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Foe to Friend: Supramolecular Nanomedicines Consisting of Natural Polyphenols and Bortezomib Changping Wang, Huajun Sang, Yitong Wang, Fang Zhu, Xinhao Hu, Xinyu Wang, Xing Wang, Yiwen Li, and Yiyun Cheng Nano Lett., Just Accepted Manuscript • DOI: 10.1021/acs.nanolett.8b03015 • Publication Date (Web): 28 Sep 2018 Downloaded from http://pubs.acs.org on September 28, 2018

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Foe to Friend: Supramolecular Nanomedicines Consisting of Natural Polyphenols and Bortezomib Changping Wang, 1, ‡ Huajun Sang, 2, ‡ Yitong Wang, 2 Fang Zhu, 3 Xinhao Hu, 3 Xinyu Wang, 2 Xing Wang, 2 Yiwen Li, 3,* and Yiyun Cheng 1, 2,* 1

South China Advanced Institute for Soft Matter Science and Technology, South China

University of Technology, Guangzhou 510640, P.R. China. 2

Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal

University, Shanghai, 200241, P.R. China 3

College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials

Engineering, Sichuan University, Chengdu 610065, China E-mail: [email protected] (Y.C.), Tel: +86 021-54341001; E-mail: [email protected] (Y.L.), Tel: +86 028-85401066. ‡

These authors contributed equally to this work.

ACS Paragon Plus Environment

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ABSTRACT: Bortezomib (BTZ) is a first-in-class boronate proteasome inhibitor used for cancer therapy, but its therapeutic efficacy is usually inhibited by dietary polyphenols due to boronatecatechol complexation. Benefiting from such dynamic covalent chemistry, herein we describe a novel class of supramolecular nanomedicines by rationally converting natural polyphenols from foe to friend through polyphenol-mediated BTZ assembly strategy. The simple conjugation of BTZ to catechol-containing natural polyphenols via boronate ester bond allows the facile formation of dynamic drug amphiphiles, with pH-dependent assembly/disassembly behaviors under different physiological conditions. Ferric ion was also incorporated into the supramolecular system via metal-phenolic coordination interaction to both introduce bioimaging function and facilitate stability of the supramolecular nanomedicines. Our investigation revealed that the supramolecular nanomedicine consisting of natural polyphenol, BTZ and ferric ion dramatically induced apoptosis on cancer cells and suppressed tumor growth in both subcutaneous and bone tumor models with limited adverse effects. Such natural polyphenolmediated small drug assembly strategy enables the robust fabrication of supramolecular nanomedicines for efficient delivery and controlled release of BTZ in targeted tumor sites, which could be further employed in other types of boronic acid-containing supramolecular therapeutics towards a wide range of diseases.

KEYWORDS: Natural Polyphenols, Catechol, Bortezomib, Supramolecular Nanomedicine, Theranostics


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As a bridge between supramolecular chemistry and nanomedicine, supramolecular nanomedicine has garnered significant interests from chemists and material scientists in recent years, owing to the fascination with several interesting examples with promising prospects for optimizing the diagnosis, treatment, and prevention of cancers and many other diseases.1-12 It refers to the supramolecular formulation of diagnostic and/or therapeutic agents in nanoscale via tunable non-covalent interactions or dynamic covalent bonding.1,

2, 13, 14

Current fabrication

strategies usually involve rationally designed hierarchical assembly process, resulting in various thermodynamically

or

kinetically

stable

nanostructures

with

precisely-controlled

diagnostic/therapeutic compositions as well as stimuli-responsive features to physiologic indicators. Those unique and brilliant properties have offered new opportunities for improving the precision and effectiveness of pharmaceutical practices.1,

4, 15-17

Although kinds of

supramolecular nanomedicines have been well exploited for more effective therapies so far, there are still considerable concerns regarding to the redundant pre-synthesis and purification work.1 For example, a majority of bioimaging and therapeutic agents (i.e. anti-cancer drugs) often need pre-loaded chemical functionalization for next-step use since they do not contain any active site(s) or supramolecular unit(s). Additionally, the pre-design and preparation of suitable nanocarriers also seem to be a necessary but high-cost step. Therefore, it is still highly desirable to generate dynamic, adaptive supramolecular nanomedicines using cheap and readily available materials as the carriers/building blocks within minimum set-up and simplest organic modification work. One possible way for this quest is looking to nature as a source of materials or inspiration, and the journey could lead to the sophisticated use of naturally occurring building blocks or


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renewable monomers derived from natural resources for further supramolecular nanomedicine fabrication.18-20 Natural polyphenols represent a large class of plant-derived compounds structurally possessing two or more phenol units, which include tannin, catechin, lignans and many other bioactive molecules.21 Although most current strategies for natural polyphenol-based supramolecular engineering generally focus on the construction of various (semi-)2D functional metal-phenolic network materials like membranes or capsules,22, 23 we believe that their excellent structural and functional features could lead to more extensive exploration of their use in 3D supramolecular nanomedicines with rigorously controlled chemical/physical parameters for drug delivery, and disease diagnosis and imaging.24-26 For the structural feature aspect, the multiple phenolic hydroxyl groups on natural polyphenols provide ideal scenarios in establishing kinds of non-covalent interactions (such as multiple hydrogen bonding27,

28

), and dynamic covalent

bonding (particularly for catechol-boronic acid reversible chemistry29-31 as well as metal-organic coordination interactions32-34) for supramolecular structural variation. Moreover, the hydrophilic nature of natural polyphenols also enables the facile introducing amphiphilic feature into supramolecular system for further hierarchical assembly. For the functional feature aspect, long time selection and evolution have ensured natural polyphenols also perform as a promising class of multipotent chemo-preventive and anti-cancer agents for inducing apoptosis and inhibiting cancer cell growth by significantly influencing the expression of proteins signaling, cell cycle regulatory proteins and several physiological pathways involved in cell growth, transformation, and metastasis.35 Considering both excellent features offered by natural polyphenol building blocks, we consider it timely to prepare a variety of nanomedicines by rational supramolecular design for targeted delivery of anticancer drugs and bioimaging materials in cancer diagnosis and therapy.


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The general design principle in the desirable supramolecular nanomedicines seeks to develop 3D supramolecular nanomaterials directly from natural polyphenol and commercial boronic

acid-containing

hydrophobic

drug

building

blocks.

The

incorporation

of

pharmaceutically relevant drugs to natural polyphenols via dynamic covalent catechol-boronate chemistry could simultaneously facilitate the formation of supramolecular nanostructures with amphiphilic driving forces for assembly governed by the balance between carrier (natural polyphenol) and therapeutic agent (drug). Note that several previous investigations have demonstrated that natural polyphenols could negate the anticancer effects of bortezomib (BTZ) and other kinds of boronic acid-based proteasome inhibitors by chemically blocking their boronic acid active sites.36, 37 Our supramolecular design in this study strives to convert natural polyphenols from foe to friend for boronic acid-containing drug delivery through the dynamic amphiphiles formation (Figure 1a). In this design, both of natural polyphenol and drug molecule perform as structural and functional synthons for the construction of dynamic amphiphiles, and additional functional motifs (i.e. bioimaging agents) can be further introduced into the systems via metal-phenolic coordination or hydrogen bonding interactions. In this work, we report our first effort towards this goal through the rational design and facile preparation of supramolecular nanomedicines consisting of natural polyphenols, BTZ, and iron(III) and the elucidation of their potentials in cancer theranostics (Figure 1b). BTZ, one kind of typical dipeptidyl therapeutic proteasome inhibitor with antiproliferative effects against tumors, was selected as the hydrophobic boronic acid-containing model drug in this study.38, 39 Moreover, iron(III) was also incorporated into the supramolecular amphiphiles to both introduce magnetic resonance imaging function and improve the stability of the supramolecular nanomedicine via the formation of interchain, multiple iron(III)-catecholate coordination bonds


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(Figure 1b).40, 41 Notably, even compared with the well-established BTZ delivery approaches by using different synthetic catechol-presenting polymers,29, 30, 42 this natural polyphenol-mediated small drug assembly strategy still unambiguously holds a few unique advantages, such as good biocompatibility and biodegradability, high and controlled drug loading, simple operation and set-up, no pre-synthetic work and non-chromatographic purification. We first demonstrated the generality and modularity of this material design strategy by using four kinds of natural polyphenols including catechin, epigallocatechin gallate (EGCG), tannic acid (TA), and procyanidin (Figure 2a-2d). All those four natural polyphenols have been widely used as the food and drink additives for quite a long time, suggesting their excellent biocompatibility and bioavailability.21 The desirable supramolecular nanomedicine precursors can be simply prepared by rapidly mixing of different natural polyphenols with BTZ in a defined stoichiometric ratio (i.e. 1:5 for TA:BTZ, 1:1 for EGCG/catechin/procyanidin:BTZ), respectively. During this fast assembly process, catechol-boronate dynamic covalent bond (Figure 1b) could be simultaneously formed, successfully resulting in four types of supramolecular nanoparticles with distinct polyphenol compositions. Those obtained welldefined spherical morphologies were then characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS) (Figure 2a-2d), demonstrating diameters for those nanoparticles of approximately 100 nm. And those micellar nanoparticles could be further reinforced by incorporation of iron(III) ions via interchain iron(III)-catecholate coordination bond, which enables stable supramolecular nanomedicines additional with promising bioimaging function (Figure 1b). Notably, both forming bonds in Figure 1b are chemically reversible in pHsensitive manners, which further induce the supramolecular formation/dissociation behaviors under different physiological conditions.29, 43


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Figure 1. (a) Foe to friend strategy for intracellular delivery of BTZ by natural polyphenols. (b) Proposed supramolecular nanomedicine consisted of natural polyphenols, BTZ and iron (III) in cancer therapy. And two kinds of bonds involved in the supramolecular nanomedicine: catecholboronate dynamic covalent bond, and interchain iron (III)-catecholate coordination bond. Considering the common features of the four supramolecular nanomedicines, we used BTZTA-iron(III) (BTI) as the representative sample for further characterization and activity evaluation. For example, the content of iron(III) in the BTI nanoparticle was about 1.24 % (wt) as determined by inductively coupled plasma mass spectrometry (ICP-MS). X-ray photoelectron spectroscopy (XPS) was also carried out to confirm the existence of O 1s, N 1s, C 1s, and B 1s in BTI (Figure S1). Interestingly, the formed BTI nanoparticles exhibit promising long-term stability in PBS buffer (pH=7.4) and biological media (i.e. serum and cell media), particularly compared to the BTZ-TA (BT) nanoparticles without iron(III) chelation. For example, the prepared BT nanoparticles were observed to be rapidly disassembled in PBS buffer (Figure 2e), and both the size and zeta-potential (Figure 2f) of the BT nanoparticles were significantly changed during the incubation time, while no change of the BTI nanoparticles was observed even after 3 days. Regarding to the stability issue of BTI, we believe that the formation of


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interchain, multiple iron(III)-catecholate coordination bonds could greatly improve the stability of whole nanoparticle via generating inside cross-linking networks in PBS buffer (pH=7.4). Those cross-linking structures could further lead to the BTI particles being stable for more than 3 days in 10% fetal bovine serum (FBS) and cell culture medium (Figure 2g). Those observations match well with the stability testing results from iron(III)-catecholate micellar systems in previous studies.41 Moreover, note that the BTI particles also exhibited quite high stability even after 4 days’ incubation in glucose (100 mg/dL) buffer solution, as evident by the TEM and DLS results shown in Figure S2.

Figure 2. TEM images and DLS of different supramolecular nanomedicines: BTZ-catechin (PDI=0.165) (a), BTZ-EGCG (PDI=0.157) (b), BTZ-TA (PDI=0.124) (c), and BTZ-procyanidin (PDI=0.146) (d). Scale bars: 200 nm (a-d). (e) DLS of BTI and BT nanoparticles incubated with or without PBS buffer (left); TEM images of BTI nanoparticles incubated with (upper) and without (lower) PBS buffer. Scale bars: 200 nm. (f) Size and zeta-potential changes of BTI and BT nanoparticles when incubated in PBS buffer for 72 h. (g) Size changes of BTI nanoparticles incubated with PBS buffer, FBS, and cell culture medium for 72 h.


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We next measured the in vitro release of BTZ and TA from BTI nanoparticles under different conditions to reveal the pH-responsive property of supramolecular nanomedicine. Three typical kinds of pH conditions (7.4, 6.5, and 5.0) were employed to mimic the physiological pH values in normal tissues and blood, the tumor extracellular environment, and subcellular lysosome, respectively. As shown in Figure 3a-3b, no burst release profiles for BTZ and TA were observed at pH 7.4, while both BTZ and TA showed more rapid release profiles from BTI with the decrease of pH value from 7.4 to 5.0. These results were consistent with the observed results from TEM and DLS data shown in Figure S3. So it clearly indicated the pH-dependent degradation of BTI nanoparticles, which might be attributed to the dissociation of formed boronate ester bond29 and interchain iron(III)-catecholate coordination (generally changing from iron(III)(catecholate)3 and iron(III)(catecholate)2 to iron(III)(catecholate))44 at acidic conditions. The pH-triggered release behavior allows the protection of BTZ from premature release in normal tissues, and rapid release of drugs intracellularly in cancer cells activated by tumor acidity, which was also proved on cell viability assay by 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide (MTT). It was observed that BTI nanoparticles and other non-drug components inside (i.e. TA and iron(III)) all exhibited low cytotoxicity on NIH 3T3 cells (Figure 3c). Cell viability was maintained at approximately 100% in those groups up to 200 nM BTZ dosage, while only 25% of the cells survived when incubated with BTZ, which suggested that the cytotoxicity of free BTZ can be strongly decreased by BTI supramolecular nanomedicine under neutral physiological condition. Similar result was also observed on MDA-MB-231 cells at pH 7.4 (Figure 3d). However, BTI particles were found to exhibit significant toxicity in acidic solutions (pH 6.5 and 5.0), particularly its IC50 value at pH 5.0 even almost approached to that of free BTZ (Figure 3d). Such pH-dependent cytotoxicity of BTI on MDA-MB-231 cells was


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further confirmed by the acridine orange/ethidium bromide (AO/EB) double staining assay. As demonstrated in Figure 3e, BTI did not induce obvious toxicity at pH 7.4, while it could display comparable anticancer activity at pH 5.0 to that of free BTZ. All the evidences unambiguously supported the promising pH-triggered drug release behaviors in BTI supramolecular nanomedicine which can be activated by the tumor extracellular or lysosomal acidity.

Figure 3. (a) In vitro release of BTZ and (b) TA from BTI at pH 7.4, 6.5 and 5.0. (c) In vitro cytotoxicity of BTI, BTZ, TA and Iron(III) on NIH 3T3 cells for 48 h. (d) In vitro cytotoxicity of BTI nanoparticles (pH 7.4, 6.5 and 5.0) on MDA-MB-231 cells for 48 h. (e) AO/EB-stained MDA-MB-231 cells after incubation with BTI nanoparticles at different pH (100 nM BTZ). The pH of the complex solution was adjusted to 7.4 and 5.0 before incubation with the cells. Cells without treatment or treated with free BTZ (100 nM) were tested as controls. Scale bars: 400 µm. We further investigated the in vivo theranostic performance of BTI supramolecular nanomedicine in a subcutaneous tumor model (Figure 4a). For the diagnostic issue, the magnetic resonance (MR) relaxometry experiment was performed at a clinically relevant field strength (Bo = 7.0 T) to quantitatively measure the longitudinal relaxivity value of BTI in aqueous solution (r1= 5.15 mM-1s-1) (Figure S4), and the corresponding T1-weighted MR images also exhibited T1 signal enhancement in a concentration-dependent manner (Figure 4b). More importantly, the in


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vivo positive signal enhancement of T1-weighted MRI images in MDA-MB-231 tumor was also clearly observed even after 24 h intravenous injection of BTI nanoparticles (Figure 4c), demonstrating its potential as a highly efficient and biocompatible contrast agent. Note that the in vivo biodistribution analysis of iron(III) concentration in different organs showed that nearly 9.27 % (%ID/gram tissue) BTI nanomedicine remained in tumors after 24 h injection (Figure S5), probably due to the enhanced permeability and retention (EPR) effect. For the therapeutic issue, intravenous administration of BTI could greatly inhibit tumor growth while inducing minimal toxicity to the animals (Figure 4d-4g). For example, both of BTI and free BTZ (1 mg BTZ/kg mice) could prevent the growth of MDA-MB-231 tumors compared to the control groups treated with PBS, TA or iron(III), suggesting the release of BTZ from BTI nanoparticles triggered by tumor extracellular acidity (Figure 4d). But it was also observed that BTI could exhibit even better performance after 5 days’ treatment on the inhibition of tumors compared with free BTZ, which is probably attributed to the benefit from its EPR effect. This observation was in consistent with the apoptosis analysis result in tumors by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay (Figure S6), which clearly demonstrated that more apoptotic cells were found in the tumor site treated with BTI compared with that treated with free BTZ. Moreover, the injection of free BTZ could induce a significant decrease in body weight of mice (even worse, only one mouse in the BTZ group was finally survived, see Figure 4e), while the BTI treating mouse did not change the body weight compared with the PBS group (Figure 4f), supporting the decreased toxicity of BTI nanomedicine. The good in vivo biocompatibility of BTI was further studied by complete blood counting (Figure 4g and Figure S7) and histological analysis (Figure S8). In particular, Figure 4g revealed that the number of white blood cells (WBC), platelets (PLT), basophil(BASO#), and lymphocytes (LYMPH#) in


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normal animals treated with BTI is similar to those treated with PBS, while the BTZ group was found a significant decrease in blood cell counts. Additionally, histological analysis of heart, liver, spleen, lung, and kidney by hematoxylin and eosin (H&E) staining were shown in Figure S8, which also confirmed the good biocompatibility of BTI.

Figure 4. (a) pH-triggered BTZ release from BTI at the tumor site. (b) In vitro T1-weighted MR images of BTI in aqueous solution versus iron(III) concentration (mM). BT solution and PBS buffer were set as the control. (c) In vivo T1-weighted MR images of the MDA-MB-231 tumor bearing mouse before and after intravenous injection of BTI solution. The red circle points the tumor sites. Relative tumor volume (d), the photographs of excised tumors (e) and body weight (f) in MDA-MB-231 tumor bearing mice after intravenous administration of PBS buffer, FeCl3 solution, TA solution, BTZ and BTI solution (BTZ dose, 1 mg/kg). (g) Hematological parameters of normal mice injected with PBS buffer, BTZ and BTI solution (BTZ dose, 1 mg/kg). *p < 0.05, **p < 0.01 and ***p < 0.001 analyzed by student's t-test.


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Finally, the high biocompatibility as well as the enhanced therapeutic effect of BTI were further investigated in a bone tumor model. Bone tumor treatment has been regarded as one of the most challenging tasks in cancer therapy due to the lack of efficient delivery of therapeutics to bone tumors.45, 46 The in vivo luminescence images of mice bearing MDA-MB-231 metastatic bone tumors before and after treatments were shown in Figure 5a and Figure S9, which indicated that the luminescence intensity of tumors treated by BTI (1.0 mg/kg) was significantly decreasing compared to that of the tumors treated by PBS and BTZ (0.5 mg/kg). None of animals was survived after treatment with BTZ (1.0 mg/kg) during the therapeutic period. It clearly suggested that BTI could efficiently depress the bone tumor growth without inducing serious adverse effects. The bone tumors were then carefully isolated from the animals for further measurement. As shown in Figure S10 and S11, the tumor size and leg circumference of mice in BTI (1.0 mg/kg) group were both much smaller than the ones in other three control groups, proving the successful tumor inhibition. This was further confirmed by apoptosis analysis via TUNEL assay (Figure S12) and mice body weight measurement experiment (Figure S13). We further analyzed the osteoclastic bone resorption, which is usually observed in bone tumors and could induce kinds of severe complications, in the treated mice by 3D micro-CT analysis. The 3D micro-CT reconstructions of the tibias were firstly performed to check comminuted fractures in proximal tibia from mice with different treatments. It was found that only the tibias in mice from the high dosage BTI (1.0 mg/kg) group maintained their shapes well, only with limited erosive lesions (Figure 5b), which supported the efficient bone resorption inhibition feature of BTI. This conclusion was also supported by the testing results from the 3D transverse sections and profiles of the tibia fragments from different groups. The details shown in Figure 5c and Figure S14 again indicated that the tibias in high dosage BTI (1.0 mg/kg) group kept their


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integrity in shape with little erosive holes in bone walls, while the ones in PBS and BTZ (0.5 mg/kg) groups were observed to contain some pieces of bone fragments corroded. Further quantitative analysis on the architecture parameters of bone including bone surface (BS), trabecular numbers (TN), tibia space (TS) and bone volume (BV) was summarized in Figure 5d5g, respectively. It could be observed that the parameters like BS, TN and BV in the high dosage BTI (1.0 mg/kg) treated group were higher than those parameters in other three groups; Correspondingly, the TS value in the high dosage BTI (1.0 mg/kg) group was lower than the ones in other groups. Both results revealed that BTI with suitable dosage could protect the skeletal microstructure of bone from damage in bone tumors efficiently. Above all, this study fully demonstrated the excellent osteoclastic bone resorption inhibition and tumor growth depression properties of BTI supramolecular nanomedicine.

Figure 5. Luminescence imaging (a), 3D micro-CT reconstruction of the tibias (b) and 3D transverse sections of tibia fragments (c) of mice from different groups. Plots of the architecture parameters of bone (BS (d), TN (e), TS (f) and BV (g)). **p < 0.01 and ***p < 0.001 analyzed by student's t-test.


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In summary, we reported the facile fabrication of novel supramolecular nanomedicines containing natural polyphenols and BTZ for efficient delivery and controlled release of BTZ in targeted tumor sites. This unique supramolecular design provides numerous advantages to the theranostic system, including high and precisely controlled drug loading, excellent biodegradability and biocompatibility, easy operation and set-up, no pre-synthetic work and nonchromatographic purification. The resulting BTI supramolecular nanomedicine exhibits high biocompatibility to blood and normal tissue as well as the enhanced antitumor therapeutic effect, particularly useful for the treatment of bone tumors. We believe that this work could stimulate further development of more kinds of natural polyphenol-based supramolecular nanomedicines with various biological functionalities, and tunable shapes and sizes for a wide range of diseases.

ASSOCIATED CONTENT Supporting Information. Experimental details including detailed synthetic methods, release study and analysis, and supplementary in vitro and in vivo biological investigations. This material is available free of charge via the Internet at http:// pubs.acs.org. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] (Y.C.), Tel: +86 021-54341001; E-mail: [email protected] (Y.L.), Tel: +86 028-85401066. Author Contributions C. Wang and H. Sang contributed equally to this work. Notes


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The authors declare no competing financial interests.

ACKNOWLEDGMENT This work was supported by National Natural Science Foundation of China (21725402, 21474030 and 21774079), the Fok Ying Tong Education Foundation (151036), the Shanghai Municipal Science and Technology Commission (17XD1401600), and State Key Laboratory of Polymer Materials Engineering, Sichuan University (sklpme2018-2-04).

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(17) Xu, S.; Zhu, X.; Zhang, C.; Huang, W.; Zhou, Y.; Yan, D. Nat. Commun. 2018, 9, 2053. (18) Ragauskas, A. J.; Williams, C. K.; Davison, B. H.; Britovsek, G.; Cairney, J.; Eckert, C. A.; Frederick Jr., W. J.; Hallett, J. P.; Leak, D. J.; Liotta, C. L.; Mielenz, J. R.; Murphy, R.; Templer, R.; Tschaplinski, T. Science 2006, 311, 484-489. (19) Dodds, D. R.; Gross, R. A. Science 2007, 318, 1250-1251. (20) Sheldon, R. A. Green Chem. 2014, 16, 950-963. (21) Quideau, S.; Deffieux, D.; Douat-Casassus, C.; Pouysegu, L. Angew. Chem. Int. Ed. 2011, 50, 586-621. (22) Ejima, H.; Richardson, J. J.; Caruso, F. Nano Today 2017, 12, 136-148. (23) Ejima, H.; Richardson, J. J.; Liang, K.; Best, J. P.; Van Koeverden, M. P.; Such, G. K.; Cui, J.; Caruso, F. Science 2013, 341, 154-157. (24) Xiang, S.; Yang, P.; Guo, H.; Zhang, S.; Zhang, X.; Zhu, F.; Li, Y. Macromol. Rapid Commun. 2017, 38, 1700446. (25) Kharissova, O. V.; Dias, H. V. R.; Kharisov, B. I.; Pérez, B. O.; Pérez, V. M. J. Trends Biotechnol. 2013, 31, 240-248. (26) Guo, J.; Tardy, B. L.; Christofferson, A. J.; Dai, Y.; Richardson, J. J.; Zhu, W.; Hu, M.; Ju, Y.; Cui, J.; Dagastine, R. R.; Yarovsky, I.; Caruso, F. Nature Nanotech. 2016, 11, 1105-1111. (27) Kozlovskaya, V.; Xue, B.; Lei, W.; Padgett, L. E.; Tse, H. M.; Kharlampieva, E. Adv. Health. Mater. 2015, 4, 686-694. (28) Patil, N.; Jérôme, C.; Detrembleur, C. Prog. Polym. Sci. 2018, 82, 34-91. (29) Su, J.; Chen, F.; Cryns, V. L.; Messersmith, P. B. J. Am. Chem. Soc. 2011, 133, 1185011853. (30) Faure, E.; Falentin-Daudré, C.; Jérôme, C.; Lyskawa, J.; Fournier, D.; Woisel, P.; Detrembleur, C. Prog. Polym. Sci. 2013, 38, 236-270. (31) Ye, Q.; Zhou, F.; Liu, W. Chem. Soc. Rev. 2011, 40, 4244-4258. (32) Lee, B. P.; Messersmith, P. B.; Israelachvili, J. N.; Waite, J. H. Annu. Rev. Mater. Res. 2011, 41, 99-132. (33) Wang, Z.; Xie, Y.; Li, Y.; Huang, Y.; Parent, L. R.; Ditri, T.; Zang, N.; Rinehart, J. D.; Gianneschi, N. C. Chem. Mater. 2017, 29, 8195-8201. (34) Rahim, M. A.; Björnmalm, M.; Suma, T.; Faria, M.; Ju, Y.; Kempe, K.; Müllner, M.; Ejima, H.; Stickland, A. D.; Caruso, F. Angew. Chem. Int. Ed. 2016, 55, 13803-13807.


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