Two-Photon-Triggered Photorelease of Caged Compounds from

Research Article Cite This: ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

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Two-Photon-Triggered Photorelease of Caged Compounds from Multifunctional Harmonic Nanoparticles ́ y Vuilleumier,† Geoffrey Gaulier,‡ Raphaël De Matos,† Daniel Ortiz,§ Laure Menin,§ Jeŕ em Gabriel Campargue,‡ Christophe Mas,∥ Samuel Constant,∥,⊥ Ronan Le Dantec,# Yannick Mugnier,# Luigi Bonacina,‡ and Sandrine Gerber-Lemaire*,†

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†

Institute of Chemical Sciences and Engineering, Group for Functionalized Biomaterials, Ecole Polytechnique Fédérale de Lausanne, EPFL SB ISIC SCI-SB-SG, Station 6, CH-1015 Lausanne, Switzerland ‡ Department of Applied Physics, Université de Genève, 22 Chemin de Pinchat, CH-1211 Genève 4, Switzerland § Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, SSMI, Batochime, CH-1015 Lausanne, Switzerland ∥ Oncotheis, 18 Chemin des Aulx, Plan-les-Ouates, CH-1228 Geneva, Switzerland ⊥ Epithelix, 18 Chemin des Aulx, Plan-les-Ouates, CH-1228 Geneva, Switzerland # Univ. Savoie Mont Blanc, SYMME, F-74000 Annecy, France S Supporting Information *

ABSTRACT: The design of stimuli-responsive nanocarriers has raised much attention to achieve higher local concentration of therapeutics and mitigate the appearance of drug resistance. The combination of imaging properties and controlled photorelease of active molecules within the same nanoconjugate has a great potential for theranostic applications. In this study, a system for NIR light-triggered release of molecular cargos induced by the second harmonic emission from bismuth ferrite harmonic nanoparticles (BFO HNPs) is presented. Silica-coated BFO HNPs were covalently conjugated to a photocaging tether based on coumarin (CM) and L-tryptophan (Trp) as a model molecular cargo. Upon femtosecond pulsed irradiation at 790 nm, Trp was efficiently released from the NP surface in response to the harmonic emission of the nanomaterial at 395 nm. The emitted signal induced the photocleavage of the CM-Trp carbamate linkage resulting in the release of Trp, which was monitored and quantified by ultrahigh performance liquid chromatography−mass spectrometry (UHPLC−MS). While a small fraction of the uncaging process could be attributed to the nonlinear absorption of CM derivatives, the main trigger responsible for Trp release was established as the second harmonic signal from BFO HNPs. This strategy may provide a new way for the application of functionalized HNPs in dual imaging delivery theranostic protocols. KEYWORDS: coumarin-based photosensitive tether, harmonic nanoparticles, light-triggered uncaging, release quantification, surface functionalization

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INTRODUCTION Harmonic nanoparticles (HNPs), which are composed by noncentrosymmetric metal oxide nanocrystals presenting a highly efficient nonlinear response, were introduced in recent years for multiphoton imaging applications with the aim of overcoming some limitations of fluorescent probes.1−5 Most of traditional nanophotonic approaches (quantum dots,6 plasmonic NPs,7 and upconversion NPs8) are constrained by fixed excitation bands, often in the UV−visible spectral domain. HNPs can be easily imaged using their second harmonic emission in response to excitation from the UV to IR.9 Despite their lower brightness compared to fluorescent probes, these nanomaterials present a series of favorable properties, including the absence of photobleaching, blinking, and saturation as well as spectrally narrow emission signals,10 © XXXX American Chemical Society

which make them ideal candidates for in vitro and in vivo bioimaging applications.11−13 Among various types of HNPs, which have been assessed for their harmonic efficiency,14 bismuth ferrite (BiFeO3, BFO) HNPs have been identified as highly promising nonlinear imaging probes due to their very high second-order nonlinear efficiency15 and their good biocompatibility once coated with poly(ethylene glycol) (PEG) derivatives.16 Recently, we demonstrated the suitability of PEG-coated BFO HNPs for selective imaging and cell tracking in tissue samples by exploiting the simultaneous acquisition of the second and third harmonic signals to Received: May 7, 2019 Accepted: July 5, 2019 Published: July 5, 2019 A

DOI: 10.1021/acsami.9b07954 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

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ACS Applied Materials & Interfaces segregate their optical response from endogenous background sources.17,18 However, to the best of our knowledge, the harmonic emission from HNPs, which has been recently exploited to increase photosensitization efficiency for photodynamic therapy,19 has not yet been exploited for triggering the uncaging of molecular cargos. There has been a growing interest in the engineering of inorganic nanoparticles, which combine efficient imaging capability with surface properties amenable to chemical functionalization with stimuli-responsive molecules. Seminal achievements were reported with mesoporous silica NPs, which present inner pores fitting with the immobilization of guest payload therapeutics and an outside particle surface suitable for external functionalization with imaging probes and gating molecules responsive to changes in redox potential or pH, light activation, or enzymatic cleavage.20 In particular, nanocomposites based on gold NPs combined with mesoporous silica NPs were highlighted for the intracellular delivery of chemotherapeutic agents.21−24 Most of the systems, which rely on light activation for releasing caged molecular cargos, make use of high-energy UV light for excitation of the photoresponsive scaffolds (2-nitrobenzyl, coumarin, and nitrodibenzofuran),25,26 thus limiting their practical biomedical applications due to poor penetration depth and damaging effects to living cells and tissues. Nearinfrared (NIR) light presents high tissue penetration depth and reduced photodamage in living systems. In this respect, lanthanide-doped upconversion NPs based on NaYF4 nanocrystals can convert continuous NIR laser radiation into UV or visible photons via a multiphoton process. Taking advantage of this property, several upconversion nanostructures were developed for the targeted release of small interfering RNA27,28 and anticancer chemotherapeutics29,30 in cancer cell lines31 and tumor-bearing mice models.32−38 The inherent flexibility of HNPs associated with their tunable response and the possibility to apply double excitation protocols through adjustable wavelengths17,18 would be highly advantageous in the context of light-triggered uncaging of molecular cargos conjugated at the surface of these nanomaterials. It would indeed allow for decoupling the imaging modality from photoactivation processes and for enabling the sequential release of several caged compounds responsive to different wavelength activations.39,40 Herein, we present the first effective NIR light-responsive nanocarrier system based on functionalized BFO HNPs (Figure 1). In our approach, L-tryptophan (Trp) was selected as a model molecular cargo, which was covalently conjugated at the surface of the nanoparticles through a photoresponsive tether based on coumarin (CM). Trp, which is the key ingredient for the production of serotonin, was intensively studied for the treatment of depressive disorders.41 The delivery of Trp from nanocarriers could provide a valuable therapeutic approach for clinical conditions requiring systemic Trp concentrations.42 As previously established by our group,43 the conjugation strategy made use of copper-free azide−alkyne [3 + 2] cycloaddition (click reaction) at the surface of coated BFO HNPs. First, we quantified the release of Trp from the nanoconjugate under direct irradiation from the UV-A source (366 nm). Then, upon femtosecond pulsed NIR radiation at 790 nm, the second harmonic emission from functionalized BFO HNPs caused photocleavage of the CMbased tether resulting in the uncaging of Trp, which was monitored and quantified by ultrahigh performance liquid chromatography−mass spectrometry (UHPLC−MS). We

Figure 1. Controlled uncaging of molecular cargo triggered by the harmonic emission of functionalized BFO HNPs. BFO HNPs are coated and post-functionalized through the copper-free click reaction with a caged (CM-based tether) molecular cargo (Trp). NIR excitation (790 nm) of BFO HNPs results in harmonic emission at 395 nm, which triggers the photocleavage of the CM-Trp linkage and subsequent release of Trp.

ensured that the conditions of the laser pulsed irradiation inducing Trp uncaging and exposure to functionalized BFO HNPs did not induce any significant cytotoxicity in HCC827 cells. In this study, the covalent linkage to the surface of coated BFO HNPs makes the nanocarrier system highly stable in a physiological environment, thus preventing any premature release of the molecular cargo. In addition, due to the multiharmonic response, which can be obtained from BFO HNPs, this work is an important step in the development of nanocarrier platforms allowing decoupled imaging in tissue depth and on-demand release of therapeutics.

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EXPERIMENTAL SECTION

Materials and Methods. Reagent grade solvents (Fluka and Riedel-de-Haën) and chemicals (Aldrich, Acros, Fluka, Sigma, Maybridge, TCI Chemicals, Apollo, and Fluorochem) were used without further purification. All reactions were performed in flamedried glassware under an inert atmosphere of nitrogen. All products were dried under vacuum (10−2 bar) before analytical characterization. Reactions were monitored by thin-layer chromatography (TLC) on precoated aluminum plates SiO2 60 F254 (Merck, Darmstadt, Germany). The compounds were visualized by 254 nm light or stained with solutions of KMnO4, Pancaldi reagent [(NH4)6MoO4, Ce(SO4)2, H2SO4, H2O], ninhydrin, or iodine vapors. B


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ACS Applied Materials & Interfaces

Scheme 1. Synthesis of Trp-CM Derivative 4 To Be Conjugated to BFO HNPs through Copper-Free Azide−Alkyne [3 + 2] Cycloaddition

Purifications were performed by flash chromatography (FC) on silica gel (Merck N 9385 silica gel 60, 240−400 mesh, particle size 40−63 μm). NMR spectra were recorded on Bruker Avance III-400, Bruker Avance-400, or Bruker DRX-400 spectrometers (Bruker, Billerica, MA, USA) at room temperature (rt), unless otherwise stated. 1H frequency is at 400.13 MHz, and 13C frequency is at 100.62 MHz. Chemical shifts are reported downfield from tetramethylsilane. 1H signals are reported in ppm with the internal chloroform signal at 7.26 ppm, the internal methanol signal at 3.31 ppm, or the internal DMSO signal at 2.50 ppm as internal references. 13C NMR signals are reported in ppm with the internal chloroform signal at 77.00 ppm, the internal methanol signal at 49.00 ppm, or the internal DMSO signal at 39.5 ppm as internal references. The resonance multiplicity is described as s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), and m (multiplet). Broad signals are indicated as br. Coupling constants (J) are given in hertz (Hz). IR spectra were recorded on a Jasco FT/IR-4100 spectrometer outfitted with a PIKE technology MIRacle ATR accessory as neat films compressed onto a zinc selenide window. The spectra are reported in cm−1 (w = weak, m = medium, s = strong, sh = shoulder). The qualitative accurate masses were measured by ESI-TOF using the Xevo G2-S QTOF (Waters) and nanoESI-FT-MS using the Elite Hybrid Ion Trap-Orbitrap (ThermoFisher) mass spectrometer (more details in Supporting Information S-16). Quantitative MS analyses were performed on a 6530 Accurate-Mass Q-TOF LC−MS mass spectrometer coupled to the 1290 Infinity UHPLC system (Agilent Technologies, USA). The separation was achieved using an ACQUITY UPLC BEH C18 1.7 μm column, 2.1 mm × 50 mm (Waters) heated at 30 °C using water and acetonitrile as mobile phases. Measurements of the dynamic light scattering and zeta potential were obtained using a Malvern NanoZ instrument (Malvern Instruments, Malvern, U.K.). Centrifugations were performed on a HERAEUS Biofuge 13 centrifugator. Scanning transmission electron microscopy (STEM) was performed at the Interdisciplinary Centre for Electron Microscopy (CIME, EPFL, Lausanne, Switzerland) on a FEI Titan Themis 60−300 microscope. Release of Trp under UV-A Irradiation. UV-induced photolysis experiments were performed with a Sylvania UV-light tube (366 nm, 8 W). BFO-APTES-CM-Trp NPs (2 mg) were suspended in PBS (1 mL; pH = 7.4, 144 mg/L KH2PO4, 9000 mg/L NaCl, 795 mg/L Na2HPO4·7H2O) and sonicated for 30 min to achieve good dispersion. The resulting suspension was placed in eight-well

borosilicate coverglass polystyrene chambers (Nunc Lab-Tek II, Merck) and irradiated at 366 nm. Aliquots (135 μL) of the suspension were withdrawn at the indicated time points, diluted with PBS to 270 μL, and centrifuged (20 min, 13,000 rpm). Quantification of Trp in the supernatant (triplicates) was performed by LC−MS. Details of the parameters for UHPLC-ESI-HRMS analysis and calibration curves are provided in the Supporting Information (S-18 and Figure S1). Two-Photon Release Experiments. The setup was based on an amplified Ti:sapphire laser system (Astrella, Coherent) with a 5 W average output at a 1 kHz repetition rate. The system delivers laser pulses centered at 790 nm with a 35 nm bandwidth corresponding to a 27 fs transform limited pulse duration. The actual duration measured by a second harmonic generation frequency-resolved optical gating (SHG-FROG) device (PulseCheck, APE Berlin) yields a value of 35 fs. The beam diameter, measured using a beam profiler (Newport) placed at the laser output, corresponds to 6.5 mm (FWHM). The beam was directed to the bottom surface of the multiwell plate containing the sample solution through a 45° dielectric mirror, without focusing. The peak intensity at the sample corresponds to 430 GW/cm2. Given the comparatively high peak intensity, we ensured that the optical properties of BFO NPs in solution do not change upon irradiation (Figure S8). Functionalized BFO HNPs (2 mg) were suspended in PBS (1 mL; pH = 7.4, 144 mg/L KH2PO4, 9000 mg/L NaCl, 795 mg/L Na2HPO4·7H2O) and sonicated for 30 min to achieve good dispersion. The resulting suspension was placed in eight-well borosilicate coverglass polystyrene chambers (Nunc Lab-Tek II, Merck) and irradiated at 790 nm. Aliquots (135 μL) of the suspension were withdrawn at the indicated time points, diluted with PBS to 270 μL, and centrifuged (20 min, 13,000 rpm). Quantification of Trp in the supernatant (triplicates) was performed by LC−MS. Details of the parameters for UHPLCESI-HRMS analysis and calibration curves are provided in the Supporting Information (S-18 and Figure S1). Determination of Cytotoxicity. HCC827 cells were grown at a density of 3 × 104 cells/cm2 in an RPMI-1640 culture medium (Merck) supplemented with 10% calf serum. Then, the medium was changed, and cells were irradiated for 15 min at 790 nm and 25 °C, using the laser setup conditions described above. After irradiation, the cytotoxicity was evaluated by dosing lactate dehydrogenase (LDH) C


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ACS Applied Materials & Interfaces Scheme 2. Preparation of Functionalized BFO HNPs for Photo-Triggered Uncaging of Trpa

a

BFO HNPs are coated with a silica layer displaying surface amino and azido groups. Trp is conjugated via copper-free azide-strained alkyne [3 + 2] cycloaddition with (BFO-APTES-CM-Trp) or without (BFO-APTES-Trp) a photosensitive caging group. 0.56 mmol, 1.1 equiv) and DIPEA (0.17 mL, 1.02 mmol, 2.0 equiv) in dry DCM (2 mL) was added, and the solution was stirred at rt under an argon atmosphere for 24 h. The solvent was removed under reduced pressure, and the residue was purified by FCC (PE/EtOAc 7:3 to 3:7) to afford tert-butyl-(((7-(ethyl(prop-2-yn-1-yl)amino)-2oxo-2H-chromen-4-yl)methoxy)carbonyl)-L-tryptophanate as a yellow foam (0.193 g, 0.35 mmol, 69%). 1H NMR (400 MHz, chloroform-d, δ): 8.35 (s, 1H, NHindole), 7.60 (d, J = 8.0 Hz, 1H, indole-H), 7.37 (d, J = 8.1 Hz, 1H, coumarin-H), 7.29 (d, J = 8.6 Hz, 1H, indole-H), 7.22−7.15 (m, 1H, indole-H), 7.12 (dt, J = 7.8, 1.4 Hz, 1H, indoleH), 7.05 (d, J = 2.3 Hz, 1H, indole-H), 6.68 (d, J = 8.2 Hz, 2H, 2× coumarin-H), 6.06 (t, J = 1.4 Hz, 1H, coumarin-H), 5.45 (d, J = 8.3 Hz, 1H, NHamide), 5.19 (ddd, J = 77.8, 15.5, 1.4 Hz, 2H, CH2coumarin), 4.68−4.58 (m, 1H, CHtryptophan), 4.07 (d, J = 2.4 Hz, 2H, R2N− CH2CCH), 3.52 (q, J = 7.1 Hz, 2H, R2N−CH2−CH3), 3.37 (dd, J = 14.8, 5.4 Hz, 1H, CH2tryptophan), 3.23 (dd, J = 14.9, 6.7 Hz, 1H, CH2tryptophan), 2.24 (t, J = 2.4 Hz, 1H, R2N−CH2CCH), 1.43 (s, 9H, 3× CH3tert‑butyl), 1.29−1.23 (m, 3H, R2N−CH2−CH3). HRMS (ESI): [M + Na]+ calcd for C31H33N3NaO6+, 566.2262; found, m/z 566.2265 (mass error: 0.5 ppm). 1H-NMR and 13C NMR spectra and IR data (Supporting Information S-9). TFA (2.5 mL) was added to a solution of this intermediate (0.270 g, 0.49 mmol, 1.0 equiv) in DCM (10 mL), and the reaction mixture was stirred at rt for 6 h under dark conditions. The volatiles were removed under reduced pressure, and the residue was purified by FCC (DCM/MeOH 9:1) to afford 2 as a yellow foam (0.164 g, 0.34 mmol, 68%). 1H NMR (400 MHz, DMSO-d6, δ): 10.85 (d, J = 2.3 Hz, 1H, NH indole), 7.62 (bs, 1H, NHamide), 7.54 (d, J = 8.0 Hz, 1H,

released in the culture supernatant (see Supporting Information S-26 for detailed experimental conditions). A suspension of BFO-APTES-CM-Trp NPs (2 mg) in EtOH (1 mL) was centrifuged for 10 min. The solvent was removed and replaced by a cell culture medium (RPMI-1640 supplemented with 10% calf serum, 1 mL). The suspension was sonicated for 30 min and diluted with a cell culture medium to reach a concentration of 10 μg/ mL. HCC827 cells were incubated with the resulting BFO-APTESCM-Trp NPs suspension for 16 h at 37 °C. At the end of the treatment, cell viability was evaluated by dosing LDH released in the culture supernatant (see Supporting Information S-26 for detailed experimental conditions). Additionally, HCC827 cells incubated with BFO-APTES-CM-Trp NPs for 16 h at 37 °C were irradiated for 15 min at a 1 kHz repetition rate at 790 nm and 25 °C using the laser setup conditions described above. After irradiation, cell viability was evaluated by dosing LDH released in the culture supernatant (see Supporting Information S-26 for detailed experimental conditions). All experiments were conducted in triplicates. Synthesis Protocols. Designation of the compounds refers to the chemical structures presented in Schemes 1 and 2. Preparation of (((7-(Ethyl(prop-2-yn-1-yl)amino)-2-oxo-2H-chromen-4-yl)methoxy)carbonyl)-L-tryptophan (2). Compound 1 (0.132 g, 0.51 mmol, 1.0 equiv) and 4-nitrophenyl chloroformate (0.124 g, 0.62 mmol, 1.2 equiv) were dissolved in dry DCM (10 mL) under an argon atmosphere and placed under dark conditions. DIPEA (0.28 mL, 1.64 mmol, 4.0 equiv) was added, and the reaction mixture was stirred at rt for 16 h. A solution of tert-butyl-L-tryptophanate (0.167 g, D


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ACS Applied Materials & Interfaces indole-H), 7.46 (d, J = 9.0 Hz, 1H, coumarin-H), 7.32 (d, J = 8.0 Hz, 1H, indole-H), 7.14 (d, J = 2.3 Hz, 1H, indole-H), 7.07 (t, J = 7.5 Hz, 1H, indole-H), 6.96 (t, J = 7.3 Hz, 1H, indole-H), 6.78 (dd, J = 9.1, 2.6 Hz, 1H, coumarin-H), 6.68 (d, J = 2.5 Hz, 1H, coumarin-H), 6.06 (d, J = 1.5 Hz, 1H, coumarin-H), 5.20 (q, J = 16.0 Hz, 2H, CH2coumarin), 4.23 (d, J = 2.5 Hz, 2H, R2N−CH2CCH), 4.15 (td, J = 8.2, 4.5 Hz, 1H, CHtryptophan), 3.52 (d, J = 11.6 Hz, 2H, R2N− CH2−CH3), 3.25 (dd, J = 14.6, 8.7 Hz, 1H, CH2tryptophan), 3.19 (t, J = 2.3 Hz, 1H, R2N−CH2CCH), 3.02 (dd, J = 14.5, 8.7 Hz, 1H, CH2tryptophan), 1.15 (t, J = 7.0 Hz, 3H, R2N−CH2−CH3). HRMS (ESI): [M + H]+ calcd for C27H26N3O6+, 488.1816; found, m/z 488.1819 (mass error: 0.6 ppm). 1H NMR and 13C NMR spectra and IR data (Supporting Information S-10). Preparation of (((7-(((1-(2-(2-(2-(2-Aminoethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)(ethyl)amino)-2-oxo-2H-chromen-4-yl)methoxy)carbonyl)- L-tryptophan hydrochloride (3). Compound 2 (65.4 mg, 0.13 mmol, 1.0 equiv) was added to a solution of azido-PEG3-amine hydrochloride (37.5 mg, 0.15 mmol, 1.1 equiv) that dissolved in a mixture of THF/H2O (5 mL, 1:1). CuSO4 (10.4 mg, 0.07 mmol, 0.5 equiv) and sodium ascorbate (26.2 mg, 0.13 mmol, 1.0 equiv) were added, and the reaction mixture was stirred at rt under an argon atmosphere and dark conditions for 24 h. The solvents were removed under reduced pressure, and the residue was purified by preparative TLC (CH3CN/H2O 8:2) to afford 3 as a brown salt (60.7 mg, 0.8 mmol, 61%). 1H NMR (400 MHz, Methanol-d4, δ): 7.79 (s, 1H, triazole-H), 7.64 (d, J = 7.8 Hz, 1H, indole-H), 7.41 (d, J = 9.0 Hz, 1H, coumarin-H), 7.31 (d, J = 8.0 Hz, 1H, indole-H), 7.13 (s, 1H, indole-H), 7.05 (t, J = 7.5 Hz, 1H, indoleH), 6.97 (t, J = 7.4 Hz, 1H, indole-H), 6.76 (dd, J = 9.0, 2.5 Hz, 1H, coumarin-H), 6.61 (d, J = 2.5 Hz, 1H, coumarin-H), 6.10 (s, 1H, coumarin-H), 5.16 (dd, J = 4.0 Hz, 2H), CH2coumarin), 4.71 (s, 2H, R2N−CH2−triazole), 4.51 (t, J = 4.9 Hz, 2H, R−CH2−CH2− triazole), 4.34 (dd, J = 7.6, 4.5 Hz, 1H, CHtryptophan), 3.78 (t, J = 4.9 Hz, 2H, R−CH2−CH2−triazole), 3.62 (dd, J = 14.3, 7.2, 2H, R2N− CH2−CH3), 3.48 (t, J = 5.1 Hz, 2H, R−CH2−CH2−NH2), 3.42 (t, J = 4.5 Hz, 1H, CH2tryptophan), 3.32 (m, 8H, CH2−O−CH2), 3.14 (dd, J = 14.5, 7.6 Hz, 1H, CH2tryptophan), 2.97 (t, J = 5.1 Hz, 2H, R−CH2− CH2−NH2), 1.25 (t, J = 7.0 Hz, 3H, R2N−CH2−CH3). HRMS (nanochip-ESI/LTQ-Orbitrap) m/z: [M + H] + calcd for C35H44N7O9+, 706.3195; found, m/z 706.3180 (mass error: 2.1 ppm). 1H NMR and 13C NMR spectra and IR data (Supporting Information S-11). Preparation of Photosensitive Tether 4. DIPEA (9.4 μL, 53.8 ummol, 2.0 equiv) was added to a stirred solution of 3 (20.0 mg, 26.9 μmol, 1.0 equiv) in dry DMF (1 mL) under an argon atmosphere and dark conditions. Compound 6 (11.4 mg, 29.6 μmol, 1.1 equiv) was added, and the reaction mixture was stirred at rt for 24 h. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC (DCM/MeOH 8.5:1.5) to afford 4 as a yellow solid (8.7 mg, 9.1 μmol, 34%). 1H NMR (400 MHz, methanol-d4, δ): 7.83 (s, 1H, triazole-H), 7.62 (d, J = 7.8 Hz, 1H, indole-H), 7.54 (d, J = 7.6 Hz, 1H, coumarin-H), 7.37−7.24 (m, 9H, indole-H and CHAr‑cyclooctyne), 7.12 (s, 1H, indole-H), 7.05 (t, J = 7.5 Hz, 1H, indole-H), 6.97 (t, J = 7.5 Hz, 1H, indole-H), 6.73 (dd, J = 9.0, 2.6 Hz, 1H, coumarin-H), 6.60 (s, 1H, coumarin-H), 6.07 (s, 1H, coumarin-H), 5.42−5.30 (m, 1H, CHcyclooctyne), 5.25−5.05 (m, 2H, CH2coumarin), 4.65 (s, 2H, R2N−CH2−triazole), 4.48 (t, J = 5.1 Hz, 2H, R−CH2−CH2−triazole), 4.45 (dd, J = 7.9, 4.4 Hz, 1H, CHtryptophan), 3.80−3.77 (m, 2H, R−CH2−CH2−triazole), 3.66 (s, 2H, O−CH2−CH2−NHRamide), 3.56 (q, J = 6.9 Hz, 2H, R2N−CH2− CH3), 3.50−3.42 (m, 8H, CH2−O−CH2), 3.40−3.35 (m, 1H, CH2tryptophan), 3.29−3.22 (m, 2H, O−CH2−CH2−NHRamide), 3.21− 3.10 (m, 1H, CH2tryptophan), 2.76 (dd, J = 15.1, 4.3 Hz, 1H, CHcyclooctyne), 2.06 (dd, J = 15.5, 8.6 Hz, 2H, CHcyclooctyne), 1.20 (t, J = 7.1 Hz, 3H, R2N−CH2−CH3). HRMS (ESI/QTOF) m/z: [M + Na]+ calcd for C52H53N7NaO11+, 974.3695; found, m/z 974.3701(mass error: 0.6 ppm). 1H NMR and 13C NMR spectra and IR data (Supporting Information S-13). Coating and Functionalization of BFO HNPs. Cyclohexane (2 mL) was added to a suspension of BFO nanoparticles in EtOH (2 mg,

2 mL), and the mixture was ultrasonicated for 30 min. Si(OEt)4 (2.0 μL, 10 μmol, 2.0 equiv), APTES (1.2 μL, 5 μmol, 1.0 equiv), and a solution of 7 (1.7 mg, 5 μmol, 1.0 equiv) in EtOH (100 μL) were added, and the suspension was ultrasonicated for 30 min. NH4OH aq (0.1 mL, 25%) was added, and the suspension was ultrasonicated at 40 °C for 16 h under an argon atmosphere. The suspension was divided into Eppendorf tubes and centrifuged (10 min, 13,000 rpm), and the supernatant was removed. The solid residue was sequentially washed and centrifuged with EtOH (four times, 1 mL), and the resulting BFO-APTES-N3 NPs were suspended in EtOH (1 mL) for storage. BFO-APTES-N3 NPs (2 mg) were suspended in EtOH/DMF (1:1, 2 mL), and a 2 mM solution of 4 (25.0 μL) in DMF was added. The suspension was ultrasonicated at 40 °C for 16 h under dark conditions. The suspension was divided into Eppendorf tubes and centrifuged (10 min, 13,000 rpm). The solid residue was sequentially washed and centrifuged with EtOH (three times, 1 mL) and PBS (three times, 1 mL). Finally, the resulting BFO-APTES-CM-Trp NPs were suspended in PBS (1 mL) for further experiments. The same protocol was applied to produce BFO-APTES-Trp NPs. In Figure S7, we provide a comparison of the nonlinear response (SHG and multiphoton-excited fluorescence) of BFO (Figure S7C,D) and BFOAPTES-CM-Trp NPs (Figure S7A,B).

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RESULTS AND DISCUSSION

Preparation of Caged Trp Derivatives for Conjugation to BFO HNPs. In view of the possibility to introduce chemical modifications at different positions of CM resulting in a tunable absorption range from 320 to 475 nm, the design of the photosensitive tether made use of 7-amino-coumarin derivative 1 (synthesis adapted from the protocol reported by Zhao et al.,37 described in Supporting Information S-3) as a central core for sequential functionalizations (Scheme 1). Activation of the primary alcohol as 4-nitrophenylcarbonate, followed by condensation with the tert-butyl ester of Trp, afforded the CM-Trp carbamate linkage, which will be cleaved by UV irradiation. To modulate the polarity of the system, azido-PEG3-amine (5) was appended through the click reaction with the terminal alkyne to afford intermediate 3 in a 61% yield. To achieve high reactivity toward BFO HNPs displaying azido groups on their coated surface, the 4dibenzocyclootyne moiety was introduced by coupling with derivative 644 (synthesis described in Supporting Information S-6) affording the targeted photolabile tether 4 in a moderate yield. Coating and Functionalization of BFO HNPs. We previously established a robust protocol for surface coating of metal oxide NPs, which makes use of (triethoxy)silyl groups for stable surface silanization.45 Similarly, BFO HNPs (prepared by a precipitation route46) were coated in the presence of a 1:1 mixture of (3-aminopropyl)triethoxysilane (APTES) and azido-terminated derivative 7 (synthesis described in Supporting Information S-14) to provide a suspension of NPs displaying surface reactive groups for subsequent functionalization (Scheme 2). In agreement with previous report,46 BFO nanocrystals prepared by a chelating agent-free precipitation route presented a mean diameter around 100 nm (observed by dynamic light scattering) without morphology control. Their second harmonic conversion efficiency has recently been estimated from SH scattering spectroscopy experiments leading to a strong orientation-averaged second-order susceptibility measured at ∼200 pm/V for a 780 nm excitation wavelength.47 After addition of the silica coating layer, the average size from TEM observations is at about 80−90 nm E


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ACS Applied Materials & Interfaces (Figure 2). The resulting coated BFO-APTES-N3 NPs were subjected to spontaneous [3 + 2] cycloaddition between the

Figure 3. Extinction spectra of compound 4, BFO NPs, BFOAPTES-N3 NPs, and BFO-APTES-CM-Trp NPs irradiated between 200 and 700 nm.

Figure 2. Representative scanning transmission electron microscopy images of BFO-APTES-N3 NPs: (A) Bi EDX map; (B) Fe EDX map; (C) high-angle annular dark-field image.

strained alkyne moiety of photosensitive tether 4 and the surface azido groups of the coating layer. After ultrasonication at 40 °C for 16 h in the dark conditions, functionalized HNPs were separated from an unreacted material by cycles of centrifugation (10 min, 13,000 rpm) and washing (EtOH, three times; then PBS, three times), followed by final resuspension in PBS. Upon coating and functionalization, the zeta potential value of HNPs shifted from −28.1 ± 0.6 mV (BFO) to 20.2 ± 0.4 mV (BFO-APTES-N3) and − 3.0 ± 0.4 mV (BFO-APTESCM-Trp), which is consistent with the evolution of the surface composition (introduction of amino groups during the coating procedure and of carboxylate moieties from Trp). Functionalized nanoparticles were sonicated for 30 min to achieve good dispersion before the photorelease process. The initial concentration of Trp conjugated to coated HNPs was evaluated at 3.29 μM/mg by comparison of the UV−vis absorption spectrum of BFO-APTES-CM-Trp NPs to standard curves of compound 4 between 0 and 1000 μM (Figure 3). As control for the light-triggered release experiments, Trp was conjugated to coated BFO HNPs without the CM-containing caging group, affording BFO-APTES-Trp nanoconjugates. UV Light-Triggered Release of Trp from Functionalized BFO HNPs. A first set of experiments was carried out to characterize the photocleavage and subsequent release of Trp from CM-Trp conjugate 4 using a UV lamp (366 nm, 8 W). A sample of 4 in PBS (4 μM) was irradiated for 6 h, and the products released in solution were monitored by LC−MS (Figure 4). The unique component released in the medium was confirmed to be Trp because of its coelution with the Trp standard after 1.5 min and its accurate measured mass ( 0.05; *p < 0.05; **p < 0.01; ***p < 0.001.

irradiation at a 1 kHz repetition rate at 790 nm for 15 min at 25 °C, cell viability remained high (more than 80%). The same results were obtained upon incubation of HCC827 cells for 16 h at 37 °C in the presence of BFO-APTES-CM-Trp NPs, followed by 15 min irradiation at 790 nm and 25 °C. Then, the release of Trp from the surface of BFO-APTESCM-Trp NPs suspended in PBS was evaluated using the same laser pulsed irradiation conditions. After 15 min, the release of Trp reached almost 60% and continued at a slower rate to provide more than 70% release after 30 min (Figure 6) (the ratio and percentage of released Trp are given in Table S4 with SD values). As noted for the UV-light triggered release experiment, the unique component released in the medium upon NIR irradiation was confirmed to be Trp by UHPLC− MS. To establish that the uncaging process resulted from the photocleavage of the CM-Trp carbamate linkage induced by the second harmonic emission from BFO-HNPs, two comparative experiments were carried out. First, Trpconjugated BFO HNPs, which do not contain the CM-based

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CONCLUSIONS A synthetic route was developed to prepare a photosensitive CM-Trp conjugate, which was covalently conjugated to coated BFO HNPs using copper-free azide−alkyne [3 + 2] cycloaddition. The resulting nanoconjugates were assessed for their ability to release Trp under direct UV light irradiation and, in a two-photon setup, the harmonic emission from the HNPs triggering the uncaging of Trp. The covalent functionalization strategy based on the formation of a triazole moiety offers high stability toward a large range of external stimuli (pH variation and enzymatic cleavage) and thus preserves the nanocarrier system from premature undesired release. Comparison of the G


Research Article

ACS Applied Materials & Interfaces Funding

Trp release profiles from BFO-APTES-CM-Trp NPs irradiated at 366 and 790 nm demonstrated the efficiency of the second harmonic generation to induce the photolytic cleavage of the CM-Trp linkage as compared to direct two-photon absorption. Complementary experiments involving Trp-conjugated BFO HNPs but lacking the CM-based tether established the light-triggered cleavage of the CM-Trp carbamate bond to be responsible for the release of Trp in a PBS medium. In addition, the irradiation conditions resulting in the release of Trp from the surface of BFO-APTES-CMTrp NPs did not induce any significant detrimental effect on the viability of HCC827 cells. Noteworthy, the versatility of BFO HNPs for multiharmonic imaging in cells and tissue combined with the covalent photocaging of the molecular cargo at their surface paves the way for decoupled imaging and photoactivation protocols based on functionalized BFO HNPs. Alternatively, the conjugation of several caging groups sensitive to distinct excitation wavelengths could be used for the sequential on-demand release of different molecular cargos, and the second harmonic emission from BFO HNPs is being controlled by the laser excitation wavelength. The caging pathway herein presented makes use of a carbamate linkage with the amino group from Trp. However, as the photolytic cleavage of coumarin-4-yl methoxy carbonyl derivatives operates similarly for the release of amines, alcohols, thiols, and carboxylic acids, a large variety of molecular cargos, including drugs,50 could thus be envisaged for conjugation to coated BFO HNPs.

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The authors acknowledge financial support from the FranceSwitzerland Interreg program (Interreg fédéral, Vaud state, Geneva state) and from the 2015−2020 French Contract Plan Etat Région (project E-TIME). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are thankful to Prof. Jérôme Kasparian (Nonlinearity and Climate Group, Group of Applied Physics & Institute for Environmental Sciences, University of Geneva) for granting us access to his femtosecond laser platform. The authors thank Drs Pascal Miéville and Aurélien Bornet for their support with NMR experiments and Dr. Thomas LaGrange (EPFL, CIME) for STEM experiments.

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ABBREVIATIONS APTES, (3-aminopropyl)triethoxysilane BFO, bismuth ferrite CM, coumarin DCM, dichloromethane DIPEA, N,N-diisopropylethylamine DMF, N,N-dimethylformamide FCC, flash column chromatography HNP, harmonic nanoparticle LDH, lactacte dehydrogenase NIR, near infrared PBS, phosphate-buffered saline PEG, poly(ethylene glycol) rt, room temperature SD, standard deviation TFA, trifluoroacetic acid TLC, thin-layer chromatography Trp, L-tryptophan UHPLC−MS, ultrahigh performance liquid chromatography−mass spectrometry

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsami.9b07954.

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Analytical data (1H and 13C NMR spectra); quantitative analysis by UHPLC-ESI-HRMS; characterization of the release of Trp from BFO-APTES-CM-Trp NPs; evaluation of cytotoxicity by dosing LDH release; multiphoton multispectral microscopy for BFOAPTES-CM-Trp NPs (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: sandrine.gerber@epfl.ch. ORCID

Yannick Mugnier: 0000-0002-1923-6553 Luigi Bonacina: 0000-0003-0476-4473 Sandrine Gerber-Lemaire: 0000-0002-6519-2782 Author Contributions

The manuscript was written through contributions of all authors. J.V. designed and performed the functionalization pathways, prepared, and characterized the functionalized nanoparticles, contributed to the uncaging experiments and analyzed tryptophan release. G.G. designed and performed the multiphoton uncaging experiments. R.D.M. developed functionalization pathways. D.O. and L.M. performed the quantification of tryptophan release. G.C. performed the multiphoton imaging experiments. C.M. and S.C. designed and performed the cell assays. R.D.L. and Y.M. designed and performed the preparation of the harmonic nanocrystals. L.B. and S.G.-L. supervised the project, designed the experiments, and prepared the manuscript. H


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Two-Photon-Triggered Photorelease of Caged Compounds from

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