COMMUNICATION Photocleavable Polymers www.mrc-journal.de Coumarin-Caged Polyphosphazenes with a Visible-Light Driven On-Demand Degradation Aitziber Iturmendi, Sabrina Theis, Dominik Maderegger, Uwe Monkowius, and Ian Teasdale* desired response. Consequently, several Polymers that, upon photochemical activation with visible light, undergo photo-responsive polymers have been pre- rapid degradation to small molecules are described. Through functionaliza- pared that have great promise in diverse tion of a polyphosphazene backbone with pendant coumarin groups sensitive applications such as drug delivery, porous membranes, and film patterning.[4b,9] to light, polymers which are stable in the dark could be prepared. Upon irra- Macromole cules that undergo photo- diation, cleavage of the coumarin moieties exposes carboxylic acid moieties chemical backbone degradation are also along the polymer backbone. The subsequent macromolecular photoacid is of significant interest.[10] Most reported found to catalyze the rapid hydrolytic degradation of the polyphosphazene photo-cleavable systems require ultraviolet backbone. Water-soluble and non-water-soluble polymers are reported, which (UV) light to achieve cleavage, which can due to their sensitivity toward light in the visible region could be significant be a drawback especially in biomedical environments due to low penetration and as photocleavable materials in biological applications. biocompatibility, hence a shift to longer wavelengths is required.[11] Coumarin and its analogs are widely employed in There is considerable demand for stimuli-responsive polymers various fields such as medicine, polymer science, cosmetics, that can undergo chemical or physical changes in response to and biology.[12] Coumarin derivatives can be readily synthesized triggers such as pH,[1] biomolecules,[2] temperature, oxidation,[3] and functionalized to red-shift the light absorption,[12] cage the and light.[4] Macromolecules which undergo triggered backbone desired molecule as protecting groups,[13] and/or to be incorpo- disassembly or degradation upon response to stimuli could be of rated on the polymer main chain as photoresponsive units.[14] particular importance for a range of future applications including It is also reported that coumarin photocages can be cleaved via sensory materials, lithography, and triggered release systems.[5] two-photon processes with near-infra-red irradiation.[15] In addi- One approach involves self-immolative polymers[6] which are tion, functionalized aliphatic polycarbonates,[16] photodegradable designed to undergo end-to-end disassembly upon a triggering hydrogels,[17] and drug delivery systems[18] based on coumarin event.[7] More recently, a small number of chain-shattering poly- derivatives have been developed. Furthermore, the ability of some mers have been described, a term used to describe polymers coumarin polyesters to undergo chain scission or crosslinking with multiple responsive cleavage sites along the backbone.[3b,8] upon certain wavelength irradiation has been demonstrated.[14,19] Among the investigated stimuli, light is notably attractive Herein, we present a novel approach to photodegradable due to its ability to exert spatial and temporal control over the polymers based on coumarin-functionalized polyphospha- zenes. Polyphosphazenes are unique due to their hydrolytically Dr. A. Iturmendi, D. Maderegger, Prof. I. Teasdale unstable backbone which can be tailored through the incorpo- Institute of Polymer Chemistry ration of different substituents.[20] Furthermore, the polyphosp- Johannes Kepler University Linz hazene degradation pathway is known to be acid-catalyzed,[21] a Altenberger Strasse 69, 4040 Linz, Austria E-mail: [email protected] process which can be intramolecular when acidic substituents [22] Dr. S. Theis are present on the polymer backbone. Hence we proposed Institute of Inorganic Chemistry that through functionalization of polyphosphazenes with a Johannes Kepler University Linz coumarin-caged amino acid as a pendant group along the back- Altenberger Strasse 69, 4040 Linz, Austria bone, the sensitivity of the polymers to hydrolysis would be Prof. U. Monkowius accelerated upon irradiation by effectively producing a macro- Linz School of Education molecular photoacid which could subsequently catalyze its own Johannes Kepler University Linz Altenberger Strasse 69, 4040 Linz, Austria degradation. The ORCID identification number(s) for the author(s) of this article First 7-(N,N-diethylamino)-4-(hydroxymethyl)coumarin 1 can be found under https://doi.org/10.1002/marc.201800377. (Figure S1, Supporting Information) was prepared according [15] © 2018 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, to literature procedures. After reaction with N-(tert-butox- Weinheim. This is an open access article under the terms of the Creative ycarbonyl)glycine (Boc-gly-OH) and deprotection, this gave Commons Attribution License, which permits use, distribution and re- the coumarin-caged glycine 3 (Figures S2 and S3, Supporting production in any medium, provided the original work is properly cited. Information).[23] Coumarin 1 was chosen as caging group as it DOI: 10.1002/marc.201800377 is expected to be photochemically active in the visible region Macromol. Rapid Commun. 2018, 39, 1800377 1800377 (1 of 6) © 2018 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advancedsciencenews.com www.mrc-journal.de Figure 1. a) Photocleavage reaction of the coumarin-caged glycine 3. b) Change of the emission spectra of 3 in MeOH/H2O (4:1) solution upon irra- diation with HBO lamp (100 W, cut-off filter at 395 nm, conc. 10−7 mol L−1). (— before irradiation; …5 min irradiation; ¨10 min irradiation; •15 min 1 −1 1 irradiation; -- 25 min irradiation). c) H NMR analysis of the photocleavage of 3 in MeOD/D2O (4:1) solution (conc. 0.082 mol L ). Entire H NMR spectra are shown in Figure S5, Supporting Information. due to the electron-donating diethylamino group.[24] The chlorine atoms were substituted with either Jeffamine M-1000, kinetics of the elementary photochemical reaction of 3 has been a polyether monoamine, or glycine ethyl ester to obtain pol- investigated recently by flash-photolysis[23] but not under steady ymer P1 and polymer P2, respectively. illumination. Hence, we first investigated the photo-cleavage Polymer P1 was synthetized using Jeffamine M-1000 as the reaction of compound 3 upon irradiation (100 W, ≥395 nm) second substituent to give a water-soluble polymer. M-1000 in MeOH/H2O (4:1) solution. UV–vis spectroscopy (Figure S4, was also chosen to ensure that the hybrid polymer remained Supporting Information) showed a decrease in absorption hydrolytically stable in the timeframe of the photochemical intensity and shifted to lower wavelength (from 382 to 377 nm) reactions[21] and hence to be able to induce a photochemical after irradiation, indicative of the decaging of the glycine moiety degradation without significant interference from undesired (Figure 1a). Interestingly, an increase in intensity and slight hydrolytic degradation. The polymer was purified by dialysis hypsochromic shift (from 478 to 473 nm) was observed in the in the dark and characterized by 1H and 31P NMR spectros- emission spectra upon irradiation (Figure 1b). This ceased after copy (Figure S6, Supporting Information), size exclusion chro- approximately 25 min irradiation, indicating completion of the matography (SEC) in DMF containing 10 mM LiBr (Figure S7, 1 −1 photosolvolysis reaction. H NMR spectroscopy (Figure 1c) also Supporting Information, Mn,GPC = 149 000 g mol , and confirmed the nature of the photocleavage reaction, albeit with Mw/Mn = 1.03, measured using multidetector calibration) and a lower reaction rate due to the higher concentration required dynamic light scattering (DLS) (Figure S8, Supporting Informa- −7 −1 −1 −1 (10 mol L vs 0.082 mol L ). tion, d = 12.25 nm ± 0.38 nm in H2O at 1 mg mL ). According Our approach was to extend this photodecaging phenom- to 1H and 31P NMR spectroscopy complete backbone substi- enon to “cage” a hydrolytically unstable glycine-substituted tution in a ratio of nearly 34:66 (coumarin derivative:M-1000) phosphazene moiety through incorporation of the coumarin- could be observed with no additional peaks in the 31P NMR caged glycine onto a polyphosphazene backbone. Polydichlo- corresponding to partially substituted phosphorous atoms. rophosphazene was first prepared via phosphine-mediated UV–vis spectroscopy (Figure S9, Supporting Information) polymerization of trichlorophosphoranimine[25] (Scheme 1, showed the loading to be approximately 14 wt%, which corre- see Supporting Information for detailed procedure). First, the sponds roughly to 35:65 ratio, coumarin derivative to M-1000 coumarin-cage 3 was added in order to substitute the majority substituents. of chlorine atoms. For related amino acid esters, it is known The polymer was irradiated (100 W, ≥395 nm) in aqueous that monosubstitution at the phosphorus atom is strongly solution to investigate its photochemical properties. The photo- favored due to the higher reactivity of Cl2PN in comparison reaction was followed by UV–vis (Figure 2a) and fluorescence to ClRPN,[26] therefore, we expect a distribution of the cou- spectroscopy (Figure 2b). In the UV–vis spectra, one prominent marin groups along the backbone. Thereafter, the remaining long wavelength absorption band with a maximum at 386 nm Macromol. Rapid Commun. 2018, 39, 1800377 1800377 (2 of 6) © 2018 The