A Versatile Imaging and Therapeutic Platform Based on Dual-Band Luminescent Lanthanide Nanoparticles toward Tumor Metastasis Inhibition

Upconversion (UC) luminescent lanthanide nanoparticles (LNPs) are expected to play an important role in imaging and photodynamic therapy (PDT) <i>in vitro</i> and <i>in vivo</i>. However, with the absorption of UC emissions by photosensitizers (PSs) to generate singlet oxygen (¹O₂) for PDT, the imaging signals from LNPs are significantly weakened. It is important to activate another imaging route to track the location of the LNPs during PDT process. In this work, Nd³⁺-sensitized LNPs with dual-band visible and near-infrared (NIR) emissions under single 808 nm excitation were reported to address this issue. The UC emissions in green could trigger covalently linked rose bengal (RB) molecules for efficient PDT, and NIR emissions deriving from Yb³⁺ and magnetic resonance imaging (MRI) were used for imaging simultaneously. Notably, the designed therapeutic platform could further effectively avoid the overheating effect induced by the laser irradiation, due to the minimized absorption of biological media at around 808 nm. TdT-mediated dUTP nick end labeling (TUNEL) assay showed serious cell apoptosis in the tumor after PDT for 2 weeks, leading to an effective tumor inhibition rate of 67%. Benefit from the PDT, the tumor growth-induced liver and spleen burdens were largely attenuated, and the liver injury was also alleviated. More importantly, pulmonary and hepatic tumor metastases were significantly reduced after PDT. The Nd³⁺-sensitized LNPs provide a multifunctional nanoplatform for NIR light-assisted PDT with minimized heating effect and an effective inhibition of tumor growth and metastasis

Dual-Mode Imaging-Guided Synergistic Chemo- and Magnetohyperthermia Therapy in a Versatile Nanoplatform To Eliminate Cancer Stem Cells

Cancer stem cells (CSCs) have been identified as a new target for therapy in diverse cancers. Traditional therapies usually kill the bulk of cancer cells, but are often unable to effectively eliminate CSCs, which may lead to drug resistance and cancer relapse. Herein, we propose a novel strategy: fabricating multifunctional magnetic Fe₃O₄@PPr@HA hybrid nanoparticles and loading it with the Notch signaling pathway inhibitor <i>N</i>-[<i>N</i>-(3,5-difluorophenacetyl-l-alanyl)]-<i>S</i>-phenylglycinet-butylester (DAPT) to eliminate CSCs. Hyaluronic acid ligands greatly enhance the accumulation of the hybrid nanoparticles in the tumor site and in the CSCs. Both hyaluronase in the tumor microenvironment and the magnetic hyperthermia effect of the inner magnetic core can accelerate the release of DAPT. This controlled release of DAPT in the tumor site further enhances the ability of the combination of chemo- and magnetohyperthermia therapy to eliminate cancer stem cells. With the help of polypyrrole-mediated photoacoustic and Fe₃O₄-mediated magnetic resonance imaging, the drug release can be precisely monitored in vivo. This versatile nanoplatform enables effective elimination of the cancer stem cells and monitoring of the drugs

Superstable Magnetic Nanoparticles in Conjugation with Near-Infrared Dye as a Multimodal Theranostic Platform

Near-infrared (NIR) dyes functionalized magnetic nanoparticles (MNPs) have been widely applied in magnetic resonance imaging (MRI), NIR fluorescence imaging, drug delivery, and magnetic hyperthermia. However, the stability of MNPs and NIR dyes in water is a key problem to be solved for long-term application. In this study, a kind of superstable iron oxide nanoparticles was synthesized by a facile way, which can be used as <i>T</i>₁ and <i>T</i>₂ weighted MRI contrast agent. IR820 was grafted onto the surface of nanoparticles by 6-amino hexanoic acid to form IR820-CSQ-Fe conjugates. Attached IR820 showed increased stability in water at least for three months and an enhanced ability of singlet oxygen production of almost double that of free dyes, which will improve its efficiency for photodynamic therapy. Meanwhile, the multispectral optoacoustic tomography (MSOT) and NIR imaging ability of IR820-CSQ-Fe will greatly increase the accuracy of disease detection. All of these features will broaden the application of this material as a multimodal theranostic platform

Rapid Degradation and High Renal Clearance of Cu₃BiS₃ Nanodots for Efficient Cancer Diagnosis and Photothermal Therapy <i>in Vivo</i>

A key challenge for the use of inorganic nanomedicines in clinical applications is their long-term accumulation in internal organs, which raises the common concern of the risk of adverse effects and inflammatory responses. It is thus necessary to rationally design inorganic nanomaterials with proper accumulation and clearance mechanism <i>in vivo</i>. Herein, we prepared ultrasmall Cu₃BiS₃ nanodots (NDs) as a single-phased ternary bimetal sulfide for photothermal cancer therapy guided by multispectral optoacoustic tomography (MSOT) and X-ray computed tomography (CT) due to bismuth’s excellent X-ray attenuation coefficient. We then monitored and investigated their absorption, distribution, metabolism, and excretion. We also used CT imaging to demonstrate that Cu₃BiS₃ NDs can be quickly removed through renal clearance, which may be related to their small size, rapid chemical transformation, and degradation in an acidic lysosomal environment as characterized by synchrotron radiation-based X-ray absorption near-edge structure spectroscopy. These results reveal that Cu₃BiS₃ NDs act as a simple but powerful “theranostic” nanoplatform for MSOT/CT imaging-guided tumor ablation with excellent metabolism and rapid clearance that will improve safety for clinical applications in the future

Use of Synchrotron Radiation-Analytical Techniques To Reveal Chemical Origin of Silver-Nanoparticle Cytotoxicity

To predict potential medical value or toxicity of nanoparticles (NPs), it is necessary to understand the chemical transformation during intracellular processes of NPs. However, it is a grand challenge to capture a high-resolution image of metallic NPs in a single cell and the chemical information on intracellular NPs. Here, by integrating synchrotron radiation-beam transmission X-ray microscopy (SR-TXM) and SR-X-ray absorption near edge structure (SR-XANES) spectroscopy, we successfully capture the 3D distribution of silver NPs (AgNPs) inside a single human monocyte (THP-1), associated with the chemical transformation of silver. The results reveal that the cytotoxicity of AgNPs is largely due to the chemical transformation of particulate silver from elemental silver (Ag⁰)_<i>n</i>, to Ag⁺ ions and Ag–O–, then Ag–S– species. These results provide direct evidence in the long-lasting debate on whether the nanoscale or the ionic form dominates the cytotoxicity of silver nanoparticles. Further, the present approach provides an integrated strategy capable of exploring the chemical origins of cytotoxicity in metallic nanoparticles

Gd-Dots with Strong Ligand–Water Interaction for Ultrasensitive Magnetic Resonance Renography

Magnetic resonance imaging contrast agents with both significantly enhanced relaxivity and minimal safety risk are of great importance for sensitive clinical diagnosis, but have rarely been reported. Herein, we present a simple strategy to improve relaxivity by introducing surface ligands with strong interaction to water molecules. As a proof of concept, NaGdF₄ nanoparticles (NPs) capped by poly­(acrylic acid) (PAA) show superior relaxivity to those capped by polyethylenimine and polyethylene glycol, which is attributed to the strong hydrogen-bond capacity of PAA to water molecules as revealed by theoretical calculation. Furthermore, benefiting from PAA and ultrasmall particle size, Gd-dots, namely PAA-capped GdOF NPs (2.1 ± 0.2 nm), are developed as a high-performance contrast agent, with a remarkable ionic relaxivity of ∼75 mM^–1 s^–1 in albumin solution at 0.5 T. These Gd-dots also exhibit efficient renal clearance with <3% of injected amount left 12 h post-injection. Ultrasensitive MR renography achieved with Gd-dots strongly suggests their great potential for practical applications