Ultra-wideband-responsive photon conversion through co-sensitization in lanthanide nanocrystals.

Distinctive upconversion or downshifting of lanthanide nanocrystals holds promise for biomedical and photonic applications. However, either process requires high-energy lasers at discrete wavelengths for excitation. Here we demonstrate that co-sensitization can break this limitation with ultrawide excitation bands. We achieve co-sensitization by employing Nd3+ and Ho3+ as the co-sensitizers with complementary absorptions from the ultraviolet to infrared region. Symmetric penta-layer core-shell nanostructure enables tunable fluorescence in the visible and the second near-infrared window when incorporating different activators (Er3+, Ho3+, Pr3+, and Tm3+). Transient spectra confirm the directional energy transfer from sensitizers to activators through the bridge of Yb3+. We validate the features of the nanocrystals for low-powered white light-emitting diode-mediated whole-body angiography of mice with a signal-to-noise ratio of 12.3 and excitation-regulated encryption. This co-sensitization strategy paves a new way in lanthanide nanocrystals for multidirectional photon conversion manipulation and excitation-bandwidth-regulated fluorescence applications.

Silent region barcode particle arrays for ultrasensitive multiplexed SERS detection.

Suspension arrays are a critical components of next generation multiplexed detection technologies. Current fluorescence suspension arrays are limited by a multiplexed coding ceiling and difficulties with ultrasensitive detection. Raman mode is a promising substitute, but the complex spectral peak distributions and extremely weak intrinsic signal intensity severely diminish Raman signal performance in suspension arrays. To address these limitations, we constructed a Raman suspension array system using plasmonic microbeads as barcode substrates and Au nanoflowers as reporter carriers. The well-designed shell morphology and plasmonic microbead composition enabled significant surface enhancement Raman scattering (SERS) such that we were able to adjust silent region Raman-coding intensity levels. Due to synergistic SERS effects from the plasmonic shell and the multi-branched Au nanoflower nanostructure, the reporting signal was greatly improved, enabling ultrasensitive detection of 5-plexed lung cancer markers. Detection in patient serum samples demonstrated good consistency with the standard electrochemiluminescence method. Thus, this silent region SERS barcode-based suspension array is a developmental advance for modern multiplexed biodetection, potentially providing a powerful early disease screening and diagnosis tool.

Recent Progress and Trends in X-ray-Induced Photodynamic Therapy with Low Radiation Doses.

The prominence of photodynamic therapy (PDT) in treating superficial skin cancer inspires innovative solutions for its congenitally deficient shadow penetration of the visible-light excitation. X-ray-induced photodynamic therapy (X-PDT) has been proven to be a successful technique in reforming the conventional PDT for deep-seated tumors by creatively utilizing penetrating X-rays as external excitation sources and has witnessed rapid developments over the past several years. Beyond the proof-of-concept demonstration, recent advances in X-PDT have exhibited a trend of minimizing X-ray radiation doses to quite low values. As such, scintillating materials used to bridge X-rays and photosensitizers play a significant role, as do diverse well-designed irradiation modes and smart strategies for improving the tumor microenvironment. Here in this review, we provide a comprehensive summary of recent achievements in X-PDT and highlight trending efforts using low doses of X-ray radiation. We first describe the concept of X-PDT and its relationships with radiodynamic therapy and radiotherapy and then dissect the mechanism of X-ray absorption and conversion by scintillating materials, reactive oxygen species evaluation for X-PDT, and radiation side effects and clinical concerns on X-ray radiation. Finally, we discuss a detailed overview of recent progress regarding low-dose X-PDT and present perspectives on possible clinical translation. It is expected that the pursuit of low-dose X-PDT will facilitate significant breakthroughs, both fundamentally and clinically, for effective deep-seated cancer treatment in the near future.

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.

Pnictogen Semimetal (Sb, Bi)-Based Nanomaterials for Cancer Imaging and Therapy: A Materials Perspective.

Innovative multifunctional nanomaterials have attracted tremendous interest in current research by facilitating simultaneous cancer imaging and therapy. Among them, antimony (Sb)- and bismuth (Bi)-based nanoparticles are important species with multifunction to boost cancer theranostic efficacy. Despite the rapid development, the extensive previous work treated Sb- and Bi-based nanoparticles as mutually independent species, and therefore a thorough understanding of their relationship in cancer theranostics was lacking. We propose here that the identical chemical nature of Sb and Bi, being semimetals, provides their derived nanoparticles with inherent multifunction for near-infrared laser-driven and/or X-ray-based cancer imaging and therapy as well as some other imparted functions. An overview of recent progress on Sb- and Bi-based nanoparticles for cancer theranostics is provided to highlight the relationship between chemical nature and multifunction. The understanding of Sb- and Bi-based nanoparticles in this way might shed light on the further design of smart multifunctional nanoparticles for cancer theranostics.

Multifunctional magnetic iron oxide nanoparticles: an advanced platform for cancer theranostics.

Multifunctional magnetic nanoparticles and derivative nanocomposites have aroused great concern for multimode imaging and cancer synergistic therapies in recent years. Among the rest, functional magnetic iron oxide nanoparticles (Fe3O4 NPs) have shown great potential as an advanced platform because of their inherent magnetic resonance imaging (MRI), biocatalytic activity (nanozyme), magnetic hyperthermia treatment (MHT), photo-responsive therapy and drug delivery for chemotherapy and gene therapy. Magnetic Fe3O4 NPs can be synthesized through several methods and easily surface modified with biocompatible materials or active targeting moieties. The MRI capacity could be appropriately modulated to induce response between T1 and T2 modes by controlling the size distribution of Fe3O4 NPs. Besides, small-size nanoparticles are also desired due to the enhanced permeation and retention (EPR) effect, thus the imaging and therapeutic efficiency of Fe3O4 NP-based platforms can be further improved. Here, we firstly retrospect the typical synthesis and surface modification methods of magnetic Fe3O4 NPs. Then, the latest biomedical application including responsive MRI, multimodal imaging, nanozyme, MHT, photo-responsive therapy and drug delivery, the mechanism of corresponding treatments and cooperation therapeutics of multifunctional Fe3O4 NPs are also be explained. Finally, we also outline a brief discussion and perspective on the possibility of further clinical translations of these multifunctional nanomaterials. This review would provide a comprehensive reference for readers to understand the multifunctional Fe3O4 NPs in cancer diagnosis and treatment.

Tetramodal Imaging and Synergistic Cancer Radio-Chemotherapy Enabled by Multiple Component-Encapsulated Zeolitic Imidazolate Frameworks.

The abundant species of functional nanomaterials have attracted tremendous interests as components to construct multifunctional composites for cancer theranostics. However, their distinct chemical properties substantially require a specific strategy to integrate them in harmony. Here, we report the preparation of a distinctive multifunctional composite by encapsulating small-sized semiconducting copper bismuth sulfide (CBS) nanoparticles and rare-earth down-conversion (DC) nanoparticles in larger-sized zeolitic imidazolate framework-8 (ZIF8) nanoparticles, followed by loading an anticancer drug, doxorubicin (DOX). Such composites can be used for tetramodal imaging, including traditional computed tomography and magnetic resonance imaging and, recently, for photoacoustic imaging and fluorescence imaging. With a pH-responsive release of the encapsulated components, synergistic radio-chemotherapy with a high (87.6%) tumor inhibition efficiency is achieved at moderate doses of the CBS&DC-ZIF8@DOX composite with X-ray irradiation. This promising strategy highlights the extending capacity of zeolitic imidazolate frameworks to encapsulate multiple distinct components for enhanced cancer imaging and 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.

W-doped TiO2 nanoparticles with strong absorption in the NIR-II window for photoacoustic/CT dual-modal imaging and synergistic thermoradiotherapy of tumors.

Multifunctional nanomaterials that have integrated diagnostic and therapeutic functions and low toxicity, and can enhance treatment efficacy through combination therapy have drawn tremendous amounts of attention. Herein, a newly developed multifunctional theranostic agent is reported, which is PEGylated W-doped TiO2 (WTO) nanoparticles (NPs) synthesized via a facile organic route, and the results demonstrated strong absorbance of these WTO NPs in the second near-infrared (NIR-II) window due to successful doping with W. These PEGylated WTO NPs can absorb both NIR-II laser and ionizing radiation, rendering them well suited for dual-modal computed tomography/NIR-II photoacoustic imaging and synergistic NIR-II photothermal/radiotherapy of tumors. In addition, the long-term in vivo studies indicated that these PEGylated WTO NPs had no obvious toxicity on mice in vivo, and they can be cleared after a 30-day period. In summary, this multifunctional theranostic agent can absorb both NIR-II laser and ionizing radiation with negligible toxicity and rapid clearance, therefore it has great promise for applications in imaging and therapeutics in biomedicine.

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.

Black hollow silicon oxide nanoparticles as highly efficient photothermal agents in the second near-infrared window for in vivo cancer therapy.

Semiconductor nanoparticles with localized surface plasmon resonance (LSPR) have gained increasing interest due to their potential for use in nanomedicine, particularly in the area of cancer photothermal therapy. In this study, we have synthesized non-stoichiometric hollow silicon oxide nanoparticles (H-SiOx NPs) using a magnesiothermic reduction process. The black NPs generated a desired LSPR in the second near-infrared (NIR-II) window, as was demonstrated by a photothermal conversion efficiency of up to 48.6% at 1064 nm. Such an efficiency is the highest reported among the noble metal and semiconductor-based NPs as NIR-II PTT photothermal agents. In addition, H-SiOx NPs exhibited excellent in vivo photoacoustic (PA) imaging properties, and thus can be used for highly efficient in vivo cancer treatment via irradiation with a 1064 nm laser, even at 0.6 W cm-2. The findings described are the first to demonstrate the existence of LSPR in non-stoichiometric silicon-based nanoparticles with a low-toxicity degradation pathway for in vivo application, and provide new insights towards understanding the role of new semiconductor nanoparticles in nanomedicine.

Ultrasmall Semimetal Nanoparticles of Bismuth for Dual-Modal Computed Tomography/Photoacoustic Imaging and Synergistic Thermoradiotherapy.

Multifunctional nanomaterials with integrated diagnostic and therapeutic functions, combination therapy to enhance treatment efficacy, as well as low toxicity have drawn tremendous attentions. Herein, we report a multifunctional theranostic agent based on peptide (LyP-1)-labeled ultrasmall semimetal nanoparticles of bismuth (Bi-LyP-1 NPs). Ultrasmall Bi NPs (3.6 nm) were facilely synthesized using oleylamine as the reducing agent and exhibited a higher tumor accumulation after being conjugated with the tumor-homing peptide LyP-1. The abilities to absorb both ionizing radiation and the second near-infrared (NIR-II) window laser radiation ensured that Bi-LyP-1 NPs are capable of dual-modal computed tomography/photoacoustic imaging and efficient synergistic NIR-II photothermal/radiotherapy of tumors. Moreover, Bi-LyP-1 NPs could be rapidly cleared from mice through both renal and fecal clearance and almost completely cleared after 30 days. Such multifunctional nanoparticles as efficient cancer theranostic agents, coupled with fast clearance and low toxicity, shed light on the future use of semimetal nanoparticles for biomedicine.

Synergistic thermoradiotherapy based on PEGylated Cu3BiS3 ternary semiconductor nanorods with strong absorption in the second near-infrared window.

In this work, we report a successful synthesis of copper bismuth sulfide nanorods (NRs) with broad and strong photoabsorption ranging from ultraviolet (UV) to near-infrared (NIR) wavelengths, which can be used as a 1064 nm-laser-driven photothermal agent with the photothermal conversion efficiency of 40.7%, noticeably higher than most of the reported PTT agents working in NIR-II window. The as-prepared PEGylated Cu3BiS3 NRs were used as photoacoustic imaging (PAI) and CT imaging agents due to their strong NIR absorption and large X-ray attenuation coefficient of bismuth. We are the first to demonstrate that a small quantity of PEGylated Cu3BiS3 NRs in tumors can concentrate radiation energy and trigger mild PTT under NIR-II irradiation and thus, these particles could be used as a novel, synergistic thermoradiotheraputic agent that enhances the efficacy of radiotherapy.

Identification of an inhibitory mechanism of luteolin on the insulin-like growth factor-1 ligand-receptor interaction.

Using single-molecule force measurement and fluorescence imaging, we have demonstrated that luteolin has an inhibitory effect on IGF-1 ligand-receptor binding, the initial step in IGF-1 signaling. This inhibition mechanism, which was confirmed by flow cytometry and molecular docking, could play a role in cancer therapy.