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研究生： 奇 倫
Chiranjeevi, Korupalli
論文名稱： 幾丁聚醣衍生物奈米粒子於光熱治療及疫苗接種之應用評估
Applications of Chitosan-Based Nanoparticles in Photothermal Therapy and Vaccination
指導教授： 宋信文
SUNG, HSING-WEN
口試委員: 胡育誠
Hu, Yu-Chen
江啟勳
Chiang, Chi-Shiun
許源宏
Hsu, Yuan-Hung
胡宇方
Hu, Yu-Fang
學位類別： 博士
Doctor
系所名稱： 工學院 - 化學工程學系
Department of Chemical Engineering
論文出版年： 2019
畢業學年度： 107
語文別： 英文
論文頁數： 59
中文關鍵詞： 殼聚醣 、皮下膿腫 、光熱療法 、pH響應納米粒子 、電荷轉換 、納米複合水凝膠 、單次注射疫苗
外文關鍵詞： Chitosan, subcutaneous abscesses, photothermal therapy, pH-responsive nanoparticles, charge conversion, nanocomposite hydrogel, single-injection vaccine
相關次數： 點閱：3  下載：0 
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    • 殼聚醣納米顆粒(CSNPs)在生物醫學應用中引起了相當大的關注，源自於它們是可生物降解的、生物相容的，且能夠進行表面修飾並靶向至特定器官或細胞。然而，殼聚醣納米粒子在中性和鹼性環境下水性介質中的溶解度並不佳，因此，在本篇研究中開發了可溶於所有酸鹼範圍水性介質的殼聚糖基底製成的奈米顆粒，此類水溶性殼聚醣衍生物可被應用於局部感染的光熱消融治療和疫苗接種。
    由抗生素抗性細菌引起的局灶性感染正成為影響人類健康的一大挑戰。為了應對這一挑戰，我們在本篇論文第二章節開發了一種酸鹼敏感的聚苯胺-共軛二醇殼聚醣(PANI-GCS)兩親聚合物，它可以於原位自組裝成奈米顆粒。聚苯胺-共軛二醇殼聚醣奈米顆粒在局部被酸環境誘導後，產生的表面電荷轉換針對特異性細菌引起聚集效應而不直接接觸宿主細胞。在接枝上二醇殼聚醣後，聚苯胺的光吸收峰波段向紅外光區域紅移，這過程使吸光後的聚苯胺-共軛二醇殼聚醣奈米顆粒產生大量熱量，並將其發散到鄰近區域。經由紅外光照射過後的聚苯胺-共軛二醇殼聚醣奈米顆粒引起局部區域溫度比周圍組織溫度提高約攝氏五度，此確保對聚集後的特異性細菌進行直接加熱。因此，這過程減少對周圍組織的損傷並加速了傷口癒合。上述結果表明聚苯胺-共軛二醇殼聚醣奈米顆粒可用於局部感染的光熱消融治療。
    此外，疫苗接種是預防疾病的有效醫療介入措施。然而，在沒有佐劑的協助下，大多數亞單位疫苗的免疫原性不佳。因此，在本論文第三章中開發了一種由生物啟發的奈米複合透明質酸水凝膠系統，該系統結合了N-三甲基殼聚醣奈米顆粒(TMC / NPs)、及攜帶亞單位模式疫苗卵清蛋白(OVA)，用來引發強效和延長的抗原特異性體液反應。實驗結果表明，奈米複合水凝膠系統(NPs-Gel)保留大部分通過共價/靜電相互作用鍵合的N-三甲基殼聚醣奈米顆粒，並延長了包裹於其中的卵清蛋白的釋放，使其能夠在水凝膠的注射部位中存放較長時間。帶正電荷的N-三甲基殼聚醣奈米顆粒可以被樹突細胞有效內化，顯著地提升樹突細胞成熟反應，表明N-三甲基殼聚醣在卵清蛋白遞送系統中提供其佐劑的效用。在小鼠的皮下植入之後，奈米複合水凝膠系統充當原位貯庫，其募集免疫細胞前來並提升免疫細胞的局部數量。此系統中與水凝膠網絡沒有形成任何相互作用的N-三甲基殼聚醣奈米顆粒快速釋放並被鄰近的免疫細胞內化，作為初次引起免疫反應的初免劑量；保留在奈米複合水凝膠內的顆粒，隨著時間推移被募集前來、高濃度的免疫細胞攝取內化，作為加強劑量，引起高強度的卵清蛋白特異性抗體反應。這些實驗結果表明，整合此由生物啟發的水凝膠系統顆粒疫苗可作為單次注射初免-加強免疫疫苗，從而實現有效和持久的體液免疫應答。

    Chitosan nanoparticles (CSNPs) have fascinated considerable attention in biomedical applications because they are biodegradable, biocompatible, and enable surface modification and target particular organs or cells. However, the solubility of CSNPs in aqueous media at neutral and alkaline pH values is poor. Therefore, in this work, CS-based NPs that are soluble in aqueous media at all pH ranges are developed, using water-soluble chitosan derivatives for photothermal ablation of focal infections and vaccination.
    Focal infections that are caused by antibiotic-resistant bacteria are becoming an ever-growing challenge to human health. To address this challenge, a pH-responsive amphiphilic polymer of polyaniline-conjugated glycol chitosan (PANI-GCS) that can self-assemble into nanoparticles (NPs) in situ is developed in chapter two. The PANI-GCS NPs undergo a unique surface charge conversion that is induced by their local pH, favoring bacterium-specific aggregation without direct contact with host cells. Following conjugation onto GCS, the optical-absorbance peak of PANI is red-shifted toward the near-infrared (NIR) region, enabling PANI-GCS NPs to generate a substantial amount of heat, which is emitted to their neighborhood. The local temperature of the NIR-irradiated PANI-GCS NPs is estimated to be approximately 5°C higher than their ambient tissue temperature, ensuring specific and direct heating of their aggregated bacteria; hence, damage to tissue is reduced and wound healing is accelerated. The above results demonstrate that PANI-GCS NPs are practical for use in the photothermal ablation of focal infections.
    Besides, vaccination is an effective medical intervention for preventing disease. However, without an adjuvant, most subunit vaccines are poorly immunogenic. Therefore, a bioinspired nanocomposite hyaluronic acid hydrogel system that incorporates N-trimethyl chitosan nanoparticles (TMC/NPs) that carry a model subunit vaccine ovalbumin (OVA) that can elicit a potent and prolonged antigen-specific humoral response, is developed in chapter three. Experimental results indicate that the nanocomposite hydrogel system (NPs-Gel) can retain a large proportion of its TMC/NPs that are bonded by covalent/electrostatic interactions and extend the release of the encapsulated OVA, enabling their localization at the site of hydrogel injection. The positively charged TMC/NPs can be effectively internalized by dendritic cells, significantly augmenting their maturation, suggesting that TMC can function as an adjuvant-based OVA delivery system. Upon subcutaneous implantation in mice, the NPs-Gel acts as an in situ depot that recruits and concentrates immune cells. The TMC/NPs that do not have any specific interactions with the hydrogel network are released rapidly and internalized by the neighboring immune cells, providing a priming dose, while those retained inside the NPs-Gel are ingested by the recruited and concentrated immune cells over time, acting as a booster dose, eliciting high titers of OVA-specific antibody responses. These experimental results suggest particulate vaccines that are integrated in such a bioinspired hydrogel system may be used as single-injection prime-boost vaccines, enabling effective and persistent humoral immune responses.

    中文摘要…………………….……………………………………………………i Abstract…………………………………………………………………..ii Table of Contents………………………………….…………………………….iv List of Figures…...………………………………………………………………viii List of Tables…….…………………………………………………………...…….xi Chapter 1. Introduction………………………………………………...1 Chapter 2. Acidity-Triggered Charge-Convertible Nanoparticles that Can Cause Bacterium-Specific Aggregation In Situ to Enhance Photothermal Ablation of Focal Infection……...6 2-1. Introduction………………………………………………………………………7 2-2. Materials and Methods…………………………………………………………..9 2-2.1. Materials………………………………………………………………….9 2-2.2. Synthesis of Copolymer PANI-GCS…………………………………....10 2-2.3. Characterization of PANI-GCS………………………………………....10 2-2.4. Optical and Photothermal Properties of PANI-GCS……………….……11 2-2.5. In vitro Interactions of PANI-GCS NPs and Bacteria…………..………11 2-2.6. Evaluation of Bacterial Viability………………………………………12 2-2.7. Animal Model…………………………………………………………...12 2-2.8. In vivo Biodistribution and Thermographic Images…………………….13 2-2.9. In vivo Antimicrobial Activity………………………………………..…13 2-2.10. Statistical Analysis……………………………………………………...14 2-3. Results and Discussion………………………………………………………….14 2-3.1. Characterization of PANI-GCS…………………………………………14 2-3.2. Optical and Photothermal Properties of PANI-GCS................................15 2-3.3. pH-Dependent Bacterium-Specific Interactions of PANI-GCS NPs.......17 2-3.4. Local Temperature of NIR-Irradiated PANI-GCS NPs and Their Antimicrobial Activity..............................................................................19 2-3.5. In vivo Aggregation of Bacteria by PANI-GCS NPs................................21 2-3.6. In vivo Photothermal Ability and Antimicrobial Efficacy of f-PANI-GCS NPs...........................................................................................................22 2-4. Conclusions……………………………………………………………………...25 Chapter 3. Single-Injecting, Bioinspired Nanocomposite Hydrogel that Can Recruit Host Immune Cells In Situ to Elicit Potent and Long-Lasting Humoral Immune Responses..26 3-1. Introduction……………………………………………………………………..27 3.2. Materials and Methods…………………………………………………………30 3-2.1. Materials………………………………………………………………...30 3-2.2. Synthesis and Characterization of TMC………………………………...31 3-2.3. Preparation and Characterization of TMC/NPs…………………………31 3-2.4. Synthesis and Characterization of HA-CA Conjugates…………………32 3-2.5. Preparation, Optimization, and Release Kinetics of NPs-Gel…………33 3-2.6. Characterization of NPs-Gel……………………………………………33 3-2.7. In Vitro Cytotoxicities of NPs-Gel and its Constituents………………...34 3-2.8. Animal Studies………………………………………………………….34 3-2.9. Uptake of TMC/NPs by Bone Marrow-Derived Dendritic Cells (BMDCs) and Their Maturation……………………………………………………34 3-2.10. In Vivo Recruitment of Immune Cells in NPs-Gel…………………….35 3-2.11. In Vivo Degradability and Potential Toxicity of NPs-Gel……………..36 3-2.12. In Vivo OVA-Specific Humoral Immune Responses Obtained by NPs-Gel………………………………………………………………...36 3-2.13. Statistical Analysis……………………………………………………..37 3-4. Results and Discussion………………………………………………………….37 3-3.1. CharacteristicsofTMC/NPs……………………………………………..37 3-3.2. Characteristics of HA-CA Conjugates………………………………….39 3-3.3. Optimization of NPs-Gel and Their Release Kinetics……………….....40 3-3.4. Characteristics of NPs-Gel……………………………………………...42 3-3.5. Uptake of TMC/NPs by BMDCs and Their Maturation………………..45 3-3.6. In Vivo Recruitment of Immune Cells in NPs-Gel……………………...47 3-3.7. In Vivo Degradability and Potential Toxicity of NPs-Gel………………49 3-3.8. In Vivo OVA-Specific Humoral Immune Responses of NPs-Gel………50 3-4. Conclusions……………………………………………………………………...51 Chapter 4. References………………………………………………….52   List of Figures Fig. 2-1. Self-assembly of PANI-GCS NPs in an aqueous environment and their acidity-triggered surface-charge conversion that can specifically aggregate bacteria in situ, enhancing photothermal ablation of focal infections..……………………………9 Fig. 2-2. FT−IR and 1H NMR spectra of synthesized PANI-GCS................................14 Fig. 2-3. (a) TEM micrograph of PANI-GCS NPs and (b) their surface-charge conversion in response to changes in environmental pH..............................................15 Fig. 2-4. Optical absorbance spectra of aqueous PANI-GCS, GCS, and PANI at pH 6.3………………………………………………………………………………...…...16 Fig. 2-5. (a) Temperature evolution curves and (b) corresponding thermographic images of PANI-GCS or PANI irradiated by NIR laser………………………………17 Fig. 2-6. Zeta potential of bacteria before and after incubation with PANI-GCS NPs at pH 6.3…………………………………………………………………………………18 Fig. 2-7. SEM images of bacteria (pH 6.3 & pH 7.4) and NIH/3T3 fibroblasts (pH 7.4) before and after incubation with NPs………………………………………………...18 Fig. 2-8. (a) Viabilities of bacteria that were thermally treated at various temperatures using a heat block or an NIR laser in the presence of PANI-GCS NPs. (b) Estimation of local temperatures around NIR-irradiated PANI-GCS NPs based on viability of bacteria that were incubated with test NPs at pH 6.3 and heated in a heat block at various temperatures. (c) Measured ambient temperatures and estimated local temperatures around NIR-irradiated NPs. n.s.: not significant……………………….20 Fig. 2-9. (a) Confocal images of live/dead staining and (b) quantitative results of viability assay of bacteria under various treatment conditions. *P < 0.05; n.s.: not significant……………………………………………………………………………..21 Fig. 2-10. (a) Fluorescence images of f-PANI-GCS NPs subsequent to subcutaneous implantation and (b) thermographic images of f-PANI-GCS NPs upon exposure to NIR. *P < 0.05; n.s.: not significant…………………………………………………..22 Fig. 2-11. Thermographic images of mice following various treatments…………….23 Fig. 2-12. (a) Photographs of bacterial CFUs and (b) corresponding quantitative results under various treatment conditions. *P < 0.05; n.s.: not significant………….24 Fig. 2-13. (a) Gross appearances and (b) representative H&E staining images of infected skins that received various treatments……………………………………….25 Fig. 3-1. Composition/structure of nanocomposite hydrogel of NPs-Gel and mechanisms by which its incorporated TMC/NPs that carry OVA induce humoral immune responses in a mouse model…………………………………………………30 Fig. 3-2. (a) FT−IR and (b) 1H NMR spectra of chitosan and N-trimethyl chitosan (TMC)………………………………………………………………………………...37 Fig. 3-3. TEM micrograph of TMC/NPs………………………………….………….38 Fig. 3-4. (a) 1H NMR and (b) UV−Vis spectra of synthesized HA-CA conjugates with various degrees of substitution (DS) of catechol (CA)………………………….……39 Fig. 3-5. Photographs of HA-CA hydrogel before and after gelation………………..40 Fig. 3-6. Kinetics of in vitro release of TMC/NPs from various formulations of NPs-Gel (a) with various DS of CA in HA-CA conjugates and (b) at various concentrations of HA-CA17 conjugates…………………………………………...…..41 Fig. 3-7. Kinetics of in vitro release of OVA from free TMC/NPs, Gel, or NPs-Gel..42 Fig. 3-8. Rheometric analysis in time sweep mode to study gelation kinetics of Gel and NPs-Gel. The crossover point of G′and G″ was the gelation time…..…………43 Fig. 3-9. SEM micrographs of lyophilized Gel and NPs-Gel………………………...43 Fig. 3-10. Rheometric analysis of Gel and NPs-Gel in (a) strain sweep mode and (b) frequency sweep mode. (c) Compressive Young’s moduli of Gel and NPs-Gel. n.s.: not significant……………………………………………………………………………..44 Fig. 3-11. (a) Swelling properties of Gel and NPs-Gel during incubation at 37 °C for seven days. (b) Viability of NIH/3T3 fibroblasts cultured in media treated with extracts of TMC/NPs, Gel, or NPs-Gel for various durations. n.s.: not significant…………...45 Fig. 3-12. (a) CLSM images and (b) flow-cytometry analysis of BMDCs that were incubated with medium alone (untreated), fluorescein-labeled TMC/NPs, or NPs-Gel for 24 h………………………………………………………………………………..46 Fig. 3-13. Expressions of costimulatory molecules CD40 and CD80 on BMDCs and secretions of IL-6 in culture supernatants after they had been treated with medium alone (untreated), OVA, TMC/NPs, NPs-Gel, or LPS for 48 h. *P < 0.05; n.s.: not significant……………………………………………………………………………..47 Fig. 3-14. (a) Photomicrographs of histological sections and (b) numbers of total recruited cells, macrophages, dendritic cells, and cells that ingested fluorescein-labeled TMC/NPs in NPs-Gel that were implanted subcutaneously in mice for indicated durations. *P < 0.05; n.s.: not significant……………………………………………..48 Fig. 3-15. Changes in volume of NPs-Gel over time after it had been implanted subcutaneously in mice……………………………………………………………….49 Fig. 3-16. Histopathological photomicrographs of tissues of major organs that were harvested from untreated mice and mice that had been treated with TMC/NPs or NPs-Gel four days or 12 weeks post-injection………………………………………..50 Fig. 3-17. Results of analysis of OVA-specific IgG in sera following immunization with single-dose OVA, two-dose OVA, TMC/NPs, NPs-Gel, or Alum/OVA. †P < 0.05 vs. TMC/NPs; *P < 0.05 vs. OVA/Alum……………………………………………...51 List of Tables Table 3-1. Loading efficiency (LE) and loading content (LC) of OVA in TMC/NPs that were prepared with various feeding ratios of TMC:γ-PGA:OVA (n = 6 batches).38 Table 3-2. Degrees of substitution of catechol (CA) in HA-CA conjugates that were synthesized using various feeding molar ratios of DA:HA (n = 6 batches)…………..40

    [1] A.L. Harkins, S. Duri, L.C. Kloth, C.D. Tran, J. Biomed. Mater. Res B 2014, 102, 1199.
    [2] L. Casettari, D. Vllasaliu, J.K.W. Lam, M. Soliman, L. Illum, Biomaterials 2012, 33, 7565.
    [3] F.L. Mi, Y.Y. Wu, Y.H. Lin, K. Sonaje, Y.C. Ho, C.T. Chen, J.H. Juang, H.W. Sung, Bioconjugate Chem. 2008, 19, 1248.
    [4] A. Lardner, J. Leukocyte Biol. 2001, 69, 522.
    [5] I.M. Chiu, B.A. Heesters, N. Ghasemlou, C.A. Von Hehn, F. Zhao, J. Tran, B. Wainger, A. Strominger, S. Muralidharan, A.R. Horswill, J.B. Wardenburg, S.W. Hwang, M.C. Carroll, C.J. Woolf, Nature 2013, 501, 52.
    [6] N. Kojic, E.M. Pritchard, H. Tao, M.A. Brenckle, J.P. Mondia, B. Panilaitis, F. Omenetto, D.L. Kaplan, Adv. Funct. Mater. 2012, 22, 3793.
    [7] S.M. Lehar, T. Pillow, M. Xu, L. Staben, K.K. Kajihara, R.V. Andlen, L. DePalatis, H. Raab, W.L. Hazenbos, J.H. Morisaki, J. Kim, S. Park, M. Darwish, B.C. Lee, H. Hernandez, K.M. Loyet, P. Lupardus, R.N. Fong, D.H. Yan, C.C. Halouni, E. Luis, Y. Khalfin, E. Plise, J.C. Heong, J.P. Lyssikatos, M. Strandh, K. Koefoed, P.S. Andersen, J.A. Flygare, M.W. Tan, E.J. Brown, S.M. Ariathasan, Nature 2015, 527, 323.
    [8] E.G. Ju, K. Dong, Z. Liu, F. Pu, J.S. Ren, X.G. Qu, Adv. Funct. Mater. 2015, 25, 1574.
    [9] W. Wu, S.Y. Lee, X.B. Wu, J.Y. Tyler, H. Wang, Z. Ouyang, K. Park, X.M. Xu, J.X. Cheng, Biomaterials 2014, 35, 2355.
    [10] S.A. Plotkin, Clin. Vaccine Immunol. 2010, 17, 1055.
    [11] S. Lu, Curr. Opin. Immunol. 2009, 21, 346.
    [12] L. Feng, X.R. Qi, X.J. Zhou, Y. Maitani, S.C. Wang, Y. Jiang, T. Nagai, J. Control. Release 2006, 112, 35.
    [13] S.Y. Tzeng, K.J. McHugh, A.M. Behrens, S. Rose, J.L. Sugarman, S. Ferber, R. Langer, A. Jaklenec, P. Natl. Acad. Sci. USA 2018, 115, E5269.
    [14] D.T. O'Hagan, M. Singh, R.K. Gupta, Adv. Drug Deliver. Rev. 1998, 32, 225.
    [15] M.M. Pakulska, I.E. Donaghue, J.M. Obermeyer, A. Tuladhar, C.K. McLaughlin, T.N. Shendruk, M.S. Shoichet, Sci Adv 2016, 2.
    [16] S. Rahimian, J.W. Kleinovink, M.F. Fransen, L. Mezzanotte, H. Gold, P. Wisse, H. Overkleeft, M. Amidi, W. Jiskoot, C.W. Lowik, F. Ossendorp, W.E. Hennink, Biomaterials 2015, 37, 469.
    [17] F. Yang, S. Liu, X.L. Liu, L. Liu, M.J. Luo, S.H. Qi, G.Q. Xu, S. Qiao, X.H. Lv, X.N. Li, L. Fu, Q.M. Luo, Z.H. Zhang, Theranostics 2016, 6, 1453.
    [18] H.Y. Liu, B. Ojha, C. Morris, M.T. Jiang, E.P. Wojcikiewicz, P.P.N. Rao, D.G. Du, Biomacromolecules 2015, 16, 2363.
    [19] F. Lebre, C.H. Hearnden, E.C. Lavelle, Adv. Mater. 2016, 28, 5525.
    [20] F. Wang, W.W. Gao, S. Thamphiwatana, B.T. Luk, P. Angsantikul, Q.Z. Zhang, C.M.J. Hu, R.H. Fang, J.A. Copp, D. Pornpattananangkul, W.Y. Lu, L.F. Zhang, Adv. Mater. 2015, 27, 3437.
    [21] C.W. Hsiao, H.L. Chen, Z.X. Liao, R. Sureshbabu, H.C. Hsiao, S.J. Lin, Y. Chang, H.W. Sung, Adv. Funct. Mater. 2015, 25, 721.
    [22] S.D. Kobayashi, N. Malachowa, F.R. DeLeo, Am. J. Pathol. 2015, 185, 1518.
    [23] L.M. Ma, Y.R. Wang, M.X. Wang, Y.W. Tian, W. Kang, H.H. Liu, H. Wang, J. Dou, C.L. Zhou, Biomaterials 2016, 87, 32.
    [24] M.H. Kim, I. Yamayoshi, S. Mathew, H. Lin, J. Nayfach, S.I. Simon, Ann. Biomed. Eng. 2013, 41, 598.
    [25] M.C. Wu, A.R. Deokar, J.H. Liao, P.Y. Shih, Y.C. Ling, ACS Nano 2013, 7, 1281.
    [26] J. Yang, J. Choi, D. Bang, E. Kim, E.K. Lim, H. Park, J.S. Suh, K. Lee, K.H. Yoo, E.K. Kim, Y.M. Huh, S. Haam, Angew. Chem. Int. Edit. 2011, 50, 441.
    [27] B.P. Jiang, L. Zhang, Y. Zhu, X.C. Shen, S.C. Ji, X.Y. Tan, L. Cheng, H. Liang, J. Mater. Chem. B 2015, 3, 3767.
    [28] Y.D. Lee, C.K. Lim, S. Kim, I.C. Kwon, J. Kim, Adv. Funct. Mater. 2010, 20, 2786.
    [29] W.Y. Pan, C.C. Huang, T.T. Lin, H.Y. Hu, W.C. Lin, M.J. Li, H.W. Sung, Nanomed-Nanotechnol. 2016, 12, 431.
    [30] P. Marcasuzaa, S. Reynaud, F. Ehrenfeld, A. Khoukh, J. Desbrieres, Biomacromolecules 2010, 11, 1684.
    [31] D.O. Lapotko, Theranostics 2013, 3, 138.
    [32] C.W. Hsiao, E.Y. Chuang, H.L. Chen, D.H. Wan, C. Korupalli, Z.X. Liao, Y.L. Chiu, W.T. Chia, K.J. Lin, H.W. Sung, Biomaterials 2015, 56, 26.
    [33] J. Yue, P. Zhao, J.Y. Gerasimov, M. van de Lagemaat, A. Grotenhuis, M. Rustema-Abbing, H.C. van der Mei, H.J. Busscher, A. Herrmann, Y.J. Ren, Adv. Funct. Mater. 2015, 25, 6756.
    [34] K. Rolston, C. Mihu, J. Tarrand, Wounds 2010, 22, 132.
    [35] W.L. Chiang, T.T. Lin, R. Sureshbabu, W.T. Chia, H.C. Hsiao, H.Y. Liu, C.M. Yang, H.W. Sung, J. Control. Release 2015, 199, 53.
    [36] X.J. Zhang, X.F. Wei, L.X. Liu, G.P. Marti, M.S. Ghanamah, M.J. Arshad, L. Strom, R. Spence, J. Jeng, S. Milner, J.W. Harmon, G.L. Semenza, Arch. Surg-Chicago 2010, 145, 259.
    [37] J.J. Moon, B. Huang, D.J. Irvine, Adv. Mater. 2012, 24, 3724.
    [38] B.P. Koppolu, S.G. Smith, S. Ravindranathan, S. Jayanthi, T.K.S. Kumar, D.A. Zaharoff, Biomaterials 2014, 35, 4382.
    [39] A. Malik, M. Gupta, R. Mani, H. Gogoi, R. Bhatnagar, Front. Immunol. 2018, 9.
    [40] D.Q. Shi, X.Q. Xu, Y.Q. Ye, K. Song, Y.X. Cheng, J. Di, Q.Y. Hu, J.X. Li, H.X. Ju, Q. Jiang, Z. Gu, ACS Nano 2016, 10, 1292.
    [41] J.K. Xu, S. Strandman, J.X.X. Zhu, J. Barralet, M. Cerruti, Biomaterials 2015, 37, 395.
    [42] H. Lee, N.F. Scherer, P.B. Messersmith, P. Natl. Acad. Sci. USA 2006, 103, 12999.
    [43] A. Polnok, G. Borchard, J.C. Verhoef, N. Sarisuta, H.E. Junginger, Eur J Pharm Biopharm 2004, 57, 77.
    [44] Y.T. Lim, S.M. Shim, Y.W. Noh, K.S. Lee, D.Y. Choi, H. Uyama, H.H. Bae, J.H. Kim, K.S. Hong, M.H. Sung, H. Poo, Small 2011, 7, 3281.
    [45] E. Lih, S.G. Choi, D.J. Ahn, Y.K. Joung, D.K. Han, J. Tissue Eng. 2016, 7.
    [46] K. Ghosh, X.Z. Shu, R. Mou, J. Lombardi, G.D. Prestwich, M.H. Rafailovich, R.A.F. Clark, Biomacromolecules 2005, 6, 2857.
    [47] S.K. Seidlits, Z.Z. Khaing, R.R. Petersen, J.D. Nickels, J.E. Vanscoy, J.B. Shear, C.E. Schmidt, Biomaterials 2010, 31, 3930.
    [48] K. Belal, F. Stoffelbach, J. Lyskawa, M. Fumagalli, D. Hourdet, A. Marcellan, L. De Smet, V.R. de la Rosa, G. Cooke, R. Hoogenboom, P. Woisel, Angew. Chem. Int. Edit. 2016, 55, 13974.
    [49] W.Z. Zhu, Y. Peck, J. Iqbal, D.A. Wang, Biomaterials 2017, 147, 99.
    [50] M.B. Lutz, N. Kukutsch, A.L.J. Ogilvie, S. Rossner, F. Koch, N. Romani, G. Schuler, J. Immunol. Methods 1999, 223, 77.
    [51] E. Morgan, R. Varro, H. Sepulveda, J.A. Ember, J. Apgar, J. Wilson, L. Lowe, R. Chen, L. Shivraj, A. Agadir, R. Campos, D. Ernst, A. Gaur, Clin. Immunol. 2004, 110, 252.
    [52] G. Yang, Z.H. Xiao, H.Y. Long, K.L. Ma, J.P. Zhang, X.M. Ren, J. Zhang, Sci. Rep-Uk 2018, 8.
    [53] Y.H. Lee, H. Lee, Y.B. Kim, J.Y. Kim, T. Hyeon, H. Park, P.B. Messersmith, T.G.Park, Adv. Mater. 2008, 20, 4154.
    [54] S. Hong, K. Yang, B. Kang, C. Lee, I.T. Song, E. Byun, K.I. Park, S.W. Cho, H. Lee, Adv. Funct. Mater. 2013, 23, 1774.
    [55] B.P. Purcell, D. Lobb, M.B. Charati, S.M. Dorsey, R.J. Wade, K.N. Zellars, H. Doviak, S. Pettaway, C.B. Logdon, J.A. Shuman, P.D. Freels, J.H. Gorman, R.C. Gorman, F.G. Spinale, J.A. Burdick, Nat. Mater. 2014, 13, 653.
    [56] J. Shin, J.S. Lee, C. Lee, H.J. Park, K. Yang, Y. Jin, J.H. Ryu, K.S. Hong, S.H. Moon, H.M. Chung, H.S. Yang, S.H. Um, J.W. Oh, D.I. Kim, H. Lee, S.W. Cho, Adv. Funct. Mater. 2015, 25, 3814.
    [57] J. Bajzert, M. Gorczykowski, J. Galli, T. Stefaniak, Microb. Pathogenesis 2018, 115, 100.
    [58] S.J. Buwalda, T. Vermonden, W.E. Hennink, Biomacromolecules 2017, 18, 316.
    [59] X. Xu, A.K. Jha, D.A. Harrington, M.C. Farach-Carson, X.Q. Jia, Soft Matter 2012, 8, 3280.
    [60] M. Patenaude, S. Campbell, D. Kinio, T. Hoare, Biomacromolecules 2014, 15, 781.
    [61] R.M. Schweller, J.L. West, ACS Biomater. Sci. Eng. 2015, 1, 335.
    [62] R.S. Kalupahana, P. Mastroeni, D. Maskell, B.A. Blacklaws, Immunology 2005, 115, 462.
    [63] F. Borriello, C. Pietrasanta, J.C.Y. Lai, L.M. Walsh, P. Sharma, D.N. O'Driscoll, J. Ramirez, S. Brightman, L. Pugni, F. Mosca, D.J. Burkhart, D.J. Dowling, O. Levy, Front. Immunol. 2017, 8.
    [64] Z.Z. Liu, P.A. Roche, Front. Physiol. 2015, 6.
    [65] F. Azmi, A.A.A. Fuaad, M. Skwarczynski, I. Toth, Hum. Vacc. Immunother. 2014, 10, 778.
    [66] S.M. Bal, B. Slutter, E. van Riet, A.C. Kruithof, Z. Ding, G.F.A. Kersten, W. Jiskoot, J.A. Bouwstra, J. Control. Release 2010, 142, 374.
    [67] C.N. Zhang, G.N. Shi, J. Zhang, H.J. Song, J.F. Niu, S.B. Shi, P.S. Huang, Y.M. Wang, W.W. Wang, C. Li, D.L. Kong, J. Control. Release 2017, 256, 170.
    [68] R.N. Germain, Cell 1994, 76, 287.
    [69] C.A. Fromen, T.B. Rahhal, G.R. Robbins, M.P. Kai, T.W. Shen, J.C. Luft, J.M. DeSimone, Nanomed-Nanotechnol 2016, 12, 677.
    [70] I. Mellman, R.M. Steinman, Cell 2001, 106, 255.
    [71] K. Kranzer, A. Eckhardt, M. Aigner, G. Knoll, L. Deml, C. Speth, N. Lehn, M. Rehli, W. Schneider-Brachert, Infect. Immun. 2004, 72, 4416.
    [72] J.M. Anderson, A. Rodriguez, D.T. Chang, Semin. Immunol. 2008, 20, 86.
    [73] M.D. Turner, B. Nedjai, T. Hurst, D.J. Pennington, Bba-Mol. Cell. Res. 2014, 1843, 2563.
    [74] J. Banchereau, R.M. Steinman, Nature 1998, 392, 245.
    [75] D.M. Mosser, J.P. Edwards, Nat. Rev. Immunol. 2008, 8, 958.
    [76] Y.R. Liu, L. Xiao, K.I. Joo, B.L. Hu, J.X. Fang, P. Wang, Biomacromolecules 2014, 15, 3836.
    [77] W.Y. Xia, W. Liu, L. Cui, Y.C. Liu, W. Zhong, D.L. Liu, J.J. Wu, K.H. Chua, Y.L. Cao, J. Biomed. Mater. Res. B 2004, 71b, 373.
    [78] X.H. Qin, P. Gruber, M. Markovic, B. Plochberger, E. Klotzsch, J. Stampfl, A. Ovsianikov, R. Liska, Polym. Chem-Uk 2014, 5, 6523.
    [79] W. Chen, R. Wang, T.T. Xu, X.B. Ma, Z. Yao, B. Chi, H. Xu, J. Mater. Chem. B 2017, 5, 5668.
    [80] D.M. Pascual, R.D. Morales, E.D. Gil, L.M. Munoz, J.E. Lopez, O.L.J. Casanueva, Vaccine 2006, 24, S88.

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