Editorial pubs.acs.org/Biomac
Click Chemistry in Biomaterials, Nanomedicine, and Drug Delivery he term “click chemistry” is generally used to describe reactions that are quick, highly selective, versatile, and high yielding when connecting two molecular components.1,2 Since the initial recognition of the copper catalyzed azide− alkyne cycloaddition as a click chemistry, a number of reactions have now been so classified, and the concept was further extended by designating certain chemistries as bioclick or bioorthogonal. The latter terms have been reserved for those reactions that can occur in the presence of living biological systems (e.g., cells) or fragile biomacromolecules (e.g., proteins) and that do not interfere with their native processes or functions.3 The bioclick reactions have grown substantially over the past decade and include Michael additions, strain promoted azide−alkyne cycloadditions (SPAACs), photoinitiated thiol−ene reactions, and inverse electron demand Diels−Alder cycloadditions (IEDDACs). These chemical reactions provide powerful and versatile tools for polymer scientists when modifying or synthesizing polymers for a diverse array of applications, ranging from matrices for regenerative medicine to improved drug delivery systems. This Virtual Issue (available at http://pubs.acs.org/page/ bomaf6/vi/biomaterials-nanomedicine.html beginning January 12, 2016) highlights a diverse collection of articles that were published in Biomacromolecules and which apply these click reactions for the preparation of novel polymeric biomaterials. These articles not only demonstrate the breadth and versatility of the modern “bio-click” toolbox, but also the range of applications that have become accessible with these reactions. One of the early examples of the use of bioclick reaction to design biomaterials was reported in 2003 by Lutolf and Hubbell, who explored Michael-type addition reactions between vinyl-sulfone-terminated 4-arm poly(ethylene glycol) (PEG) star polymers and bis-cysteine peptides to generate hydrogels.4 These peptide-functionalized materials were successfully designed to serve as local delivery vehicles to present signals to cells and as a matrix to promote wound healing. This synthetic strategy and approach has been greatly expanded in the drug delivery and tissue engineering communities to engineer materials with tailorable properties. Zhong and Feijen and co-workers have used Michael-type conjugation chemistries to prepare degradable hydrogels from thiol-functionalized dextran and vinyl-sulfone conjugated dextran or acrylate functionalized 4-arm PEG star polymers.5 More recently, Wagner and co-workers reported the use of Michael-type addition between thiols and acrylates and maleimides to synthesize biodegradable polyurethane urea elastomers.6 Over the past decade, the number of bioclick reactions that have found application in polymer science has significantly grown. Two important classes of bioclick reactions are azide− alkyne cycloadditions and thiol-X conjugation reactions. Anseth and co-workers combined these two approaches to generate biofunctional, patterned PEG hydrogels using Cu-catalyzed azide−alkyne addition (CuAAC) chemistry for gel formation and thiol−ene photocoupling for the subsequent immobiliza-
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tion of peptides.7 Another application of CuAAC chemistry was reported by Caruso et al., who combined this click reaction with layer-by-layer self-assembly to form biofunctional and biodegradable microcapsules.8 CuAAC has also been successfully used for the surface modification of cellulosic materials in aqueous media,9 as well as for the fabrication of patterned PEG hydrogel films.10 While CuAAC is widely applied in polymer science, concerns about the toxicity of the copper catalyst and the concomitant need for additional purification have restricted some of the use of these conjugation reactions in biomaterials applications. As a consequence, there has been a strong interest in the development of metal-free bioclick reactions, and one of the earliest reports came from the Bertozzi group, who introduced SPAACs,11 which proceed without the need for a copper catalyst. SPAAC has been used for the synthesis of amphiphilic triblock copolymers that self-assemble into vesicular nanostructures,12 as well as for the formation of in situ cross-linkable hyaluronan hydrogels.13 Becker and co-workers combined SPAAC together with thiol−ene coupling chemistry to produce silicon and glass surfaces that present one- and two-dimensional peptide concentration gradients.14 In addition to CuAAC and SPAAC, a number of other cycloaddition reactions are of increasing interest for the synthesis of biologically related polymers. Many of these proceed in aqueous media at room temperature without the need for a catalyst and thus are attractive alternatives to, e.g., CuAAC. For example, Soichet et al. prepared hyaluronic acid hydrogels via Diels−Alder click chemistry from furan-modified hyaluronic acid and PEG-dimaleimide.15 Ninh and Bettinger used this chemistry to synthesize reconfigurable, biodegradable shape-memory elastomers.16 Another interesting conjugation strategy is the hetero Diels−Alder reaction (HDA) between reactive dienes and highly electron deficient thiocarbonyl thio compounds. This approach is intriguing since polymers that incorporate such electron deficient groups can be prepared by RAFT polymerization using, e.g., benzylpyridine-2-yldithioformiate.17 HDA cycloaddition chemistry has been used to graft poly(isobornyl acrylate) onto cellulose substrates that present cyclopentadienyl functionalities.17 Anseth and co-workers explored the inverse electron demand Diels−Alder click reaction between tetrazine functionalized 4-arm PEG prepolymers and a dinorbornene peptide cross-linker to obtain cell instructive hydrogels.18 Beyond CuAAC and other cycloaddition reactions, a second major class of bioclick chemistries are the thiol−ene and thiol− yne addition reactions. A major advantage of these reactions is the ability to photoinitiate them, so-called photoclick chemistry. Hoyle and Bowman19 pioneered this field, demonstrating the versatility of the spatiotemporal control of the photoclick reactions for material synthesis. Recent directions now exploit the bioclick nature of the thiol−ene and thiol−yne reactions, for example, Stenzel et al. have utilized thiol−ene and thiol− Published: January 11, 2016 1
DOI: 10.1021/acs.biomac.5b01660 Biomacromolecules 2016, 17, 1−3
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Editorial
orthogonal coupling approaches to complement the current toolbox.
yne click reactions to prepare a series of platinum drug delivery carriers.20 Other examples use this class of reactions for postpolymerization modification and include the synthesis of polyesters bearing pendant amine groups (thiol−yne),21 as well as the preparation of multivalent peptide−polymer conjugates (thiol−ene).22 Thiol−ene conjugation chemistry has also been used to conjugate bioactive peptides, such as the MMP-2 substrate PVGLIG, to poly(trimethylene carbonate); these peptide conjugates have been used to prepare enzymedegradable self-assembled nanostructures.23 Another major class of conjugation reactions that has great potential for the synthesis of biorelevant materials are those between aldehydes/ketones and alkoxyamines or hydrazides to form oximes and hydrazones, respectively. While these reactions have been extensively used for the preparation of pH-sensitive polymer−drug conjugates,24 these conjugation chemistries have begun to attract interest for the formation of hydrogels. Segura and Maynard, as well as Becker et al., have used oxime click chemistry to prepare biocompatible hydrogels from multiarm aminooxy PEG prepolymers and bisfunctional aldehydes.25,26 By addition of a small amount of a ketonefunctionalized peptide to the hydrogel formulation, Segura and Maynard demonstrated the encapsulation of mesenchymal stem cells, suggesting their usefulness in regenerative medicine applications.25 Becker and co-workers used azide and alkene functional bis-aminooxy chain extenders to introduce functional groups in their hydrogels that could be postmodified via CuAAC or photo thiol−ene reactions.26 More recently, Segura and Maynard reported the preparation of hydrazine crosslinked hydrogels, which were obtained from hydrazidefunctionalized 8-arm PEG precursors and 8-arm aldehydefunctionalized PEG. The degradation time of these gels could be controlled by changing the structures of the hydrazide groups or by introducing hydroxylamines to form irreversible oxime linkages.27 Finally, two additional examples of bioclick chemistries that have emerged are highlighted. Kramer and Deming developed a new bioclick reaction that is based on the chemoselective alkylation of thioether groups in methionine residues.28 This reaction is an interesting addition to the toolbox of reactions that are available for the preparation of side-chain functional polypeptides, as it is based on the use of a natural amino acid and obviates the need for non-natural functional groups. Native chemical ligation, which is based on the chemoselective reaction between a C-terminal thioester and an N-terminal cysteine residue, is a powerful tool for the total chemical synthesis of proteins.29 In a recent paper, Groll and co-workers have used this strategy for the preparation of peptide side-chain functionalized poly(2-oxazolines).30 The articles described above and included in this Virtual Issue represent just a small fraction of the plethora of research that has been done and is currently underway in developing novel “click” methodologies, as well as exploring innovative applications for the use of these reactions in the design of polymer biomaterials, biologically active polymers, as well as polymeric biointerfaces. The contributions highlighted here are not exhaustive, but meant to bring attention to the potential and opportunities provided by modern “click” chemistries in the preparation of polymeric biomaterials. We hope that this will serve as (further) inspiration to the Biomacromolecules readership to both embrace these conjugation strategies for the design of novel materials, as well as to develop refined bio-
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Kristi S. Anseth, Associate Editor Harm-Anton Klok, Associate Editor
AUTHOR INFORMATION
Notes
Views expressed in this editorial are those of the author and not necessarily the views of the ACS.
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REFERENCES
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