quantum dot photoactivation of pt(iv) anticancer agents: evidence of an electron transfer mechanism...

Quantum Dot Photoactivation of Pt(IV) Anticancer Agents: Evidenceof an Electron Transfer Mechanism Driven by Electronic CouplingIvan Infante,*,†,# Jon M. Azpiroz,†,# Nina Gomez Blanco,‡ Emmanuel Ruggiero,‡ Jesus M. Ugalde,†

Juan C. Mareque-Rivas,‡,§ and Luca Salassa*,‡

†Kimika Fakultatea, Euskal Herriko Unibertsitatea and Donostia International Physics Center (DIPC), P.K. 1072 Donostia, Euskadi,Spain‡CIC biomaGUNE, Paseo Miramon 182, 20009 Donostia, Euskadi, Spain§Ikerbasque, Basque Foundation for Science, 48011 Bilbao, Euskadi, Spain

*S Supporting Information

ABSTRACT: Herein we elucidate the mechanism of photo-reduction of the Pt(IV) complex cis ,cis ,trans-[Pt-(NH3)2(Cl)2(O2CCH2CH2CO2H)2] (1) into Pt(II) species(among which is cisplatin) by quantum dots (QDs), a processwhich holds potential for photodynamic therapy. Densityfunctional theory (DFT) and time-dependent density func-tional theory (TDDFT) methodologies, integrated by selectedexperiments, were employed to study the interaction and thelight-induced electron transfer (ET) process occurringbetween two QD models and 1. Direct adsorption of thecomplex on the nanomaterial surface results in large electronic coupling between the LUMO (lowest unoccupied molecularorbital) of the excited QD* and the LUMO+1 of 1, providing the driving force to the light-induced release of the succinateligands from the Pt derivative. As confirmed by photolysis experiments performed a posteriori, DFT highlights that QDphotoactivation of 1 can favor the formation of preferred Pt(II) photoproducts, paving the way for the design of novel hybridPt(IV)−semiconductor systems where photochemical processes can be finely tuned.

■ INTRODUCTION

Semiconductor quantum dots1 (QDs) have become in recentyears one of the most fascinating and promising type ofmaterials with technological applications ranging from photo-voltaics2−6 and optoelectronic devices7 to biosensors8 andbioimaging agents.9 The attractiveness of QDs lies in their highoptical extinction coefficients, sharp emission spectrum, carriermultiplication ability, and high photo- and thermal stability,10,11

features which can be tuned by varying QD size, shape, andcomposition. A key ubiquitous process in QD chemistry iselectron transfer (ET). For example, efficient charge separationat the interface between a QD (or a film of QDs) and an oxidesemiconductor material, e.g., TiO2, is mandatory to obtainhighly performing photovoltaic cells,6 while field-effecttransistor devices engineered from thin film of QDs rely onefficient charge hopping between adjacent QD units.12 QDs arealso being explored as light-induced ET activators with verypromising results in other research areas, as, for example,photoactivatable protein inhibitors, photodynamic therapy(PDT),13,14 and photocatalysis.15,16

Thorough understanding of the ET mechanism in thesesystems, in particular the role played by parameters such asreorganization energy, Gibbs free energies, and electroniccoupling, is therefore paramount for researchers involved in theadvance of QD-based applications.

Density functional theory (DFT) is a powerful tool toachieve such goals as recently demonstrated in the ETmechanism elucidation of QD−metal oxide17 and QD−fullerene systems.18 Indeed DFT is able to provide a gooddescription of QDs electronic structure and model theirinteraction with molecules and material surfaces, ultimatelyproviding useful insights into the thermodynamic and kineticfactors ruling ET.In this work we present a combination of DFT calculations

and selected experiments in the context of rationalizingthe ET process from a core−shell CdSe@ZnS QD into aP t ( IV) an t i c ance r ag en t , name l y , c i s , c i s , t r a n s -[PtIV(NH3)2(Cl)2(O2CCH2CH2CO2H)2] (1). Pt(IV) com-plexes have been extensively studied as prodrugs whose activitycan be switched on in vitro and in vivo by biologicalreductants19−24 or by light excitation.25−28 Nanoparticle-mediated photoactivation of anticancer complexes is nowbecoming a hot topic as demonstrated by several ground-breaking results reported lately.29−32

Mareque and co-workers have recently employed core-onlyand core−shell QDs to control Pt(IV) → Pt(II) reduction and

Received: February 10, 2014Revised: March 26, 2014Published: March 27, 2014

Article

pubs.acs.org/JPCC

© 2014 American Chemical Society 8712 dx.doi.org/10.1021/jp501447q | J. Phys. Chem. C 2014, 118, 8712−8721

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deliver cisplatin,33,34 synthesizing a QD−Pt composite withpotential value as a theranostic agent for cancer therapy andmultimodal imaging.34 In such a system, a core−shell CdSe@ZnS QD (ca. 5 nm diameter), complex 1, and the γ-emitterradioactive fac-[99mTc(H2O)3(CO)3]

+ complex are transportedby a high-stability micelle to the target site. The 99mTccompound gives SPECT (single-photon emission computedtomography) imaging capability while the Pt(IV) and the QDsare exploited for therapy, with QDs being suitable for opticalimaging as well. In such composite, QDs can efficientlyphotoactivate the Pt(IV) complex via ET using visible light upto 630 nm, a wavelength currently in use for clinical PDT.These hybrid systems have the potential to overcome the poorabsorption properties of metal complexes in the visible,particularly in the therapeutic window (630−700 nm).In this study, we initially investigate the behavior of 1 under

UV light irradiation and elucidate how dicarboxylato Pt(IV)prodrugs are transformed under chemically reducing con-ditions. Successively, modeling QD-1 adducts we show how the

energy alignment between the QD and 1 favors the injection ofthe photoexcited electron from the former to the latter, withthe concomitant reduction of the Pt(IV) complex into Pt(II).In particular, DFT indicates that QD injects electrons not onlyto the LUMO (lowest unoccupied molecular orbital) level of 1,but also and more efficiently to the LUMO+1, favoring therelease of selected ligands and the formation of the preferredphotoproducts (among which is cisplatin). Photolysis experi-ments performed a posteriori support such outcome, high-lighting that QD surfaces can be tailored for photoactivation ofspecific target states of metal complexes, potentially openingnew opportunities to control a wide range of photochemicalprocesses for different applications. Structures of all the modelsinvestigated in our study are reported in Chart 1.

■ COMPUTATIONAL SECTION

All calculations were performed with the Gaussian 09program.35 Ground- and excited-state properties of all thesystems employed in this work were analyzed with DFT and

Chart 1. DFT Optimized Structures of the Models Investigated in This Study (PBE0/def2-SV(P) Level)

Table 1. Selected Bond Distances (Å) for the X-ray and DFT-Optimized Geometries of 1, 1a, and 1b, Together with Pt AtomicCharges Calculated with Different Methods

PBE0/def2-SV(P)

complex 1 Pt−O4 Pt−O9 Pt−N14 Pt−N18 Pt−Cl2 Pt−Cl3

X-ray 1.993(4) 2.008(4) 2.050(5) 2.065(5) 2.3108(15) 2.3194(15)GS 2.014 2.016 2.057 2.049 2.344 2.333S1a 2.278 2.291 2.081 2.043 2.291 2.322ll-T 2.301 2.320 2.078 2.071 2.308 2.319ll-T2 1.998 1.996 2.384 2.065 2.353 2.488complex 1−

1a 2.380 2.386 2.059 2.045 2.369 2.3631b 2.048 2.045 2.372 2.046 2.378 2.669

charges 1-GS 1-S1 1-ll-T 1-ll-T2 1−(1a) 1−(1b)

Mulliken 0.444 0.414 0.387 0.530 0.228 0.307Hirshfeld 0.467 0.481 0.439 0.981 0.642 0.726NPA 0.841 0.792 0.729 0.888 0.642 0.726

aS1 geometry was obtained using the CAM-B3LYP functional. All attempts to optimize the structure of S1 with PBE0 functional failed.

The Journal of Physical Chemistry C Article

dx.doi.org/10.1021/jp501447q | J. Phys. Chem. C 2014, 118, 8712−87218713

time-dependent DFT (TDDFT), using the PBE0/def2-SV(P)combination. Such functional and basis set was chosen aftercareful benchmarking (Supporting Information) against avail-able experimental data of 136 and because it has been recentlydemonstrated to perform extremely well for the QDs studiedhere.37 Calculations on 1 and its derivatives were performedusing the polarized continuum model (PCM) with water asimplicit solvent38 (as this is the environment in which theirphotophysical and photochemical properties were studied),while calculations including the QD alone and the QD withcomplex 1 were performed using as implicit solvent hexane, to

approximate the micelle environment. The nature of allstationary points was confirmed by normal-mode analysis.For the QD-1 complexes, the basis set superposition error(BSSE) was considered by means of the counterpoisemethod.39,40 TDDFT calculations on a reduced space (videinfra) were carried out with Q-Chem 4.0.41

For analysis and visualization of computational results, thesoftware packages GAUSSSUM 2.2,42 AOMix,43,44 andChimera45 were employed.Details on materials and experimental methods are reported

in the Supporting Information.

Figure 1. (a) Comparison between experimental (black) and calculated (blue) absorption spectra for 1 in water (PCM) calculated at the PBE0/def2-SV(P) level. Singlet−singlet transitions are shown as vertical bars with heights equal to their oscillator strengths. The theoretical curves wereobtained using GAUSSSUM 2.2 (fwhm = 3000 cm−1). Inset: PL spectrum of QDs used in this work. (b) Selected EDDMs of singlet−singletelectronic transitions and molecular orbitals for 1 in water (PCM) calculated at the PBE0/def2-SV(P) ground-state geometry. In the EDDMs, greenindicates a decrease in electron density, while orange indicates an increase. (c) Energy diagram for complexes 1, 1a, 1b, 2, and 3 calculated at thePBE0/def2-SV(P) level in water (PCM). For complexes 1a and 1b the spin density surface is reported in the figure (isovalue 0.0005).

Figure 2. (a) Selected regions of the 1H NMR spectrum of 1 in H2O/D2O (5:1, [1] = 1 mM) in the dark (bottom) and after irradiation with 385nm light (top, 2 min, ∼40 mW·cm−2); Pt 4f XPS spectra of 1 in the dark (bottom) and after irradiation (top) with 385 nm light (15 min, ∼40 mW·cm−2).



■ RESULTS AND DISCUSSION

Complex 1: Photochemistry and Redox Properties.Ground- and excited-state structure and electronic properties ofcis,cis,trans-[PtIV(NH3)2(Cl)2(O2CCH2CH2CO2H)2] (1) andrelated species (vide infra) were investigated by DFT andTDDFT to characterize the photochemical and redox behaviorof the complex (Table 1 and Figure 1a−c). The DFT ground-state (GS) geometry of 1 displays bond distances in goodagreement with the X-ray values. Similarly, the TDDFTsimulated spectrum (Figure 1a) correctly reproduces theexperimental absorption in the 275−450 nm range. Electrondensity difference maps (EDDMs), which graphically describechanges in electron density (Figure 1b), indicate the singlet−singlet low-energy transitions in the UV region are mixed d−d/LMCT (ligand-to-metal charge transfer) and have dissociativenature due to significant contributions from the σ-antibondingorbitals LUMO and LUMO+1 (Supporting Information,Tables S2 and S3).46

Optimization of excited-state structures (singlet withTDDFT method and triplet with unrestricted Kohn−Shammethod) was performed to obtain snapshots of transientspecies and characterize the excited-state dynamics of 1 uponUV light excitation. In the S1 excited state, 1 shows significantlyelongated Pt−O distances (ca. 0.25 Å) compared to the GS,while the other Pt−L bond lengths are only slightly changed(Table 1). It is reasonable that population of S1, which hasmajor contributions from the LUMO+1 orbital, leads tosuccinate release, whereas S2 and S3, mainly involving theLUMO orbital, should promote the formation of free Cl− andNH3. Triplet-state optimizations gave similar results affordingtwo lowest-lying triplet geometries, ll-T and ll-T2 (ΔE = 0.29eV), suggesting dissociation of succinate as well as Cl− andNH3 ligands could take place. In particular, ll-T geometryresembles the S1 geometry with elongated Pt−O bond lengths(ca. 0.3 Å) with respect to the GS, whereas ll-T2 showselongated Pt−Cl (2.384 Å) and Pt−N (2.488 Å) bond lengths.In principle, photosubstitution via these excited-state speciescan involve a single monodentate ligand as well as thesimultaneous release of two ligands. Furthermore, subsequentisomerization reactions should not be ruled out, indicating thatthe formation of several photoproducts is likely to occur underlight irradiation.Photolysis experiments on 1 (Figure 2a) clearly show

appearance of the free succinate signal in the NMR spectrumwithin a few minutes of UV light irradiation (385 nm, ∼40mW·cm−2). Moreover, the NH3 multiplet of 1 (1J14N‑1H = 54Hz, 2J195Pt‑1H = 27 Hz) at 6.3 ppm decreases in intensity whilepeaks corresponding to free NH3 (1J14N‑1H = 52 Hz) and anumber of Pt(IV) photoproducts appear nearby, consistentlywith the possibility of multiple photochemical pathways.However, it is significant that XPS (X-ray photoelectronspectroscopy) measurements performed on UV-irradiatedsolution of 1 (Figure 2b) show little or no formation of Pt(II)species compared to the dark control (a fraction of Pt(II) ispresent due to direct reduction of the metal under the X-raybeam as visible in the control spectrum). Consistently with theprevalent photogeneration of inert Pt(IV), binding experimentswith GMP (guanosine 5′-monophosphate) exclude theformation of Pt(II)−GMP adduct and the presence ofcisplatin-like complexes (Supporting Information, FigureS13). Pt charge calculations performed with different methods(Table 1) confirm these experimental results.47−49 One of the

most likely photoproducts formed upon release of the succinatecould be the complex cis,cis,trans-[PtIV(NH3)2(Cl)2(OH)2] inagreement with the NMR data and the in vitro activity observedfor solutions of 1 in the dark and after UV irradiation(Supporting Information, Figure S14 and S15).For the sake of comparison with the excited-state computa-

tional characterization and to gain further insights, the first stepin the reduction of 1 was investigated by performing geometryoptimization calculations on the complex cis,cis,trans-[PtIII(NH3)2(Cl)2(O2CCH2CH2CO2H)2]

−, which results fromthe addition of one electron (1e) to 1. Chemical reduction ofPt(IV) complexes is a fundamental process in the biologicalmechanism of action of this family of prodrugs.19,20,50

Conversion of octahedral Pt(IV) to square planar Pt(II) canbe promoted by endogenous reducing agents and occurthrough simultaneous ligand dissociation pathways.19,50,51

Two geometries were obtained corresponding to electronicstructures where the extra electron is localized either on theLUMO+1 (1a) or on the LUMO (1b) (ΔE = 0.15 eV).Consistently with the shape of the orbitals hosting the unpairedelectron (see spin density surface in Figure 1c), 1a ischaracterized by elongated Pt−O bonds (Table 1), similarlyto S1 and ll-T. Instead 1b shows one longer Pt−Cl and Pt−Ndistance compared to 1 (Table 1), in agreement with the ll-T2geometry of 1. Plausibly, release of succinate occurs from 1a,while Cl− and NH3 can dissociate from 1b.Adopting 1a, 1b, and the GS structures as a starting point,

the 2e-reduced structure of 1 was also optimized employing theaforementioned approach. As shown in Figure 1c, two differentPt(II) reduction products were obtained: cis-[PtII(NH3)2(Cl)2](2, cisplatin) + 2 O2CCH2CH2CO2H from 1a, and trans-[PtII(NH3)(Cl)(O2CCH2CH2CO2H)2] (3) + Cl− and NH3from 1b and the GS.Such result suggests the presence of distinct reductive

pathways and formation of different Pt(II) species19,50,51 and isin agreement with cell toxicity tests.34

QD-1: The Model and the Interaction. As shown earlierfor complex 1 and other related compounds,33,34 an efficientapproach to promote Pt(IV) to Pt(II) reduction using (morepenetrating and less harmful) visible light is by excitation of atailored-synthesized QD in the proximity of the Pt complex. Insuch a way, the photoactivated QD* can transfer the excitedelectron from its conduction band to the Pt(IV) complex, (e.g.,1) which rapidly undergoes ligand dissociation and formationof Pt(II) toxic species at the target cancer cells.Full modeling of the interaction between 1 and the QD is

not straightforward due to the complexity and heterogeneity ofthe system (even more when the composite is designed toreach the target site inside water-soluble poly(ethylene glycol)micelles). Nevertheless, QD-1 models where the complex isdirectly anchored on the surface of the nanomaterials are a validapproximation, able to provide a satisfactory description of theelectronic phenomena taking place on the QD surface. This issupported by recent results showing that Ru metal complexesbearing COOH-functionalized ligands can directly be attachedonto the QD surface despite the presence of bulky organicligands.16,52,53 Indeed, photoluminescence (PL) quenchingexperiments were carried out (Figure 3 and SupportingInformation, Figure S16) and indicate that 1 is adsorbed onthe QD surface (K ∼ 5 × 104 M−1) as demonstrated by betterfitting to the Langmuir isotherm (surface adsorption)compared to the Stern−Volmer expression (collisional dynamicquenching).



On the bases of such experimental findings, we explored QD-1 models where the metal complex is directly anchored to thesurface of the nanomaterial. Furthermore, being the compositesdeveloped by Mareque and co-workers made of a core−shellCdSe@ZnS QDs of about 5 nm (ca. 2000−3000 atoms),34 asize untreatable by current theoretical approaches like DFT,QD dimensions were scaled down as much as possible but stillkept them large enough to reflect the instantaneous interactionsbetween the QD and 1. At first, we chose a small bare CdSecomposed of 24 atoms, i.e., a (CdSe)12 (Chart 1), and then weadded a ZnS layer to provide a model for the core−shellsystem. The final QD is composed by a (CdSe)12 core coveredby a shell of (ZnS)48, for a size of approximately 1.5 nm (Chart1).Structural optimization for the (CdSe)12-1 and

(CdSe)12@(ZnS)48-1 adducts shows that in both cases complex1 is attached to the QD with three anchoring groups, the twocarboxylates and one of the chlorine atoms. The chlorine andthe oxygen of the carboxy groups are directly adsorbed on theCd atoms (or Zn atoms in the core−shell adduct), while theO−H group of the succinates form hydrogen bonds with the Seatoms (or S atoms in the core−shell). The instantaneousinteraction energy between complex 1 and the QD is stabilizingby about 32.5 kcal/mol in (CdSe)12-1 and 78.4 kcal/mol in(CdSe)12@(ZnS)48-1. When the counterpoise correction isapplied, the interaction energies are 22.6 and 60.0 kcal/mol,respectively. If preparation energies are also included (i.e., theenergy required to deform the fragments from their equilibriumstructure to the geometry they adopt in the interactingcomplex), the interaction energies reduce further to 12.3 and

32.1 kcal/mol, respectively. The larger stabilization in thecore−shell complex is most likely associated with the largersurface area of adsorption with respect to the much smaller(CdSe)12 complex, where the strain forces to accommodatecomplex 1 are augmented. Bond decomposition analysis revealsthat the nature of QD-1 interaction is about 60% electrostaticand 40% covalent for both the bare and core−shell QDs. Inparticular, complex 1 transfers about 0.09 electrons to the bare(CdSe)12 and 0.29 electrons to (CdSe)12@(ZnS)48. Suchcharge transfer has important effects on the electronic structureof (CdSe)12-1 and (CdSe)12@(ZnS)48-1. In Figure 4a and b,the density of states (DOS) and molecular orbital (MO) energylevels of both adducts are plotted.

As it is immediately clear, the charge donation from complex1 to any of the two QDs raises the MOs energy levels of theQDs and lowers those of complex 1. The latter indeed becomesslightly more cationic, with the consequence of increasing itsionization energy (IP), roughly approximated to the negativevalue of the HOMO (highest occupied molecular orbital)energy.54,55 The HOMO (or IP) of 1 passes from −7.62 eV inthe isolated conformation to −7.77 eV in (CdSe)12-1 and to−8.28 eV in (CdSe)12@(ZnS)48-1. The larger IP of the latter isa consequence of the larger charge transfer to the core−shellcomplex. On the other hand, the QD becomes more negative

Figure 3. Core−shell CdSe@ZnS PL quenching plots as a function ofthe concentration of 1. (a) Data fitting with the Langmuir absorptionisotherm (R-square = 0.99) and (b) with the Stern−Volmer model fordynamic collisional quenching (R-square = 0.80). Fitting details arereported in the Supporting Information. Error bars were determinedby comparing three PL spectra for each point and propagating theerror in an additive fashion.

Figure 4. MOs energy levels and DOS for the (CdSe)12-1 (a) and(CdSe)12@(ZnS)48-1 (b) compounds. The MOs for the QDs arealways depicted in black, while the MOs of 1 are in red. The MOs ofthe final complex are shown in the center and are split into thosemostly localized on the QD (in black) and those mostly localized on 1(in red). Solid (dashed) arrows refer to HOMO−LUMO (TDDFT)gaps. For the core@shell model, the shaded region corresponds to theprojection of the DOS on the core atoms.



and more prone to ionization (HOMO level raised). TheHOMO of the isolated (CdSe)12 is indeed shifted from −6.46to −6.39 eV, whereas that of (CdSe)12@(ZnS)48 moves from−6.25 to −6.02 eV. One might think that these effects on theMO energy levels are dampened in a much larger QD than theone employed in the calculation; however, in a realistic systemis also more likely that each QD absorbs more than onemolecule of complex 1, maintaining in this way the trendshown here.Moreover, it is well-known that ligands affect the QD

absorption spectrum by shifting their excitation energies.56,57

For this reason, the first excitation energy of (CdSe)12-1,associated with the HOMO−LUMO transition within the bare(CdSe)12, is blue-shifted by about 0.1 eV, from 3.27 to 3.38 eVupon bond formation at the TDDFT level of theory. Note thatthe TDDFT HOMO−LUMO gap localized in the QD hasbeen computed within a reduced single-excitation subspace toavoid the interference of low-lying charge transfer statesinduced by the Pt complex. Remarkably, the HOMO−LUMO gap estimation taken from the MO energies (Kohn−Sham orbitals) provides the same trend with a similar blue shiftfrom 4.00 to 4.09 eV. From these numbers, it is, however, clearthat the absolute value of the HOMO−LUMO gap within theQD is not a good approximation to the actual excitation energy,as it does not take into account relaxation effects induced by theformation of the electron−hole pair. This effect is included inthe TDDFT calculation which gives a value for the firstexcitation energy of (CdSe)12 much lower than the HOMO−LUMO gap of 4.00 eV. For the larger (CdSe)12@(ZnS)48, thefirst excitation energy decreases to 3.00 eV with respect to 3.27eV of the (CdSe)12 QD. Considering that the core has the samesize as the bare (CdSe)12 cluster, the effect can be attributedlargely to the ZnS shell. TDDFT could not be employed tocompute the HOMO−LUMO excitation energy of the QD inthe(CdSe)12@(ZnS)48-1 complex due to its large size.However, assuming that the trends are well reproduced bythe simple Kohn−Sham orbitals energy level, we can estimate ared shift of only 0.03 eV upon interaction with complex 1.QD- 1: The ET Mechanism. Under the assumption the

electron donor is the excited QD* and the acceptor is complex1, two mechanisms for the QD-mediated photoactivation of 1are possible: (a) electronic energy transfer (EET) or (b) directelectron transfer (ET). EET processes (Dexter and Forster)can be ruled out since no donor−acceptor spectral overlap ispresent, thus leaving direct ET as the only valid alternative. Thestandard theoretical framework for ET processes is the Marcustheory,57 which in the nonadiabatic and high-temperature limitsassumes the form

πλ

λλ

=ℏ

| | − Δ +⎡⎣⎢

⎤⎦⎥k

k TH

Gk T

exp( )

4ETb

DA2

2

b (1)

where kb is the Boltzmann constant, T is the temperature, andℏ is the reduced Planck constant. According to 1, the kETdepends on three tunable variables: (i) the electron couplingterm HDA; (ii) the driving force ΔG for the charge separationprocess; and (iii) the reorganization energy λ, which quantifiesthe deformation energy of the donor and acceptor upon ET.This latter term is usually decomposed into internalreorganization energy, λINT, which reflects the response of themolecular donor and acceptor systems to ET, and externalreorganization energy, λEXT, associated instead with therearrangement of the solvent upon ET. Because an excess of

organic ligands is present inside the micelle, we can assume thatthis shell behaves as a solvent with a very low dielectric, andtherefore λEXT can be expected to be negligible. The ETactivation energy is thus expressed as

λλ

Δ =Δ +⧧G

G( )4

INT2

INT (2)

Notably, λINT and ΔG have opposite signs; hence, the largestET rate is reached at values of ΔG ∼ λINT. For values of ΔG <λINT the Marcus theory predicts that the ET rate increases withthe driving force, while for ΔG > λINT a decrease of ET rateoccurs at increased driving forces (inverted regime). In Table 2

we present all the computed parameters of eq 1 for twoprocesses, one associated with the electron injection from theexcited QD* (bare and core−shell) to complex 1, to form QD+

and 1a, and the other to form complex 1b (see SupportingInformation for details on the method).

Internal Reorganization Energy. In the weak interactionlimit the reorganization energy is computed as

λ λ λλ λ λ λ

= + =+

++*→ →

**+ − ++

−−

2 2QD

INT INTQD

INT1 1 QD

QDQDQD

11

11

(3)

where λINTQD*→QD+

and λINT1→1− are the reorganization energies of

the excited QD* and complex 1 (whether as 1a or 1b),respectively, during the ET mechanism, and λB

A indicates thedeformation energy of adduct A (QD*, QD+, 1, 1−) to attainthe geometry of B (QD+, QD*, 1−, 1). As shown in Table 2, the(CdSe)12 and (CdSe)12@(ZnS)48 QDs present deformation

energies λINTQD*→QD+

of 0.33 and of 0.50 eV, respectively. Thesevalues are likely overestimated because in the real environmentthe QDs are passivated by ligands that dampen the structuralrearrangements. However, the structural deformations ofcomplex 1a and 1b are well described and show larger valuesdue to the population of the σ-antibonding Pt−X orbitals (videsupra). The elongation of the Pt−O bond distances is moreeffective and leads to a deformation energy of 1.64 eV for the1a complex, as compared to 1.21 eV for the 1b, where the Pt−Cl bond is stretched.Overall, the total reorganization energies λINT after electron

injection, computed from eq 3, are therefore quite large,

Table 2. Reorganization Energies, Gibbs Free EnergyDifferences (Absolute Values), and Electronic CouplingsCalculated for the QD-1 Nanocomposites Studied, Alongwith the Corresponding Electron Transfer Rates (s−1)Calculated by Means of the Marcus Equationa

λQDQD+

λQD+QD* λQD+

QD* λQDQD* λ1−

1 λ11−

(CdSe)12 0.22 0.33 0.89 0.59 − −(CdSe)12@(Zns)48 0.23 0.50 0.82 0.58 − −1a − − − − 1.64 1.481b − − − − 1.21 1.00

Marcus Parameters

ΔG ΔG‡ λINT HDA kET

(CdSe)12−1a 1.46 0.27 2.17 0.235 6.7 × 1013

CdSe)12−1b 0.98 0.23 1.71 0.064 2.5 × 1012

(CdSe)12@(ZnS)48−1a 1.82 0.09 2.22 0.227 2.9 × 1014

(CdSe)12@(ZnS)48−1b 1.34 0.08 1.77 0.134 8.3 × 1013

aAll energies are expressed in eV.



ranging from 2.17 eV in (CdSe)12−1a to 1.71 eV in (CdSe)12−1b.Gibbs Free Energy: Difference ΔG. The formula to evaluate

ΔG is the following (Supporting Information for furtherdetails)

ω λ ω

λ λ

Δ = − − −

− +

−− → *− *

−− → −+ −

+ −

G [( ) (

( ))]

(QD 1)QD 1 QD 1

QDQD

(QD 1)QD 1 QD 1

QDQD

11

(4)

where ω(QD−1)QD−1→QD*−1 is the TDDFT vertical excitation energy of

the QD−1a (or QD−1b) complex associated with a localized

QD → QD* HOMO−LUMO excitation; ω(QD−1)QD−1→QD+−1− is the

TDDFT vertical excitation energy associated with the charge-separation process and is usually the lowest computed excitedstate. The choice of the PBE0 functional is supposed tominimize the statistical error inherent in TDDFT for theestimation of charge transfer states.From Table 2, we can infer that the computed ΔG values are

smaller than λINT and, therefore, the ET process occurs alwaysin the normal regime of Marcus theory. For the smaller(CdSe)12 QD, the ΔG of injection to form complex 1a (1.46eV) is larger by about 0.50 eV than to form 1b (0.98 eV).However, the corresponding activation energy ΔG‡ is morefavorable for the creation of the 1b complex, owing to a lowerreorganization energy to rearrange the QD*−1 complex (seeeq 2 above). The same trend is found for the core−shell QD,which shows a larger ΔG value of injection to form 1a, butlower activation energy. Interestingly, the absolute ΔG values ofinjection from (CdSe)12@(ZnS)48 to 1 are higher than in thesmaller cluster: 1.82 (1a) and 1.34 (1b) eV versus 1.46 (1a)and 0.98 (1b) eV. The consequence is that the overall ETactivation energies are smaller for the core−shell systems, withthe effect that the larger QD might inject electrons morerapidly into the Pt complex than (CdSe)12.Electronic Coupling and Kinetics of Charge Separation.

The most significant results obtained in this work involveelectronic coupling (HDA). HDA is computed by evaluating thecharge transfer integrals between the LUMO of the QD,corresponding to the donor orbital of QD*, and the LUMO+1(for 1a) or LUMO (for 1b) of complex 1, both representingthe acceptor orbitals. The HDA is calculated on the geometry of

the supermolecular complex QD−1. According to Table 2, inboth types of QDs, the electron coupling is ca. two times largerwhen the ET induces the release of the succinate ligands toform the 1a complex. The electronic coupling enters theMarcus equation with the square of its value; therefore, onlyaccording to Fermi’s golden rule, the kinetics of ET to form the1a complex is four times larger than to form 1b. Furthermore,the electronic coupling is much smaller than the reorganizationenergy, validating the weak interaction limit of the Marcusequation. Table 2 provides estimates for the kinetics of ETcalculated as in eq 1. In absolute values, these terms might befar from the real experimental value because of the highsensitivity of the Marcus equation to the exponential term.Nevertheless, trends are qualitatively well described and showhow electron injection from both types of QD to the Ptcomplex more favorably leads to 1a than 1b, i.e., to release thesuccinate ligand and form Pt(II) species, among them cisplatin.To verify this DFT result, we followed by 1H NMR the

photolysis (λexc = 630 nm) of 1 in the presence of CdSe@ZnScore−shell QDs. NMR shows that the photoreduction is muchcleaner under such conditions compared to UV-light irradiation(Figure 5). In particular, reduction of Pt(II) and dissociation ofsuccinate appears to be favored compared to formation of thePt(IV) photoproducts responsible for the set of peaks at 5.5−7ppm. The presence of cisplatin and cisplatin-like species wasconfirmed by GMP binding experiments (Supporting Informa-tion, Figures S17 and S18) and previously by XPS.34

Calculations and experiments point out that interaction of 1with the semiconductor surface can affect the photochemicaland redox behavior of this Pt(IV) derivative. Selection ofphotochemical pathways through thermodynamic and kineticcontrol of the QD−metal complex interaction has the potentialto create new fascinating scenarios for future developments onhybrid nanosystems coupled with metal complexes for a rangeof application (e.g., phototherapy, photocatalysis).

■ CONCLUSIONS

In summary, combination of DFT/TDDFT with selectedexperiments was used to gain new insights into the photo-chemistry and reduction behavior of 1 and to investigate theQD-mediated photoactivation of the complex, a precursor of

Figure 5. Selected regions of the 1H NMR spectrum of 1 in H2O/D2O (5:1, [1] = 1 mM) in the dark (bottom), under irradiation at 385 nm(middle, 2 min, ∼ 40 mW·cm−2), and under irradiation at 630 nm in the presence of PEGylated CdSe@ZnS QDs (top, [QD] = 100 nM, 3 h, ∼ 20mW·cm−2).



cisplatin. Our study allows to draw the following keyconclusions:(a) Excitation of 1 with UV light leads to the generation of

dissociative singlet and triplet excited states which can evolvetoward the formation of different Pt(IV) photoproducts, amongwhich a likely product is the cytotoxic cis,cis,trans-[PtIV(NH3)2(Cl)2(OH)2] complex. As confirmed by XPSdata, direct UV light excitation does not seem to efficientlypromote Pt(IV) → Pt(II) conversion. On the contrary, 1 canbe transformed into at least two distinct Pt(II) complexes uponchemical reduction, including cisplatin.(b) QD-mediated light activation can promote the formation

of Pt(II) photoproducts as a result of the interaction between 1and the surface of the semiconductor material. Fitting ofquenching data shows that the complex is adsorbed onto theQD surface. Consistently, DFT calculations on two differentQD-1 models gives strong stabilization energies for suchadducts.(c) The electron transfer (ET) occurring from the QD to 1

falls in the normal regime of Marcus theory (ΔG < λINT) whereincrease in driving force favors the process. Irrespective of theQD model, the ΔG values calculated predict the formation of1a to be favored with respect to 1b; however, a higheractivation energy ΔG‡ needs to be surmounted due to anincreased reorganization energy. ET appears to be favored inthe core−shell model, as shown by the increase of ΔG and thedecrease of ΔG‡ relative to the core-only model. Crucially,computation of the electronic coupling HDA highlights thatelectrons are better transferred from the QD to the LUMO+1of 1 to generate a transient intermediate such as 1a, hence therelease of the succinate ligands. The second possible pathwayinvolving the LUMO and leading to 1b is indeed less probable,consistently with a cleaner photolysis reaction in the presenceof QDs with respect to UV excitation. Such findings suggeststhat activation through QDs might also drive the formation of thepreferred photoproduct (e.g., cisplatin) compared to simplechemical reduction or direct light excitation, a fine prospect fordeveloping anticancer agents acting through novel and selectedmechanisms of actions.

■ ASSOCIATED CONTENT*S Supporting InformationFull account of DFT and TDDFT data, materials andexperimental methods, NMR and cytotoxicity results, andelectron transfer kinetics calculation details. This material isavailable free of charge via the Internet at http://pubs.acs.org.

■ AUTHOR INFORMATIONCorresponding Authors*E-mail: [email protected].*E-mail: [email protected] Contributions#These authors contributed equally.NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTSOur work in this area was supported by Spanish Ministry ofEconomy and Competitiveness (grants CTQ2012-38496-C05-01, CTQ2011-22723, CTQ2012-39315, and PRI−PIBIN-2011-0812), the Department of Industry of the Basque Country(grant ETORTEK and grant SAIOTEK S-PC12UN003), and

the Department of Education, Universities and Research of theBasque Country (grants PI-2012-33 and IT588-13). L.S. andE.R. are supported by the MICINN of Spain with the Ramon yCajal Fellowship RYC-2011-07787 and by the MC CIGfellowship UCnanomat4iPACT (grant n. 321791). J.M.A.thanks the Spanish Ministry of Education for funding througha FPU fellowship (AP2009-1514). The SGI/IZO-SGIker UPV/EHU is gratefully acknowledged for generous allocation ofcomputational resources. We also deeply thank Serge Gorelskifor the prompt implementation of the charge transfer integralswithin AOMIX and for his help. L.S. and E.R. thank Dr. L. Yatefor his support with XPS and members of the European COSTAction CM1105 for stimulating discussions.

■ REFERENCES(1) Murphy, C. J.; Coffer, J. L. Quantum Dots: A Primer. Appl.Spectrosc. 2002, 56, 16−27.(2) Hetsch, F.; Xu, X.; Wang, H.; Kershaw, S. V.; Rogach, A. L.Semiconductor Nanocrystal Quantum Dots as Solar Cell Componentsand Photosensitizers: Material, Charge Transfer, and SeparationAspects of Some Device Topologies. J. Phys. Chem. Lett. 2011, 2,1879−1887.(3) Kamat, P. V. Quantum Dot Solar Cells. SemiconductorNanocrystals as Light Harvesters. J. Phys. Chem. C 2008, 112,18737−18753.(4) Sargent, E. H. Colloidal Quantum Dot Solar Cells. Nat. Photonics2012, 6, 133−135.(5) Kamat, P. V. Meeting the Clean Energy Demand: NanostructureArchitectures for Solar Energy Conversion. J. Phys. Chem. C 2007, 111,2834−2860.(6) Kamat, P. V. Boosting the Efficiency of Quantum Dot SensitizedSolar Cells through Modulation of Interfacial Charge Transfer. Acc.Chem. Res. 2012, 45, 1906−1915.(7) Nann, T.; Skinner, W. M. Quantum Dots for Electro-OpticDevices. ACS Nano 2011, 5, 5291−5295.(8) Hildebrandt, N. Biofunctional Quantum Dots: ControlledConjugation for Multiplexed Biosensors. ACS Nano 2011, 5, 5286−5290.(9) Medintz, I. L.; Uyeda, H. T.; Goldman, E. R.; Mattoussi, H.Quantum Dot Bioconjugates for Imaging, Labelling, and Sensing. Nat.Mater. 2005, 4, 435−446.(10) Alivisatos, A. P. Perspectives on the Physical Chemistry ofSemiconductor Nanocrystals. J. Phys. Chem. 1996, 100, 13226−13239.(11) Alivisatos, A. P. Semiconductor Clusters, Nanocrystals, andQuantum Dots. Science 1996, 271, 933−937.(12) Mora-Sero, I.; Bertoluzzi, L.; Gonzalez-Pedro, V.; Gimenez, S.;Fabregat-Santiago, F.; Kemp, K. W.; Sargent, E. H.; Bisquert, J.Selective Contacts Drive Charge Extraction in Quantum Dot Solids viaAsymmetry in Carrier Transfer Kinetics. Nat. Commun. 2013, 4, 2272.(13) Maldonado, C. R.; Salassa, L.; Gomez-Blanco, N.; Mareque-Rivas, J. C. Nano-Functionalization of Metal Complexes for MolecularImaging and Anticancer Therapy. Coord. Chem. Rev. 2013, 257, 2668−2688.(14) Garaikoetxea Arguinzoniz, A.; Ruggiero, E.; Habtemarian, A.;Hernandez-Gil, J.; Salassa, L.; Mareque-Rivas, J. C. Light Harvestingand Photoemission by Nanoparticles for Photodynamic Therapy. Part.Part. Syst. Charact. 2014, 31, 46−75.(15) Peterson, M. D.; Holbrook, R. J.; Meade, T. J.; Weiss, E. A.Photoinduced Electron Transfer from PbS Quantum Dots toCobalt(III) Schiff Base Complexes: Light Activation of a ProteinInhibitor. J. Am. Chem. Soc. 2013, 135, 13162−13167.(16) Tseng, H.-W.; Wilker, M. B.; Damrauer, N. H.; Dukovic, G.Charge Transfer Dynamics between Photoexcited CdS Nanorods andMononuclear Ru Water-Oxidation Catalysts. J. Am. Chem. Soc. 2013,135, 3383−3386.



http://pubs.acs.org

mailto:[email protected]

mailto:[email protected]

(17) Long, R.; Prezhdo, O. V. Ab Initio Nonadiabatic MolecularDynamics of the Ultrafast Electron Injection from a PbSe QuantumDot into the TiO2 Surface. J. Am. Chem. Soc. 2011, 133, 19240−19249.(18) Chaban, V. V.; Prezhdo, V. V.; Prezhdo, O. V. Covalent LinkingGreatly Enhances Photoinduced Electron Transfer in Fullerene−Quantum Dot Nanocomposites: Time-Domain Ab Initio Study. J.Phys. Chem. Lett. 2012, 4, 1−6.(19) Varbanov, H. P.; Jakupec, M. A.; Roller, A.; Jensen, F.; Galanski,M.; Keppler, B. K. Theoretical Investigations and Density FunctionalTheory Based Quantitative Structure−Activity Relationships Modelfor Novel Cytotoxic Platinum(IV) Complexes. J. Med. Chem. 2013, 56,330−344.(20) Gramatica, P.; Papa, E.; Luini, M.; Monti, E.; Gariboldi, M.;Ravera, M.; Gabano, E.; Gaviglio, L.; Osella, D. AntiproliferativePt(IV) Complexes: Synthesis, Biological Activity, and QuantitativeStructure−Activity Relationship Modeling. J. Biol. Inorg. Chem. 2010,15, 1157−1169.(21) Mukhopadhyay, S.; Barnes, C. M.; Haskel, A.; Short, S. M.;Barnes, K. R.; Lippard, S. J. Conjugated Platinum(IV)−PeptideComplexes for Targeting Angiogenic Tumor Vasculature. BioconjugateChem. 2008, 19, 39−49.(22) Graf, N.; Bielenberg, D. R.; Kolishetti, N.; Muus, C.; Banyard, J.;Farokhzad, O. C.; Lippard, S. J. αVβ3 Integrin-Targeted PLGA-PEGNanoparticles for Enhanced Anti-Tumor Efficacy of a Pt(IV) Prodrug.ACS Nano 2012, 6, 4530−4539.(23) Dhar, S.; Daniel, W. L.; Giljohann, D. A.; Mirkin, C. A.; Lippard,S. J. Polyvalent Oligonucleotide Gold Nanoparticle Conjugates asDelivery Vehicles for Platinum(IV) Warheads. J. Am. Chem. Soc. 2009,131, 14652−14653.(24) Dhar, S.; Liu, Z.; Thomale, J.; Dai, H.; Lippard, S. J. TargetedSingle-Wall Carbon Nanotube-Mediated Pt(IV) Prodrug DeliveryUsing Folate as a Homing Device. J. Am. Chem. Soc. 2008, 130,11467−11476.(25) Farrer, N. J.; Salassa, L.; Sadler, P. J. PhotoactivatedChemotherapy (PACT): the Potential of Excited-State d-Block Metalsin Medicine. Dalton Trans. 2009, 10690−10701.(26) Schatzschneider, U. Photoactivated Biological Activity ofTransition-Metal Complexes. Eur. J. Inorg. Chem. 2010, 1451−1467.(27) Farrer, N. J.; Woods, J. A.; Salassa, L.; Zhao, Y.; Robinson, K. S.;Clarkson, G.; Mackay, F. S.; Sadler, P. J. A Potent Trans-DiiminePlatinum Anticancer Complex Photoactivated by Visible Light. Angew.Chem., Int. Ed. 2010, 49, 8905−8908.(28) Westendorf, A. F.; Woods, J. A.; Korpis, K.; Farrer, N. J.; Salassa,L.; Robinson, K.; Appleyard, V.; Murray, K.; Gruenert, R.; Thompson,A. M.; Sadler, P. J.; Bednarski, P. J. Trans,trans,trans-[PtIV(N3)2(OH)2(py)(NH3)]: A Light-Activated Antitumor PlatinumComplex That Kills Human Cancer Cells by an Apoptosis-Independent Mechanism. Mol. Cancer Ther. 2012, 11, 1894−1904.(29) Burksa, P. T.; Ford, P. C. Quantum Dot Photosensitizers.Interactions with Transition Metal Centers. Dalton Trans. 2012, 41,13030−13042.(30) Ruggiero, E.; Habtemariam, A.; Yate, L.; Mareque-Rivas, J. C.;Salassa, L. Near Infrared Photolysis of a Ru Polypyridyl Complex byUpconverting Nanoparticles. Chem. Commun. 2014, 50, 1715−1718.(31) Min, Y.; Li, J.; Liu, F.; Yeow, E. K. L.; Xing, B. Near-InfraredLight-Mediated Photoactivation of a Platinum Antitumor Prodrug andSimultaneous Cellular Apoptosis Imaging by Upconversion-Lumines-cent Nanoparticles. Angew. Chem., Int. Ed. 2014, 53, 1012−1016.(32) Dai, Y.; Xiao, H.; Liu, J.; Yuan, Q.; Ma, P.; Yang, D.; Li, C.;Cheng, Z.; Hou, Z.; Yang, P.; Lin, J. In Vivo Multimodality Imagingand Cancer Therapy by Near-Infrared Light-Triggered trans-PlatinumPro-Drug-Conjugated Upconverison Nanoparticles. J. Am. Chem. Soc.2013, 135, 18920−18929.(33) Blanco, N. G.; Maldonado, C. R.; Mareque-Rivas, J. C. EffectivePhotoreduction of a Pt(IV) Complex with Quantum Dots: A FeasibleNew Light-Induced Method of Releasing Anticancer Pt(II) Drugs.Chem. Commun. 2009, 5257−5259.(34) Maldonado, C. R.; Gomez-Blanco, N.; Jauregui-Osoro, M.;Brunton, V. G.; Yate, L.; Mareque-Rivas, J. C. QD-Filled Micelles

Which Combine SPECT and Optical Imaging with Light-InducedActivation of a Platinum(IV) Prodrug for Anticancer Applications.Chem. Commun. 2013, 49, 3985−3987.(35) Frisch, M. J.; et al.. Gaussian 09, revision B.01; Gaussian, Inc.:Wallingford, CT, 2009.(36) Reithofer, M. R.; Valiahdi, S. M.; Jakupec, M. A.; Arion, V. B.;Egger, A.; Galanski, M.; Keppler, B. K. Novel Di- andTetracarboxylatoplatinum( IV) Complexes. Synthesis, Characteriza-tion, Cytotoxic Activity, and DNA Platination. J. Med. Chem. 2007, 50,6692−6699.(37) Azpiroz, J. M.; Ugalde, J. M.; Infante, I. Benchmark Assessmentof Density Functional Methods on Group II-VI MX (M = Zn, Cd; X =S, Se, Te) Quantum Dots. J. Theor. Comput. Chem. 2014, 10, 76−89.(38) York, D. M.; Karplus, M. A Smooth Solvation Potential Basedon the Conductor-Like Screening Model. J. Phys. Chem. A 1999, 103,11060−11079.(39) Simon, S.; Duran, M.; Dannenberg, J. J. How Does Basis SetSuperposition Error Change the Potential Surfaces for Hydrogen-Bonded Dimers? J. Chem. Phys. 1996, 105, 11024.(40) Boys, S. F.; Bernardi, F. The Calculation of Small MolecularInteractions by the Differences of Separate Total Energies. SomeProcedures with Reduced Errors. Mol. Phys. 1970, 19, 553.(41) Krylov, A. I.; Gill, P. M. W. Q-Chem: An Engine for Innovation.WIREs Comput. Mol. Sci. 2013, 3, 317−326.(42) O’Boyle, N. M.; Tenderholt, A. L.; Langner, K. M. cclib: aLibrary for Package-Independent Computational Chemistry Algo-rithms. J. Comput. Chem. 2008, 29, 839−845.(43) Gorelsky, S. I. AOMix: Program for Molecular Orbital Analysis,6.81 ed.; University of Ottawa: Ottawa, Canada, 2012.(44) Gorelsky, S. I.; Lever, A. B. P. Electronic Structure and Spectraof Ruthenium Diimine Complexes by Density Functional Theory andINDO/S. Comparison of the Two Methods. J. Organomet. Chem.2001, 635, 187−196.(45) Pettersen, E. F.; Goddard, T. D.; Huang, C. C.; Couch, G. S.;Greenblatt, D. M.; Meng, E. C.; Ferrin, T. E. UCSF ChimeraAVisualization System for Exploratory Research and Analysis. J. Comput.Chem. 2004, 25, 1605−1612.(46) Garino, C.; Salassa, L. The Photochemistry of Transition MetalComplexes Using DFT. Philos. Trans. R. Soc. A 2013, 20120134.(47) Mulliken, R. S. Electronic Population Analysis on LCAO-MOMolecular Wave Functions. I. J. Chem. Phys. 1955, 23, 1833−1840.(48) Hirshfeld, F. L. Bonded-Atom Fragments for DescribingMolecular Charge Densities. Theor. Chem. Acc. 1977, 44, 129−38.(49) Foster, J. P.; Weinhold, F. Natural Hybrid Orbitals. J. Am. Chem.Soc. 1980, 102, 7211−7218.(50) Nemirovski, A.; Vinograd, I.; Takrouri, K.; Mijovilovich, A.;Rompel, A.; Gibson, D. New Reduction Pathways for ctc-[PtCl2(CH3CO2)2(NH3)(Am)] Anticancer Prodrugs. Chem. Commun.2010, 46, 1842−1844.(51) Zhang, J. Z.; Wexselblatt, E.; Hambley, T. W.; Gibson, D.Pt(IV) Analogs of Oxaliplatin That Do Not Follow the ExpectedCorrelation between Electrochemical Reduction Potential and Rate ofReduction by Ascorbate. Chem. Commun. 2012, 48, 847−849.(52) Koposov, A. Y.; Cardolaccia, T.; Albert, V.; Badaeva, E.; Kilina,S.; Meyer, T. J.; Tretiak, S.; Sykora, M. Formation of AssembliesComprising Ru−Polypyridine Complexes and CdSe NanocrystalsStudied by ATR-FTIR Spectroscopy and DFT Modeling. Langmuir2011, 27, 8377−8383.(53) Sykora, M.; Petruska, M. A.; Alstrum-Acevedo, J.; Bezel, I.;Meyer, T. J.; Klimov, V. I. Photoinduced Charge Transfer betweenCdSe Nanocrystal Quantum Dots and Ru−Polypyridine Complexes. J.Am. Chem. Soc. 2006, 128, 9984−9985.(54) Koopmans, T. Uber die Zuordnung von Wellenfunktionen undEigenwerten zu den Einzelnen Elektronen Eines Atoms. Physica 1934,1, 104−113.(55) Theoretically, there is still some debate whether Koopman’sTheorem hold within DFT. However, in this contest, it provides usefulinformation on IP trends.



(56) Shalom, M.; Ruhle, S.; Hod, I.; Yahav, S.; Zaban, A. EnergyLevel Alignment in CdS Quantum Dot Sensitized Solar Cells UsingMolecular Dipoles. J. Am. Chem. Soc. 2009, 131, 9876−9877.(57) Kilina, S.; Ivanov, S.; Tretiak, S. Effect of Surface Ligands onOptical and Electronic Spectra of Semiconductor Nanoclusters. J. Am.Chem. Soc. 2009, 131, 7717−7726.



quantum dot photoactivation of pt(iv) anticancer agents: evidence of an electron transfer mechanism...

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