Specific Interaction of Tricyclic Antidepressants with Gold and Silver

Article pubs.acs.org/JPCC

Specific Interaction of Tricyclic Antidepressants with Gold and Silver Nanostructures as Revealed by Combined One- and Two-Photon Vibrational Spectroscopy Vesna Ž ivanović,†,‡ Fani Madzharova,† Zsuzsanna Heiner,†,‡ Christoph Arenz,†,‡ and Janina Kneipp*,†,‡ †

Department of Chemistry, Humboldt-Universität zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany School of Analytical Sciences Adlershof SALSA, Humboldt-Universität zu Berlin, Albert-Einstein-Str. 5−11, 12489 Berlin, Germany

‡

S Supporting Information *

ABSTRACT: We report two-photon excited nonresonant surface-enhanced hyper Raman scattering (SEHRS) spectra of tricyclic antidepressant (TCA) molecules during their interaction with biocompatible gold nanostructures and with silver nanostructures. The SEHRS spectra of amitriptyline, desipramine, and imipramine are compared with surface-enhanced Raman scattering (SERS) spectra on both kinds of nanoparticles, obtained with excitation at 532 and 785 nm. The SEHRS spectra of the TCA molecules show several intense contributions by infrared-active vibrations. Combining SEHRS with SERS therefore enables a comprehensive vibrational characterization of the interaction of the molecules with the nanostructures. SEHRS and SERS data indicate that the molecules interact with the silver nanostructures mainly via their ring moiety. In contrast, in the interaction with gold, the methylaminopropyl side chain plays a very important role, along with parts of the ring system. It is possible to obtain the spectra of the molecules with near-infrared excitation and with gold nanoparticles in cell culture media. The spectral signatures of the drug molecules collected at low pH values characteristic of late endosomal stages or of acidified tissues are very stable and show only small changes in the interaction of the TCA with the gold nanoparticles. The results will help to develop tools for the characterization of new nanoparticle-based drug delivery platforms in real biological environments.

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INTRODUCTION Tricyclic antidepressants (TCAs) are an important group of drugs. Initially used for the clinical treatment of major depression disorders, TCA have been suggested as potential treatments for a variety of other diseases, such as neuropathic pain disorders1 or irritable bowel syndrome.2 Furthermore, TCA molecules have anti-inflammatory, antimicrobial,3 and antitumoral activity.4 They were shown to have an influence on lipid metabolism,5 specifically, TCAs reduce the acitivity of the acid sphingomyelinase and acid ceramidase enzymes in the lysosomes.6,7 A destabilization of the lysosomal membranes has been proposed as a main cause of cell death and ultimately antitumoral activity of the compounds,8−11 yet details about the molecular interaction of the TCA molecules with the biological environment and different bioorganic molecules must be elucidated. Vibrational spectra, particularly Raman scattering and infrared (IR) absorption spectra, can provide detailed information about the structure and interactions of active substances and biological molecules12−14 and have become important tools for studying complex biological samples, such as cells and tissues in healthy and diseased state.15,16 The twophoton excited analogue of the spontaneous Raman scattering process, hyper-Raman scattering (HRS), can be used to obtain complementary vibrational information by probing infrared© XXXX American Chemical Society

active and silent vibrational modes that cannot be observed in the normal, one-photon excited Raman spectrum.17−19 The intrinsically weak HRS process becomes very strong when the local optical fields of plasmonic nanostructures are employed in surface-enhanced hyper Raman scattering (SEHRS).20−24 As we and others have shown in the last years, by SEHRS, vibrational information complementary to surface-enhanced Raman scattering (SERS) spectra can be obtained from organic molecules and complex biosamples,25−31 and specifically from their interaction with the surface of metal nanostructures. Recent findings suggest that SEHRS is much more sensitive toward small changes in molecular structure and local adsorbate environments than SERS is.28,32,33 As will be shown here as well, SEHRS can provide additional chemical information. Because some of the vibrations and molecular groups are observed in only one spectrum and not the other, the two kinds of vibrational spectra provide more comprehensive information about the TCA molecules and their orientation with respect to the gold or silver surface than SERS spectra alone. Combining SEHRS and SERS can give better insight into the interaction of Received: August 11, 2017 Revised: September 15, 2017 Published: September 18, 2017 A

DOI: 10.1021/acs.jpcc.7b08026 J. Phys. Chem. C XXXX, XXX, XXX−XXX

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The Journal of Physical Chemistry C

10−4 M to 10−7 M, depending on the particular experiment. Concentrations are given with the respective spectra in Results and Discussion. For experiments in the cell culture media, the nanoparticles with the molecules were mixed with Dulbecco’s Modified Eagle Medium supplemented with 10% of fetal calf serum (FCS) in a final concentration of TCA molecules of 9 × 10−7 M. To adjust pH values, NaOH was used. The Raman setup was described in ref 32 before. Surfaceenhanced hyper-Raman (SEHRS) spectra were excited at 1064 nm with an excitation intensity of 2.1 × 1011 W cm−2 using a mode-locked laser producing 7 ps pulses with a repetition rate of 76 MHz. One-photon excitation at 532 nm was generated as second harmonic signal from the picosecond 1064 nm laser; the applied intensity was 1.2 × 1010 W cm−2. Excitation at 785 nm was provided by a CW laser with an excitation intensity of 2.0 × 105 W cm−2. The sample solution was placed in a microcontainer, and the excitation light was focused on the samples through a microscope objective. SEHRS spectra were accumulated for 5 min, while SERS spectra were accumulated for durations of 1−5 s. The Raman light was collected in backscattering geometry and detected by a liquid nitrogen-cooled CCD (Horiba, Munich, Germany). After frequency calibration using a spectrum of toluene, the SEHRS spectra were background corrected using the method provided in ref 38. Most spectral analyses were carried out on averaged spectra; averages were separately calculated from 100 SERS spectra and 30 SEHRS spectra.

the active molecules with the nanoparticles as well as with other bioorganic compounds, in vitro and in cells. In this paper, we report SEHRS spectra of the three tricyclic antidepressant (TCA) molecules amitriptyline (Ami), desipramine (Des), and imipramine (Imi) (Figure 1) and discuss

Figure 1. Structure and labeling of antidepressant molecules, imipramine (Imi), desipramine (Des), and amitriptyline (Ami).

them in comparison to their one-photon excited SERS spectra. The SERS spectra of the molecules have been published previously,14,30,34 and propositions regarding their interaction with the surface of silver nanoparticles have been made.30 Using the two-photon excited SEHRS spectra here, and by employing both gold and silver nanoparticles, the comprehensive vibrational characterization reveals that the interaction of the molecules with nanostructure surfaces, as well as with other molecular species, strongly differs for silver and gold surfaces and is very characteristic even at varied concentration and pH. With potential applications in cells and tissues in mind, we report spectra from biocompatible gold nanostructures,35 obtained under conditions that are relevant for experiments in biological environments, such as cell culture media. Our findings may have implications for the application of combined one- and two-photon vibrational characterization in therapeutic drug monitoring, studies of drug-biomolecule interactions, as well as for the construction of new multifunctional nanocarriers based on gold nanoparticles.

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RESULTS AND DISCUSSION In order to investigate the interactions of the antidepressant molecules with gold and silver nanoparticles, both one- and two-photon excited surface-enhanced Raman scattering, that is, SERS and SEHRS, were employed. Both, gold and silver nanostructures were synthesized using citrate as reducing agent and stabilizer. Transmission electron micrographs of the nanostructures used in the experiments are shown in Figure 2, together with ultraviolet−visible (UV−vis) absorbance spectra at the condition of the respective experiment, that is,

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MATERIALS AND METHODS Desipramine hydrochloride, imipramine hydrochloride, amitriptyline hydrochloride, gold(III) chloride hydrate, silver nitrate, sodium hydroxide, sodium chloride, and hydrochloric acid were purchased from Sigma-Aldrich. Fetal calf serum (FCS) and Dulbecco’s Modified Eagle Medium (DMEM) were purchased from Biochrom. All solutions were prepared using Milli-Q water. Different batches of gold nanoparticles with an average size of 30 and 60 nm termed here Au30 and Au60, respectively, were obtained by the reduction of gold(III) chloride hydrate with sodium citrate according to the protocols reported in refs 36 and 37 yielding a concentration for Au30 of 4 × 10−10 M and for Au60 of 7 × 10−11 M. Silver nanoparticles (AgNP) were prepared according to ref 36 by reduction of silver nitrate with sodium citrate, resulting in a nanoparticle concentration of 2 × 10−11 M. Desipramine hydrochloride, imipramine hydrochloride, and amitriptyline hydrochloride were separately dissolved in water and mixed with the nanoparticles/nanoaggregates at a volume ratio of 1:10, yielding final concentrations in the range from

Figure 2. Transmission electron micrographs of (A) silver nanoparticles (Ag), (B) the gold nanoparticles with average size 30 nm (Au30), and (C) gold nanoparticles with average size 60 nm (Au60). (D) UV−vis absorbance spectra of the AgNP (black line), Au30 (red line), and Au60 (blue line) with addition of desipramine (Des). B


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Figure 3. (A) SEHRS and (B) SERS spectra of the antidepressants imipramine, desipramine and amitriptyline obtained with silver and gold nanostructures. Concentration of the TCA moelcules: 9 × 10−5 M for Au and 9 × 10−4 M for Ag nanostructures. (A) Excitation wavelength, 1064 nm; intensity, 2.1 × 1011 W cm−2; acquisition time, 5 min. (B) Excitation wavelength, 532 nm; laser intensity, 1.2 × 1010 W cm−2; acquisition time, 5 s. Scale bars: (A) SEHRS, 0.1 cps; (B) SERS, 50 cps.

in the presence of the TCA molecules. The silver nanoparticles have a size of 110 nm (Figure 2A). Two different samples of citrate-stabilized gold nanoparticles were used, one with a mean diameter of 30 nm (Figure 2B), the other with a diameter of 60 nm (Figure 2C). Figure 2D shows the absorbance of the plasmonic nanostructures in the presence of one of the TCA molecules, desipramine. Prior to the addition of the TCA molecules, the citrate-reduced silver and gold nanoparticles exhibit the typical absorbance maxima around 420 nm for silver, and 530 and 542 nm for the two different batches of gold nanoparticles, respectively (Figure S1 in the Supporting Information). After the addition of the TCA molecules, all nanoparticles indicate absorbance by a broad, extended plasmon resonance (Figure 2D). A change in color is also observed by eye when the TCA molecules are added. As shown in Figure 3A, it was possible to obtain high-quality nonresonant SEHRS spectra of all three compounds, using both silver and gold nanoparticles. The SEHRS spectra of amitriptyline (Ami), desipramine (Des), and imipramine (Imi) (Figure 1) were excited at a wavelength of 1064 nm (Figure 3A), and corresponding one-photon excited SERS spectra using 532 nm excitation were measured (Figure 3B). The SEHRS

signals with silver and gold nanoparticles are on the same order of magnitude; this is in accordance with the main contribution of the SEHRS enhancement being discussed to result from the local fields of nanoaggregate structures,39,40 whose formation is indicated in the absorbance spectra (Figure 2D). To date, relatively few reports on SEHRS spectra using gold nanoparticles are known.41,42 In the case of the system studied here, SEHRS and SERS spectra obtained with gold nanostructures are of particular interest because of the biocompatibility of the gold and its potential use as drug carrier. SEHRS and SERS Spectra Give Complementary Information. Both one- and two-photon excited spectra with the two types of nanoparticles are characteristic of the three TCA molecules, and the SERS spectra on silver nanoparticles obtained here (Figure 3B, second, fourth, and bottom traces) are in good agreement with those reported previously.30,34 We obtained very similar SEHRS spectra (Figure 3A) and very similar SERS spectra (Figure 3B) of the three different drugs, and as discussed in detail below, the spectra indicate an interaction characteristic of gold and silver nanostructures (cf. every second spectrum in Figure 3A,B). At first glance the spectral differences between spectra on silver and gold appear C


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The Journal of Physical Chemistry C greater than the differences between the three molecules. Nevertheless, as will be shown, the spectra of the molecules display significant qualitative differences, depending on their structure and specific interaction with a particular kind of nanoparticle (cf. every second spectrum in Figure 3A,B). Band assignments for the spectra of Ami, Des, and Imi are provided in Tables 1, 2, and 3, respectively. After common spectral

Table 2. Raman Shift Values in the SEHRS and SERS Spectra of Desipramine and Assignment to Vibrations of the Desipramine Molecule, Based on Refs 30, 43, 67, and 68 Raman shift (cm−1) SEHRS

SERS

assignmentsa

1630 − 1575 1487 1475 − 1386 1329 1296 1280 1232 1206 1155 1107 1055 1039 1018 − − − − − − 765 − 677 622 585 566 − −

− 1597 1576 − 1472 1440 1363 1335 1295 − 1229 1207 1152 − 1056 1040 − 973 865 846 812 791 774 − 685 673 620 585 562 538 496

str (CC/RII) i-p bend (CC/RI,RII) str (CC/RI), str (CC/RII) bend (CH2) def (CH2)3, def (CH3) sciss (CH2/aliph) symm def (CH3), i-p bend (CH2/aliph) str (CC/RIII, bridge bond) i-p bend (CH2) str (NC/RIII), rock (CH/RI), twist (CH2/RIII) str (CC/RIII), i-p bend (RI,II), str (CC/RI,II) rock (CH/RI,II) bend (CH/RI,II) str (CC/RI), rock (CH/RI) str (CC/aliph), str (CC/RII) str (CC/RI,II) str (CC/RIII), rock (CH2/RIII) o-o-p bend (CH/RI) bend (CH2) o-o-p bend (CH/RI,II) bend (CH2), bend (RI) twist (RI,II), wag (N2H), i-p bend (RI,II), str (CC/RIII) def CH (RI,II) i-p bend (RI,II), str (CC/RIII), twist (RI,II) i-p bend (RI,II) twist (RI,II), i-p bend (RIII) twist (RI,II,III) i-p bend (RI,II,III), wag (N1C/aliph) i-p bend (CH2), twist (RI) twist (RI,II,III), i-p bend (RI,II), wag (N1C/aliph)

Table 1. Raman Shift Values in the SEHRS and SERS Spectra of Amitriptyline and Assignment to Vibrations of the Amitriptyline Molecule, Based on Refs 30, 43, 67, and 68 Raman shift (cm−1) SEHRS

SERS

assignmentsa

1623 1590 1575 1487 1464 − − − 1360 − 1295 1280 − 1206

1614 1590 1556 1486 1462 1438 1428 1378 1363 1335 1290 1273 1221 1207

1177 1161 −

1170 − 1159

− 1039 1018 − − 782 − − 775 724 − 633 − 585 − 533

1055 1040 − 973 870 791 846 812 774 710 685 635 620 585 562 533

− −

485 445

i-p bend (CC/RI,RII) str (CC/RI,II), def (CH/RI,II) str (CC/RI,II) bend (CH2) bend (CH2/aliph), str (RI) bend (CH2/aliph), str (RI) i-p bend (NC/Me) i-p bend (CH2) rock (CH2/aliph), str (CC/RIII), def CH3 bend (CH2/aliph) str (CC/RIII, bridge bond) i-p bend (CH/RI,II), bend (CH2/aliph), str (RI) i-p bend (RI,II) str (CC/RIII), i-p bend (RI,II), rock (CH/RII), str (CC/ RI,II) i-p bend (CH2) rock (CH/RI,II) str (CC/RIII), rock (CH/RI), i-p bend (RI,II), str (CC/ RI,II) str (CC/RI), rock (CH/RI) str(CC/aliph), rock (CH/RII) str (CC/RI,II) str (CC/RIII), rock (CH2/RIII), i-p bend (RI) o-o-p bend (CH/RI,II) twist (RI,II), wag (N2H), i-p bend (RI,II), str (CC/RIII) i-p bend (CH2) o-o-p bend (CH/RI,II) twist (RI,II), wag (N2H), i-p bend (RI,II), str (CC/RIII) twist (RI,RII) i-p bend (RI,II), str (CC/RIII) def (RI,II) twist (RI,II), i-p bend (RIII) twist (RI,II,III) i-p bend (RI,II,III)1 i-p bend (RII), twist (RI,II), str (CC/RIII), i-p bend (CC/ RIII) in-plane bend (RI,II) twist (RI,II,III)

a

str, stretching; def, deformation; bend, bending; sciss, scissoring; wag, wagging; rock, rocking; twist, twisting; i-p bend, in-plane bending; o-o-p bend, out-of-plane bending.

two-photon excited case, although with varied relative intensities. This similarity of the SEHRS and the SERS spectra is expected, because the interaction of the molecules with the nanoparticles’ surface lowers their symmetry further, specifically of the ring moieties. As examples, contributions by the C−C stretching modes, together with C−H deformation vibrations of the rings, are found in most examples, as indicated by the bands around 1206 cm−1, e.g. in the spectra obtained with the silver nanoparticles (second, fourth, and bottom traces in Figures 3A and 3B), and at ∼1160 cm−1 (all spectra in Figure 3A,B). Similarly, a C−C stretching vibration of the sevenmembered ring at ∼1295 cm−1 is found both in SEHRS and SERS spectra, when the molecules interact with a silver surface. Furthermore, C−C stretching from the aliphatic tail at ∼1040 cm−1 appears in both SERS and SEHRS spectra, with very similar relative intensity, except in SEHRS of Des and Imi on gold nanostructures. Even though the SEHRS spectra share many of the bands with the SERS spectra, they are very different with respect to many of them as well. A large number of modes in the fingerprint region of the spectra occur either in the SEHRS or

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features for all three molecules are evaluated first, some further specifics in the SEHRS spectrum of each TCA are discussed in a separate paragraph. The respective SEHRS and SERS spectra differ greatly for each molecule and type of nanostructure (compare each line in the combined Figure 3A,B) over the whole spectral range. Many of the bands are present in both the one-photon and the D


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dibenzazepine ring at 973 cm−1,30 probably of a six-membered ring, this band is not found in any of the SEHRS spectra. This observation is in accord with the absence of bands of this and similar modes in the SEHRS spectra of other organic molecules in our previous studies.27,28 Vice versa, a strong band at 765 cm−1 is particularly enhanced in SEHRS of Des and Imi, but is absent from their SERS spectra (Figure 3A,B, red and black traces). It is not seen in the normal Raman spectra either (Figure S2), but it makes a very intense contribution to the IR spectrum of Des. There, the band is assigned to a deformation vibration of the −CH groups in the aromatic rings. Furthermore, the SEHRS spectra, specifically on silver nanoparticles, show a strong signal at 585 cm−1, which is neither visible in the SERS data of Figure 3B nor in the normal Raman spectra (Figure S2). The IR spectrum, however, clearly reveals a band at 585 cm−1. It is possible that an in-plane bending vibration of dibenzazepine ring is probed by SEHRS here, which would be specifically enhanced upon an interaction of the ring moieties with the silver surfaces that was predicted in ref 30. Furthermore, the SEHRS spectra are all characterized by an intense band at 1487 cm−1, which we assign to a deformation mode of CH2 group(s) of the aliphatic chain, observed at this frequency also in IR spectra43 (Figure 3A, first, third, and fifth traces). In the SERS spectra in this frequency range, other deformation modes of CH2 groups at lower frequency, from both the sevenmembered ring and the aliphatic chain, dominate this spectral region, with contributions around ∼1462 and ∼1440 cm−1 (Figure 3B, first, third, and fifth traces).30,43 Also in the higherfrequency range, with a different scaling shown in the Figure S3, C−C stretching modes of the dibenzazepine ring, which have very low intensity in the normal Raman spectra (Figure S2) but are also strong in the IR spectra, e.g., the mode at 1575 cm−1, become very pronounced. The high similarity of the SEHRS spectra with IR data is in accord with previous observations in SEHRS experiments with other organic molecules27,28,33,44−46 and with predictions according to the selection rules for the hyper Raman process that can probe IR active or even silent vibrational modes. SEHRS Spectrum of Amitriptyline. Figure 3A shows the SEHRS spectra of amitriptyline (Ami) obtained with gold and silver nanostructures separately (blue traces in Figure 3A). For comparison, the one-photon excited SERS spectra of the identical samples are shown in Figure 3B (blue traces). The assignments of the bands are given in Table 1. As stated above, the spectra show intense contributions from vibrations of the dibenzazepine ring of the molecule, and also from the aliphatic chain. The dominating band at 1487 cm−1 in the SEHRS spectra of the two CH2 groups of the aliphatic chain is complemented by smaller contributions that originate from other vibrations of the chain. Furthermore, an intense band at 1206 cm−1 in the spectrum obtained on the gold nanoparticles, assigned to the C−C stretching vibration in the sevenmembered ring, is observed (Figure 3A, first spectrum). The relative intensity of this C−C stretching vibration with respect to other C−C stretching is similar to that of the mode at 1623 cm−1 (compare Figure S3A, first trace to the other traces) and for example also is higher on gold nanoparticles than on silver. Another SEHRS signal that we assign to the dibenzazepine ring is found at 782 cm−1; it has a higher frequency than the CH deformation of the phenyl rings in Imi and Des discussed above and a stronger contribution on silver nanoparticles. Its position suggests a contribution from a C−C

Table 3. Raman Shift Values in the SEHRS and SERS Spectra of Imipramine and Assignment to Vibrations of the Imipramine Molecule, Based on Refs 30, 43, 67, and 68 Raman shift (cm−1) SEHRS

SERS

assignmentsa

− 1575 − 1487 1475 − 1386 1333 1296 1284 1232

1590 1576 1556 − 1472 1440 1363 1329 1295 − 1229

− 1206 1177 1155 1055 1039 − − − − − − 765 − 677 622 585 566 − −

1221 1202 1167 1156 − 1040 1030 973 861 846 812 787 − 685 673 620 585 562 538 496

i-p bend (CC/RI,RII) str (RI,II) str (RI,II) bend (CH2) def (CH2)3, def (CH3) i-p bend (Me), sciss (CH2/aliph) symm def (CH3) i-p bend (CH2/aliph) str(CC/RIII, bridge bond) i-p bend(CH2) str (NC/RIII), rock (CH2/aliph), twist (CH2/aliph), str (NC/aliph) i-p bend (RI,II) str (CC/RIII), i-p bend (RI,II) i-p bend (CH2) rock (CH/RI,II) str (CC/RI), str (NC/aliph) str (CC/aliph), sciss (CH2/aliph), i-p bend(NC/Me) str(CC/aliph), sciss(CH2/aliph), i-p bend(NC/Me) str (CC/RIII), rock (CH2/RIII) o-o-p bend (CH/RI), i-p bend (CH2) i-p bend (CH2) o-o-p bend(CH/RI,II) o-o-p bend(CH/RI), bend(CH2) twist (RI,II), wag (N2H), i-p bend (RI,II), str (CC/RIII) i-p bend (RI,II), str (CC/RIII), twist (RI,II) i-p bend (RI,II) twist (RI,II), i-p bend (RIII) twist (RI,II,III) i-p bend (RI,II,III), wag (N1C) i-p bend (CH2), twist (RI) i-p bend (CH2/aliph), rock (NC)

a


in the SERS spectrum, or have very different relative intensities in both spectra, illustrating the complementarity of the spectral information. The fact that some vibrations contribute to the SEHRS spectrum of a molecule when interacting with, e.g., gold nanoparticles, but to the SERS spectrum of the same molecule only with silver nanoparticles, evidences the very sensitive probing of local surface interaction by both methods and indicates the strong influence that the interaction with the nanoparticles exerts on molecular symmetry. A very obvious difference between SERS and SEHRS spectra common to all three TCA molecules is the absence of the intense signal of ring deformation mode at 685 cm−1 in the SEHRS spectra on silver nanoparticles. Similarly, on gold nanoparticles, the very intense bands at 846 and 812 cm−1 (Figure 3B) that we assign to N−C deformation vibrations of the methylaminopropyl side chain are absent from the SEHRS spectra. In the normal Raman spectra, these bands, specifically the former two, are also very pronounced (Figure S2). In similarity to the SEHRS spectra, the bands are absent in IR spectra, as was reported for the case of Des.43 While most of the SERS spectra display a band of a breathing vibration of the E


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The SEHRS spectra show several smaller differences between Imi and Des, for example, the band at 1177 cm−1 in the Imi spectrum and the band at 1155 cm−1 in the Des spectrum. In both molecules, we assign it to the rocking of the CH from the phenyl rings,30 and this difference being pronounced on the silver nanoparticles underpins the conclusion of a strong interaction of the ring system with the silver surface. Also, C−C stretching modes of the phenyl ring around 1107 cm−1 and at 1055 cm−1 display slightly different contributions. On the gold nanoparticles, only very weak or no bands at this position are present. Interaction of the Molecules with Gold and Silver Nanostructures. Considering the high sensitivity of the SEHRS and the SERS spectra with respect to molecular interaction and surface environmental changes, the great differences that become evident during the discussion of the SEHRS and SERS spectra obtained on gold and silver nanoparticles must be the result of a varied interaction of the molecules with the surfaces of both kinds of nanostructures. In the SERS data, the appearance and relative intensity of a certain band can provide information on the orientation of the molecules.47−49 Specifically, the vibrational modes of the aromatic rings give this information based on the relative intensity of in-plane and out-of-plane vibrations.49,50 In SEHRS, relying on other selection rules, changes in adsorbate orientation can lead to much more pronounced changes in the spectra than in SERS,22,51,52 and the possibility of probing other adsorbate species and/or interaction sites on the same surface28,32 can add a wealth of information. Because of the complementarity of the SEHRS and SERS spectra, we use both together to discuss the differences in the interaction of the TCA molecules. Apart from the excitation of SERS spectra at 532 nm, (Figure 3B), Figure S4 also shows SERS spectra that were obtained with an excitation wavelength of 785 nm on both metal nanostructures. On the silver surface, the SEHRS spectra of all molecules contain pronounced signals assigned to several vibrational modes of the ring systems, specifically the in-plane bending modes of the phenyl rings at 622, 585, and 566 cm−1 (see Figure 3B, second, fourth, and sixth traces). Their higher intensity on the silver nanostructures suggests an interaction of the rings with the surface. On the silver nanostructures, the strong band at 765 cm−1 of the −CH deformation of the phenyl rings shows a lower ratio with respect to the in-plane deformation modes than on the gold nanoparticles (compare respective red and black spectra in Figure 3A). In the case of Ami, this is less pronounced, and a C−C stretching of the seven-membered ring appears at 782 cm−1. All SERS spectra measured with silver nanoparticles, those excited at 532 nm (Figure 3B) as well as those obtained at an excitation wavelength of 785 nm (Figure S4), support the observations made in the SEHRS spectra, which point at an interaction of the ring system with the silver surface. As examples, the breathing and strong C−C stretching modes of the ring at 973 and ∼1040 cm−1, respectively, are enhanced, and the band at 1207 cm−1 of one of the dibenzazepine C−C stretching modes is quite pronounced. The SEHRS spectra and also the SERS data observed here confirm the interaction of the molecules with the silver surface that was reported in SERS spectra previously.30 The larger enhancement of the in-plane modes of the ring system than of the out-of-plane modes in our SERS spectra obtained with the silver nanostructures is in agreement with a proposed tilted orientation.30 It has been suggested that

stretching mode of the seven-membered ring, which in Ami is lacking a nitrogen atom, hence providing an additional C−C bond compared to Des and Imi. In addition to the bands at 560 and 585 cm−1, another in-plane mode of the phenyl rings and the seven-membered ring is present at 533 cm−1 in the Ami SEHRS spectrum on silver nanoparticles, confirming the previous observation that the interaction of the ring system with silver nanoparticles differs from that of Des and Imi.30 SEHRS Spectra of Desipramine and Imipramine. The SEHRS spectra of desipramine (Des, red traces) and imipramine (Imi, black traces) obtained with gold and silver nanostructures are shown in Figure 3A. Figure 3B contains the corresponding SERS spectra excited at 532 nm. Compared to the spectra of Ami, the SEHRS spectra of Des and Imi share many characteristics, specifically regarding their interaction with the silver and the gold nanoparticles. The band assignments of the SEHRS and SERS spectra of Des and Imi are listed in Tables 2 and 3, respectively. The presence of a nitrogen atom in the seven-membered ring of both molecules leads to several vibrational modes of the N−C bonds, specifically the stretching vibration at 1232 cm−1, which is quite pronounced in all SEHRS spectra but in the SERS spectra clearly visible only when Des and Imi interact with silver nanostructures. Similarly, the C−C bridge bond vibration of the ring at 1295 cm−1 is weak only in the SERS spectra on silver nanostructures, but very strong in all the SEHRS spectra (compare Figure 3A, last four spectra with Figure 3B, fourth and sixth traces). As a very specific feature of the SEHRS spectra, the −CH deformation vibration of the phenyl rings at 765 cm−1 gives strong signals. While the breathing vibrational mode at 973 cm−1 is absent from the SEHRS spectra, different in-plane bending modes of the phenyl rings at 1206 and at 622 cm−1 are very pronounced in the SEHRS spectra. Also, the signals in the methylaminopropyl side chains of the molecules differ from those known for Ami. In addition to the intense signal at 1487 cm−1 of CH2 groups, vibrational modes that are assigned to the methyl groups are visible, for example, the CH3 symmetric deformation vibration at 1386 cm−1 and a contribution at 1475 cm−1, assigned to deformation vibrations of both CH2 and CH3 groups. Both bands have higher intensity in the SEHRS spectra obtained with gold nanostructures. In contrast, in the SERS spectra, the CH3/CH2 deformation at 1363 cm−1 is relatively weak and found only on the gold nanoparticles, pointing toward an interaction of the methylaminopropyl side chain with the gold surface. An important contribution to the band at 1363 cm−1 coming from the methyl groups is inferred from the presence of the band also in the SERS spectra of Ami (blue traces in Figure 3B), where much less signal from CH2 can be expected, but where two CH3 groups are terminating the chain. Furthermore, a band at 1325 cm−1 in Des and at 1333 cm−1 in Imi, assigned to a bending vibration of the CH2 groups in the aliphatic chain, is prominent in the spectra obtained with gold nanoparticles (Figure 3A, third and fifth spectra). In the SERS spectra measured under these conditions, a signal at 1335 cm−1 that we assign to this vibration is found as well (Figure 3B, third and fifth spectra). The different contributions of the C−H deformation modes in the alkyl chains in the SEHRS and SERS spectra indicate very clearly the presence of different kinds of specific interactions of the CH2 groups with the nanoparticle surfaces. F


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two-photon SERS spectra of the drug molecules employing biocompatible gold nanoparticles is much more attractive with potential applications in live cells or tissues in mind. Therefore, we also collected SERS spectra at an excitation wavelength of 785 nm under such conditions. As was shown already in the discussion of Figure S4, SERS spectra can be measured with the gold nanostructures at an excitation wavelength of 785 nm, and all experiments occur in a Raman microscpectroscopic setup, enabling the selection and mapping of different microscopic structures, such as live cells.29,32 Using these excitation conditions, we performed experiments using gold nanoparticles in environments that are relevant for experiments with cell cultures. Even though the spectra excited at 785 nm of Figure S4 or Figures 4−6 differ qualitatively from the spectra measured at an

one of the phenyl rings of Des is closer to the nanoparticle surface, while Imi interacts through the whole ring system.30 Even though some in-plane vibrational modes of the rings, such as the band at 560 cm−1, are strongly enhanced in the SERS spectra obtained with gold nanoparticles (see e.g., Figure S4), these data indicate in general significant increases in the enhancement of some out-of-plane vibrations, together with additional vibrations from the aliphatic chain. The former becomes evident specifically from the SERS data obtained at 532 nm (Figure 3B) and also at 785 nm (Figure S4). As an example, SERS spectra excited at 785 nm display pronounced signals at ∼760 and ∼790 cm−1, assigned to the out-of-plane deformation of the phenyl rings with a contribution of wagging of the amino group in the aliphatic tail30 (Figure S4). Furthermore, enhancement of the band of the phenyl rings twisting at ∼620 cm−130 is in accordance with the strengthening of out-of-plane modes in the flat orientation of the molecules. The strong contributions from the aliphatic chain when the TCA molecules interact with the gold surface are very obvious in the SEHRS spectra (Figure 3A). This is suggested by the wealth of deformation modes of CH2 and CH3 groups, including those at 1487, 1475, 1386, and also ∼1330 cm−1. Interaction of all molecules with the gold surfaces via the methylaminopropyl side chain is visible in the SERS spectra as well. The SERS spectra of all TCA molecules on gold contribute information on the N−C deformation vibrations of the methylaminopropyl side chain at 846 and 812 cm−1 (Figure 3B), as well as on vibrational modes of the CH2 groups other than those found in SEHRS, at 1462, ∼1440, 1363, and also at 1335 and 1030 cm−1 (Figures 3B and S4). According to the presented data, the Des and Imi molecules interact with the gold nanostructure with both the ring system and aliphatic tail. Because of the rigidity of the Ami molecule that is caused by the CC double bond in the aliphatic chain, the spectra show an interaction of the dibenzazepine system with the gold surface different from Des and Imi, as evidenced, e.g., by the relative intensities of the C−C modes at 1206 and 1623 cm−1 (first traces in Figures 3A and S3A). An interaction with the surface via the phenyl rings would force the molecules into a tilted position. This is supported by the presence of both outof-plane and in-plane modes in the spectrum.48 In such a tilted orientation, an additional interaction through the amino group in the aliphatic chain can take place. Both SEHRS and SERS data indicate that the molecular orientation on the surface compared to the interaction with the silver is very different. The decrease in the intensity of the inplane vibration of the ring system in the spectra on the gold nanostructures suggests a change in the orientation from tilted to the flat in Des and Imi.50 Furthermore, the increase in the intensity of the mode from aliphatic tail suggests closeness of this part of the molecule to the surface of gold nanoparticles. The different interaction of the gold surface with the ring moiety and the important function of the alkyl chain in the interaction could render part of the ring structure more easily accessible for interaction with potential biological targets, for example with lipid membranes.53 In Vitro Spectra in Biological Experiments. In the discussion and interpretation of the near-infrared (NIR) (1064 nm) excited SEHRS spectra, the SERS data excited at the corresponding second harmonic wavelength (532 nm) were very useful because of the same frequency range of the hyper Raman and Raman light (Figure 3). Nevertheless, the possibility to use NIR excitation to obtain both one- and

Figure 4. SERS spectra of the antidepressant desipramine obtained using gold nanostructures with a diameter of 30 nm (Au30) and a diameter of 60 nm (Au60). Excitation wavelength, 785 nm; excitation intensity, 2.0 × 105 W cm−2; acquisition time, 1 s; concentration, 9 × 10−7 M; scale bars, 20 cps.

excitation wavelength of 532 nm (Figure 3B, first, third, and fifth traces) because of known effects in Raman experiments at different wavelengths, such as varied detector and optics sensitivity or ν4-dependence of the Raman signal, they appear specifically favorable with respect to the SERS signals. This is due to the plasmonic properties of the gold nanoaggregates in the presence of the molecules, providing high electromagnetic G


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Figure 5. SERS spectra of the antidepressants desipramine obtained using gold nanostructures without the DMEM-FCS and in the presence of DMEM-FCS. Excitation wavelength, 785 nm; excitation intensity, 2.0 × 105 W cm−2; acquisition time, 1 s; concentration of desipramine, 9 × 10−7 M; scale bars, 50 cps. The bands highlighted in red show slight intensity variations and are discussed in the text. Figure 6. SERS spectra of the antidepressant desipramine obtained using gold nanostructures at pH 3.4, pH 4.4, and pH 6.0. Excitation wavelength, 785 nm; excitation intensity, 2.0 × 105 W cm−2; acquisition time, 1 s; concentration of desipramine, 9 × 10−7 M; scale bars, 30 cps. The bands highlighted in red show slight intensity variations and are discussed in the text.

enhancement and low reabsorption of the SERS light.39,54−57 The varied relative intensities and greater wealth of bands specifically in the frequency region below 900 cm−1 indicates that both electromagnetic and chemical enhancement determine the spectral signatures. The spectra were measured at several concentrations, ranging from 10−4 M to 10−7 M, all yielding very similar spectral fingerprints. We estimate that full coverage of the nanoparticle’s surface is achieved around 10−6 M concentration. Furthermore, spectra were obtained with the different batches of gold nanoparticles, possessing citrate as stabilizing species but of varying size. As an example, Figure 4 shows the spectra of desipramine obtained with gold nanoparticles of a diameter of 30 and 60 nm, respectively. They indicate very small differences in two twisting vibrations of the rings with a slight relative increase of the band at 703 cm−1 on the larger nanoparticles (Figure 4, upper spectrum). An important step is to assess the stability of the nanoparticles and the spectral signatures in the biological conditions and interaction with components of potential delivery media. Components present in cell culture growth

medium, used for delivery of the nanoparticles-drug system, have an effect on the cellular uptake and further behavior of nanoparticles in cells.58 Upon entering the cell culture medium, and later inside the cellular environment, nanoparticles are usually coated with proteins present in the surroundings that become visible in the SERS spectra.59−61 To understand whether components from the cell culture media may influence nanoparticle−drug interaction, spectra were obtained in the presence of a typical cell culture medium DMEM and FCS, which is an important constituent of cell culture media. UV−vis spectra of the drugs adsorbed on gold nanoparticles were obtained in the cell culture medium, and Figure S5 shows the example of desipramine. As discussed, Des causes an aggregation of the nanoparticles (Figure 2D). After addition of the DMEM- FCS to the nanoparticles-drug system, a slight H


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drug.66 Obtained SERS and SEHRS spectra here, especially under the biological conditions, may be used for further investigation of nanoparticle-based drug delivery platforms for tricyclic antidepressants.

blue shift of the extended plasmon band is visible, indicating interaction of the molecules from the culture medium with the nanoaggregates surface. The SERS spectrum of Des in the presence and absence of DMEM-FCS is shown in Figure 5. It does not exhibit great changes. Nevertheless, some smaller changes are noted. The relative intensity of the bands at 760 and 791 cm−1 is changed. The slight decrease of the signal assigned to the twisting of the phenyl ring coupled with wagging of NH in aliphatic chain at 791 cm−1 could indicate a slightly more upright position in the presence of potentially coadsorbed components from the cell culture medium. Furthermore, the relative intensity in the band at 1538 cm−1 decreases in the presence of DMEM-FCS. Nevertheless, neither the main vibrational signature of desipramine including relative intensities nor the overall enhancement is influenced in the presence of the culture medium. Considering the strong affinity that some of the components of DMEM-FCS have toward the surface of gold nanoparticles,62,63 we can conclude that interaction between the TCA molecules and nanoparticles is very stable. In biological surroundings, nanoparticle-based drug delivery systems can encounter very different pH values, depending on the route of delivery and uptake into tissues and cells. In Figure 6, the SERS spectra of Des at different pH values are shown. The characteristic spectrum is not influenced; nevertheless, small changes in some relative intensities occur. The band at 535 cm−1 decreases when pH decreases from pH 6 to pH 3.4. At the same time, the in-plane bending mode of the dibenzazepine ring at 585 cm−1 intensifies (compare top trace in Figure 6 with middle and bottom traces), while the ring twisting mode at 710 cm−1/703 cm−1 becomes weaker. Changes in these vibrational modes indicate a slight reorientation of the ring systems with respect to the gold nanoparticle surface, when pH is lowered. Similarly, the band at 772 cm−1, assigned to ring deformation modes of the phenyl rings and C−C stretching of the seven-membered ring, disappears, maybe pointing toward a more tilted orientation when pH decreases. Additionally, smaller influences on bands at 1534 and 1570 cm−1 can be seen. Because the TCA are molecules with a very high pKa value (∼9.5), we do not expect that the change in pH values has a direct influence on the protonation/deprotonation of molecules themselves but rather indirectly on the interaction by protonation and deprotonation of the stabilizing species and interaction with the citrate molecules on the nanoparticle surfaces. The robustness of the spectral signature nanoparticle−drug system to changing pH suggests that studies inside the endosomal system, where pH lowers significantly over time, are feasible. Previously reported pH values of the early endosomes are around 6, and during the process of maturation, pH becomes more acidic and reaches as low as 4 in the lysosome.64 Furthermore, several pathologies are associated with very low pH values in the tissues.65 The fact that the TCA−gold nanostructure assemblies are so stable could inspire new kinds of multifunctional nanocarriers for TCA molecules. In general, nanoparticle-based drug carriers can offer many advantages for targeted delivery including optical imaging and monitoring possibilities. Our results here show that the characterization of the interaction of a gold− TCA drug delivery system would in principle be feasible. The function of SERS and SEHRS therein would lie in a sensitive probing of the molecules attached to the surface and possibly also the cellular environment and its response to the delivered

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CONCLUSIONS We have reported the acquisition of nonresonant SEHRS and SERS spectra of the three TCA molecules amitriptyline, desipramine, and imipramine, exploiting the interaction of the molecules with gold nanostructures, and compare them to the interaction with silver nanostructures. The SEHRS spectra of the TCA molecules differ greatly from the SERS spectra because of the different selection rules of the one- and twophoton excited Raman processes. Specifically, they show several characteristics of infrared-active vibrations. We find that Raman and hyper Raman active vibrational modes can be combined for the comprehensive analysis of the molecules’ interaction with the nanostructures. From the SEHRS spectra excited at 1064 nm and SERS spectra obtained at two different excitation wavelengths (532 and 785 nm), we infer that the molecules interact with the silver nanostructures mainly via their ring moiety and less intensely with the alkyl chain, which is in line with previous findings by SERS.30 In contrast, as revealed from the SEHRS and SERS spectra obtained on biocompatible gold nanostructures, in all three molecules, the methylaminopropyl side chain plays a very important role in the interaction with the gold, along with parts of the ring system. This is very different from the interaction with the silver nanostructures. The NIR excited SERS spectra of the TCA−gold nanoparticles are greatly invariant with respect to changes in TCA concentration and size of the biocompatible gold nanostructures. They show remarkable stability in the presence of cell culture media and upon decrease of pH in the typical ranges of pH values in late endosomal structures. These findings suggest the combined one- and two-photon vibrational spectroscopic approach as a tool for monitoring and characterization of new nanoparticle-based drug delivery platforms and their interaction in real biological environments.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpcc.7b08026. UV−vis absorbance spectra of the gold and silver nanostructures (Figure S1); Raman spectra of tricyclic antidepressants, desipramine, imipramine, and amitriptyline (Figure S2); SEHRS and SERS spectra of the antidepressants in the range 1400−1700 cm−1 (Figure S3); SERS spectra of the antidepressants imipramine, desipramine, and amitriptyline obtained using silver and gold nanostructures with 785 nm excitation wavelength (Figure S4); UV−vis absorbance spectra of the gold nanostructure in the presence of desipramine and DMEM-FCS (Figure S5) (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Janina Kneipp: 0000-0001-8542-6331 I


Article

The Journal of Physical Chemistry C Notes

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The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Harald Kneipp for valuable discussions and support in setting up experiments. V.Ž . and Z.H. are grateful for fellowships provided by DFG GSC 1013 SALSA; F.M. acknowledges funding by a Chemiefonds Fellowship of FCI (Fonds der Chemischen Industrie), C.A. by DFG Grant No. AR376/12-1, and J.K. by ERC Grant No. 259432 MULTIBIOPHOT.

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Specific Interaction of Tricyclic Antidepressants with Gold and Silver

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