NIR Light-Activated and RGD-Conjugated Ultrasmall Fe/PPy Nanopolymers for Enhanced Tumor Photothermal Ferrotherapy and MR Imaging.

Iron-based nanomaterials have shown great promise for tumor ferrotherapy in recent years. However, nanoparticle-induced ferroptosis has low therapeutic efficacy owing to unsatisfactory Fenton reaction activity in a typical tumor microenvironment. In this study, NIR light-activated Fe/PPy-RGD nanopolymers were developed to combine photothermal therapy and ferrotherapy and achieve enhanced antitumor activity. Importantly, Fe/PPy-RGD exhibited excellent therapeutic performance under NIR light activation both in vitro and in vivo. Under irradiation with NIR light, the heat generated by Fe/PPy-RGD not only induced a therapeutic photothermal effect but also enhanced the release of iron ions and the Fenton reaction by inducing ferroptosis. Additionally, by virtue of RGD conjugation and its ultrasmall size, Fe/PPy-RGD could effectively accumulate at tumor sites in living mice after systemic administration and could be monitored via MR imaging. Hence, this study provides a promising approach for integrating ferrotherapy with photothermal therapy to achieve enhanced tumor treatment.

Vitamin D supplementation is effective for olanzapine-induced dyslipidemia.

Olanzapine is an atypical antipsychotic drug that is clinically applied in patients with schizophrenia. It increases the risk of dyslipidemia, a disturbance of lipid metabolic homeostasis, usually characterized by increased low-density lipoprotein (LDL) cholesterol and triglycerides, and accompanied by decreased high-density lipoprotein (HDL) in the serum. In this study, analyzing the FDA Adverse Event Reporting System, JMDC insurance claims, and electronic medical records from Nihon University School of Medicine revealed that a co-treated drug, vitamin D, can reduce the incidence of olanzapine-induced dyslipidemia. In the following experimental validations of this hypothesis, short-term oral olanzapine administration in mice caused a simultaneous increase and decrease in the levels of LDL and HDL cholesterol, respectively, while the triglyceride level remained unaffected. Cholecalciferol supplementation attenuated these deteriorations in blood lipid profiles. RNA-seq analysis was conducted on three cell types that are closely related to maintaining cholesterol metabolic balance (hepatocytes, adipocytes, and C2C12) to verify the direct effects of olanzapine and the functional metabolites of cholecalciferol (calcifediol and calcitriol). Consequently, the expression of cholesterol-biosynthesis-related genes was reduced in calcifediol- and calcitriol-treated C2C12 cells, which was likely to be mediated by activating the vitamin D receptor that subsequently inhibited the cholesterol biosynthesis process via insulin-induced gene 2 regulation. This clinical big-data-based drug repurposing approach is effective in finding a novel treatment with high clinical predictability and a well-defined molecular mechanism.

Coordinating the Mechanisms of Action of Ferroptosis and the Photothermal Effect for Cancer Theranostics.

Combination therapy based on different mechanisms of cell death has shown promise in tumor therapy. However, when different modalities are integrated, the maximum synergy of the therapeutic effects is often lacking in the design. Herein, we report a cancer theranostic nanomedicine formula developed by considering the mechanisms of action of ferroptosis and the photothermal effect in combination therapy. The croconaine molecule was encapsulated as both a photothermal converter and an iron-chelating agent with BSA, thus leading to biocompatible and stable Cro-Fe@BSA nanoparticles (NPs). The Cro-Fe@BSA NPs in the tumor milieu showed an activated photothermal effect leading to enhanced radical formation owing to the temperature-dependent Fenton reaction kinetics, while radical formation during ferroptosis in turn prevented the heat-induced formation of heat shock proteins and thus the self-protection mechanism of cancer cells in response to heat. The activatable photoacoustic and magnetic resonance imaging performance of the Cro-Fe@BSA NPs also enabled safe and reliable cancer theranostics.

Genetically engineered magnetic nanocages for cancer magneto-catalytic theranostics.

The clinical applications of magnetic hyperthermia therapy (MHT) have been largely hindered by the poor magnetic-to-thermal conversion efficiency of MHT agents. Herein, we develop a facile and efficient strategy for engineering encapsulin-produced magnetic iron oxide nanocomposites (eMIONs) via a green biomineralization procedure. We demonstrate that eMIONs have excellent magnetic saturation and remnant magnetization properties, featuring superior magnetic-to-thermal conversion efficiency with an ultrahigh specific absorption rate of 2390 W/g to overcome the critical issues of MHT. We also show that eMIONs act as a nanozyme and have enhanced catalase-like activity in the presence of an alternative magnetic field, leading to tumor angiogenesis inhibition with a corresponding sharp decrease in the expression of HIF-1α. The inherent excellent magnetic-heat capability, coupled with catalysis-triggered tumor suppression, allows eMIONs to provide an MRI-guided magneto-catalytic combination therapy, which may open up a new avenue for bench-to-bed translational research of MHT.

Anisotropic nanomaterials for shape-dependent physicochemical and biomedical applications.

This review contributes towards a systematic understanding of the mechanism of shape-dependent effects on nanoparticles (NPs) for elaborating and predicting their properties and applications based on the past two decades of research. Recently, the significance of shape-dependent physical chemistry and biomedicine has drawn ever increasing attention. While there has been a great deal of effort to utilize NPs with different morphologies in these fields, so far research studies are largely localized in particular materials, synthetic methods, or biomedical applications, and have ignored the interactional and interdependent relationships of these areas. This review is a comprehensive description of the NP shapes from theory, synthesis, property to application. We figure out the roles that shape plays in the properties of different kinds of nanomaterials together with physicochemical and biomedical applications. Through systematic elaboration of these shape-dependent impacts, better utilization of nanomaterials with diverse morphologies would be realized and definite strategies would be expected for breakthroughs in these fields. In addition, we have proposed some critical challenges and open problems that need to be addressed in nanotechnology.

Gadolinium Metallofullerene-Polypyrrole Nanoparticles for Activatable Dual-Modal Imaging-Guided Photothermal Therapy.

Accurate diagnosis of tumor is promising to guide photothermal therapy (PTT) for efficacious tumor ablation with minimal damage to healthy tissues. Here, we report an activatable dual-modal imaging agent, which is based on PEGylated-gadolinium metallofullerene-polypyrrole nanoparticle (PEG-GMF-PPy NP) for imaging-guided PTT. A contrast agent (gadolinium metallofullerene, GMF) with excellent magnetic resonance imaging (MRI) performance and an ultra-pH-responsive polymer (PEG-PC7A) are successively modified to the surface of photothermal agent (PPy NP). The prepared PEG-GMF-PPy NPs show strong absorption in the near-infrared (NIR) region, so they can be utilized for photoacoustic imaging. Furthermore, in a tumor extracellular environment, the PEG-GMF-PPy NPs can achieve pH-enhanced MRI because of the hydrophobic-to-hydrophilic conversion of the PC7A. Upon accurate diagnosis-guided NIR laser irradiation, excellent tumor ablation effect is achieved. The results suggest that the PEG-GMF-PPy NPs are promising agents for activatable imaging-guided PTT.

Glutathione-Responsive Self-Assembled Magnetic Gold Nanowreath for Enhanced Tumor Imaging and Imaging-Guided Photothermal Therapy.

Designing nanomaterials with advanced functions and physical properties to improve cancer diagnosis and treatment has been an enormous challenge. In this work, we report the synthesis of magnetic gold nanowreaths (AuNWs) by combining wet-chemical synthesis with layer-by-layer self-assembly. The presence of Au branches, small junctions, and central holes in AuNWs led to improved photothermal effect compared with Au nanoring seeds and thick Au nanoring with smooth surface. The self-assembly of exceedingly small magnetic iron oxide nanoparticles (ES-MIONs) on the surfaces of AuNWs not only effectively quenched the T1-weighted magnetic resonance imaging (MRI) ability due to the enhanced T2 decaying effect but also provided the responsiveness to glutathione (GSH). After intravenous injection, the T1 signal of magnetic AuNWs initially in the "OFF" state can be intelligently switched on in response to the relatively high GSH concentration in tumor, and the formation of larger assemblies of ES-MIONs improved their tumor delivery compared to ES-MIONs themselves. Thus, the magnetic AuNWs showed higher MRI contrast than ES-MIONs or commercial Magnevist in T1-weighted MR imaging of tumor. Furthermore, the magnetic AuNWs have absorption in near-infrared range, leading to strong photoacoustic signal and effective photoablation of tumor. Therefore, our GSH-responsive self-assembled magnetic AuNWs could enhance T1-weighted MRI and photoacoustic imaging of tumor and be used for imaging-guided photothermal therapy.

Self-Assembly of Semiconducting-Plasmonic Gold Nanoparticles with Enhanced Optical Property for Photoacoustic Imaging and Photothermal Therapy.

Although various noble metal and semiconducting molecules have been developed as photoacoustic (PA) agents, the use of semiconducting polymer-metal nanoparticle hybrid materials to enhance PA signal has not been explored. A novel semiconducting-plasmonic nanovesicle was fabricated by self-assembly of semiconducting poly(perylene diimide) (PPDI) and poly(ethylene glycol (PEG) tethered gold nanoparticles (Au@PPDI/PEG). A highly localized and strongly enhanced electromagnetic (EM) field is distributed between adjacent gold nanoparticles in the vesicular shell, where the absorbing collapsed PPDI is present. Significantly, the EM field in turn enhances the light absorption efficiency of PPDI, leading to a much greater photothermal effect and a stronger photoacoustic signal compared to PDI nanoparticle or gold nanovesicle alone. The optical property of the hybrid vesicle can be further tailored by controlling the ratio of PPDI and gold nanoparticle as well as the adjustable interparticle distance of gold nanoparticles localized in the vesicular shell. In vivo imaging and therapeutic evaluation demonstrated that the hybrid vesicle is an excellent probe for cancer theranostics.

Core-Satellite Polydopamine-Gadolinium-Metallofullerene Nanotheranostics for Multimodal Imaging Guided Combination Cancer Therapy.

Integration of magnetic resonance imaging (MRI) and other imaging modalities is promising to furnish complementary information for accurate cancer diagnosis and imaging-guided therapy. However, most gadolinium (Gd)-chelator MR contrast agents are limited by their relatively low relaxivity and high risk of released-Gd-ions-associated toxicity. Herein, a radionuclide-64 Cu-labeled doxorubicin-loaded polydopamine (PDA)-gadolinium-metallofullerene core-satellite nanotheranostic agent (denoted as CDPGM) is developed for MR/photoacoustic (PA)/positron emission tomography (PET) multimodal imaging-guided combination cancer therapy. In this system, the near-infrared (NIR)-absorbing PDA acts as a platform for the assembly of different moieties; Gd3 N@C80 , a kind of gadolinium metallofullerene with three Gd ions in one carbon cage, acts as a satellite anchoring on the surface of PDA. The as-prepared CDPGM NPs show good biocompatibility, strong NIR absorption, high relaxivity (r 1 = 14.06 mM-1 s-1 ), low risk of release of Gd ions, and NIR-triggered drug release. In vivo MR/PA/PET multimodal imaging confirms effective tumor accumulation of the CDPGM NPs. Moreover, upon NIR laser irradiation, the tumor is completely eliminated with combined chemo-photothermal therapy. These results suggest that the CDPGM NPs hold great promise for cancer theranostics.

Rational Design of Branched Nanoporous Gold Nanoshells with Enhanced Physico-Optical Properties for Optical Imaging and Cancer Therapy.

Reported procedures on the synthesis of gold nanoshells with smooth surfaces have merely demonstrated efficient control of shell thickness and particle size, yet no branch and nanoporous features on the nanoshell have been implemented to date. Herein, we demonstrate the ability to control the roughness and nanoscale porosity of gold nanoshells by using redox-active polymer poly(vinylphenol)-b-(styrene) nanoparticles as reducing agent and template. The porosity and size of the branches on this branched nanoporous gold nanoshell (BAuNSP) material can be facilely adjusted by control of the reaction speed or the reaction time between the redox-active polymer nanoparticles and gold ions (Au3+). Due to the strong reduction ability of the redox-active polymer, the yield of BAuNSP was virtually 100%. By taking advantage of the sharp branches and nanoporous features, BAuNSP exhibited greatly enhanced physico-optical properties, including photothermal effect, surface-enhanced Raman scattering (SERS), and photoacoustic (PA) signals. The photothermal conversion efficiency can reach as high as 75.5%, which is greater than most gold nanocrystals. Furthermore, the nanoporous nature of the shells allows for effective drug loading and controlled drug release. The thermoresponsive polymer coated on the BAuNSP surface serves as a gate keeper, governing the drug release behavior through photothermal heating. Positron emission tomography imaging demonstrated a high passive tumor accumulation of 64Cu-labeled BAuNSP. The strong SERS signal generated by the SERS-active BAuNSP in vivo, accompanied by enhanced PA signals in the tumor region, provide significant tumor information, including size, morphology, position, and boundaries between tumor and healthy tissues. In vivo tumor therapy experiments demonstrated a highly synergistic chemo-photothermal therapy effect of drug-loaded BAuNSPs, guided by three modes of optical imaging.

Multi-spin echo spatial encoding provides three-fold improvement of temperature precision during intermolecular zero quantum thermometry.

PURPOSE: Intermolecular multiple quantum coherences (iMQCs) are a source of MR contrast with applications including temperature imaging, anisotropy mapping, and brown fat imaging. Because all applications are limited by signal-to-noise ratio (SNR), we developed a pulse sequence that detects intermolecular zero quantum coherences with improved SNR. METHODS: A previously developed pulse sequence that detects iMQCs, HOMOGENIZED with off resonance transfer (HOT), was modified with a multi-spin echo spatial encoding scheme (MSE-HOT). MSE-HOT uses a series of refocusing pulses to generate a stack of images that are averaged in postprocessing for higher SNR. MSE-HOT performance was quantified by measuring its temperature accuracy and precision during hyperthermia of ex vivo red bone marrow samples. RESULTS: MSE-HOT yielded a three-fold improvement in temperature precision relative to previous pulse sequences. Sources of improved precision were 1) echo averaging and 2) suppression of J-coupling in the methylene protons of fat. MSE-HOT measured temperature change with an accuracy of 0.6°C. CONCLUSION: MSE-HOT improved the temperature accuracy and precision of HOT to a level that is sufficient for hyperthermia of bone marrow.