Molecular Assemblies of Biomimetic Microcapsules - Langmuir (ACS

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Molecular Assemblies of Biomimetic Microcapsules Yi Jia, and Junbai Li Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.8b04319 • Publication Date (Web): 13 Feb 2019 Downloaded from http://pubs.acs.org on February 15, 2019

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Molecular Assemblies of Biomimetic Microcapsules Yi Jia† and Junbai Li*,†,‡ †Beijing

National Laboratory for Molecular Sciences, CAS Key Lab of Colloid, Interface and

Chemical Thermodynamics, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China ‡University

of Chinese Academy of Sciences, Beijing, 100049, China

ABSTRACT: Layer-by-layer (LbL) assembly is a most commonly used method to prepare various microcapsules based on the electrostatic interactions, hydrogen bonding and covalent bonding so on. Among these interactions, Schiff base bond formed in covalent assembly not only has an advantage in stability, but also enables the assembled microcapsules with autofluorescence and pH-sensitivity. In this feature article, we will mainly describe the construction of biomimetic microcapsules through Schiff base mediated LbL assembly. The structures and properties of the assembled microcapsules are introduced and their application as drug carriers are highlighted.

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INTRODUCTION

Multilayer microcapsules are of great interest due to their potential application in diverse fields.1-6 Layer-by-Layer (LbL) assembly is a well-known and the most frequently used method to prepare the multilayer microcapsules. The first exploration of LbL assembly technique to fabricate hollow microcapsules was put forward by Möhwald’s group in 1998.7 The oppositely charged polyelectrolytes were alternately deposited onto the surfaces of sacrificial templates through electrostatic interactions. After removal of the templates, hollow polyelectrolyte microcapsules can be obtained. This brought to a sheer explosion in the past two decades and opened up the work of modern LbL assembly.8-14 Nowadays, the LbL technique is not limited to charged compounds. A wide range of materials are available for LbL assembly, including proteins, polysaccharides, inorganic particles, dendrimers, vesicles, micelles, virus particles, and so on.15-19 Correspondingly, the driving forces for LbL assembly have also extended from electrostatic interactions to hydrogen bonds, covalent bonds, metal coordination, charge transfer, biospecific recognition, and so on.15,20 This lead to a large variety of multilayer microcapsules with diverse applications.15-17,21-23

In recent few years, covalent Schiff base bond (Figure 1) formed between aldehyde group and amino group has attracted great attention and has been widely used in LbL assembly of microcapsules.15 Dynamic Schiff base bond provides multilayer microcapsules with unique and excellent properties. (i) Covalent Schiff base bond enables the microcapsules with improved stability compared to that fabricated based on the weak interactions.24,25 (ii) Schiff base bond endows the microcapsules with autofluorescent property due to the n-π* transition in the C=N bonds.26-30 (iii) Schiff base bonded microcapsules are pH-responsive since Schiff base bond is liable to hydrolyze under low pH condition.31,32 These characteristics enable the Schiff base


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bonded microcapsules potential applications in biomedicine, especially for controlled drug delivery and biological tracing. In this feature article, we will mainly introduce the molecular assemblies of biomimetic microcapsules through Schiff base mediated LbL assembly. They are divided into two categories in terms of used cross-linkers. The structures and properties of the Schiff base bonded microcapsules are described and their application as drug carriers are highlighted.

Figure 1. Schematic illustration of the Schiff base reaction. GLUTARALDEHYDE CROSSLIKED BIOMIMETIC MICROCAPSULES Glutaraldehyde (GA) is a frequently used crosslinking agents in biomedicine because of its high water solubility, bifunctionality and easy accessibility.33-35 It can readily react with aminocontaining compounds through covalent Schiff base reaction. Since proteins contain many amino groups, we fabricate hollow hemoglobin (Hb) microcapsules by using GA as a cross-linker (Figure 2A).36 Manganese carbonate (MnCO3) particles were chosen as sacrificial templates. The GA and Hb were alternately adsorbed onto the surfaces of MnCO3 particles. The Schiff base bonds were formed between the aldehyde group of GA and the amino group of Hb. After removal of the template particles, GA crosslinked Hb microcapsules were obtained. The hollow structures of microcapsules were obviously observed from the transmission electron microscopy (TEM) image (Figure 2B) and confocal laser scanning microscopy (CLSM) image (Figure 2C). Cyclic voltammetry and potential-controlled amperometric measurements confirmed that the Hb assembled in the microcapsules remained its native structure and showed a good electroactivity.36


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Since the stability of Schiff base bond decreases with the decreased pH, the permeability of Hb microcapsules to fluorescence probe FITC-dextran (Mw 2000 kDa) were studied by incubating with different pH buffers. When the pH is lower than 5.8, the fluorescence intensities of the exterior and interior of microcapsules are almost same, indicating that FITC-dextran could penetrate into microcapsules through the wall. However, the interior of the microcapsules remained dark at pH higher than 7.8, while the exterior was fluorescent, indicating that at this pH the microcapsules were impermeable for FITC-dextran. The result demonstrated that Hb microcapsules possess pH-responsive property. This is highly attractive in controlled drug delivery.

Figure 2. (A) Schematic illustration of GA crosslinked Hb microcapsules. (B) TEM image and (C) CLSM image of GA crosslinked Hb microcapsules. Reproduced from ref. 36. Copyright 2006 Elsevier.


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In subsequent studies, we further fabricated glucose oxidase (GOD) microcapsules,37 photosystem II (PSII) microspheres38 and creatine phosphate kinase microspheres39 via GA mediated Schiff base interaction. Besides, we also extend this approach to prepare dual-proteins microcapsules, such as Hb/GOD microcapsules40 and catalase (Cat)/GOD microcapsules.41 These two proteins can couple together and achieve enzymatic cascade reactions in confined space of microcapsules. Taking Hb/GOD microcapsules as an example, GOD can catalyze the oxidation of glucose to gluconic acid and H2O2, while Hb catalyzes the decomposition of H2O2 due to its peroxidase activity. Thus, two enzymatic reactions were coupled together. This reaction is monitored by using non-fluorescent Amplex red, which can be oxidized by H2O2 into fluorescent resorufin (Figure 3A).40 Upon the addition of glucose, the fluorescence intensity of Hb/GOD microcapsules increased with time (Figure 3B), proving the gradual production of resorufin by the coupled enzymatic reactions. As the consumption of glucose can be directly observed from the increased fluorescence intensity, it is anticipated that this system may be used as a fluorescence sensor for the detection of glucose. Besides, the pH variation induced by the production of gluconic acid was also investigated by encapsulating a pH probe pyranine in the microcapsules. As shown in Figure 3C, the fluorescence intensities of pyranine at 406 nm increased and the intensities at 460 nm decreased with increasing time, demonstrating the gradually acidifying in the interior of the microcapsules. The decreased pH would further lead to the degradation of Schiff base bond, thus loosened the wall structure and enhanced the permeability. To validate it, the permeability of capsules to FITC-dextran (2000 kDa) were examined in the absence and presence of glucose solution, respectively. It was observed from Figure 3D that the microcapsules are impermeable to FITC-dextran in phosphate buffer solution, while they are permeable to FITC-dextran after adding


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glucose solution. This proved that the addition of glucose improved the permeability of the microcapsule walls, which make these microcapsules glucose-sensitive.

Figure 3. (A) Schematic illustration of the Schiff base bonded Hb/GOD microcapsules and the coupled enzymatic reactions. (B) CLSM image of Hb/GOD microcapsules and the fluorescence intensity changes after adding glucose. (C) Fluorescence spectra of pyranine loaded in the Hb/GOD microcapsules at different reaction times. (D) The permeability of Hb/GOD microcapsules before and after adding glucose. The scale bars represent 5 μm. Reproduced from ref. 40. Copyright 2009 American Chemical Society. ALDEHYDE POLYSACCHARIDES CROSSLIKED BIOMIMETIC MICROCAPSULES


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In addition to the routine use of GA, aldehyde polysaccharide is a good alternative because of its low toxicity, biocompatibility and biodegradability. Most of polysaccharides have vicinal diol groups in their structures. Since mild periodates can oxidize vicinal diols to aldehydes or ketones, it is frequently used to open the polysaccharide chain into aldehyde groups.42 We used sodium periodate to oxidize alginate (ALG) for the synthesis of alginate dialdehyde (ADA).28 The obtained ADA was then used as a wall component to crosslink with the amino groups of chitosan (CHI) to prepare microcapsules. After the assembly of desired CHI/ADA multilayers, hollow microcapsules were obtained by the removal of template particles (Figure 4A). In comparison to electrostatic assembled CHI/ALG microcapsules, the stability of CHI/ADA microcapsules are well improved under harsh acid/alkali condition. More interestingly, the Schiff base bonded CHI/ADA multilayer microcapsules were found to display intriguing autofluorescence owing to the n-π* transition in C=N bonds (Figure 4B, 4C). The autofluorescence of the microcapsules is favorable for detecting and monitoring their distribution and location, avoiding external fluorochromes used in biological tracing. Besides, Schiff base bond formed between the wall components endowed the CHI/ADA microcapsules with pH-dependent permeability. At pH 5, FITC-dextran can penetrate into the interior of the CHI/ADA microcapsules (Figure 4D), while they were impermeable at pH 7 (Figure 4E) and pH 9 (Figure 4F). Based on periodate oxidation, we further synthesized dialdehyde starch (DAS) and dialdehyde heparin (DHP), and also prepare microcapsules by crosslinking them with CHI. The results demonstrated that the method used is also applicable to other polysaccharides and their derivatives.


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Figure 4. (A) TEM image and (B, C) CLSM images of CHI/ADA microcapsules. (D-F) The permeability of CHI/ADA microcapsules to 20 kDa FITC-dextran at pH 5, pH 7 and pH 9 (from left to right). Reproduced from ref. 28. Copyright 2011 Royal Society of Chemistry. To endow the microcapsules with multi-responsive properties, we chose cystamine dihydrochloride (CM) as a wall component and crosslinked with ADA through Schiff base reaction.30 The CM contains disulfide bond in its structure that can be cleaved to form thiols at reducing conditions. Same to above mentioned microcapsules, the Schiff base bonded ADA/CM multilayer microcapsules also exhibit autofluorescence and pH-responsive property. The FITCdextran can penetrate into microcapsules at pH 5, but impermeable at pH 7.4. However, when adding a reducing agent dithiothreitol (DTT) to pH 7.4 media, it was found that the ADA/CM microcapsules turned into permeable for FITC-dextran. The enhanced permeability were due to the breakage of –S–S– within formed multilayers upon the addition of reducing agent. That is, the Schiff base bonded ADA/CM microcapsules are pH and redox-responsive. In view of the low pH


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and high concentration of glutathione around tumor tissues, this dual-responsive microcapsules may have great potential as effective anticancer drug carriers. BIOMEDICAL APPLICATIONS OF SCHIFF BASE BONDED BIOMIMETIC MICROCAPSULES The most widespread application of biomimetic microcapsules is to serve as smart drug carriers. The versatile LbL assembly enable easy loading and unloading of drugs.43 It also provides readily surface modification of the microcapsules to endow specific recognition or other properties. Moreover, the sensitivity of the microcapsules can be facile manipulated by changing the components or driving forces, thus allow controlled drug release. These characteristics open up various possibilities for the LbL microcapsules in drug delivery application. Anticancer Drug Carriers. The most common application of biomimetic microcapsules is anticancer drug carriers. The environment around tumor cells is known to have lower pH compared to those of normal tissue.44 Since the Schiff base bond is unstable at low pH, Schiff base bonded microcapsules are good candidate as anticancer drugs carriers. The anticancer drugs can be directly absorbed into the shells of the microcapsules through the co-incubation45,46 or coprecipitation into the template particles during the particle preparation.30,47 Doxorubicin (Dox) is a widely used anticancer drug. Considering that Dox possesses abundant amino groups in its structure, we directly used ADA to crosslink with Dox to prepare microcapsules (Figure 5A).48 The Schiff base bonded Dox/ADA microcapsules demonstrated good pH-responsive property that gradually released Dox at pH 5.5, while little Dox released at pH 7.4 (Figure 5B). The cell cytotoxicity experiments also confirmed the high efficiency of Dox/ADA microcapsules against tumor cell proliferation (Figure 5C, 5D).


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Figure 5. (A) Schematic illustration of DOX/ADA microcapsules. (B) The pH-dependent release of DOX from DOX/ADA microcapsules. (C, D) Cytotoxicity results for MCF-7 cells with (C) different drug concentration and (D) different incubation time. Reproduced from ref. 48. Copyright 2013 Wiley. Phototherapy has recently arouse continuous attentions and is considered as a much more promising anticancer therapy. Phototherapy possesses remarkable advantages such as remote controllability, high spatiotemporal precision and minimal side effects.49-52 Therefore, many researchers take use of biomimetic microcapsules to encapsulate photosensitizers to produce reactive oxygen species (ROS) and achieve photodynamic therapy (PDT).20,45-47,53,54 However, tumor tissue is pathologically featured with extreme hypoxia, this dramatically restricted the PDT efficiency.55,56 To increase the availability of O2, we constructed an oxygen-generating CAT/ADA


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microcapsules based on Schiff base interaction.57 Hydrogen peroxide (H2O2) is enriched in the microenvironment of malignant tumors. Therefore, catalase (CAT) in the microcapsules can catalyze the decomposition of excess H2O2 into H2O and O2. Then produced O2 can be utilized by photosensitizer to generate 1O2 under the excitation of light and thereby effectively improved the efficacy of PDT. In addition, the decreased concentration of H2O2 may also help to inhibit tumor proliferation. Besides oxygen concentration, the penetration depth of light is another big obstacle in PDT,58,59 especially for treating deep-seated tumors. Most efforts have been devoted to employ near-infrared (NIR) light to achieve efficient PDT.47,53,60,61 Here, we introduced a distinct method by constructing an internal self-illuminating system.62 This system was constructed via alternately assembly of luciferase and ADA on luciferin loaded CaCO3 particles. In the presence of oxygen, ATP and Mg2+, luciferase can catalyze the oxidation of its substrate luciferin to generate bioluminescence. The bioluminescence can activate photosensitizer and produce reactive oxygen (1O2). The cell cytotoxicity experiments demonstrated that photosensitizers encapsulated in the microcapsules can be excited by bioluminescent microcapsules under dark and inhibit the proliferation of tumor cells. Such bioluminescent microcapsules achieved PDT without using external light, providing a solution to the limitation of light penetration depth in conventional PDT. Hypoglycemic Drug Carriers. Since Schiff base bonded GOD-containing microcapsules are glucose- and pH-sensitive,40 they may be suitable to serve as hypoglycemic drug carriers and achieve controlled release in response to glucose. We chose insulin as a model drug and prepared insulin particles by the salting out method.41 Taking the prepared insulin particles as the core, Cat and GOD were alternately coated onto the surface of insulin particle by using GA as crosslinker. TEM images confirmed the successful coating of Cat/GOD multilayers on the insulin particles.


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Then the release behaviors of insulin from the Cat/GOD microcapsules in the absence and presence of glucose were studied, respectively. In the phosphate buffer solution, little insulin was released from the Cat/GOD multilayers. While incubating with glucose solution, insulin was continuously released from the Cat/GOD multilayes in the first 3 h. After that, the release rate was gradually decreased. The glucose-responsive release behavior is due to the fact that the hydrolysis of glucose by Cat/GOD multilayer reduces the pH value of the microenvironment, which lead to increased solubility of insulin and the degradation of Schiff base bond in the Cat/GOD multilayer. Therefore, the Cat/GOD multilayers covered on the surface of insulin particle can manipulate the release rate of insulin, and they have great potential as a glucose-sensitive carriers for other hypoglycemic drugs. Oxygen Carriers. Aside from conventional drug carriers, Schiff base bonded microcapsules are also explored to be used as oxygen carriers.29 Hemoglobin (Hb) is a vital protein in the red blood cells (RBCs). It can reversibly bind and release oxygen that transports oxygen to tissues. However, free hemoglobin cannot be used directly as viable oxygen carriers because it readily dissociated into dimer and resulted in renal toxicity.63 Despite various approaches have been developed to overcome these problems, adverse reaction still occurred in some cases because of the strikingly different morphology from RBCs.64-69 Using the LbL assembly technique, we prepared hollow Hb microcapsules by aldehyde polysaccharides mediated Schiff base interaction to mimic RBCs (Figure 6A, 6B).29 Dialdehyde heparin (DHP) is chose as the crosslinker due to its biocompatibility and biodegradability. Besides, it also provides Hb microcapsules with good hemocompatibility that the DHP/Hb microcapsules show lower anticoagulant property compared to heparin, which preventing severe bleeding complications. The aldehyde groups of DHP were reacted with amino groups of Hb, the formed Schiff base bonds effectively inhibited the


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dissociation of the Hb tetramer into dimer, preventing the renal toxicity. Moreover, the Hb assembled in the microcapsules retained their activity that capable of binding and releasing oxygen. In the subsequent study, we further fabricated highly loaded Hb microspheres by coprecipitation with porous CaCO3 through GA mediated Schiff base interaction (Figure 6C).70 Compared to the hollow Hb microcapsules, both the interior and the shell of the microspheres are filled with Hb (Figure 6D). The density of Hb in an individual CaCO3 particle is up to 1.36 g cm3.

The high loading of Hb is favorable for clinical application, especially in terms of urgent need

with large amounts. The stability of the assembled Hb microspheres was studied under different temperature. The characteristic peaks of Hb at 540 and 575 nm were shown to decrease with the increased temperature. When the temperature is higher than 60 °C, the bimodal spectrum still existed in crosslinked Hb (Figure 6E), while nearly disappeared in free Hb (Figure 6F). This indicated that GA crosslinked Hb microspheres may resist a higher temperature in comparison to free Hb. With the good thermo-stability, Hb microspheres may not need special storage conditions and can be maintained for a long time. This is advantageous for artificial oxygen carriers.


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Figure 6. (A) Schematic illustration and (B) CLSM image of the Schiff base bonded Hb/DHP microcapsules. Reproduced from ref. 29. Copyright 2012 Wiley. (C) Schematic illustration and (D) CLSM image of the Schiff base bonded Hb/GA microcapsules with the surface modified by PEG. (E, F) UV-vis absorption spectra of (E) cross-linked Hb and (F) free Hb at 25 °C and 60 °C. Inset images in detail show the absorption between 450 and 700 nm. Reproduced from ref. 70. Copyright 2012 American Chemical Society. CONCLUSIONS In this feature article, we summarized the recent progress on the assembly of biomimetic microcapsules through Schiff base interactions. It shows that Schiff base bonded microcapsules possess good stability, autofluorescent property as well as pH-sensitivity. These assembled microcapsules can be considered as drug carriers for a controlled release. Taking the advantages


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of LbL assembly, other functional or responsive compounds can be combined via Schiff base interaction, finally to create the advanced systems for diverse biomedical applications. Although Layer-by-layer assembly has been developed over 20 years, it is still active in diverse research fields due to continuous injection of new elements and constant innovation. We believe that the layer-by-layer assembly are bound to embrace a brighter future and eventually realize important applications in our daily life. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] ORCID Junbai Li: 0000-0001-9575-3125 Yi Jia: 0000-0001-9812-667X Notes The authors declare no competing financial interest. Biographies


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Yi Jia graduated from Liaoning University in 2009 and received her PhD degree in 2012 from the Institute of Chemistry, the Chinese Academy of Sciences. Then she joined Prof. Li’s group and is currently an associate professor. Her research interests include layer-by-layer assembled micro/nanostructures, self-assembly of dipeptide, molecular assembly of motor proteins and their biomedical application.

Junbai Li obtained his BS, MS and PhD degrees in polymer science from Jilin University. He then spent several years carrying out postdoctoral work and joint research project at the interface department in the Max Planck Institute of Colloids and Interfaces in Germany. He is currently a Professor at the Institute of Chemistry in the Chinese Academy of Sciences. His research interests involve molecular biomimetics based on molecular assembly, molecular mechanisms and structure in assembled biological systems, microcapsules and nanostructured design. ACKNOWLEDGMENT The authors acknowledge the financial support from the National Natural Science Foundation of China (Project No. 21433010, 21872151 and 21320102004). REFERENCES (1) Ai, H., Layer-by-Layer Capsules for Magnetic Resonance Imaging and Drug Delivery. Adv. Drug Deliver. Rev. 2011, 63 (9), 772-788.


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(2) De Koker, S.; Hoogenboom, R.; De Geest, B. G., Polymeric Multilayer Capsules for Drug Delivery. Chem. Soc. Rev. 2012, 41 (7), 2867-2884. (3) del Mercato, L. L.; Rivera-Gil, P.; Abbasi, A. Z.; Ochs, M.; Ganas, C.; Zins, I.; Soennichsen, C.; Parak, W. J., Lbl Multilayer Capsules: Recent Progress and Future Outlook for Their Use in Life Sciences. Nanoscale 2010, 2 (4), 458-467. (4) Sato, K.; Yoshida, K.; Takahashi, S.; Anzai, J.-i., Ph- and Sugar-Sensitive Layer-by-Layer Films and Microcapsules for Drug Delivery. Adv. Drug Deliver. Rev. 2011, 63 (9), 809-821. (5) Shchukina, E. M.; Shchukin, D. G., LbL Coated Microcapsules for Delivering Lipid-Based Drugs. Adv. Drug Deliver. Rev. 2011, 63 (9), 837-846. (6) Ariga, K.; Ji, Q. M.; Hill, J. P., Enzyme-Encapsulated Layer-by-Layer Assemblies: Current Status and Challenges toward Ultimate Nanodevices. In Modern Techniques for Nano- and Microreactors/-Reactions, Caruso, F., Ed. 2010; Vol. 229, pp 51-87. (7) Donath, E.; Sukhorukov, G. B.; Caruso, F.; Davis, S. A.; Möhwald, H., Novel Hollow Polymer Shells by Colloid-Templated Assembly of Polyelectrolytes. Angew. Chem. Int. Ed. 1998, 37 (16), 2202-2205. (8) Berth, G.; Voigt, A.; Dautzenberg, H.; Donath, E.; Möhwald, H., Polyelectrolyte Complexes and Layer-by-Layer Capsules from Chitosan/Chitosan Sulfate. Biomacromolecules 2002, 3 (3), 579-590. (9) Dai, Z. F.; Dahne, L.; Möhwald, H.; Tiersch, B., Novel Capsules with High Stability and Controlled Permeability by Hierarchic Templating. Angew. Chem. Int. Ed. 2002, 41 (21), 40194022. (10) An, Z. H.; Möhwald, H.; Li, J. B., Ph Controlled Permeability of Lipid/Protein Biomimetic Microcapsules. Biomacromolecules 2006, 7 (2), 580-585.


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(11) Duan, L.; He, Q.; Wang, K.; Yan, X.; Cui, Y.; Möhwald, H.; Li, J., Adenosine Triphosphate Biosynthesis Catalyzed by F0f1 Atp Synthase Assembled in Polymer Microcapsules. Angew. Chem. Int. Ed. 2007, 46 (37), 6996-7000. (12) Ge, L.; Möhwald, H.; Li, J., Mechanical Property of Lipid-Coated Polyelectrolyte Microcapsules. J. Nanosci. Nanotechnol. 2006, 6 (8), 2489-2493. (13) Ge, L. Q.; Möhwald, H.; Li, J. B., Biointerfacing Polyelectrolyte Microcapsules. Chemphyschem 2003, 4 (12), 1351-1355. (14) Song, W.; He, Q.; Möhwald, H.; Yang, Y.; Li, J., Smart Polyelectrolyte Microcapsules as Carriers for Water-Soluble Small Molecular Drug. J. Control. Release 2009, 139 (2), 160-166. (15) Jia, Y.; Li, J., Molecular Assembly of Schiff Base Interactions: Construction and Application. Chem. Rev. 2015, 115 (3), 1597-1621. (16) Ariga, K.; Lvov, Y. M.; Kawakami, K.; Ji, Q.; Hill, J. P., Layer-by-Layer Self-Assembled Shells for Drug Delivery. Adv. Drug Deliver. Rev. 2011, 63 (9), 762-771. (17) He, Q.; Cui, Y.; Li, J., Molecular Assembly and Application of Biomimetic Microcapsules. Chem. Soc. Rev. 2009, 38 (8), 2292-2303. (18) Li, B. L.; Setyawati, M. I.; Chen, L.; Xie, J.; Ariga, K.; Lim, C.-T.; Garaj, S.; Leong, D. T., Directing Assembly and Disassembly of 2D MoS2 Nanosheets with DNA for Drug Delivery. ACS Appl. Mater. Inter. 2017, 9 (18), 15286-15296. (19) Rodrigues, V. C.; Moraes, M. L.; Soares, J. C.; Soares, A. C.; Sanfelice, R.; Deffune, E.; Oliveira Jr, O. N., Immunosensors Made with Layer-by-Layer Films on Chitosan/Gold Nanoparticle Matrices to Detect D-Dimer as Biomarker for Venous Thromboembolism. Bull. Chem. Soc. Jpn. 2018, 91 (6), 891-896.


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(61) Sun, B.; Wang, L.; Li, Q.; He, P.; Liu, H.; Wang, H.; Yang, Y.; Li, J., Bis(Pyrene)-Doped Cationic

Dipeptide

Nanoparticles

for

Two-Photon-Activated

Photodynamic

Therapy.

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Molecular Assemblies of Biomimetic Microcapsules - Langmuir (ACS

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