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X-ray excited persistent luminescence (XEPL) imaging has attracted increasing attention in biomedical imaging due to elimination of autofluorescence, high signal-to-noise ratio and repeatable activation with high penetration. However, optical imaging still suffers from limited for high spatial resolution. Methods: Herein, we report Mn3+-rich manganese oxide (MnOx)-coated chromium-doped zinc gallogermanate (ZGGO) nanoparticles (Mn-ZGGOs). Enhanced XEPL and magnetic resonance (MR) imaging were investigated by the decomposition of MnOx shell in the environment of tumors. We also evaluated the tumor cell-killing mechanism by detection of reactive oxygen (ROS), lipid peroxidation and mitochondrial membrane potential changes in vitro. Furthermore, the in vivo biodistribution, imaging and therapy were studied by U87MG tumor-bearing mice. Results: In the tumor region, the MnOx shell is quickly decomposed to produce Mn3+ and oxygen (O2) to directly generate singlet oxygen (1O2). The resulting Mn2+ transforms endogenous H2O2 into highly toxic hydroxyl radical (·OH) via a Fenton-like reaction. The Mn2+ ions and ZGGOs also exhibit excellent T1-weighted magnetic resonance (MR) imaging and ultrasensitive XEPL imaging in tumors. Conclusion: Both the responsive dual-mode imaging and simultaneous self-supplied O2 for the production of 1O2 and oxygen-independent ·OH in tumors allow for more accurate diagnosis of deep tumors and more efficient inhibition of tumor growth without external activation energy.

Photodynamic therapy (PDT) has shown great effectiveness in oncotherapy but has not been implemented in broad clinical applications because the limited penetration depth of the light used has been unable to reach deep-seated tumors. However, X-rays have been widely used in the clinical field for imaging and radiation therapy due to their excellent tissue penetration depth. Recently, X-rays have been established as an ideal excitation source for PDT, which holds great promise for breaking the depth limitation of traditional PDT for treatment of deep-seated tumors. This review aims to provide an overview of nanoscintillator-mediated X-ray induced PDT (X-PDT) including the concept, the design considerations of nanosensitizers for X-PDT, the modelling of nanosensitizer energy deposition, the putative mechanism by which X-PDT kills cells, and the prospects of future directions. We attempt to summarize the main developments that have occurred over the past decades. Possibilities and challenges for the clinical translation of X-PDT are also discussed.

X-ray excited persistent luminescence (XEPL) imaging has attracted increasing attention in biomedical imaging due to elimination of autofluorescence, high signal-to-noise ratio and repeatable activation with high penetration. However, optical imaging still suffers from limited for high spatial resolution. Methods: Herein, we report Mn3+-rich manganese oxide (MnOx)-coated chromium-doped zinc gallogermanate (ZGGO) nanoparticles (Mn-ZGGOs). Enhanced XEPL and magnetic resonance (MR) imaging were investigated by the decomposition of MnOx shell in the environment of tumors. We also evaluated the tumor cell-killing mechanism by detection of reactive oxygen (ROS), lipid peroxidation and mitochondrial membrane potential changes in vitro. Furthermore, the in vivo biodistribution, imaging and therapy were studied by U87MG tumor-bearing mice. Results: In the tumor region, the MnOx shell is quickly decomposed to produce Mn3+ and oxygen (O2) to directly generate singlet oxygen (1O2). The resulting Mn2+ transforms endogenous H2O2 into highly toxic hydroxyl radical (·OH) via a Fenton-like reaction. The Mn2+ ions and ZGGOs also exhibit excellent T1-weighted magnetic resonance (MR) imaging and ultrasensitive XEPL imaging in tumors. Conclusion: Both the responsive dual-mode imaging and simultaneous self-supplied O2 for the production of 1O2 and oxygen-independent ·OH in tumors allow for more accurate diagnosis of deep tumors and more efficient inhibition of tumor growth without external activation energy.

Conventional photodynamic therapy (PDT)'s clinical application is limited by depth of penetration by light. To address the issue, we have recently developed X-ray induced photodynamic therapy (X-PDT) which utilizes X-ray as an energy source to activate a PDT process. In addition to breaking the shallow tissue penetration dogma, our studies found more efficient tumor cell killing with X-PDT than with radiotherapy (RT) alone. The mechanisms behind the cytotoxicity, however, have not been elucidated. In the present study, we investigate the mechanisms of action of X-PDT on cancer cells. Our results demonstrate that X-PDT is more than just a PDT derivative but is essentially a PDT and RT combination. The two modalities target different cellular components (cell membrane and DNA, respectively), leading to enhanced therapy effects. As a result, X-PDT not only reduces short-term viability of cancer cells but also their clonogenecity in the long-run. From this perspective, X-PDT can also be viewed as a unique radiosensitizing method, and as such it affords clear advantages over RT in tumor therapy, especially for radioresistant cells. This is demonstrated not only in vitro but also in vivo with H1299 tumors that were either subcutaneously inoculated or implanted into the lung of mice. These findings and advances are of great importance to the developments of X-PDT as a novel treatment modality against cancer.

Iron oxide nanoparticles have been extensively used as T2 contrast agents for liver-specific magnetic resonance imaging (MRI). The applications, however, have been limited by their mediocre magnetism and r2 relaxivity. Recent studies show that Fe5C2 nanoparticles can be prepared by high temperature thermal decomposition. The resulting nanoparticles possess strong and air stable magnetism, suggesting their potential as a novel type of T2 contrast agent. To this end, we improve the synthetic and surface modification methods of Fe5C2 nanoparticles, and investigated the impact of size and coating on their performances for liver MRI. Specifically, we prepared 5, 14, and 22 nm Fe5C2 nanoparticles and engineered their surface by: 1) ligand addition with phospholipids, 2) ligand exchange with zwitterion-dopamine-sulfonate (ZDS), and 3) protein adsorption with casein. It was found that the size and surface coating have varied levels of impact on the particles' hydrodynamic size, viability, uptake by macrophages, and r2 relaxivity. Interestingly, while phospholipid- and ZDS-coated Fe5C2 nanoparticles showed comparable r2, the casein coating led to an r2 enhancement by more than 2 fold. In particular, casein coated 22 nm Fe5C2 nanoparticle show a striking r2 of 973 mM(-1)s(-1), which is one of the highest among all of the T2 contrast agents reported to date. Small animal studies confirmed the advantage of Fe5C2 nanoparticles over iron oxide nanoparticles in inducing hypointensities on T2-weighted MR images, and the particles caused little toxicity to the host. The improvements are important for transforming Fe5C2 nanoparticles into a new class of MRI contrast agents. The observations also shed light on protein-based surface modification as a means to modulate contrast ability of magnetic nanoparticles.

In vivo fluorescence imaging suffers from suboptimal signal-to-noise ratio and shallow detection depth, which is caused by the strong tissue autofluorescence under constant external excitation and the scattering and absorption of short-wavelength light in tissues. Here we address these limitations by using a novel type of optical nanoprobes, photostimulable LiGa5O8:Cr(3+) near-infrared (NIR) persistent luminescence nanoparticles, which, with very-long-lasting NIR persistent luminescence and unique photo-stimulated persistent luminescence (PSPL) capability, allow optical imaging to be performed in an excitation-free and hence, autofluorescence-free manner. LiGa5O8:Cr(3+) nanoparticles pre-charged by ultraviolet light can be repeatedly (>20 times) stimulated in vivo, even in deep tissues, by short-illumination (~15 seconds) with a white light-emitting-diode flashlight, giving rise to multiple NIR PSPL that expands the tracking window from several hours to more than 10 days. Our studies reveal promising potential of these nanoprobes in cell tracking and tumor targeting, exhibiting exceptional sensitivity and penetration that far exceed those afforded by conventional fluorescence imaging.

We report herein a straightforward and label-free approach to prepare luminescent mesoporous silica nanoparticles. We found that calcination at 400 °C can grant mesoporous organosilica nanoparticles with strong fluorescence of great photo- and chemical stability. The luminescence is found to originate from the carbon dots generated from the calcination, rather than the defects in the silica matrix as was believed previously. The calcination does not impact the particles' abilities to load drugs and conjugate to biomolecules. In a proof-of-concept study, we demonstrated that doxorubicin (Dox) can be efficiently encapsulated into these fluorescent mesoporous silica nanoparticles. After coupled to c(RGDyK), the nanoconjugates can efficiently home to tumors through interactions with integrin αvβ3 overexpressed on the tumor vasculature. This calcination-induced luminescence is expected to find wide applications in silica-based drug delivery, nanoparticle coating, and immunofluorescence imaging.