Electron-pump-like near-infrared emissive iridium(III) complexes for hypoxia-tolerant type I & II photodynamic therapy

{"full_text": " Journal of Organometallic Chemistry 1038 (2025) 123750\n\n\n Contents lists available at ScienceDirect\n\n\n Journal of Organometallic Chemistry\n journal homepage: www.elsevier.com/locate/jorganchem\n\n\n\n\nElectron-pump-like near-infrared emissive iridium(III) complexes for\nhypoxia-tolerant type I & II photodynamic therapy\nZejing Chen a,c , Qingchao Tu a , Peiling Dai c, Yunjian Xu d , Wenyuan Xu a , Jingjing Xue a ,\nHaiyong Ao a, Xiaoming Hu a,c,* , Wei Jiang a,b,*, Shujuan Liu c, Qiang Zhao c,*\na\n Nanchang Key Laboratory for Smart Biomaterials Regulation and Adaptation, School of Materials Science and Engineering, East China Jiaotong University, Nanchang\n330013, PR China\nb\n Institute of Carbon Neutral New Energy Research, Yuzhang Normal University, Nanchang 330031, PR China\nc\n State Key Laboratory of Flexible Electronics (LoFE) & Jiangsu Key, Laboratory of Smart Biomaterials and Theranostic Technology, Institute of Advanced Materials\n(IAM), Nanjing University of Posts & Telecommunications, Nanjing 210023, PR China\nd\n Medical Science and Technology Innovation Center, Institute of Medical Engineering and Interdisciplinary Research, Shandong First Medical University and Shandong\nAcademy of Medical Sciences, Jinan 250000, PR China\n\n\n\n\nA R T I C L E I N F O A B S T R A C T\n\nKeywords: Photodynamic therapy (PDT) faces challenges in hypoxic tumors due to oxygen-dependent type II mechanisms.\nPhotodynamic therapy Type I PDT, generating oxygen-free radicals, offers a promising alternative but requires efficient photosensitizers.\nHypoxic tumors Herein, we report a series of cyclometalated iridium(III) complexes (Ir1, Ir2, Ir3 and Ir4) incorporating electron-\nIridium(III) complexes\n rich conjugated C^N ligands and an electron-deficient N^N ligand (1,4,5,8-tetraazaphenanthrene, TAP). The\nType I\nreactive oxygen species\n synergistic interplay between these ligands enables a pump-like mechanism under photoexcitation, efficiently\n shuttling electrons to electron-accepting substrates while replenishing electrons from reducing donors, thereby\n driving robust reactive oxygen free radical generation. These complexes exhibit strong visible-light absorption,\n near-infrared luminescence with decent quantum efficiency, and effective type I & II PDT activity under hypoxia.\n In vitro and in vivo studies demonstrate negligible dark toxicity and exceptional phototoxicity upon visible-light\n irradiation. This work highlights a rational ligand-cooperative design strategy for metal complex-based type I\n photosensitizers, overcoming hypoxia limitations in conventional PDT while integrating traceable luminescence\n for potential clinical applications.\n\n\n\n\n1. Introduction forward oxygen release[6]. Fortunately, PDT based on type I mecha\u00ad\n nism, in which high-toxicity oxygen free radicals rather than singlet\n Photodynamic therapy (PDT) as a novel non-invasive therapeutic oxygen (1O2) generates has been proved to be low dependent on the\nmodality has been applied in clinical treatment for the targeted cancer oxygen, and is considered to be the most intuitive way to resolve the\n[1,2], but PDT is still in infancy, with many problems that need to be problem fundamentally[7]. Therefore, the development of\nresolved to release its full potential. For example, tumor are often high-performance photosensitizers upon type I mechanism is of great\nhypoxic, which leads to a diminished utility of conventional significance.\noxygen-dependent PDT [3\u20135]. To reverse the oxygen imbalance, various In recent years, a series of type I photosensitizers have been devel\u00ad\nself-oxygenation strategies have been established to alleviate the hyp\u00ad oped by using inorganic nanomaterials such as metal oxides, rare earth\noxic tumor microenvironment, such as the delivery of perfluorocarbon- materials, and carbon-based materials [8,9]. Nonetheless, these type I\nand hemoglobin-based oxygen carriers, the catalytic decomposition of photosensitizers based on inorganic materials may present possible\nhydrogen peroxide in situ, and the release of reactive oxygen species safety risks including immune activation, tolerability limits, and chronic\n(ROS) upon other stimulation. However, they often suffer from low toxicological effects[10]. In contrast, organic photosensitizers offer\noxygen loading, limited prerequisites for oxygen sources in tissues, and better biocompatibility and biosafety. The most typical representatives\n\n\n\n * Corresponding authors at: Nanchang Key Laboratory for Smart Biomaterials Regulation and Adaptation, School of Materials Science and Engineering, East China\nJiaotong University, Nanchang 330013, PR China.\n E-mail addresses: iamxmhu@ecjtu.edu.cn (X. Hu), jiangwei@yuznu.edu.cn (W. Jiang), iamqzhao@njupt.edu.cn (Q. Zhao).\n\nhttps://doi.org/10.1016/j.jorganchem.2025.123750\nReceived 29 May 2025; Received in revised form 11 June 2025; Accepted 17 June 2025\nAvailable online 18 June 2025\n0022-328X/\u00a9 2025 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.\n\fZ. Chen et al. Journal of Organometallic Chemistry 1038 (2025) 123750\n\n\nare porphyrin derivatives, which occupy almost all the seats of clinically hypoxic tumor PDT are urgently needed [38\u201343].\napproved photosensitizers currently[11]. Based on such macrocyclic In previous work, we synthesize two kinds of type I photosensitizers\norganic compounds, Arnaut and co-workers synthesized a series of by incorporating a coumarin and triphenylamine into cyclometalated\nbacteriochlorin (tetrahydrogenated porphyrin) photosensitizers that and polypyridyl ruthenium(II) complexes, respectively[44]. Both com\u00ad\nwork mainly via type I PDT process[12]. Lindsey and co-workers further plexes exhibit low oxidation potentials, strong absorptions in the visible\nfound that palladium(II) ion-coordinated bacteriochlorins yielded more region and efficient PDT under hypoxia, but negligible luminescence\nefficient type I PDT process than uncoordinated bacteriochlorins[13]. quantum efficiencies. Herein, we prepared a series of iridium(III) com\u00ad\nHowever, these macrocyclic compounds have certain drawbacks plexes (Ir1, Ir2, Ir3 and Ir4) by selecting four cyclometalating C^N li\u00ad\nincluding the relatively low-yield synthesis, the inherent rigid and gands with relatively large conjugated skeleton and harnessing\nplanar aromatic structure that tends to aggregate and result in dimin\u00ad electron-deficient N^N ligand (1,4,5,8-tetraazaphenanthrenem, TAP)\nished phototoxicity, and the highly defined tetrapyrrole-based backbone which has played important role in modulating photoactive behaviors\nthat limits the structural expansion and enhancement of I PDT process to (Scheme 1). Notably, these iridium(III) complexes show effective type I\na certain extent[14]. Thus, in despite of Macrocyclic PDT agents, other PDT potency via producing reactive oxygen free radicals effectively,\norganic compounds are used for developing the photosensitizers un\u00ad which differ from the reported photooxidants, iridium(III) complex\ndergoing type I PDT pathway. Ir-TAP[45]. Impressively, some of them display high quantum effi\u00ad\n As mentioned above, metalation can significantly affect the photo\u00ad ciencies in near-infrared region in addition to strong absorptions in the\nchemical processes of organic photosensitizers. Metal complexes are visible region. Further evaluations in vitro and in vivo testified that\ncharacterized by rich valence states, diverse coordination numbers, and these four iridium(III) complexes have no toxicity without excitation\nchemical structures and spatial configurations that can be nearly infi\u00ad and good excellent photolethality under the visible light, showing good\nnitely derived, and are regarded as a great treasure trove for the promise as PDT agents for hypoxic tumor.\nexploration of type I photosensitizers [15,16]. Among the numerous\nmetal complexes, d-block transition metal complexes including plat\u00ad 2. Experimental section\ninum(IV), ruthenium(II), rhodium(III), iridium(III), and osmium(II)\ncomplexes have received a lot of attention, mainly because these com\u00ad All reagents and chemicals were procured from commercial sources\nplexes have modular three-dimensional configurations, which prone to and used without further purification unless otherwise noted. All sol\u00ad\nachieve various property modulation such as charge, solubility, and vents were of analytical grade and purified according to standard pro\u00ad\nLewis acidity, metal-ligand bond strength, redox potential, and excited cedures. The detailed synthesis of complexes and related ligands can be\nstates [17\u201320]. It is worth mentioning that the type I PDT process is found in Schemes S1-S4. The 1H and 13C NMR spectra of some synthe\u00ad\nmediated by the triplet excited states of the photosensitizer as same as sized compounds in this work were recorded on a Bruker Ultra Shield\ntype II PDT way. For the above metal complexes, the heavy-atom effect Plus 400 MHz NMR spectrometer. Deuterated solvents were selected\ncould promote spin\u2013orbit coupling, facilitating formation of long-lived based on the solubility differences of the tested compounds. The mo\u00ad\ntriplet excited states and thereby obtaining efficient PDT [21\u201324]. To lecular weights of larger compounds were determined using a matrix-\ndate, ruthenium(II) complexes as photosensitizers mainly based on type assisted laser desorption ionization time-of-flight mass spectrometer\nI process have been widely and intensively studied with some success. (MALDI-TOF MS, Voyager DE-STR). The UV\u2013visible absorption spectra\nHowever, the luminescent properties of the reported type I ruthenium of some compounds were measured on a Shimadzu UV\u2013VIS spectro\u00ad\n(II) complex photosensitizers tend to be poor and unfavorable for tracing photometer (UV-2600). The emission spectra of selected compounds\nin vivo and the clinical practice of PDT[25]. were also acquired using the same Shimadzu UV-2600 spectrophotom\u00ad\n In contrast, iridium(III) complexes have superior luminescent prop\u00ad eter. The quantum yields and emission lifetimes of certain compounds\nerties, as well as better chemical- and photo-stability [26\u201328], which were determined using an Edinburgh FLS-920 steady-state and transient\nhave been widely used in organic light-emitting diodes, luminescent spectrometer, with a xenon lamp as the excitation source. Cyclic vol\u00ad\nelectrochemical cells, and biosensing and imaging [29\u201331]. Currently, a tammetry (CV) measurements were performed on a CH620B electro\u00ad\nmass of phosphorescent iridium(III) complexes with potent phototox\u00ad chemical workstation, employing a glassy carbon working electrode, a\nicity have been demonstrated to be the promising PDT agents [32,33]. platinum wire auxiliary electrode, and an Ag/Ag+ reference electrode,\nMost of these studies on iridium(III) complex photosensitizers are at a scan rate of 0.1 V/s. The electrolyte solution consisted of 0.1 M\nrelated to the common type II processes, and the design guidelines are tetrabutylammonium hexafluorophosphate, which was deoxygenated\njust limited to how to enhance the 1O2 generation[34], yet the funda\u00ad with nitrogen prior to testing. Time-dependent density functional theory\nmentals about how to promote the type I photoinduced free radicals (TD-DFT) calculations were performed using the RB3PW91/SBKJC basis\nhave not been established. Recently, Brabec and co-workers reported an set, and all computations were carried out with the GAMESS software\niridium(III) conjugated to a far-red emitting coumarin with highly package. Photostability experiments were performed in acetonitrile so\u00ad\nfavourable properties for PDT even under hypoxic conditions and lution using a xenon lamp (100 mW, 400\u2013800 nm wavelength) for 6 min\nfurther clarified that its phototoxicity is mainly derived from superoxide irradiation. A hypoxic atmosphere containing 1 % O\u2082 was established\nradicals generated by type I photochemical processes[35]. He and using two gas flow controllers (HORIBA STEC, model: SEC-E40) oper\u00ad\nworkers reported that two benzothiophenylisoquinoline (btiq)-derived ated in tandem. Specifically, nitrogen gas flow was maintained at 99\niridium(III) complexes could cause photoinduced ferroptosis in tumor times the oxygen flow rate. The two gas streams were combined via a Y-\ncells via a type I mechanism. On the other hand, Elias and co-workers shaped connector to achieve the target hypoxic condition. The details of\nreported a strong photooxidative iridium(III) complex (Ir-TAP), which experimental section were shown in the supplementary data Schemes 1\ncan directly oxidize biomolecules through photoinduced electron and 2.\ntransfer (PeT), achieving the complete destruction of 3D tumor spher\u00ad\noids with internal hypoxia[36]. Huang reported a 3. Results and discussion\nmitochondria-targeted iridium(III) complex photosensitizer that could\nphotocatalytically oxidizes 1,4-dihydronicotinamide adenine dinucleo\u00ad 3.1. Design, synthesis and characterization\ntide (NADH), generating NAD\u2022 radicals via PeT under hypoxia[37].\nNevertheless, the existing few cases provide a realistic basis could not Previous researches about iridium(III) complexes have revealed that\nclarify the principles for constructing iridium(III) complex-based pho\u00ad the degree \u03c0-conjugation of the cyclometalating ligands impact their\ntosensitizers with considerable reactive oxygen free radicals. Therefore, lowest singlet and triplet excited state characteristics. As shown in\ndeveloping more iridium(III) complexes with efficient type I process for Scheme 1, four iridium(III) complexes (Ir1\u2013Ir4) possess the constant\n\n 2\n\fZ. Chen et al. Journal of Organometallic Chemistry 1038 (2025) 123750\n\n\n\n\nScheme 1. Chemical structures of iridium(III) complexes and schematic illustration of type I PDT via an electron-pump-like mechanism or type II PDT against\nhypoxic tumors.\n\n\n\n\n Scheme 2. Synthesis of complexes Ir1\u2013Ir4.\n\n\nelectron-deficient N^N ligand TAP and diverse cyclometalating C^N li\u00ad spectrometry (MALDI-TOF-MS) unambiguously, which were presented\ngands with large \u03c0-conjugation degrees (Dpq, Dbq, Bys, Byp) were in detail in the supporting information.\ndesigned: the N^N ligands TAP was employed to earn the latent photo\u00ad\noxidizing power for these complexes, while the C^N ligands Dpq, Dbq, 3.2. Photophysical and electrochemical properties\nBys and Byp are adopted for endowing the desirable long absorption and\nemission of complexes. It is noted that Dbq or Byp have one more ben\u00ad The UV\u2013vis absorption and emission spectra of Ir1\u2013Ir4 at room\nzene ring within their conjugated system compared with Dpq or Bys, temperature in acetonitrile are presented in Fig. 1a, and the peaks and\nrespectively, which facilitates comparative analysis toward the similar extinction coefficients are tabulated in Table 1. All complexes display\ncomplexes. The four C^N ligands were synthesized by the typical Suzuki- high-energy absorption bands below about 350 nm with high molar\nMiyaura cross-coupling reaction with high yields, and the N^N ligands extinction coefficients (\u03b5 \u02c3 2 \u00d7 104 M-1 cm-1), which can be assigned to\nwere synthesized by reported methods. Then the C^N ligands and the spin-allowed ligand-centered (LC) \u03c0\u2013\u03c0* transitions located on both\nIrCl3\u22c53H2O were added into a mixed solvent of 2-ethoxyethanol and the cyclometalating C^N and N^N ligands. The moderately intense ab\u00ad\nwater (v/v = 3/1) and heated at reflux for 12 h to obtain the cyclo\u00ad sorption bands appeared from 350 to 500 nm are mainly ascribed to the\nmetalated iridium(III)-chlorobridged dimers, which was precipitated mixture of singlet metal to ligand charge transfer (1MLCT) and singlet\nwith water and directly used without further purification. Due to the ligand to ligand charge transfer (1LLCT), whereas the weaker and\npoor solubility of TAP, these iridium(III) complexes were prepared lowest-lying absorption bands (\u03b5 \u02c2 1 \u00d7 104 M-1 cm-1) at about 500\u2013600\nthrough bridge-splitting reactions of the relative dimers and subsequent nm are attributed to mixed spin-forbidden transfer 3MLCT and 3LLCT\ncomplexation with the N^N coordinating ligand in the dimethyl form\u00ad transitions. Remarkably, the absorption bands corresponding to the LC\namide at 110 \u25e6 C, which is different from the routine conditions (Scheme and CT transitions of Ir2 and Ir4 showed significant red shift in com\u00ad\n2). Subsequently, the reaction mixture was added to a saturated aqueous parison to their related model complexes Ir1 and Ir3 due to the larger\nsolution of ammonium hexafluorophosphate stirred for 2 h and the degree of \u03c0-conjugation effect.\ncomplexes were obtained by filtration, silica gel column chromatog\u00ad Upon optical excitation under ambient conditions, complexes Ir1\u2013Ir4\nraphy and recrystallization in n-hexane solution successively. All com\u00ad exhibit prominent near-infrared luminescence with spectral maxima\nplexes were characterized by 1H, 13C nuclear magnetic resonance (NMR) positioned at 658, 783, 682, 709 nm in acetonitrile solutions, respec\u00ad\nand matrix-assisted laser desorption ionization time-of-flight mass tively, and the phosphorescence characteristics of these complexes are\n\n 3\n\fZ. Chen et al. Journal of Organometallic Chemistry 1038 (2025) 123750\n\n\n\n\nFig. 1. (a) Absorbance spectra and normalized emission spectra of Ir1\u2013Ir4 in acetonitrile. (b) Calculated energy levels, HOMO-LUMO gaps and frontier molecular\norbital distributions of Ir1\u2013Ir4. (c) Cyclic voltammetry curves of ferrocene and complexes Ir1\u2013Ir4 in acetonitrile.\n\n\n observed that the Ir2 with Dbq and Ir4 with Byp as the C^N ligand shows\nTable 1\n a lower-energy emission than Ir1 with Dpq and Ir3 with Bys as the C^N\nPhotophysical data for Ir1\u2013Ir4 in acetonitrile at 298 K.\n ligands, respectively, arising from extended \u03c0-conjugation within their\n Complex \u03bbabs/nm(\u03b5/104 M-1cm-1) \u03bbmax(em)/ \u03c4/ns \u03a6 respective ligand frameworks. Notably, the calculations confirmed the\n nm\n frontier orbital energetics display distinct modulation patterns: Ir2 ex\u00ad\n Ir1 290(3.68), 372(2.07), 659 366 2.05 hibits a significantly elevated highest occupied molecular orbital\n 459(0.34)\n (HOMO) energy level and a substantially lowered lowest unoccupied\n Ir2 279(6.36), 323(4.51), 417(1.67), 483 783 481 0.12\n (0.72) molecular orbital (LUMO) energy level relative to Ir1. In contrast, Ir4\n Ir3 295(3.51), 349(2.25), 679 417 1.08 shows a pronounced HOMO shift compared to Ir3, while its LUMO en\u00ad\n 475(0.90) ergy level remains virtually identical, suggesting ligand-specific orbital\n Ir4 290(4.04), 332(2.28), 385(2.04), 493 712 414 0.12 control in these photosensitizers.\n (0.93)\n The redox profiles of complexes Ir1\u2013Ir4 versus the Ag/AgNO\u2083 refer\u00ad\n ence electrode were acquired via cyclic voltammetry (CV), with corre\u00ad\nevidenced by their sustained radiative lifetimes (366\u2013481 \u03bcs) observed sponding electrochemical data compiled in Table S5. Distinct quasi-\nin air-equilibrated solutions (Table 1). The broad and structureless reversible redox transitions are observed for Ir1 and Ir2, whereas Ir3\nphotoluminescence bands of Ir1, Ir2 and Ir4 have an obvious MLCT and Ir4 exhibit well-defined reversible processes (Fig. 1c). The onset\nfeature, evidenced by the positive solvatochromism (Table S1), while Ir3 oxidation potentials (Eonset\n ox ) are measured as 1.29, 1.50, 0.89, and 0.92 V\nmanifests comparable luminescence signatures in PL spectra, featuring a for Ir1, Ir2, Ir3, and Ir4, respectively. Applying the empirical relation\u00ad\nspectral shoulder at 730 nm indicative of hybridized triplet charge- ship EHOMO (eV) = \u2212 (Eonsetox vs Fc/Fc+ + 4.8), the calculated HOMO\ntransfer states. The time-the dependent density functional theory (TD- energy levels are \u2212 6.09, \u2212 6.30, \u2212 5.69, and \u2212 5.72 eV for Ir1\u2013Ir4,\nDFT) calculations further indicates that the emission dominantly results respectively. The previous studies with analogues reveal that iridium\nfrom a mixture of 3MLCT and 3ILCT (Fig. 1b, Tables S2 and S3). It can be complexes containing the same cyclometalating ligands as Ir3 or Ir4\n\n\n 4\n\fZ. Chen et al. Journal of Organometallic Chemistry 1038 (2025) 123750\n\n\ngenerally exhibit lower oxidation potentials and significantly elevated 3.3. Evaluation of ROS generation in aqueous media and proposed\nHOMO energy levels compared to those with ligands analogous to Ir1 or mechanism of PDT\nIr2, which aligns consistently with the cyclic voltammetry results\n[46\u201349]. During cathodic polarization scans, quasi-reversible reductive The structural stability of photosensitizers under prolonged light\ntransitions are observed for these iridium(III) complexes. The onset irradiation is a critical evaluation criterion for their clinical application.\nreduction potentials (Eonset\n red ) are determined as \u2212 1.08, \u2212 1.03, \u2212 1.09, Continuous irradiation tests were conducted on acetonitrile solutions of\nand \u2212 1.06 V for Ir1\u2013Ir4, respectively, suggesting comparable photo\u00ad Ir1\u2013Ir4 using a xenon lamp (400\u2013800 nm, 100 mW/cm\u00b2) for 6 min, with\nreductive capabilities. Utilizing these Eonset\n red values, the LUMO energy real-time monitoring through UV\u2013vis absorption spectroscopy (Fig. S1).\nlevels (ELUMO) are derived via the empirical relation ELUMO (eV) = All complexes exhibited minimal photodegradation, indicating these\n\u2212 (Eonset\n red vs Fc/Fc + 4.8) yielding values of \u2212 3.72, \u2212 3.77, \u2212 3.71, and\n +\n iridium(III) complexes possess exceptional photochemical stability\n\u2212 3.74 eV for Ir1\u2013Ir4. From these redox parameters, the electrochemical within the therapeutic wavelength range of PDT. This remarkable sta\u00ad\nband gaps (Ecv g ) are computed as 2.37, 2.53, 1.98, and 1.98 eV for bility ensures reliable maintenance of their photosensitizing function\u00ad\nIr1\u2013Ir4, respectively. The distribution of LUMOs revealed that the ality during extended light exposure in clinical PDT applications,\nancillary ligand TAP predominantly governs the LUMOs, while the four significantly enhancing their potential for practical implementation in\ncyclometalating ligands exhibit varying degrees of contribution to the cancer treatment protocols. To systematically evaluate the ROS gener\u00ad\nLUMOs, resulting in energy-level slight fluctuations of the LUMOs and ation performance of Ir1\u2013Ir4 in solution, a dual detection system was\nthereby enabling precise modulation of the energy gaps in these iridium employed for quantitative analysis of their photosensitizing capabilities.\ncomplexes (Table S4). Frontier molecular orbital analyses reveal that the As illustrated in Figs. 2a and S2, the DCFH probe assays revealed that\nHOMO electron density in iridium(III) complexes Ir1\u2013Ir4 is predomi\u00ad Ir1\u2013Ir4 exhibited substantial ROS generation capabilities under both\nnantly localized on the metal center and cyclometalating C^N ligand normoxic and hypoxic conditions, outperforming the reference complex\nframework, with calculated HOMO/LUMO energy levels of Ir-TAP by a significant margin. Notably, Ir4 demonstrated the highest\n\u2212 6.93/\u2212 2.88 eV (Ir1), \u2212 6.81/\u2212 3.01 eV (Ir2), \u2212 6.31/\u2212 2.99 eV (Ir3), ROS generation efficiency under normoxic conditions (Fig. 2a), whereas\nand \u2212 6.36/\u2212 2.73 eV (Ir4), respectively. While discrepancies in Ir3 emerged as the most potent 1O\u2082 generator under hypoxic conditions\nHOMO/LUMO energy levels and electrochemical bandgaps between mimicking the tumor microenvironment (Figs. 2b and S2). This oxygen-\nexperimental (cyclic voltammetry) and theoretical (TD-DFT) ap\u00ad dependent divergence in ROS production profiles suggests that Ir1\u2013Ir4\nproaches were observed for complexes Ir1\u2013Ir4\u2014primarily arising from may engage distinct photosensitization mechanisms to generate het\u00ad\nsolvation effects, electronic state disparities, and computational erogeneous ROS, potentially enabling adaptive therapeutic responses to\napproximations\u2014the strategic design of cyclometalating ligands effec\u00ad varying oxygen tensions in biological systems.\ntively modulated the frontier orbital energetics. Notably, these findings To precisely identify the ROS subtype, a specialized ABDA (9,10-\nestablish that the molecular architecture of the coordinating ligands anthracenediyl-bis(methylene)dimalonic acid) trapping system was\nexerts deterministic control over the electronic structure of iridium(III) employed to quantify 1O2 generation through characteristic absorption\ncoordination systems. decay at 380 nm. The reference system featured the classical Type II\n photosensitizer [Ru(bpy)3]2+ (bpy = 2,2\u2032-bipyridine). In air-saturated\n acetonitrile solutions containing Ir1\u2013Ir4, UV\u2013vis spectral monitoring\n was performed under standardized experimental conditions. For quan\u00ad\n tum yield determination, photosensitizer concentrations were adjusted\n\n\n\n\nFig. 2. (a) Emission intensity changes at 530 nm of DCFH in different iridium complexes-containing solutions during light irradiation under hypoxic conditions over\n0\u2013180 s. (b) The linear fitting curve of the absorbance variation at 400 nm for ABDA-containing solutions with different complexes under light irradiation over 0\u2013180\ns. (c) Emission intensity changes at 525 nm of DHR123 in different iridium complexes-containing solutions during light irradiation under hypoxic conditions over\n0\u201310 min. (d) Emission intensity changes at 515 nm of HPF in different iridium complexes-containing solutions during light irradiation under hypoxic conditions over\n0\u201310 min. H stands for hypoxic conditions. (e) Stern-Volmer plots obtained upon the addition of 1,4-hydroquinone to iridium complexes. (f) Stern-Volmer plots\nobtained upon the addition of 1, 4-benzoquinone to iridium complexes. Measurements made in acetonitrile.\n\n 5\n\fZ. Chen et al. Journal of Organometallic Chemistry 1038 (2025) 123750\n\n\nto achieve an absorbance of 0.3 at 450 nm prior to 180-second irradi\u00ad predominantly initiated by photoinduced electron donation, which may\nation with 450 nm light (100 mW/cm\u00b2). Temporal absorbance changes be rationalized by the dominant contribution of metal-to-ligand charge\nwere fitted to exponential decay curves for comparative analysis transfer (MLCT) excited states in the complexes[50].The proposed\n(Fig. S4). Remarkably, all iridium complexes demonstrated superior 1O2 mechanism of PDT for these complexes maybe that synergistic interplay\nquantum yields compared to [Ru(bpy)3]2+, with Ir3 and Ir4 exhibiting between electron-rich cyclometalating ligands and electron-deficient\n\u03a6\u0394 values exceeding twice that of the reference compound, which could ancillary ligands enables these complexes to operate in a pump-like\nbe attributed to the larger spin-orbit coupling constant of iridium mechanism under photoexcitation, efficiently shuttling electrons to\ncompared to rutheniu. Parallel experiments under uniform photosensi\u00ad proximal electron-accepting substrates while replenishing electrons\ntizer concentration (10 \u00b5M) revealed significantly enhanced 1O2 pro\u00ad from strongly reducing donor species (Fig. S6).\nduction by Ir2-Ir4 relative to the ruthenium benchmark. The\ncomparatively lower photosensitization efficiency of Ir1 likely origi\u00ad 3.4. PDT in vitro\nnates from its significantly lower molar extinction coefficient at 450 nm,\nhighlighting structure-property correlations in these photodynamic Building upon the promising photodynamic properties of iridium(III)\nagents. complexes Ir1\u2013Ir4, which demonstrated exceptional ROS generation\n To further validate the superoxide anion (O\u2082\u22c5\u207b) and hydroxyl radical capability in oxygen-deprived aqueous solutions under light irradiation,\n(\u22c5OH) generation capabilities of complexes Ir1\u2013Ir4, targeted fluores\u00ad we subsequently investigated their intracellular PDT efficacy. The ROS\ncence assays were performed using dihydrorhodamine 123 (DHR123) production in live cells was quantitatively monitored through applica\u00ad\nand hydroxyphenyl fluorescein (HPF) as selective molecular probes. As tion of 2\u2032,7\u2032-dichlorodihydrofluorescein diacetate (DCFH-DA) func\u00ad\ndemonstrated in Figs. 2c and S5, all iridium complexes exhibited time- tioning as a fluorogenic redox-sensitive indicator. This cell-permeable\ndependent fluorescence enhancement in DHR123-containing solutions indicator undergoes enzymatic deacetylation to form DCFH, which\nunder broadband irradiation (400\u2013800 nm), regardless of oxygen ten\u00ad subsequently reacts with multiple ROS subtypes to yield the fluorescent\nsion. Notably, Ir4 displayed the most pronounced fluorescence intensity product 2\u2032,7\u2032-dichlorofluorescein, emitting characteristic green fluores\u00ad\nincrease under both normoxic and hypoxic conditions, indicating its cence (\u03bbex = 488 nm, \u03bbem = 525 nm) upon photoexcitation. Figs. 3a and\nsuperior O\u2082\u22c5\u207b generation capacity. Complementary experiments under S7 reveal that all of four iridium complexes maintained remarkable ROS\ntumor-mimetic hypoxia (1 % O\u2082) using HPF probes (Fig. 2d) revealed generation efficiency under hypoxic conditions (1 % O2), consistent with\nsignificant irradiation-dependent fluorescence amplification for all their solution-phase performance. Notably, bright-field microscopy\ncomplexes, confirming effective \u22c5OH production. The \u22c5OH generation combined with long-pass filter imaging (>650 nm) demonstrated\nefficacy followed the hierarchy: Ir4 > Ir3 > Ir1 > Ir2. Control groups effective cellular internalization of these Ir(III) photosensitizers, while\nwithout photosensitizers or containing reference complex Ir-TAP their intrinsic luminescence in the near-infrared window (650\u2013750 nm)\nshowed negligible fluorescence changes, excluding nonspecific back\u00ad provided real-time tracking capability - a critical advantage for potential\nground signals. The differential ROS generation profiles observed across in vivo theranostic applications. To rigorously validate the photody\u00ad\noxygen gradients and detection systems suggest oxygen tension- namic mechanism, two critical control experiments were implemented\ndependent activation mechanisms in these iridium-based photosensi\u00ad (Fig. 3a). The first control group (left panel) omitted the photosensitizer\ntizers. Comprehensive evaluation integrating total ROS yield under Ir4 while maintaining DCFH-DA incubation and light irradiation,\nhypoxia, Type I ROS generation efficiency, excitation wavelength showing minimal fluorescence signal. The second control (middle panel)\ncompatibility, and luminescence quantum efficiency identified Ir4 could retained both Ir4 and DCFH-DA but excluded light activation, demon\u00ad\nbe the optimal candidate for in vivo applications targeting hypoxic tu\u00ad strating comparable basal fluorescence levels to the photosensitizer-free\nmors (Table S5). control. These orthogonal controls conclusively establish that the\n These iridium(III) complexes demonstrated predominant Type I observed ROS elevation requires both photosensitizer presence and light\nphotodynamic pathways in ROS generation assays. To elucidate the activation. Notably, the maintenance of significant ROS generation\nunderlying photochemical mechanisms, investigations of their photo- under pathologically relevant hypoxic conditions (1 % O2) suggests that\noxidation and photo-reduction behaviors were conducted via steady- these iridium(III) complexes overcome the critical oxygen dependency\nstate photoluminescence quenching studies employing hydroquinone/ limitation of conventional PDT agents. This hypoxia-tolerant photody\u00ad\nbenzoquinone (HQ/BQ) redox mediators in acetonitrile matrices. In namic activity positions Ir1\u2013Ir4 as particularly promising candidates for\nphoto-oxidation studies with HQ (Fig. 2e), significant luminescence treating solid tumors with characteristically hypoxic microenviron\u00ad\nquenching was observed for reference complex Ir-TAP with increasing ments. Furthermore, to differentiate the ROS subtypes generated during\nHQ concentration. Notably, Ir1 exhibited only marginal emission photodynamic activation, we conducted parallel experiments using\nattenuation, while Ir2-Ir4 maintained stable luminescence profiles, hydroxyphenyl fluorescein (HPF), a selective probe for \u22c5OH. As shown in\nindicating limited electron-accepting capability from HQ under irradi\u00ad Fig. 3b, distinct fluorescence signals within the 490\u2013540 nm emission\nation. This suggests that only Ir1 possesses moderate photoactivated bandpass were detected across all photosensitizer-treated groups\noxidizability through interfacial electron transfer from HQ, whereas Ir2- following light irradiation. Notably, while the fluorescence intensity\nIr4 lack substantial oxidative photochemical activity. Conversely, measured by HPF was a slight lower than that quantified using DCFH-\nphoto-reduction experiments with BQ revealed distinct phosphores\u00ad DA, this differential response aligns with the distinct chemical re\u00ad\ncence quenching patterns (Fig. 2f). Ir1, Ir3, and Ir4 displayed pro\u00ad activities of these probes: DCFH-DA detects broad-spectrum ROS\nnounced emission attenuation with BQ addition, demonstrating strong whereas HPF specifically responds to \u22c5OH. This observed hierarchy in\nphotoactivated reducibility through electron injection to BQ. The min\u00ad signal magnitude (DCFH-DA > HPF) provides mechanistic evidence that\nimal luminescence variation observed for Ir2 likely stems from its the Ir(III) complexes predominantly generate \u22c5OH through Type I\ninherently low photoluminescence quantum yield, which compromises photochemical pathways under hypoxic conditions. The concordance\ndetectable emission signal changes during redox processes. The bimo\u00ad between cellular and solution-phase analyses confirms that these met\u00ad\nlecular quenching rate constants (compiled in Table S6) approach the allophotosensitizers maintain their hypoxia-tolerant Type I photody\u00ad\ndiffusion-controlled regime, signifying marked efficiency in reductive namic activity across heterogeneous biological environments.\nquenching dynamics that align with the oxidation potentials of these To systematically investigate the hypoxia-tolerant PDT performance\ncomplexes. These results indicated that these iridium complexes enable of these iridium complexes, we employed a dual-staining assay utilizing\nefficient Type I photodynamic activity upon light. Unlike complex Ir- fluorescein diacetate (FDA) and propidium iodide (PI). FDA, a non-\nTAP, where the Type I mechanism originates from photoinduced elec\u00ad fluorescent esterase substrate, is enzymatically hydrolyzed to green-\ntron acquisition, the Type I pathway in these complexes is fluorescent fluorescein exclusively in viable cells with active\n\n 6\n\fZ. Chen et al. Journal of Organometallic Chemistry 1038 (2025) 123750\n\n\n\n\nFig. 3. (a) Representative confocal microscopy images of DCFH-stained cells with different treatments under hypoxic conditions. The light groups were irradiated\nwith white light (400\u2013800 nm, 25 mW/cm\u00b2, 3 min). (b) Confocal microscopy images of complexes-loaded cells incubated with HPF after irradiation (400\u2013800 nm, 25\nmW/cm2, 8 min) under hypoxic conditions. (c) Confocal microscopy images of complexes-loaded cells incubated with FDA and PI after irradiation under hypoxic\nconditions. (d) Dose-dependent viability of HeLa cells treated with complexes using CCK-8 assay in the dark (D). (e) Dose-dependent viability of HeLa cells treated\nwith complexes using CCK-8 assay upon light (L) irradiation (400\u2013800 nm, 25 mW/cm2, 13 min) under normoxic conditions. (f) Dose-dependent viability of HeLa\ncells treated with complexes using CCK-8 assay upon light irradiation under hypoxic conditions.\n\n\nintracellular esterases, whereas PI selectively permeates compromised 3.5. PDT in vivo\ncell membranes of nonviable cells, binding to nuclear DNA to emit red\nfluorescence. As shown in Fig. 3c, under hypoxic conditions with light Encouraged by its outstanding performance in cellular experiments,\nirradiation, cells treated with Ir1 exhibited attenuated green fluores\u00ad the in vivo PDT of Ir4 is then investigated by employing the xenograft\ncence (indicating partial esterase activity) accompanied by prominent PI Hela-subcutaneous tumor-bearing mouse model. All the mice experi\u00ad\nnuclear staining, suggesting limited PDT efficacy. In stark contrast, Ir2- ments were carried out in accordance with the relevant laws and the\nIr4-treated groups demonstrated complete loss of FDA-derived fluores\u00ad guidelines of Institutional Animal Care and Use Committee. Firstly, the\ncence with uniformly intensified PI signals, revealing near-total cell mouse was anesthetized by isoflurane for the in vivo luminescence im\u00ad\ndeath and confirming their robust hypoxia-resistant PDT performance, aging after intratumoral injection of Ir4 (1 mM, 25 mL/50 mm3 tumor)\nfurther supporting their translational potential for treating hypoxic for 4 h (Fig. 4a). The intense luminescence at the tumor site can be\ntumors. observed intuitively, which indicates that Ir4 is not metabolized quickly\n To quantitatively assess the therapeutic potential of Ir1\u2013Ir4 under and in favor of potential tumor imaging and subsequent PDT assessment.\npathologically relevant conditions, we performed CCK-8 cytotoxicity The tumor-bearing mice were then randomly divided into three groups,\nassays in hypoxic (1 % O2) and normoxic environments. As summarized with five mice in each group: the control group, the dark group and the\nin Fig. 3d\u2013f, all four complexes exhibited minimal dark toxicity (<15 % PDT group. The mice treated with light or Ir4 alone served as the control\ncell death at 10 \u00b5M) during co-incubation with HeLa cells without light group (PBS + light) and the dark group (Ir4 + Dark), respectively. For\nactivation, confirming their biocompatibility for potential clinical the mice in the PDT group (defined as Ir4 + light), a solution of Ir4 (1\ntranslation. Under white light irradiation (20 J/cm\u00b2) under normoxic mM, 25 mL/50 mm3 tumor) was injected intratumorally into the tumor-\nconditions, a dramatic reduction in cell viability was observed. The bearing mice and tumor regions were irradiated by a xenon lamp (250\nmeasured IC50 values fell below 1 \u00b5M, demonstrating a photodynamic mW/cm2, 10 min) at 0.5 h post injection. As for the other two groups,\npotency that surpasses most clinically investigated photosensitizers. tumor-bearing mice were treated with the same volume of PBS and light,\nRemarkably, even under oxygen-deprived conditions, Ir1\u2013Ir4 main\u00ad or the same solution of Ir4 only. During the in vivo PDT experiments,\ntained substantial photocytotoxicity, particularly Ir4 demonstrating Longitudinal tumor volumetry (calculated as [length \u00d7 width\u00b2]/2) and\n48.3 % cell death at 1 \u00b5M. The calculated phototoxicity indices (PI = somatic mass indices were systematically quantified at defined temporal\nIC50 dark/IC50 light) under hypoxia consistently exceeded 9.0 across all intervals throughout the therapeutic regimen. As shown in Fig. 4b, the\ncomplexes (Table S7), quantitatively validating their hypoxia-tolerant neoplasm volumes hardly increased for the mice subjected to Ir4 and\nPDT efficacy. This oxygen-independent antitumor performance mecha\u00ad light, manifesting the tumors growth of mice in the PDT group were\nnistically aligns with our earlier spectroscopic evidence of Type I- remarkably inhibited, while tumors in the mice treated with PBS and\ndominated ROS generation. The combined pharmacological and mech\u00ad irradiation or those administered with Ir4 only grew rapidly and\nanistic data position these Ir(III) complexes as first-in-class metal\u00ad exhibited barely tumor-size restraint, proving that Ir4 or the used light\nlophotosensitizers capable of overcoming the intrinsic hypoxia had no antitumor efficacy themselves. Meanwhile, the body weight-\nlimitations of conventional PDT, particularly promising for treating growth curves about all treated mice showed a slight elevation and no\ndeeply seated or poorly vascularized tumors. apparent changes in each group throughout the entire treatment period\n\n 7\n\fZ. Chen et al. Journal of Organometallic Chemistry 1038 (2025) 123750\n\n\n\n\nFig. 4. (a) In vivo photoluminescence signal images 24 h after Ir4 (1 mM, 25 mL/50 mm3) injection into the tumor. (b) Tumor growth curve of mice with different\ntreatments. (c) body weight gain curve of mice with different treatments. (d) Representative images of tumors collected from mice with different treatments. (e) H&E\nand TUNEL staining images of tumors treated with PBS or Ir4 under different conditions. The tumors were irradiated with white light (400\u2013800 nm, 250 mW/cm\u00b2,\n10 min).\n\n\n(Fig. 4c). These results revealed that Ir4 possessed an effective PDT electron-pumping mechanisms.\npotency and a little dark toxicity to these mice preliminarily. Further\u00ad\nmore, the main organs and tumors were collected for histological CRediT authorship contribution statement\nanalysis performed by hematoxylin eosin (H&E) after the mice were\nsacrificed on day 25 (Fig. 4d). Results showed that no discernible Zejing Chen: Writing \u2013 review & editing, Writing \u2013 original draft,\nstructural alterations in tumor lesions or vital organs (cardiac, hepatic, Resources, Methodology, Investigation, Formal analysis, Data curation,\nsplenic, pulmonary, and renal tissues) within tissue sections derived Conceptualization. Qingchao Tu: Writing \u2013 original draft, Methodol\u00ad\nfrom PBS- or Ir4-treated cohorts, as shown in Fig. S8. On the contrary, ogy, Formal analysis, Data curation. Peiling Dai: Methodology, Inves\u00ad\nthe tumor sections of the PDT group were sparsely aligned with large tigation. Yunjian Xu: Methodology, Data curation. Wenyuan Xu:\nnecrosis (Fig. 4e). Incidentally, the terminal deoxynucleotidyl trans\u00ad Methodology. Jingjing Xue: Validation. Haiyong Ao: Methodology.\nferase dUTP nick end labeling (TUNEL) assays were performed on tumor Xiaoming Hu: Writing \u2013 review & editing, Supervision, Methodology,\nxenografts to delineate the antitumor mechanism of Ir4 in vivo. As Funding acquisition, Conceptualization. Wei Jiang: Writing \u2013 original\ndepicted in Fig. 4e, the fluorescence TUNEL staining of tumors from draft, Investigation, Formal analysis, Data curation. Shujuan Liu: Su\u00ad\nmice subjected to various treatments clearly illustrated that a signifi\u00ad pervision. Qiang Zhao: Writing \u2013 review & editing, Supervision.\ncantly highest percentage of TUNEL-positive apoptotic cells compared\nto the other two groups. These results verified that Ir4 indeed has\nnegligible cumulative effect or adverse biological effects to the living Declaration of competing interest\nmice, and effective PDT potency under light irradiation.\n The authors declare that they have no known competing financial\n4. Conclusion interests or personal relationships that could have appeared to influence\n the work reported in this paper.\n In conclusion, to circumvent the limitations imposed by tumor\nhypoxia on photosensitizer performance and enhance therapeutic effi\u00ad Acknowledgments\ncacy under oxygen-deprived conditions, this study adopts a molecular\nengineering approach. Four cyclometalating ligands with distinct This work was supported by the National Natural Science Foundation\nconjugation architectures (Dpq, Dbq, Bys, Byp) were judiciously paired of China (22001069, 22465015 and 82302257), Natural Science Foun\u00ad\nwith the electron-deficient ancillary ligand TAP to construct near- dation of Jiangxi Province (20224BAB204007, 20242BAB22007,\ninfrared emissive (\u03bb > 650 nm) iridium(III) complexes Ir1\u2013Ir4. 20232BAB203049 and 20243BCE51136) and the open research fund of\nCompared to the benchmark complex Ir-TAP, these derivatives exhibit Key Laboratory for Organic Electronics and Information Displays.\nsignificantly enhanced photodynamic activity under visible-light irra\u00ad\ndiation. Crucially, Ir3 and Ir4 - featuring lower oxidation poten\u00ad Supplementary materials\ntials\u2014demonstrate hypoxia-tolerant Type I photodynamic behavior,\nefficiently generating superoxide radicals and hydroxyl radicals to Supplementary material associated with this article can be found, in\ntrigger apoptotic pathways. In vivo studies confirm the superior anti\u00ad the online version, at doi:10.1016/j.jorganchem.2025.123750.\ntumor efficacy of Ir4 when activated by white light. Importantly, this\nwork establishes a rational design strategy combining strong electron- Data availability\ndonating cyclometalating ligands with electron-withdrawing ancillary\nligands to engineer Type I complex photosensitizers with photoactivated Data will be made available on request.\n\n 8\n\fZ. Chen et al. Journal of Organometallic Chemistry 1038 (2025) 123750\n\n\nReferences imaging of peroxynitrite elevation In vivo, ACS Appl. Mater. Interface. 12 (11)\n (2020) 12383\u201312394.\n [25] A. 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