Multiresponsive UV-One-Photon Absorption, Near-Infrared-Two-Photon Absorption, and X/γ-Photoelectric Absorption Luminescence in One [Cu4I4] Compound.

A new Cu4I4-cluster-based compound is constructed to show multifaceted photoluminescent attributes: (1) ultraviolet (UV)-excited thermo-, mechano-, and rigido-chromic phosphorescence by the OPA (one-photon absorption) pathway, due to the interchanging emissions from cluster-centered (3CC) and halide-to-ligand charge-transfer (3XLCT) excited triplet states, (2) the ability to convert X/γ-ray and near-infrared (NIR) radiation to visible-light emission, in which the heavy Cu4I4 cores serve as the efficient X/γ-PEA (photoelectric absorption) or NIR-TPA (two-photon absorption) trapper and convertor to photons in the visible spectrum from the same emissive triplet states as those produced by UV excitation. This all-in-one compound affords a highly integrated nanolab for understanding and exploiting a wide range of photophysical phenomena simultaneously and is further fabricated into fiber-coupled long-range, in situ cryogenic thermometer and poly(methyl methacrylate) (PMMA)-embedded monolith gel, providing access to advanced applications in multifunctional optical materials and devices.

CT/MRI-Guided Synergistic Radiotherapy and X-ray Inducible Photodynamic Therapy Using Tb-Doped Gd-W-Nanoscintillators.

The use of X-rays instead of UV/Vis light to trigger photodynamic therapy, named X-ray inducible photodynamic therapy, holds tremendous promise due to a high penetration capacity in tissues and is worthy of in-depth study. In this study, a novel multifunctional nanoagent based on Merocyanine 540-coupled Gd2 (WO4 )3 :Tb nanoscintillators and the vitalization of its abilities for dual-modal computed tomography and the magnetic-resonance-imaging-guided synergistic radio-/X-ray inducible photodynamic therapy of tumors is reported. Synergistic therapies show a higher tumor growth inhibition efficiency at a lower X-ray dose than radiotherapy alone. Through this proof-of-concept work, a way to tactfully understand and utilize nanoscintillators for cancer theranostics is shown.

Antiangiogenesis Combined with Inhibition of the Hypoxia Pathway Facilitates Low-Dose, X-ray-Induced Photodynamic Therapy.

X-ray-induced photodynamic therapy (XPDT) is overwhelmingly superior in treating deep-seated cancers. However, limitations remain, owing to a combination of the poor scintillation performance of the nanoscintillator, low energy transfer efficiency of the therapeutic nanoplatform, and hypoxic environment presented in the tumor tissue. Collectively, these reduce the curative effect of XPDT. Here, we report a highly efficient, low-dose XPDT realized by systematic optimization from scintillation efficiency, nanoplatform structure, to therapeutic approach. We developed a biocompatible, codoped CaF2 nanoscintillator that emitted sufficiently green radioluminescence that was bright enough to be seen by the naked eye. Using dendrimers as a framework, we built a nanoplatform featuring a dual-core-satellite architecture, which enabled both procedurally and spatially separate dual-loading of therapeutic agents. This strategy allowed for the fabrication of a combined XPDT and antiangiogenic therapy, resulting in a therapeutic system capable of simultaneous tumor attacks. After exposure to ultralow dose radiation, XPDT resulted in marked tumor reduction while the antiangiogenic drug effectively blocked tumor vascularization exacerbated by XPDT-mediated hypoxia, rendering a pronounced synergy effect. This system also showed high biosafety, as the agents adopted had been used clinically and both Ca and F elements were widespread in the human body. Taken together, the findings presented here provided a reference for the construction of complex, multiloading architecture in coordination with structural complexity and functional diversification. This work provided a safer and more robust application of the combined XPDT and antiangiogenesis in future clinical treatment settings.

AlPcS-loaded gold nanobipyramids with high two-photon efficiency for photodynamic therapy in vivo.

Recent years have witnessed significant progress in the field of two-photon-activated photodynamic therapy (TP-PDT). However, traditional photosensitizer (PS)-based TP-PDT remains a critical challenge in clinics due to its low two-photon absorption cross sections. Here, we propose that the therapeutic activity of the current photosensitizer, sulfonated Al-phthalocyanine (AlPcS), can be efficiently excited via plasmonic-resonance energy transfer from the two-photon excited gold nanobipyramids (GBPs) and further generates cytotoxic singlet oxygen for cancer eradication. GBPs possess large two-photon absorption cross sections, excellent photostability, and biocompatibility, which can be used for a high two-photon light-harvesting material in biomedical applications. We compared the in vitro and in vivo capabilities of AlPcS-loaded GBPs as a TP-PDT agent for theranostic applications by benchmarking them against those of the extensively studied gold nanospheres (GNS) and nanorods (GNR). Although all these Au nanostructures could cause enhanced PS two-photon excitation fluorescence and improved singlet oxygen generation capability via the plasmonic resonance-energy transfer process, GBP-AlPcS exhibited the highest two-photon efficiency for photodynamic therapy. Remarkably, in vivo experiment results clearly indicated that the GBP-AlPcS caused efficient suppression of tumor growth and minimal adverse effects on orthotopic A549 human lung tumor xenografts. The system presents great efficiency in improving the treatment depth and precision of traditional photodynamic therapy.

Codoping Enhanced Radioluminescence of Nanoscintillators for X-ray-Activated Synergistic Cancer Therapy and Prognosis Using Metabolomics.

Radio- and photodynamic therapies are the first line of cancer treatments but suffer from poor light penetration and less radiation accumulation in soft tissues with high radiation toxicity. Therefore, a multifunctional nanoplatform with diagnosis-assisted synergistic radio- and photodynamic therapy and tools facilitating early prognosis are urgently needed to fight the war against cancer. Further, integrating cancer therapy with untargeted metabolomic analysis would collectively offer clinical pertinence through facilitating early diagnosis and prognosis. Here, we enriched scintillation of CeF3 nanoparticles (NPs) through codoping Tb3+ and Gd3+ (CeF3:Gd3+,Tb3+) for viable clinical approach in the treatment of deep-seated tumors. The codoped CeF3:Gd3+,Tb3+ scintillating theranostic NPs were then coated with mesoporous silica, followed by loading with rose bengal (CGTS-RB) for later computed tomography (CT)- and magnetic resonance image (MRI)-guided X-ray stimulated synergistic radio- and photodynamic therapy (RT+XPDT) using low-dose, one-time X-ray irradiation. The results corroborated an efficient tumor regression with synergistic RT+XPDT relative to single RT. Global untargeted metabolome shifts highlighted the mechanism behind this efficient tumor regression using RT, and synergistic RT+XPDT treatment is due to the starvation of nonessential amino acids involved in protein and DNA synthesis and energy regulation pathways necessary for growth and progression. Our study also concluded that tumor and serum metabolites shift during disease progression and regression and serve as robust biomarkers for early assessment of disease state and prognosis. From our results, we propose that codoping is an effective and extendable technique to other materials for gaining high optical yield and multifunctionality and for use in diagnostic and therapeutic applications. Critically, the integration of multifunctional theranostic nanomedicines with metabolomics has excellent potential for the discovery of early metabolic biomarkers to aid in better clinical disease diagnosis and prognosis.

Persistent luminescent nanoparticles as energy mediators for enhanced photodynamic therapy with fractionated irradiation.

The excitation wavelengths of most porphyrin-based photosensitizers are in the ultraviolet (UV) spectrum. Prolonged irradiation of living cells and tissues with UV light during the clinical application of photodynamic therapy (PDT) may cause DNA damage and cell death. Here, we report a novel persistent-luminescent nanoparticle (PLNP)-based PDT approach that uses the afterglow property of PLNPs to greatly reduce the dose of UV light while maintaining the desired cancer suppression effect. Multifunctional PLNPs coated with mesoporous silica layers and subsequently conjugated to a photosensitizer were evaluated. These nanoconjugates showed high colloidal stability and biocompatibility. Furthermore, they generated a moderate amount of 1O2 through efficient energy transfer from the nanoparticle to the photosensitizer, which can efficiently damage cancer cells. In addition to their UV-excited luminescence, PLNPs also exhibited a long-lasting luminescence afterglow. Thus, PLNPs can serve as a persistent light source for PDT activation after excitation by an external light source is stopped. When fractionated light was used for excitation instead of continuous light at equivalent irradiation doses, confocal microscopy revealed that the photosensitizer-conjugated PLNPs showed a significantly enhanced cancer cell killing ability. Moreover, quantitative flow cytometry showed that fractionated light irradiation (60 s/100 s on/off cycle) produced up to ten times more cancer cell apoptosis/necrosis than the same dose of continuous light irradiation did. These results indicate that photosensitizer-conjugated PLNPs combined with fractionated irradiation show good potential for low-dose UV-mediated PDT activation.