COMMUNICATION 1800588 (1 of 7) © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mrc-journal.de UV Light–Responsive Peptide-Based Supramolecular Hydrogel for Controlled Drug Delivery Michal E. Roth-Konforti, Michela Comune, Michal Halperin-Sternfeld, Irena Grigoriants, Doron Shabat,* and Lihi Adler-Abramovich* M. E. Roth-Konforti, Prof. D. Shabat School of Chemistry, Faculty of Exact Sciences Tel Aviv University Tel Aviv 69978, Israel E-mail: chdoron@post.tau.ac.il Dr. M. Comune, Dr. M. Halperin-Sternfeld, Dr. I. Grigoriants, Dr. L. Adler-Abramovich Department of Oral Biology, The Goldschleger School of Dental Medicine Sackler Faculty of Medicine Tel Aviv University Tel Aviv 69978, Israel E-mail: LihiA@tauex.tau.ac.il The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/marc.201800588. DOI: 10.1002/marc.201800588 product toxicity, pains caused by post-gela- tion swelling, and short-term release. [1,6] Among the recently developed hydrogel platforms, self-assembling peptides are particularly interesting hydrogel building blocks due to their role as structural ele- ments in biological systems, the extensive possibilities for their chemical and bio- logical decoration and functionalization as well as their facile synthesis using both natural and modified amino acids. [7–11] In addition, self-assembling peptide-based hydrogels represent a promising alterna- tive to tissue engineering scaffolds due to their structural similarity to the extracel- lular matrix, encapsulation stability, water solubility, degradability, and biocompat- ibility. [12–18] The weak forces holding the self-assembling peptide fibers together make the gels also suitable for injection, hence allowing their use in other impor- tant biomedical applications. [19–21] In gen- eral, peptide-based supramolecular hydrogels are formed by physical entanglements of filamentous assemblies as a result of several types of non-covalent interactions among the peptidic building units, including hydrogen bonding, hydrophobic, elec- trostatic, and π–π interactions. The entangled networks, once formed, are able to incorporate biological molecules and offer a stimuli-triggered and well-controlled release capability. [22–24] In this regard, bottom-up self-assembly of peptide building blocks can be rationally designed to generate reproducible hydrogels, to be used as delivery systems. [25,26] Di-phenylalanine (FF), an aromatic dipeptide, which is able to self-assemble into a variety of functional nanostructures has been evaluated as a potential vehicle for drug delivery by conjugating Rhodamine B to the peptide arrays during self-organization in the liquid phase. [27] Importantly, fluorenyl-methoxycarbonyl (Fmoc)-pro- tected diphenylalanine (Fmoc-FF) was one of the first reported dipeptides that were able to form a homogeneous, transparent, self-supporting hydrogel with fibrous nanostructure under physiological conditions, [11,28–34] suggesting its potential use in biological applications, such as controlled drug release, [11] tissue engineering, and cell culture. [29,30,32,33] Previous studies have shown the gelation of Fmoc-modified dipeptides to be medi- ated via hydrogen bonding and π–π interactions. [11,16,29,31,35–37] The Fmoc moiety is widely used to stabilize self-assembly in water via aromatic stacking interactions, [31] and certain Fmoc- protected dipeptides were found to spontaneously form fibrous Hydrogels Low-molecular-weight self-assembled peptides may serve as promising hydrogelators for drug delivery applications by changing their structural network in response to external stimuli. Herein, inspired by the well-studied low-molecular-weight peptide hydrogelator, fluorenyl-methoxycarbonyl- diphenylalanine (Fmoc-FF), a novel peptide is designed and synthesized to include an ultraviolet (UV)-sensitive phototrigger. Similar to Fmoc-FF, 6-nitroveratryloxycarbonyl-diphenylalanine (Nvoc-FF) self-assembles to form a 3D, self-supporting, nanofibrous hydrogel. The Nvoc-FF hydrogel exhibits good mechanical properties with a storage modulus of 40 kPa. UV irradiation of the Nvoc-FF hydrogel encapsulating insulin-fluorescein isothiocyanate (insulin-FITC) results in the cleavage of Nvoc-FF peptide to produce unmasked FF, thereby facilitating the degradation of the hydrogel and the release of insulin-FITC. This release is in linear correlation to the irradiation time. In the present study, a first insight into this rigid, fibrous, light-responsive hydrogel is provided, allowing the fabrication of a novel drug delivery system for controlled release of large molecules. Hydrogels are natural or synthetic water-soluble polymer net- works characterized by high water absorbance capacities and tunable physicochemical properties that can provide spatial and temporal control over the release of loaded cargo, including chemotherapeutic drugs, proteins, or cells. [1–4] The delivery of therapeutic molecules using hydrogels has been widely explored over the past two decades, mainly focusing on synthetic polymer hydrogels. [5] However, the use of these hydrogels is hindered by several limiting factors, such as component, degradation Macromol. Rapid Commun. 2018, 1800588