A luminescent Ir( iii ) complex has been embedded into Au@SiO ₂ nanoparticles for simultaneous imaging and phototherapeutic human cancer cell treatment.

Background: Based on the established role of cancer-stroma cross-talk in tumor growth, progression and chemoresistance, targeting interactions between tumor cells and their stroma provides new therapeutic approaches. Dual-targeted nanotherapeutics selectively acting on both tumor and stromal cells may overcome the limits of tumor cell-targeting single-ligand nanomedicine due to the complexity of the tumor microenvironment. Methods: Gold-core/silica-shell nanoparticles embedding a water-soluble iridium(III) complex as photosensitizer and luminescent probe (Ir_en-AuSiO₂_COOH) were efficiently decorated with amino-terminated EGFR (CL4) and PDGFRβ (Gint4.T) aptamers (Ir_en-AuSiO₂_Aptamer). The targeting specificity, and the synergistic photodynamic and photothermal effects of either single- and dual-aptamer-decorated nanoparticles have been assessed by confocal microscopy and cell viability assays, respectively, on different human cell types including mesenchymal subtype triple-negative breast cancer (MES-TNBC) MDA-MB-231 and BT-549 cell lines (both EGFR and PDGFRβ positive), luminal/HER2-positive breast cancer BT-474 and epidermoid carcinoma A431 cells (only EGFR positive) and adipose-derived mesenchymal stromal/stem cells (MSCs) (only PDGFRβ positive). Cells lacking expression of both receptors were used as negative controls. To take into account the tumor-stroma interplay, fluorescence imaging and cytotoxicity were evaluated in preclinical three-dimensional (3D) stroma-rich breast cancer models. Results: We show efficient capability of Ir_en-AuSiO₂_Aptamer nanoplatforms to selectively enter into target cells, and kill them, through EGFR and/or PDGFRβ recognition. Importantly, by targeting EGFR⁺ tumor/PDGFRβ⁺ stromal cells in the entire tumor bulk, the dual-aptamer-engineered nanoparticles resulted more effective than unconjugated or single-aptamer-conjugated nanoparticles in either 3D spheroids cocultures of tumor cells and MSCs, and in breast cancer organoids derived from pathologically and molecularly well-characterized tumors. Conclusions: Our study proposes smart, novel and safe multifunctional nanoplatforms simultaneously addressing cancer-stroma within the tumor microenvironment, which are: (i) actively delivered to the targeted cells through highly specific aptamers; (ii) localized by means of their luminescence, and (iii) activated via minimally invasive light, launching efficient tumor death, thus providing innovative precision therapeutics. Given the unique features, the proposed dual targeted nanoformulations may open a new door to precision cancer treatment.

Two series of novel NBu₄ ⁺ salts of anionic cyclometallated Pt(II) complexes were synthesized and fully characterized. These highly luminescent compounds (NBu₄[(C^N)Pt(O^N)] and NBu₄[(C^N)Pt(O^O)]) are incorporated as testing examples of cyclometallating ligands 2-phenylpyridine (PhPy), 2-(2,4-difluorophenyl)-pyridine (F₂PhPy) and 2-thienylpyridine (ThPy), and a benzo[h]quinoline (Bzq) fragment. All complexes display a square-planar coordination sphere, wherein the “(C^N)Pt” fragment is completed either by an O^N orotate (Ort) or an O^O tetrabromocatecholate (Cat) ligand. The HOMO and LUMO levels of all complexes were estimated by cyclic voltammetry and a comprehensive electrochemical and photophysical study was performed. The new complexes are emissive in solution at 298 K and the NBu₄[(ThPy)Pt(Ort)] complex displays good photosensitizing properties (Φ = 28% in deaerated solution vs. Φ = 1.4% in the presence of O₂). Both series of NBu₄[(C^N)Pt(Ort)] and NBu₄[(C^N)Pt(Cat)] complexes are highly luminescent in the solid state (emission quantum yields from 10 to 85%). Remarkably, the square-planar Pt(II) anionic complexes showed an important increase in luminescence quantum yields on changing from the dilute solution to the solid state (the most significant from 0.13% to 85% for the NBu₄[(PhPy)Pt(Ort)] complex, an ideal candidate as an active species for LEECs).

Novel anionic cyclometalated Pt(II) square-planar complexes NBu₄[(C^N)Pt^II(S^S)], containing 2-phenylpyridine H(PhPy), 2-(2,4-difluorophenyl)-pyridine H(F₂PhPy) and benzo[h]quinoline H(Bzq), respectively, as a cyclometalated ligand and the dianionic 1,2-benzenedithiolate (Thio)²⁻ fragment as an (S^S) ligand, were synthesised. By the simple addition of an equivalent of (Thio)²⁻ to the NBu₄[(C^N)Pt^II(Thio)] complexes, octahedral anionic NBu₄[(C^N)Pt^IV(Thio)₂] analogues were obtained, representing, to the best of our knowledge, the first examples of Pt(IV) anionic cyclometalated complexes. The molecular structures of the obtained complexes in the case of the NBu₄[(Bzq)Pt^II(Thio)] and the NBu₄[(Bzq)Pt^IV(Thio)₂] complexes were confirmed by single crystal X-ray diffraction analysis. Furthermore, the electrochemical and photophysical properties of the two series of Pt(II) and Pt(IV) newly synthesised complexes were studied and DFT and TD-DFT calculations were performed in order to comprehensively investigate the displayed behaviour. All Pt(II) and Pt(IV) complexes show intense luminescence in the solid state, with remarkable enhancement of the emission quantum yields, proving to be excellent examples of aggregation-induced emission systems.