory reaction induced by EG45DA27 was dramatically enhanced. The level of inflammatory response caused by EG45DA27 was much stronger than that caused by EG45RA, and the inflammatory level induced by EG45RA was higher than that induced by EG45LA28. This phenomenon indicated that the component D-alanine in the thermogels led to the controlled tissue inflammation after subcutaneous implantation. Moreover, the inflammatory cytokines in the surrounding tissue of thermogels were examined to determine the levels of inflammation induced by the implantations. Tumor necrosis factor (TNF-α) is a typical inflammatory cytokine, which triggers a strong lymphocyte response. Interleukin-1β (IL-1β) can activate T cell to generate IL-2, which has a positive effect on immune response. IL-6 can induce B cell differentiation, produce antibodies, as well as induce T cell proliferation and differentiation. Therefore, immunohistochemistry of TNF-α, IL-1β, and IL-6 was conducted to detect the inflammatory cytokines of adjacent tissues after subcutaneous injection of thermogels. As depicted in Figure 3A, the signals of TNF-α, IL-1β, and IL-6 around the injection site were caught by a confocal laser scanning microscope (CLSM) and then semi-quantitatively analyzed. In the CLSM image, the inflammatory cytokines were marked with fluorescein

isothiocyanate

(FITC),

and

the

cell

nuclei

were

stained

by

4',6-diamidino-2-phenylindole (DAPI), as shown in Figure 3A. It was obvious that the level of



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inflammatory reaction in the surrounding rat tissues injected with EG45DA27 was stronger than those injected by EG45LA28 or EG45RA. The semi-quantitative analyses of TNF-α, IL-1β, and IL-6 were further conducted to compare the inflammation caused by the thermogels with different chiralities (Figure 3B). The expression levels of TNF-α, IL-1β, and IL-6 around the injection sites induced by EG45DA27 were 3.62, 1.52, and 4.55 times higher than those caused by EG45RA, and 4.52, 7.38, and 7.96 times higher than those induced by EG45LA28, respectively. The results confirmed that the inflammatory response of the thermogels could be adjusted by the content of component D-alanine, which was in step with the findings of pathological analyses. In addition, the individual CLSM images were shown to manifest the levels of inflammatory factors in Supplementary Figure S7. The above results indicated that the content of D-amino acid could affect the degree of inflammatory response directly. In summary, three kinds of polypeptide thermogels with different chiralities were facilely prepared. The EG45LA28 and EG45DA27 thermogels exhibited comparable G′ and G″, both of which were about two times higher than those of the racemic EG45RA thermogel. The gelation mechanism was demonstrated to be due to the interactions of the polypeptides with β-sheet configuration and the aggregation of polypeptide nanoparticles. More interestingly, the polypeptide thermogels with different contents of D-alanine can induce controlled levels of inflammatory reaction. The controlled inflammatory reaction could recruit the immune cells for immunomodulation, indicating their potential application prospect as immunoadjuvant.

ASSOCIATED CONTENT Supporting Information


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The Supporting Information is available free of charge on the ACS Publications website at DOI:

Materials and Methods, 1H NMR and FT-IR spectra of Ala NCA monomers with different chiralities, CD spectrum of EG45MA25, diameter variations of polypeptide nanoparticles in aqueous solution, 13C NMR spectra variations of PEG segment at different temperature, photos of remaining polypeptide thermogel in vivo, and CLSM images of immunofluorescence sections.

AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected] (J.D.). *E-mail: [email protected] (Y.Y). ORCID Yue Wang: 0000-0003-4660-6940 Zhongyu Jiang: 0000-0002-3077-2525 Weiguo Xu: 0000-0002-0146-8532 Yanan Yang: 0000-0002-5917-4350 Jianxun Ding: 0000-0002-5232-8863 Xuesi Chen: 0000-0003-3542-9256 Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.



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Notes The authors declare no competing financial interest.

ACKNOWLEDGEMENTS This research was financially supported by the National Natural Science Foundation of China (Nos. 51873207, 51673190, 51603204, 51673187, 51473165, and 51520105004), the Science and Technology Development Program of Jilin Province (No. 20190201068JC), and the National Key Research and Development Program of China (Grant No. 2016YFC1100701). REFERENCE 1.

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Chiral Polypeptide Thermogels Induce Controlled Inflammatory

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