Uril-Based Monodisperse Microcapsules Self- Assembled Within Microfluidic Droplets

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Cucurbit[n]uril -based Monodisperse Microcapsules Self - Assembled within Microfluidic Droplets: A Versatile Approach for Supramolecular Architectures and Materials

Journal: Accounts of Chemical Research

Manuscript ID ar-2016-00429g.R2

Manuscript Type: Article

Date Submitted by the Author: 22-Nov-2016

Complete List of Authors: Liu, Ji; Melville Laboratory for Polymer Synthesis, Department of Chemistry Lan, Yang; University of Cambridge, Melville Laboratory for Polymer Synthesis, Department of Chemistry Yu, Ziyi; University of Cambridge, Chemistry Tan, Cindy; University of Cambridge, Melville Laboratory for Polymer Synthesis, Department of Chemistry; MARA University of Technology - Sarawak Campus Parker, Richard; University of Cambridge, Chemistry Abell, Chris; University of Cambridge, Chemistry Scherman, Oren; University of Cambridge, Melville Laboratory for Polymer Synthesis, Department of Chemistry

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1 2 3 4 5 Cucurbit[n]uril-based Microcapsules Self-Assembled within Microfluidic 6 Droplets: A Versatile Approach for Supramolecular Architectures and Materials 7 Ji Liu,† Yang Lan,† Ziyi Yu,∗,‡ Cindy S.Y. Tan,†,¶ Richard M. Parker,‡ Chris Abell,∗,‡ and 8 Oren A. Scherman∗,† 9 † Melville Laboratory for Polymer Synthesis, Department of Chemistry, University of Cambridge, Lensfield 10 Road, Cambridge CB2 1EW, UK. 11 ‡ Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. 12 ¶Faculty of Applied Sciences, Universiti Teknologi MARA, 94300 Kota Samarahan, Sarawak, Malaysia. 13 Received November 19, 2016; E-mail: [email protected]; [email protected]; [email protected] 14 15 Conspectus disperse supramolecular microcapsules, fab- 16 ricated through the integration of traditional 17 Microencapsulation is a fundamental con- microfluidic techniques and interfacial host- 18 cept behind a wide range of daily applica- guest chemistry, specifically cucurbit[n]uril 19 tions ranging from paints, adhesives and pes- (CB[n])-mediated host-guest interactions. 20 ticides to targeted drug delivery, transport Three different strategies: colloidal particle- 21 of vaccines and self-healing concretes. The driven assembly, interfacial condensation- driven assembly and electrostatic interaction- 22 beauty of microfluidics to generate microcap- driven assembly, are classified and discussed 23 sules arises from the capability of fabricat- in details, presenting the methodology in- 24 ing mono-disperse and micron-scale droplets, which can lead to microcapsules/particles volved in each microcapsule formation pro- 25 with fine-tuned control over size, shape and cess. We highlight the state-of-the-art in 26 hierarchical structure, as well as high repro- design and control over structural complex- 27 ducibility, efficient material usage and high- ity with desirable functionality, as well as 28 throughput manipulation. The introduction promising applications, such as cargo deliv- 29 of supramolecular chemistry, such as host- ery stemming from the assembled microcap- 30 guest interactions, endows the resultant mi- sules. On account of its dynamic nature, 31 crocapsules with stimuli-responsiveness and the CB[n]-mediated host-guest complexation 32 self-adjusting capabilities, and facilitates hi- has demonstrated efficient response toward 33 erarchical microstructures with tuneable sta- various external stimuli such as UV light, 34 bility and porosity, leading to the maturity of pH change, redox chemistry, and compet- 35 current microencapsulation industry. itive guests. Herein, we also demonstrate 36 Supramolecular architectures and materi- different microcapsule modalities, which are n 37 als have attracted immense attention over the engineered with CB[ ] host-guest chemistry and also can be destroyed with the aid of 38 last decade, as they open the possibility to external stimuli, for triggered release of pay- 39 obtain a large variety of aesthetically pleas- ing structures, with myriad applications in loads. In addition to the overview of recent 40 biomedicine, energy, sensing, catalysis and achievements and current limitations of these 41 biomimicry, on account of the inherent re- microcapsules, we finally summarize several 42 versible and adaptive nature of supramolecu- perspectives in tuneable cargo loading and 43 lar interactions. As a subset of supramolecu- triggered release, directions and challenges 44 lar interactions, host-guest molecular recogni- for this technology, as well as possible strate- 45 tion involves the formation of inclusion com- gies for further improvement, which will lead 46 plexes between two or more moieties, with to substaintial progress of host-guest chem- 47 specific three-dimensional structures and spa- istry in supramolecular architectures and 48 tial arrangements, in a highly controllable materials. 49 and cooperative manner. Such highly selec- 50 tive, strong yet dynamic interactions could be 1. Introduction 51 exploited as an alternative methodology for 52 programmable and controllable engineering of supramolecular architectures and materi- The synthesis and self-assembly of polymer building 53 blocks for the construction of functional supramolecular 54 als, exploiting reversible interactions between complementary components. Through the micro-/nano-structures are a major part of the emerging 55 1,2 engineering of molecular structures, assem- field of Supramolecular Polymer Chemistry. The intro- 56 blies can be readily functionalized based on duction of non-covalent supramolecular interactions such as 57 host-guest interactions, with desirable physic- hydrogen bonding, host-guest complexation or electrostatic 58 ochemical characteristics. interactions offers great opportunities to impart novel fea- 3 59 In this account, we summarize the current tures and functions to these polymer systems. As an exam- 60 state of development in the field of mono- ple of such self-assembled architectures, microcapsules have ACS Paragon Plus Environment 1 Submitted to Accounts of Chemical Research Page 2 of 20

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capsules requires future investigation, device design, and in fragment-based drug discovery. He also has research in- 1 process optimization. An important direction for future terests in developing microdroplets as a novel experimental 2 work will be expanding the range of stimuli, which can be platform, which led to the co-founding of Sphere Fluidics 3 incorporated in microcapsule formulations, featuring quanti- (2010) and Aqdot (2013). 4 tative functions and responses that can be activated in these Oren Scherman is the Director of the Melville Labora- 5 dynamic assemblies in a well-controlled manner. A future tory for Polymer Synthesis in the Department of Chemistry 6 challenge is to develop a monitoring strategy, which not only at the University of Cambridge and Professor of Supramolec- 7 controls the microcapsule integrity, but also tracks in situ ular and Polymer Chemistry. His current research projects 8 the cargoes delivery . Further in vitro and in vivo studies include the application of macrocyclic host-guest chem- 9 will be indispensable before CB[n]-based microcapsules are istry using cucurbit[n]urils in the development of novel 10 used for any biomedical applications, as most current stud- supramolecular hydrogels and microcapsules, drug-delivery 11 ies focus on the methodology of microcapsule construction systems based on dynamic hydrogels, the conservation and 12 and state-of-art techniques to trigger the structural destruc- restoration of important historical artefacts through the 13 tion with internal or external stimuli, thus release of the exploitation of supramolecular polymer chemistry and sens- 14 cargoes. Addressing these issues will benefit the design and ing and catalysis using self-assembled nanophotonic systems. 15 fabrication of next-generation supramolecular hierarchical structures and functional materials. Acknowledgement 16 17 J. L. is financially supported by the Marie Curie FP7 SASSYPOL ITN (607602) programme. C.S.Y.T. thanks the 18 Biography Ministry of Education of Malaysia and Universiti Teknologi 19 Ji Liu obtained his PhD in 2013 under the co-supervision MARA for their financial support. Z.Y. and C.A. were 20 of Prof. Christine Jerome at the University of Liege and in receipt of funding from BBSRC sLoLa award reference 21 Prof. Etienne Duguet at the University of Bordeaux. He BB/L002957/1, EPSRC and Institutional Sponsorship 2012- 22 joined the group of Prof. Oren Scherman at the University University of Cambridge EP/K503496/1 and the Transla- 23 of Cambridge as a postdoctoral research associate in 2014 tional Grant EP/ H046593/1. O.A.S thanks the EPRSC 24 and then as a Marie Curie research fellow since 2015. His (EP/F0355351 and EP/G060649/1) and the ERC (ASPiRe, 25 current research is mainly focused on cucurbit[n]uril-based 240629) for their funding. 26 supramolecular host-guest interactions for polymeric self- assembly, supramolecular transient networks and dynamic 27 References 28 interfacial adhesion. Yang Lan completed his PhD at the University of Cam- (1) Brunsveld, L.; Folmer, B.; Meijer, E.; Sijbesma, R. Supramolec- 29 ular polymers. Chem. Rev. 2001, 101, 4071–4098. 30 bridge in 2014 under the supervision of Prof. Oren Scher- (2) Tsivgoulis, G. M.; Lehn, J. M. Photonic molecular devices: re- man. He continued as a joint postdoctoral research asso- versibly photoswitchable fluorophores for nondestructive read- 31 out for optical memory. Angew. Chem. Int. Ed. 1995, 34, 1119– ciate with Prof. Oren Scherman and Dr. Erika Eiser in the 32 1122. Cavendish Laboratory. His current research is centred on (3) Aida, T.; Meijer, E.; Stupp, S. Functional supramolecular poly- 33 mers. 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1 aqueous phase 2 Applications oil 3 sensing 4 oil cell study 5 microreactor 6 drug delivery 7 ... 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 11 Submitted to Accounts of Chemical Research Page 12 of 20

1 Formation of polymer microcapsules strengthened with CB[n] host-guest interactions 2(a) 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 + 22 23 24 25 26 CB[8] 27 28 29 30 31 32 33 34 35 36 st nd 37 1 guest-containing 2 guest-containing 38 polymeric self-assemblies 39 40 polymer 1 polymer 2 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 Phase 1 59 60 Phase 2 Oil

(b) Stepwise formation of CB[8]. Guest 1. Guest 2 ternary complex CB[8] Guest 2 Guest 1

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 (d) 16 17 18 19 20 21 22 23 24 25 (b)26 27 28 (e) 29 30 31 32 33 34 35 36 ACS Paragon Plus Environment 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Submitted to Accounts of Chemical Research Page 14 of 20

1(a) (c) 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31(b) 32 33 34 35 36 (d) 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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(a) (c) 1 2 3 4 Water 5 6 7 8 9 10 11 12 13 14 15 16 17 18 (b)19 20 21 22 23 24 25 26 (g) (d)27 (e) (f) 28 29 30 31 32 33 34 35 36 ACS Paragon Plus Environment 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 (a) Submitted to Accounts of Chemical Research (c) Page 16 of 20

P1 1 micelle 2 Water 3 4 + 5 P2 CB[8] 6 Oil 7 (d) (b)8 C12H25S S CN 9 co b COOH 1-x x n m S COOH 10 O O O O 11 12 O P1 3 13 14 N 15 N 16 17 CN (e) 18 HOOC co co H 19 1-x-y y x N q 20 O O O 21 P2 Cl 22 OH ACSN Paragon Plus Environment 23 24 N I 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 17 of 20 Submitted to Accounts of Chemical Research

(a)1 2 hv1 hv1 3 4 5 hv hv2 6 2 7 8 9 10 11 12 (b)13 14 (c) 15 16 17 180 s 19 20 0 h 3 h 6 h 10 h 21 22 23 24 2530 s 26 27 0 h 3 h 6 h 10 h 28 29 30 31 3260 s 33 ACS Paragon Plus Environment 34 35 0 h 3 h 6 h 10 h 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Submitted to Accounts of Chemical Research Page 18 of 20 Redox-triggered release

1 + e 2 (a) + . (b) 3 + 4 - e . + 5 6 7 + + N N 8 in Na2S2O4 solution Cl- - 9 Cl 10 11 . + + . N N 12 - - 13 Cl Cl 14 15 16 in H2O 17 18 19 Photo-triggered release 20 21 22 hv 23(c) + (d) 24 UV 120 s 25 (365 nm) 26 27 40 min 28 40 min 29 N N N N 30 31 trans cis 32 33 34 35 Competitive guest-triggered release 36 37 38 (g) 39(e) (f) 40 + + 41 42 43 ACS Paragon Plus Environment 44 H2N 45 before rehydration 46 addition of ADA (1 mM) 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 19 of 20 Submitted to Accounts of Chemical Research

(a) Interfacial dendritic (b) 1 2 microcapsule 3 4 5 6 7 8 9 10 11 12 13 (c) 14 15 16 17 18 19 20 21 22 23 24 (d)25 (g) 26 (e) 27 28 29 30 31 32 33 34 35 36 37 38 (f) 39 40 41 42 43 44 ACS Paragon Plus Environment 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Submitted to Accounts of Chemical Research Page 20 of 20 s pha aqueou se 1 2 3 Applications 4 oil 5 sensing 6 7 8 cell study 9 oil 10 microreactor 11 12 drug delivery 13 14 ... 15 16 17 18 19 20 21 22 23 24 25 26 27 ACS Paragon Plus Environment 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60