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Review

Recent Development of Heavy Atom-Free Triplet Photosensitizers for Photodynamic Therapy

by
Xiao Xiao
1,
Kaiyue Ye
1,
Muhammad Imran
1 and
Jianzhang Zhao
1,2,*
1
State Key Laboratory of Fine Chemicals, Frontier Science Center for Smart Materials, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China
2
State Key Laboratory of Chemistry and Utilization of Carbon Based Energy Resources, College of Chemistry, Xinjiang University, Urumqi 830017, China
*
Author to whom correspondence should be addressed.
Appl. Sci. 2022, 12(19), 9933; https://doi.org/10.3390/app12199933
Submission received: 27 August 2022 / Revised: 21 September 2022 / Accepted: 28 September 2022 / Published: 2 October 2022
(This article belongs to the Special Issue Photochemistry and Photodynamics)
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Abstract

:
Photodynamic therapy (PDT) is an attractive method for cancer treatment. Triplet photosensitizers (PSs) are critical for this method; upon photoexcitation, efficient intersystem crossing (ISC) occurs for triplet PSs, the triplet-excited state of the triplet PSs is populated, then via intermolecular triplet energy transfer, the O2, in triplet-spin multiplicity at ground state, is sensitized to the singlet-excited state, i.e., singlet oxygen (1O2) is produced. This strong reactive oxygen species (ROS) will oxidize the biomolecules in the tumor tissue. Thus, the design of novel triplet PSs as efficient PDT agents is vital. In this review article, we will introduce the recent development of the heavy atom-free triplet PSs used for PDT, including those based on spin-orbit charge transfer ISC (SOCT-ISC), twisting of the π-conjugation framework-induced ISC, radical enhanced ISC, and thionated carbonyl-induced ISC. The ISC mechanisms and molecular structure design rationales are discussed. The less studied electron spin selectivity of the ISC of the triplet PSs is also introduced. This information is helpful for the future design of new efficient triplet PSs for PDT.

1. Introduction

Photodynamic therapy (PDT) is an important method for the treatment of cancer [1,2,3,4,5,6,7,8,9,10,11]. For this method, the triplet photosensitizers (PSs), which are responsible for the production of singlet oxygen (1O2) upon photoexcitation, are critical. PS is photoexcited to the singlet-excited state (for instance, S1) and the subsequent intersystem crossing (ISC) produced the triplet-excited state (T1) state, then via the intermolecular triplet-triplet-energy transfer, the singlet oxygen (1O2) is produced. This is the type II PDT, whereas in type I PDT, other reactive oxygen species (ROS, such as superoxide radical anion, O2−•) are produced via electron transfer or hydrogen abstraction (Scheme 1). The highly reactive 1O2 can oxidize the biomolecules and causes cell death. Due to the short lifetime of 1O2 (typically a few microseconds), the treatment is confined to the tumor tissue, given that the PDT reagents are delivered in a targeted way. Because of the triplet spin multiplicity of O2 at ground state, efficient ISC is required for the triplet PSs to be used as efficient PDT reagents. ISC of organic compounds can be enhanced by heavy atom effect [12,13,14], but the triplet PSs prepared with this method suffer from disadvantages of toxicity and high cost of synthesis [15], etc. Moreover, the triplet-state lifetime of the triplet PSs can be reduced by the heavy atom effect, because the heavy atom can enhance both S1→T1 and T1→S0 transitions [16]. Heavy atom-free triplet PSs with a longer triplet-state lifetime are desired because they are more efficient in sensitizing 1O2 in the hypoxia microenvironment of the tumor tissue [17,18,19].
In photochemistry, it is challenging to design a molecular structure showing efficient ISC without the heavy atom effect, because without the heavy atom effect, it is difficult to predict the ISC ability of an organic chromophore [15,20]. The hydrophobic nature of organic triplet PSs is another challenge in their use for PDT. However, this can be overcome by developing the triplet PSs-loaded nanoparticles or encapsulating them with a drug delivery carrier or by attaching hydrophilic moieties to the triplet PSs molecules. In recent years, some ISC mechanisms without the heavy atom effect have been studied, and the related compounds have been used for PDT studies. It should be noted that there are type I and type II triplet PSs for PDT (Scheme 1). For the former, ROS are produced, for instance, the O2−•, peroxide (O22−), hydroxyl (OH•) radicals, etc. For the latter, 1O2 is produced [21,22]. The majority of the previously reported triplet PSs are based on type II mechanism, which is oxygen-dependent. In this review, we will focus on the introduction of the recent development of the organic molecular triplet PSs for 1O2 production.

2. Spin-Orbit Charge Transfer Intersystem Crossing (SOCT-ISC)

Charge recombination (CR)-induced ISC in electron donor-acceptor dyads, typically via the radical pair ISC (RP-ISC), has been studied for decades [23,24,25,26,27,28]. However, the conventional electron donor-acceptor compounds are not ideal to be used as triplet PSs because the synthesis is challenging, and the ISC yield is not satisfactory [25]. Recently, efficient CR-induced ISC was observed in compact orthogonal electron donor-acceptor dyads, which contain a single bond linker between the donor and acceptor [9,16,29,30,31]. For the charge transfer (CT) in these dyads, the molecular angular momentum change during CR compensates the spin angular momentum change of ISC; as such the ISC is enhanced. This ISC mechanism is termed SOCT-ISC. Early electron donor-acceptor dyads show very weak absorption of visible light (Figure 1) [32], which is unsuitable for PDT application. Formation of triplet state via SOCT-ISC mechanism in compounds 1 and 2 was confirmed by nanosecond-transient absorption (ns-TA) spectroscopy, but the ISC quantum yields were not reported [32]. Orthogonal orientation between the donor and acceptor is beneficial for SOCT-ISC, for instance, no ISC was observed for 3, but triplet-state formation was observed in 4 and 5 [33]. Senge et al. prepared anthryl-Bodipy dyads (6 and 7, Figure 1), and efficient ISC was observed (singlet oxygen quantum yield ΦΔ = 91%) [34]. The triplet-state lifetime was determined as 41 μs (in N,N-dimethylformamide, DMF). Recently they show these compounds can be used as efficient PDT reagents [35].
It is important to note that in dyads 4 and 5, the methyl groups in the electron donor part are introduced for conformation restriction purpose, so that the π-planes of the electron donor and acceptor will adopt orthogonal geometry. We found that with the connection at the N-position of the phenothiazine (PTZ) moiety, the conformation restriction is effective due to the repulsion of the peri H atoms on the PTZ and the anthryl moieties (8–10, Figure 2, especially for 9) [36]. All the three dyads show satisfactory ISC in toluene (TOL), dichloromethane (DCM) and acetonitrile (ACN) (ΦΔ is up to 77%). Anthryl-localized triplet state was observed for the dyads, and the triplet state lifetime is up to 469 μs.
We prepared anthryl-Bodipy dyads, which show larger topological diversity (Figure 3) [37,38]. Dyads 11 and 12 are similar to the dyads reported by Senge et al. [34], but the topological feature of 13 and 14 is unique, although for both dyads the donor and acceptor adopt orthogonal geometry for the energy minima at the ground state. We found that the triplet lifetime is highly solvent polarity-dependent, triplet-state lifetime up to 345 μs was observed [37,38]. It should be pointed out that the triplet state can be quenched by the triplet-triplet-annihilation (TTA) effect, thus a kinetic model with TTA taken into account was used [39]. Interestingly, we found the ΦΔ values of the dyads were different. For 11 and 12, the ΦΔ were in the range of 82~95% in DCM and ACN, but ΦΔ < 10% in TOL. The topological analogues 13 and 14 showed much smaller ΦΔ values (11~20%) [37]. This was an interesting finding, that the SOCT-ISC efficiency was not dependent only on the orthogonal geometry; an additional descriptor was necessary for evaluating the relationship between the molecular geometry of the dyads and the SOCT-ISC efficiency [16]. We demonstrated the application of these novel heavy atom-free triplet PSs in TTA upconversion [40,41,42,43,44], and upconversion quantum yield (ΦUC) up to 15.8% was observed.
PTZ is a stronger electron donor (EOX = +0.3 V, vs. Fc/Fc+) than anthryl (EOX = +1.11 V, vs. Fc/Fc+), thus we used PTZ as an electron donor to construct dyads with Bodipy unit as the electron acceptor (15 and 16, Figure 4) [45]. The molecular conformation restriction was exerted by the 1,7-dimethyl groups on the Bodipy chromophore. With a stronger electron donor, the CT state energy would decrease [16,29]. For instance, the CT state energy of 16 in TOL and DCM were 2.42 eV and 1.79 eV, respectively (approximated by the fluorescence emission data). For 12, however, the corresponding CT state energies were 2.43 eV and 2.05 eV in TOL and DCM, respectively [38]. As a result, the relative energy order of the CT and the Tn states would change, so that the solvent polarity dependency of the ISC of the dyads would also change. The ΦΔ of 12 in TOL and DCM were 3% and 80%, respectively, whereas for 16, the corresponding ΦΔ values of the dyad in the two solvents were 67.3% and 1.3%. Femtosecond transient absorption spectra (fs-TA) demonstrated fast charge separation in 15 and 16 (0.2 ps), but the CR was slower. Ns-TA spectra showed the triplet state lifetime of 16 is 116 μs [45]. The triplet-state lifetimes of the Bodipy chromophore in these dyads were much longer than that obtained with the heavy atom effect (for 2,6-diiodoBodipy, apparent lifetime τT = 57 μs) [46].
Zhang et al. prepared Bodipy derivatives with electron-donating groups attached at the meso-position (17−22, Figure 5) [47]. They found for the derivatives containing methyl groups at 1,7-position, the ΦΔ (up to 64%) were higher than those without methyl groups at 1,7-position (ΦΔ < 45%). This was attributed to the molecular conformation restriction effect. Qian et al. studied the dyads with carbazole (Cz) as electron donor and Bodipy unit as electron acceptor, triethylene glycol monomethyl ether moiety was attached to the N-position of the Cz moiety to improve the solubility in aqueous solution. The Cz-Bodipy dyad exhibited negligible dark cytotoxicity and high phototoxicity (IC50: 0.45 μM) [48].
With perylene-Bodipy dyads (23−26, Figure 6), we showed that these heavy atom-free triplet PSs could be used as novel potent PDT reagents [18]. Perylene-Bodipy dyads showed strong absorption of green light (molar absorption coefficient ε = 77,000 M−1 cm−1 at 515 nm in tetrahydrofuran, THF), and the triplet state lifetime was 442 μs (the T1 triplet state of the dyads was localized on the perylene moiety), which was much longer than that produced via heavy atom effect (3-bromoperylene. τT = 62 μs). The advantage of the long-lived triplet state in 1O2 photosensitizing was shown by dyad 25, the ΦΔ value was 34% even in hypoxia atmosphere (0.2% O2 in mixture with N2, v/v).
The PDT effect with live cells was studied with 24 (Figure 7) [18]. Compared to the 2,6-diiodoBodipy, the dark toxicity of 24 was much lower, the EC50 values were 6.0 μM and 78.1 μM, respectively. Photo irradiation (500 nm; 9.6 J cm−2) induced strong PDT effect (EC50 = 75 nM). In comparison the 2,6-diiodoBodipy showed a light toxicity of EC50 = 4 nM. Yoon et al. demonstrated that the triplet PSs based on the SOCT-ISC mechanism could also be used as PDT reagents effectively to produce 1O2 [49].
For the compact electron donor-acceptor dyads, given the electronic coupling between the donor and acceptor was strong, CT absorption bands (S0→1CT transition) would result [33]. This property could be used for increasing the anti-Stokes shift in TTA upconversion [50,51,52,53]. For 24, we observed a broad CT absorption band in the range 535−635 nm and the LE absorption of the perylene moiety was retained to a large extent [54]. Although the energy-minimized geometry of 24 is not orthogonal (dihedral angle between the perylene and the Bodipy part is 60°) [18], satisfactory ISC efficiency was observed (ΦΔ = 31%) [54]. Note the attaining of this red-shifted CT absorption band in electron donor-acceptor dyads is different from the conventional derivatization of chromophores by extension of the π-conjugation framework or attaching of electron pushing/withdrawal groups to the π-conjugation framework, in both cases, the T1 state energy of the chromophore may be decreased, as a result of the substantially perturbed π-conjugation framework of the chromophore. In the electron donor/acceptor dyads such as 24, in which there is limited yet non-negligible electronic coupling between the donor and acceptor, a red-shifted CT absorption band resulted, but the T1 state energy of the chromophore may not be reduced, which is a desired property for a triplet PS (i.e., by attaching of an electron donor or acceptor to the chromophore, red-shifted absorption results, and the T1 state energy keeps high). The T1 state energy of 24 was determined as 1.57 eV (almost similar to the pristine perylene). We demonstrated this advantage by using 24 as triplet PS for TTA upconversion, a large anti-Stokes shift of 0.65 eV was observed by excitation into the CT absorption band (Figure 8) [54]. In comparison, upon photoexcitation into the normal LE absorption, a smaller anti-Stokes shift of 0.37 eV was observed. This method may become a new, general approach to attained red-shifted absorption band yet un-reduced T1 state energy.
Zhang et al. prepared dyads with Bodipy as electron donor and found that no SOCT-ISC occurs, but SOCT-ISC does occur for analogous dyads in which the Bodipy units act as electron acceptor (27–29, Figure 9) [55]. The results were discussed based on molecular orbital energies. However, we found that in some dyads, a specific chromophore could act as either electron donor or acceptor, and all the corresponding dyads showed efficient SOCT-ISC, for instance, the dyads with perylene chromophore as either the electron acceptor or donor [56,57], or dyads with anthryl unit as either electron donor or acceptor [33,34,36,37,38]. Recently it was found that for some triplet PSs based on the SOCT-ISC mechanism, the 1O2 production could be enhanced by aggregation effect [58]. Moreover, Bodipy dimers were prepared and efficient SOCT-ISC was observed [59,60].
We also found that for some compact electron donor/acceptor dyads, charge separation occurred and fluorescence was quenched, but the ISC efficiency was low [61,62,63]. The reason may be attributed to the un-matching of the CT and triplet state energies or poor molecular conformation restrictions, and fast charge recombination led to the direct relaxation of the CT state to the ground state (S0). The solvent polarity-dependent ISC efficiency of the compact orthogonal dyads does not necessarily act as a persistent drawback. We have shown that by tuning the electron donating ability (30 and 31, Figure 10), the dyad based on SOCT-ISC mechanism can show high ISC efficiency in both low polar and high polar solvents [64]. For instance, the ΦΔ of 31 in TOL, THF, DCM and ACN were 0.48, 0.53, 0.99 and 0.72, respectively. However, for 30, the ΦΔ in TOL, THF, DCM and ACN were 0.07, 0.42, 0.94 and 0.71, respectively.
Blacha-Grzechnik et al. prepared a class of borafluorene−ligand dyads 32−34, for which the ISC is based on SOCT-ISC mechanism (Figure 11) [65]. The electronic features of borafluorene make it an electron donor. The electron donor and acceptor moieties are connected by a spiro geometry, and the two moieties adopt orthogonal alignment. These characteristics of the dyads enhance the ISC to produce the triplet state. The ΦΔ of 32, 33 and 34 in DCM are 0.78, 0.56 and 0.27, respectively.
Thompson et al. prepared a series of Zn dipyrrin complexes 35–38 (Figure 12) containing no large aryl appendant that was shown to undergo symmetry-breaking charge transfer (SBCT) and ISC, but the triplet-state yield is low [66]. Later Bradforth et al. showed that for Zn chlorodipyrrin complexes 39 (Figure 12), the ISC yield was much higher and was dependent on the solvent polarity. The ISC quantum yields in cyclohexane, TOL and ACN were 30%, 89% and 76%, respectively. The variation of the ISC quantum yields was assigned to the changing of the CT state energies in different solvents and the matching of the CT state with the coordinated dipyrrin ligand [67]. It should be noted that the ISC in these complexes was not due to the heavy atom effect of the Zn(II) ions.
Matching the S1 and Tn state energy may enhance the ISC [68,69,70,71]. The role of the intermediate triplet states in the SOCT-ISC efficiency was demonstrated by aryl-appended Zn dipyrrin complexes [72]. SBCT was observed for the aryl-appended Zn dipyrrin complexes 40−43 (Figure 13), but high ISC efficiency was observed only for the complex 43 with anthryl appendant. The reason is attributed to the 3An state (1.73 eV, which is close to the CT state of the complexes 2.32 eV). Recently it was shown that the SOCT-ISC strategy can be extended to the chromophores showing longer absorption wavelength [19,73,74]. Moreover, compounds that show thermally activated delayed fluorescence (TADF), which are important in organic light-emitting diodes (OLEDs), can be considered as a special case of SOCT-ISC [16]. Recent studies show that the electron donor-acceptor type of TADF molecules can be used as a novel type of PDT reagents [75].

3. Twisted π-Conjugation Framework-Induced ISC

Recently a novel heavy atom-free triplet PS molecular structure profile was proposed, i.e., the compounds with molecular structures of twisted π-conjugation framework [16,76]. It has been known for decades that helicene and aromatic hydrocarbons with twisted π-conjugation framework show ISC [77,78]. However, helicene compounds usually show weak absorption in visible spectral range and the synthesis is difficult.
Fu and Wang reported that perylenebisimide (PBI) derivatives with twisted molecular structures show efficient ISC [79]. These compounds show strong absorption in visible spectral region (ε of the two compounds are 48,900 M−1 cm−1 at 671 nm and 47,900 M−1 cm−1 at 655 nm, respectively), The fluorescence quantum yields of the two compounds are low (ΦF is 3% and 7%, respectively). ISC efficiency was determined as 94%. ISC was also observed for other chromophores showing twisted molecular structures, such as tolanes [80,81,82], but these compounds showed weak absorption in visible spectral region. Hariharan prepared phenanthrene-fused twisted PBI derivatives, which show efficient ISC (triplet quantum yields ΦT = 10~30%) [83]. The triplet-state lifetimes were determined as 3.7 μs −19.6 μs. These lifetimes are much longer than the triplet state of PBI accessed with heavy atom effect (246 ns) [84], but it is much shorter than the non-twisted PBI (up to 504 μs) [85,86,87].
Bodipy derivatives with twisted π-conjugation frameworks were reported (Figure 14), but the ISC of those compounds was not studied [88,89]. Bodipy derivative 44 was reported to have a twisted molecular structure (Figure 14) [89]; it showed strong absorption in the red spectral range, indicating allowed S0→S1 transition, but the fluorescence was weak. Thus, we studied the ISC of 44 [90].
Nanosecond and sub-nanosecond transient absorption spectra indicated that the ISC of compound 44 took ca. 8 ns, and the triplet-state lifetime was up to 492 μs. The triplet quantum yield was 52%. Pulsed laser-excited time-resolved electron paramagnetic resonance (TREPR) spectra show that the triplet-state wave function was delocalized on the whole π-conjugation framework of the molecular structure, shown by the zero-field splitting (ZFS) D parameter (−595 G), in comparison the D parameter of the triplet state of 2,6-diiodoBodipy was −1050 G). Nanoparticles prepared with the helical bodipy showed efficient PDT, with an ultra-low dose (0.25 μg kg−1), which is hundred times more potent than the currently available PDT reagents.
Recently we also confirmed that another twisted 45 (Figure 14) had efficiency ISC (ΦΔ is 55%), and it was effective in vitro PDT study [91,92]. Hasobe et al. reported that twisted benzo[a]phenanthrene-fused Bodipy showed ISC (ΦT = 60%), and the ISC was supposed to be via vibrational coupling [93]. Interestingly, our recent study shows that there was no simple correlation between the twisting of the molecular structure and the ISC efficiency, at least for the Bodipy derivatives. For instance, compound 46 was reported previously [94]. We found the molecular structure of 46 was only slightly distorted [95]. However, this compound showed a very weak fluorescence (ΦF < 0.1%) and a short fluorescence lifetime (0.1–0.7 ns, solvent dependent). Interestingly, the ISC of this compound with a slightly distorted molecular structure was moderate (up to 29.2% in hexane). In stark contrast, 47 has a more distorted molecular structure [96], it should show efficient ISC given it followed the trend of the Photophysics of helicenes (more twisted structure induces more efficient ISC), however, this compound was highly fluorescent (quantum yield is up to ca. 70% in hexane), and the ISC was negligible [95]. Thus, although the above preliminary studies show that the compounds have twisted molecular structures may have ISC ability, it was also clear that more study is needed in this area.

4. Radical Enhanced ISC: ISC by Electron Spin-Spin Interaction between a Persistent Radical and an Electronically Excited State of a Chromophore

ISC is an electron spin forbidden process in ordinary organic compounds, the most typical method to enhance this transition is by using spin-orbit coupling (SOC) [68]. Another method to enhance ISC in organic compounds is using the electron spin-spin interaction [97,98,99], for instance, the interaction between a stable free radical and the photoexcited organic chromophore [97]. For this approach, the typical method is to attach a radical moiety to a chromophore, but with an appropriate separation between the two units, for instance, to attach TEMPO to the perylenebisimide (PBI) unit [100,101,102,103], etc. The quenching of the chromophore fluorescence by radical is known [98,104,105]. Upon photoexcitation of the visible light-absorbing chromophore in the dyad, the singlet-excited state of the chromophore is firstly produced. A three-electron spin system may form, i.e., a state with overall spin multiplicity of doublet (e.g., D2, the excited chromophore is in closed-shell electronic configuration). ISC of the visible light-absorbing chromophore will bring the overall spin multiplicity of the dyad to be either doublet (D1) or quartet (Q); in both cases, the chromophore part is an open-shell electronic configuration (Figure 15) [102]. Thus, the ISC of the chromophore becomes electron spin allowed, and the ISC is enhanced [98,99].
For most of the previous studies of the radical labeled chromophores, the investigations are focused on the electron spin dynamics, mainly by using TEEPR spectroscopy (such as 49, Figure 15) [97,98,101,106,107,108,109,110], limited attention has been paid to the ISC efficiency and triplet state lifetime, for triplet PSs preparation. For the nitroxide radical-labeled PBI (48, Figure 15), the triplet quantum yield is ca. 23%, and the triplet-state lifetime of the PBI part is ca. 0.5 μs (note the transient-optical absorption spectra usually do not differentiate D1 and Q states) [102]. In a compact perylene-nitroxide dyad, the triplet-state lifetime is shorter (100 ns), due to the strong spin-spin interaction [99]. Concerning triplet PSs’ molecular structure design, the D1→D0 is a spin-allowed process, which may reduce the triplet-state lifetime of the chromophore. However, in some radical chromophore dyads, it was found that the ISC of the chromophore can not be enhanced by the radical part [111].
Triplet PSs based on radical-enhanced ISC (REISC) effect were prepared with Bodipy as the visible light-absorbing chromophore (Figure 16) [112]. It is critical to tune the electron spin-spin interaction between the two units. Strong interaction ensures efficient ISC, but shorter triplet-state lifetime, whereas weak spin-spin interaction may produce poor ISC efficiency [99]. Following these rationales, TEMPO-Bodipy dyads 50 and 51, were prepared, using two different lengths of linkers (Figure 16) [112].
Both dyads show strong absorption of visible light. 50 shows non-efficient ISC (ΦΔ = 14%), and longer triplet-state lifetime (τT = 190 μs) than 51 (ΦΔ = 56% and τT = 62 μs). With TREPR spectra, quartet state (Q) was observed, confirming the electron spin-spin interaction between the radical and the triplet chromophore. With the ZFS parameter D value, we predicted the distance between the radical and the chromophore, which was in agreement with the single crystal X-ray diffraction analysis and the DFT optimizations. We used the radical-based triplet PSs for TTA upconversion, and the quantum yield was 6.7% [112].
Later we used this strategy to prepare the radical-Bodipy triad (Figure 17) [113]. Our expected molecular structure is 52, based on the previously reported amino substitution at the meso-position of Bodipy (with the meso-chloromethyl Bodipy as the starting material). However, carefully 1H NMR analysis and single-crystal X-ray diffraction show the molecular structure was actually 53 (Figure 17). Thus, an unexpected nucleophilic substitution occurred on the methyl groups at 3- (or 5-) position of Bodipy (which is without any chloro substitution) [113].
UV-Vis absorption spectra showed a strong interaction between the two Bodipy units in the triad 53 at the ground state, indicated by the splitting of the absorption band, but the splitting character was different from that resulting from exciton coupling and H-/J-aggregation. The fluorescence of the Bodipy unit in 53 was significantly quenched, and ΦΔ was up to 59%. Interestingly, the triplet-state lifetime was determined as 2.8 μs, much shorter than that of 54 (27 μs). Similarly, nitronyl nitroxide radical-induced ISC was also observed in oligothiophenes [114].
The above TEMPO-Bodipy compounds absorb green light. Amino-substituted NDI was used to prepare radical-based heavy atom-free triplet PS showing red light absorption (Figure 18. ε = 20000 M−1 cm−1 at 606 nm) [115]. Different from the analogue-without-radical unit, i.e., 56 (ΦF = 24%), the ΦF is decreased for 55 (ΦF = 3%). Interestingly, the ΦΔ of 55 is significantly increased (ΦΔ = 50%) as compared to the reference compound 56 (ΦΔ = 2%). Fs-TA spectra indicate the radical-enhanced ISC took 338 ps. The triplet-state lifetime of the 55 was 8.7 μs, much shorter than 56 (τT = 242 μs). Liposomes prepared from NDI-TEMPO showed strong PDT effect (phototoxicity EC50 = 3.22 μM) [115].
A similar strategy was used by Song et al. to prepare radical containing triplet PSs by attaching TEMPO to the meso-position of a Cy7 dye (57, Figure 19) [116], which absorbs at 660 nm. The triplet-state lifetime of the 57 was determined as 9.16 μs, and the ΦΔ is 20%. The dyad showed a desired low dark cytotoxicity (IC50 = 715.4 μM), and the light toxicity was IC50 = 14.2 μM. These results showed that the radical-chromophore dyads triplet PSs could become a new kind of PDT reagents.

5. Triplet PSs with Thionated Carbonyl Groups

Recently, another heavy atom-free triplet PSs’ molecular structure profile was proposed, i.e., to use a molecular structure with thionated carbonyl group. Upon thionation of the carbonyl group in a chromophore, the ISC of the chromophore is usually enhanced, due to the thionation-induced n-π*→π–π* (or vice versa) ISC channel; in this case, the El Sayed rule is satisfied (conservation of angular momentum) [117,118]. We prepared thionated naphthlenediimide (NDI) derivatives (58, Figure 20), the absorption was at 674 nm (ε = 25,000 M−1 cm−1). The ΦΔ was 56%, the triplet-state lifetime was 14.4 μs. Yoon et al. prepared a series of thionated naphthalimide (NI) derivatives (59–61, Figure 20) [119], and found that with amino substitution on the NI unit, i.e., compound 61, the thionated derivative showed maximal absorption at ca. 536 nm (ε = 28,000 M−1 cm−1), and the ΦΔ was close to unity. The ROS generation of 61 was suppressed under physiological conditions due to the self-assembly, but it was recovered in cancer cells. More importantly, cellular experiments showed that 61 produced ROS even under severely hypoxic conditions (1% O2) [119,120].

6. Population Rates of the Three Sublevels of the Triplet State: Time-Resolved EPR Spectra (TREPR)

Normally transient optical absorption or luminescence spectroscopic methods were used to study the ISC and the triplet state, the most typical spectral methods are fs-TA and ns-TA spectroscopic methods [16,29]. However, some fundamental photochemistry information for ISC process is missing in these optical spectral characterizations, i.e., the electron spin selectivity of the ISC, or the electron spin polarization (ESP) of the triplet state [121]. Due to the anisotropy of the spin-orbit coupling and the ZFS of the triplet state, the population of the three sublevels of the T1 state (Tx, Ty, Tz, in the absence of an external magnetic field) was unequal, as a result, the population rates of the three sublevels of the T1 state are usually deviated from Boltzmann distribution [20,122,123]. This information can be well characterized by pulsed laser excited TREPR spectroscopy [122,123,124], the data was critical for elucidation of the ISC mechanisms and understanding of the spatial distribution of the triplet state wave function, and the molecular geometry at the triplet excited state [29,125], etc.
Usually, different ISC mechanisms have different electron spin selectivity, i.e., the ESP of TREPR spectra of the triplet state will be different. TREPR spectrum of anthracene shows an (e, e, e, a, a, a) ESP at the canonical orientation (randomly oriented samples, in frozen solution at 85 K. e stands for emissive and a stands for enhanced absorptive signal) [33]. Interestingly, the triplet state TREPR spectra of 4 and 5 showed an (e, a, e, a, e, a) ESP pattern (Figure 21). The population rates of the sublevels of the triplet state were different. For anthracene, it is AX:AY:AZ = 0.78:1.00:0.07, whereas it was AX:AY:AZ = 0.26:1.00:0.21 for 4. The ZFS parameters of D and E were very close for the dyads and the pristine anthracene (74 mT and −8.0 mT, respectively), indicating the triplet states of the dyads were localized on the anthryl moiety, not delocalized on the donor and acceptor simultaneously. The different ESP clearly demonstrated that the ISC mechanism of the dyads was different from the pristine anthracene, i.e., SOCT-ISC was responsible for the formation of triplet state in the dyads.
Our recent study on the TREPR of the compact electron donor/acceptor dyads shows that one should be careful in the interpretation of the relationship between the ESP pattern of the triplet-state TREPR spectra and the ISC mechanisms. For instance, the ESP phase pattern of the triplet-state TREPR spectrum of 2,6-diiodoBodipy is (e, e, e, a, a, a), but the electron donor/acceptor dyad 11 shows the same ESP phase pattern (Figure 22), although the population rates of the sublevels of the T1 state are different [38]. We observed a similar phenomenon in orthogonal Bodipy-phenoxazine dyads [126], and Bodipy-Cz dyads [127]. These results suggest that the ESP phase pattern of the TREPR spectrum of triplet state is not strictly ISC mechanism-specific [16,29].
For the conventional electron donor/acceptor dyads with large separation between the donor and acceptor, the CT state was identified as spin-correlated radical pair (SCRP) [128,129], 3CT state was rarely observed [130,131]. With the compact electron donor/acceptor dyads, however, we observed 3CT states, as well as the upper triplet state. For instance, for 12, we observed the 3An, 3CT and 3BDP states, simultaneously (Figure 22) [38]. This information indicates that the electron spin-spin interaction of the electron donor and acceptor is in the strong interaction regime (otherwise, SCRP will be resulted), and the upper triplet state may be involved in the SOCT-ISC mechanism [33]. Transient optical spectra can hardly detect the minor components in the triplet state manifolds, and it is almost impossible to discriminate the 1CT, 3CT states, and the radical pairs that without spin-spin interaction. We observed similar results with Bodipy-phenoxazine dyads [126], NI-PTZ dyad [132], NI-derived Tröger’s base [133], and PBI-Cz dyads [87]. Observation of the 3CT state with TREPR spectra in these compact electron donor/acceptor dyads indicates that the S0→S1→3CT→3LE are possible, although it was supposed the photophysical processes of SOCT-ISC are S0→S1→1CT→3LE [33]. We studied the triplet state confinement of organic triplet PSs, and the results show that in general, the triplet state wave function is delocalized on the molecular skeleton, but exceptions do exist [16,95,134,135].

7. Concluding Remarks and Outlook

In summary, the recent development of the small organic molecule triplet photosensitizers (PSs) for photodynamic therapy (PDT) is introduced in this review article. We focused on the heavy atom-free triplet PSs because these organic compounds have the advantages of low cost of preparation and low dark toxicity. These features are beneficial for the application of these compounds as PDT reagents. The triplet PSs we introduced include those based on spin-orbit charge transfer ISC (SOCT-ISC), twisted π-conjugation framework-induced ISC, radical-enhanced ISC, and thionated carbonyl-induced ISC. The ISC mechanisms and molecular structure design rationales are discussed. We briefly introduced the study of the electron spin selectivity of the ISC of the triplet PSs with pulsed laser-excited time-resolved electron paramagnetic resonance (TREPR) spectroscopy. Moreover, the hydrophobicity is a disadvantage of these triplet PSs and it still needs to be addressed for clinical translation. The rigid molecular structures of triplet PSs can cause the issue of poor water solubility when applied in PDT and bioimaging. By attaching targeting groups to PSs, water-soluble and nonaggregating PSs can be developed and by introducing nano drug delivery systems, tumor imaging and therapeutic efficacy can be improved. This information is useful for the future design of new efficient triplet PSs suitable for PDT application.

Author Contributions

Literature survey and writing, X.X., K.Y., M.I. and J.Z.; supervision and writing, J.Z. All authors have read and agreed to the published version of the manuscript.

Funding

J.Z. thanks the NSFC (U2001222), the State Key Laboratory of Fine Chemicals, the Fundamental Research Funds for the Central Universities (DUT22LAB610) and the Department of Education of the Xinjiang Uyghur Autonomous Region for financial support.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Scheme 1. Photophysical processes involved in PDT.
Scheme 1. Photophysical processes involved in PDT.
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Figure 1. Electron donor/acceptor dyads based on acridinium, anthracene (An) and Bodipy chromophores showing SOCT-ISC.
Figure 1. Electron donor/acceptor dyads based on acridinium, anthracene (An) and Bodipy chromophores showing SOCT-ISC.
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Figure 2. Anthryl-PTZ dyads showing efficient SOCT-ISC.
Figure 2. Anthryl-PTZ dyads showing efficient SOCT-ISC.
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Figure 3. Anthryl-Bodipy dyads adopting orthogonal geometry but more dimensions of mutual orientation of the donor and acceptors.
Figure 3. Anthryl-Bodipy dyads adopting orthogonal geometry but more dimensions of mutual orientation of the donor and acceptors.
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Figure 4. Phenothiazine-Bodipy dyads showing SOCT-ISC.
Figure 4. Phenothiazine-Bodipy dyads showing SOCT-ISC.
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Figure 5. Molecular structures of the Bodipy-derived dyads with electron-donating moieties attached at the meso-position.
Figure 5. Molecular structures of the Bodipy-derived dyads with electron-donating moieties attached at the meso-position.
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Figure 6. Molecular structures of the perynyl-Bodipy dyads showing SOCT-ISC.
Figure 6. Molecular structures of the perynyl-Bodipy dyads showing SOCT-ISC.
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Figure 7. Confocal laser scanning microscopy images of HeLa cells after incubation with 24 (c = 10 μm). (a) Green channel (500–600 nm) fluorescence image, λex = 488 nm. (b) Bright field image. (c) Merged image. Scale bar: 20 μm. Comparison of the cell viability of HeLa cells pre-treated with increasing doses of 24 and 2,6-diiodoBodipy (IBDP), (d) with light irradiation (500 nm, 9.6 J·cm−2), (e) without light irradiation. 20 °C. Reproduced with permission from reference [18], copyright 2019, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Figure 7. Confocal laser scanning microscopy images of HeLa cells after incubation with 24 (c = 10 μm). (a) Green channel (500–600 nm) fluorescence image, λex = 488 nm. (b) Bright field image. (c) Merged image. Scale bar: 20 μm. Comparison of the cell viability of HeLa cells pre-treated with increasing doses of 24 and 2,6-diiodoBodipy (IBDP), (d) with light irradiation (500 nm, 9.6 J·cm−2), (e) without light irradiation. 20 °C. Reproduced with permission from reference [18], copyright 2019, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Figure 8. Simplified energy diagram showing the advantage of the creation of CT absorption band in electron donor-acceptor compounds: absorption wavelength is red-shifted, but the chromophore-localized triplet state does not decrease. (i) ISC (ii) TTET (iii) TTA and delayed fluorescence. Reproduced with permission from reference [54], copyright 2019, Royal Society Chemistry.
Figure 8. Simplified energy diagram showing the advantage of the creation of CT absorption band in electron donor-acceptor compounds: absorption wavelength is red-shifted, but the chromophore-localized triplet state does not decrease. (i) ISC (ii) TTET (iii) TTA and delayed fluorescence. Reproduced with permission from reference [54], copyright 2019, Royal Society Chemistry.
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Figure 9. Dyads with Bodipy as electron donor. No SOCT-ISC was observed.
Figure 9. Dyads with Bodipy as electron donor. No SOCT-ISC was observed.
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Figure 10. Donor-Donor-Acceptor triads showing SOCT-ISC in both low polar and high polar solvents.
Figure 10. Donor-Donor-Acceptor triads showing SOCT-ISC in both low polar and high polar solvents.
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Figure 11. Borafluorene-ligand dyads showing SOCT-ISC.
Figure 11. Borafluorene-ligand dyads showing SOCT-ISC.
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Figure 12. Zn dipyrrin and chlorodipyrrin complexes showing SBCT and ISC. The solvent polarity-dependent photophysical processes of the Zn chlorodipyrrin complex are shown at the bottom. * indicates the excited state. Reproduced with permission from reference [67], copyright 2018, American Chemical Society.
Figure 12. Zn dipyrrin and chlorodipyrrin complexes showing SBCT and ISC. The solvent polarity-dependent photophysical processes of the Zn chlorodipyrrin complex are shown at the bottom. * indicates the excited state. Reproduced with permission from reference [67], copyright 2018, American Chemical Society.
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Figure 13. Molecular structures of homoleptic Zn(II) complexes with different substituents.
Figure 13. Molecular structures of homoleptic Zn(II) complexes with different substituents.
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Figure 14. Bodipy derivatives with molecular structure of twisted π-conjugation framework.
Figure 14. Bodipy derivatives with molecular structure of twisted π-conjugation framework.
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Figure 15. Simplified energy diagrams showing (a) the electron spin forbidden ISC in organic chromophore and (b) the electron spin allowed ISC of the chromophore in a chromophore-radical three electron spin system. Reproduced with permission from reference [101], copyright 2001, American Chemical Society. (c) Molecular structures of some typical radical-chromophore triplet PSs.
Figure 15. Simplified energy diagrams showing (a) the electron spin forbidden ISC in organic chromophore and (b) the electron spin allowed ISC of the chromophore in a chromophore-radical three electron spin system. Reproduced with permission from reference [101], copyright 2001, American Chemical Society. (c) Molecular structures of some typical radical-chromophore triplet PSs.
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Figure 16. TEMPO-Bodipy dyads as radical-chromophore heavy atom-free triplet PSs.
Figure 16. TEMPO-Bodipy dyads as radical-chromophore heavy atom-free triplet PSs.
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Figure 17. TEMPO-Bodipy triad 53 prepared based on an unexpected nucleophilic substitution reaction of Bodipy. 54 is a reference compound. Triad 52 is the anticipated product, base on the previously reported Bodipy derivatization chemistry. However, it was not obtained in our synthesis.
Figure 17. TEMPO-Bodipy triad 53 prepared based on an unexpected nucleophilic substitution reaction of Bodipy. 54 is a reference compound. Triad 52 is the anticipated product, base on the previously reported Bodipy derivatization chemistry. However, it was not obtained in our synthesis.
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Figure 18. NDI-TEMPO dyad 55 as red light-absorbing triplet PS and the reference compound 56.
Figure 18. NDI-TEMPO dyad 55 as red light-absorbing triplet PS and the reference compound 56.
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Figure 19. TEMPO-Cy7 dyad 57 as triplet PS for PDT studies.
Figure 19. TEMPO-Cy7 dyad 57 as triplet PS for PDT studies.
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Figure 20. Representative triplet PSs with thionated carbonyl groups.
Figure 20. Representative triplet PSs with thionated carbonyl groups.
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Figure 21. TREPR spectra of the compounds of anthracene, 4 and 5 in toluene at 85 K and the delay time was 900 ns following the excitation at 416 nm (355 nm for An). The canonical orientations of each transition are indicated. Smooth curves below the experimental spectra are simulation results of the triplet spectra. Reproduced with permission from reference [33], copyright 2008, American Chemical Society.
Figure 21. TREPR spectra of the compounds of anthracene, 4 and 5 in toluene at 85 K and the delay time was 900 ns following the excitation at 416 nm (355 nm for An). The canonical orientations of each transition are indicated. Smooth curves below the experimental spectra are simulation results of the triplet spectra. Reproduced with permission from reference [33], copyright 2008, American Chemical Society.
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Figure 22. (a) TREPR spectra of the anthryl-Bodipy dyads and (b) observation of the three triplet states of 3CT, 3An and 3BDP simultaneously for dyad 12. IBDP refers to 2,6-diiodoBodipy; BDP refers to Bodipy. Reproduced with permission from reference [38], copyright 2019, American Chemical Society.
Figure 22. (a) TREPR spectra of the anthryl-Bodipy dyads and (b) observation of the three triplet states of 3CT, 3An and 3BDP simultaneously for dyad 12. IBDP refers to 2,6-diiodoBodipy; BDP refers to Bodipy. Reproduced with permission from reference [38], copyright 2019, American Chemical Society.
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Xiao, X.; Ye, K.; Imran, M.; Zhao, J. Recent Development of Heavy Atom-Free Triplet Photosensitizers for Photodynamic Therapy. Appl. Sci. 2022, 12, 9933. https://doi.org/10.3390/app12199933

AMA Style

Xiao X, Ye K, Imran M, Zhao J. Recent Development of Heavy Atom-Free Triplet Photosensitizers for Photodynamic Therapy. Applied Sciences. 2022; 12(19):9933. https://doi.org/10.3390/app12199933

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Xiao, Xiao, Kaiyue Ye, Muhammad Imran, and Jianzhang Zhao. 2022. "Recent Development of Heavy Atom-Free Triplet Photosensitizers for Photodynamic Therapy" Applied Sciences 12, no. 19: 9933. https://doi.org/10.3390/app12199933

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