Feasibility of Gd-Based prostate cancer targeted magnetic resonance agents using prostate specific membrane antigen.

The aim of this work was to evaluate Gd-FC705, a prostate-specific membrane antigen (PSMA)-targeted MRI contrast agent. The r1 and r2 relaxivities of Gd-FC705 are 5.94 mM-1s-1 and 17.77 mM-1s-1, respectively, in HSA solution (0.67 mM) at 3 T, which are higher than those of Gd-DOTA. Specific targeting efficacy was found with a 3-fold enhancement between PSMA-negative (PSMA-) and PSMA-positive (PSMA+) cells. The in vivo targeting and bio-distribution of Gd-FC705 were further confirmed using nude mice bearing PC3 human prostate cancer xenografts, which showed a 2-fold increase in the contrast-to-noise ratio (CNR) for PSMA+ tumors compared to PSMA- tumors 1 h post injection and a longer circulation time than Gd-DOTA. These results demonstrate that Gd-FC705 has great potential as a diagnostic agent for prostate cancer.

Development of a Stereotactic Radiosurgery Frame Adapter for a Multichannel MRI Coil.

BACKGROUND: The usage of multichannel brain MRI coils, which have several advantages over single-channel brain coils used for stereotactic radiosurgery (SRS), requires a frame adapter device to fit the frames inside the multichannel brain coils. However, such a frame adapter has not been developed until now. OBJECTIVE: to develop an SRS frame adapter for multichannel MRI coils and verify the geometrical accuracy and signal-to-noise ratio (SNR) of the MR images obtained using multichannel MRI coils. METHODS: We fabricated an SRS frame adapter for a 48-channel MRI coil using a three-dimensional (3D) printer. Furthermore, we obtained phantom and human-brain MR images with a 3.0 Tesla MRI scanner using multi- and single-channel coils. Computed tomography (CT) phantom images were also obtained as reference. We compared the coordinate errors of the multi- and single-channel coils to evaluate the geometrical accuracy. Two neurosurgeons measured the coordinates. In addition, we compared the SNR differences between multi- and single-channel coils using the T1- and T2-weighted brain images. RESULTS: For the CT coordinate measurements, the correlation coefficient r = 1 and p < 0.001 with respect to the 3 axes (Δx, Δy, and Δz) and 3D errors (Δr) showed no interpersonal differences between the 2 neurosurgeons. The results obtained using the T1-weighted images showed that a multichannel coil had smaller coordinate errors in Δx, Δy, Δz, and Δr than that observed in case of a single-channel coil (p < 0.001). In case of the SNR measurements, most of the brain areas showed higher SNRs when using a multichannel coil compared with that observed when using a single-channel coil in the T1- and T2-weighted images. CONCLUSION: Compared with single-channel coils, the use of multichannel MRI coils with a newly developed frame adapter is expected to ensure successful SRS treatments with improved geometrical accuracy and SNR.

Bioaccumulation and in vivo tracking of radiolabeled 4-nonylphenol in mice.

4-Nonylphenol (4NP) is concerning due to its growing presence and endocrine-disrupting nature, raising concerns about its impact on health. In this study 124I-labeled 4NP was synthesized for in vivo tracing. Positron emission tomography imaging and biodistribution studies showed significant accumulation in various tissues after oral or intraperitoneal administration, emphasizing its intricate distribution and potential long-term effects, crucial for future risk assessments.

Ultrasmall cerium oxide nanoparticles as highly sensitive X-ray contrast agents and their antioxidant effect.

Owing to their theranostic properties, cerium oxide (CeO2) nanoparticles have attracted considerable attention for their key applications in nanomedicine. In this study, ultrasmall CeO2 nanoparticles (particle diameter = 1-3 nm) as X-ray contrast agents with an antioxidant effect were investigated for the first time. The nanoparticles were coated with hydrophilic and biocompatible poly(acrylic acid) (PAA) and poly(acrylic acid-co-maleic acid) (PAAMA) to ensure satisfactory colloidal stability in aqueous media and low cellular toxicity. The synthesized nanoparticles were characterized using high-resolution transmission electron microscopy, X-ray diffraction, Fourier transform-infrared spectroscopy, thermogravimetric analysis, dynamic light scattering, cell viability assay, photoluminescence spectroscopy, and X-ray computed tomography (CT). Their potential as X-ray contrast agents was demonstrated by measuring phantom images and in vivo CT images in mice injected intravenously and intraperitoneally. The X-ray attenuation of these nanoparticles was greater than that of the commercial X-ray contrast agent Ultravist and those of larger CeO2 nanoparticles reported previously. In addition, they exhibited an antioxidant effect for the removal of hydrogen peroxide. The results confirmed that the PAA- and PAAMA-coated ultrasmall CeO2 nanoparticles demonstrate potential as highly sensitive radioprotective or theranostic X-ray contrast agents.

Development of an Angiography Guide Indicator for Stereotactic Radiosurgery for High Precision.

BACKGROUND: Stereotactic radiosurgery (SRS) is effectively used for treating various cerebrovascular diseases, including arteriovenous malformations. As image-based surgery is the gold standard technique in SRS, the quality of stereotactic angiography images greatly influences the surgical approach for cerebrovascular diseases. Despite several studies in the relevant literature, research on auxiliary devices, including angiography indicators used for cerebrovascular disease surgeries, is limited. Thus, the development of angiographic indicators may provide meaningful data for stereotactic surgery. METHODS: A centerline was drawn, and a guideline was attached such that the "+" and "X" centers of the existing angiography guide indicator intersect. Further, a guideline wire connecting "+" and "X" was fixed using a tape. Based on the presence or absence of the guide indicator, angiography anterior-posterior (AP) and lateral (LAT) images were taken 10 times each, and statistical analysis was performed. RESULTS: The average and standard deviation of the conventional AP and LAT indicators were 10.22 ± 0.53 mm and 9.02 ± 0.33 mm, and those of the developed AP and LAT indicators were 10.3 ± 0.57 mm and 8.92 ± 0.23 mm, respectively. CONCLUSIONS: The results confirmed that the use of the lead indicator developed in this study provides higher accuracy and precision compared to that of the use of the conventional indicator. Furthermore, the developed guide indicator may provide meaningful information during SRS.

Facile Synthesis and X-ray Attenuation Properties of Ultrasmall Platinum Nanoparticles Grafted with Three Types of Hydrophilic Polymers.

Ultrasmall platinum nanoparticles (Pt-NPs) grafted with three types of hydrophilic and biocompatible polymers, i.e., poly(acrylic acid), poly(acrylic acid-co-maleic acid), and poly(methyl vinyl ether-alt-maleic acid) were synthesized using a one-pot polyol method. Their physicochemical and X-ray attenuation properties were characterized. All polymer-coated Pt-NPs had an average particle diameter (davg) of 2.0 nm. Polymers grafted onto Pt-NP surfaces exhibited excellent colloidal stability (i.e., no precipitation after synthesis for >1.5 years) and low cellular toxicity. The X-ray attenuation power of the polymer-coated Pt-NPs in aqueous media was stronger than that of the commercial iodine contrast agent Ultravist at the same atomic concentration and considerably stronger at the same number density, confirming their potential as computed tomography contrast agents.

Development of an Animal Stereotactic Device for Preclinical Research on Tumor Response After Stereotactic Radiosurgery.

BACKGROUND: In gamma knife radiosurgery, the tumor response to radiation is an important predictor of clinical treatment results. Since brain tumors have different characteristics and growth patterns, depending on the type, the tumors' response to radiation are also different. Compared with various other clinical treatments, there is a dearth of research on the development of gamma knife-magnetic resonance imaging (MRI) preclinical experimental equipment. Hence, the identification of preclinical equipment necessity for experimental animals will provide meaningful data for the provision of clinical assistance to humans. OBJECTIVES: A device for stereotactic radiosurgery capable of MRI in small animals was developed. The feasibility of creating a preplan by means of small animal images was then assessed. METHODS: A device for stereotaxic surgery of small animals using a 48-channel MRI coil was developed using a 3 dimensional printer. Rat brain-MRI images were obtained with a 3.0 T MRI scanner using a multi-channel coil. The acquired MRI images were transferred to a GammaPlan workstation to establish a preplan. RESULTS: To gamma rays to the targeted site on animals, a positioning device combined with a G-frame was mounted on a gamma knife. Planning of radiosurgery based on MRI images became possible with GammaPlan workstations. CONCLUSIONS: Preclinical experiments using small animals are possible with the use of stereotactic devices. In clinical treatment, preclinical experimental results will provide meaningful information.

Development of Brain-Tumor-Targeted Benzothiazole-Based Boron Complex for Boron Neutron Capture Therapy.

Boron neutron capture therapy (BNCT) is a precision treatment technology that ideally damages only boron-accumulating cells. The effectiveness of BNCT depends on the amount of boron in the tumor cells and the concentration ratio between normal and tumor tissues. Therefore, for successful brain-tumor treatment using BNCT, it is essential to develop a drug with high blood-brain barrier (BBB) permeability and high tumor accumulation. The benzothiazole-based boron complex 4-(benzo[d]thiazol-2-yl)phenylboronic acid (BTPB) is a hydrophobic, low-molecular-weight compound that has shown high BBB permeability and brain accumulation. The highest boron concentration of BTPB is 36.11 ± 2.73 µg/g (at 1 h post-injection) in the brain, and the highest brain/blood ratio is 3.94 ± 0.46 (at 2 h post-injection), which is sufficient for the BNCT drug condition. In addition, BTPB showed good tumor-targeting ability in vivo in a U87MG glioma tumor model. In this study, we conducted a biological evaluation of BTPB compared to boronophenylalanine as a novel drug for BNCT.

Effect of Structural Fine-Tuning on Chelate Stability and Liver Uptake of Anionic MRI Contrast Agents.

The purpose of this study is to assess the physicochemical properties and MRI diagnostic efficacy of two newly synthesized 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-type Gd chelates, Gd-SucL and Gd-GluL, with an asymmetric α-substituted pendant arm as potential hepatocyte-specific magnetic resonance imaging contrast agents (MRI CAs). Our findings show that fine conformational changes in the chelating arm affect the in vivo pharmacokinetic behavior of the MRI CA, and that a six-membered chelating substituent of Gd-SucL is more advantageous in this system to avoid unwanted interactions with endogenous species. Gd-SucL exhibited a general DOTA-like chelate stability trend, indicating that all chelating arms retain coordination bonding. Finally, the in vivo diagnostic efficacy of highly stable Gd-SucL as a potential hepatocyte-specific MRI CA was evaluated using T1-weighted MR imaging on an orthotopic hepatocarcinoma model.

Porphyrin-Based Tumor-Targeting Theranostic Agent: Gd-TDAP.

The aim of this work was to evaluate a tumor-targeting porphyrin-based gadolinium complex (Gd-TDAP) for use as an MR/optical imaging agent and potential therapeutic agent. Gd-TDAP had higher longitudinal relaxivity (11.8 mM-1 s-1) than a commercial MRI contrast agent (Omniscan; 3.7 mM-1 s-1) in HSA solution (0.67 mM) at 3 T. The tumor-targeting characteristics were confirmed by T1-weighted MR imaging and optical imaging using an orthotopic brain tumor mouse model, which showed 1.3-fold higher uptake in tumor compared to normal brain tissues. The cell fraction data using U87MG glioblastoma cells indicated the potential for gadolinium neutron capture therapy (Gd-NCT), which requires gadolinium to be inside the cell nucleus. In addition, porphyrin derivatives can be used for photodynamic therapy (PDT), and the results demonstrated that Gd-TDAP has great potential not only as a bimodal imaging agent but also for treatment.

Image-Based Evaluation of Irradiation Effects in Brain Tissues by Measuring Absolute Electrical Conductivity Using MRI.

Radiation-induced injury is damage to normal tissues caused by unintentional exposure to ionizing radiation. Image-based evaluation of tissue damage by irradiation has an advantage for the early assessment of therapeutic effects by providing sensitive information on minute tissue responses in situ. Recent magnetic resonance (MR)-based electrical conductivity imaging has shown potential as an effective early imaging biomarker for treatment response and radiation-induced injury. However, to be a tool for evaluating therapeutic effects, validation of its reliability and sensitivity according to various irradiation conditions is required. We performed MR-based electrical conductivity imaging on designed phantoms to confirm the effect of ionizing radiation at different doses and on in vivo mouse brains to distinguish tissue response depending on different doses and the elapsed time after irradiation. To quantify the irradiation effects, we measured the absolute conductivity of brain tissues and calculated relative conductivity changes based on the value of pre-irradiation. The conductivity of the phantoms with the distilled water and saline solution increased linearly with the irradiation doses. The conductivity of in vivo mouse brains showed different time-course variations and residual contrast depending on the irradiation doses. Future studies will focus on validation at long-term time points, including early and late delayed response and evaluation of irradiation effects in various tissue types.

Highly brain-permeable apoferritin nanocage with high dysprosium loading capacity as a new T2 contrast agent for ultra-high field magnetic resonance imaging.

High sensitivity at ultra-high field (UHF) and sufficient potential to penetrate the brain are the most desirable characteristics in the development of contrast agents (CAs) for magnetic resonance imaging (MRI). However, incorporating such qualities into a single nanocarrier is challenging. Herein, we report a new strategy for a highly brain-permeable MR CA with high sensitivity at UHF by loading dysprosium chelates (DyL) in apoferritin cavities (Apo-DyL). We also design the chelate ligand structure to increase DyL loading capacity within the apoferritin cavity. Using the intracerebroventricular (ICV) injection approach as a new delivery route for Apo-DyL, we demonstrate that apoferritin loaded with DyL can penetrate the brain-ventricular barrier and diffuse into the brain. This brain-permeable capability is unique to Apo-DyL, compared with other types of nanoparticles used in MRI. Apo-DyL also shows significant increase in MR sensitivity of DyL at UHF. Furthermore, based on brain tumor imaging at UHF, Apo-DyL can significantly enhance the tumor for a lower dose of the CA than the previously reported Gd- or Mn-loaded apoferritin nanoplatform. Therefore, Apo-DyL can be a novel nanoplatform that is a highly sensitive and versatile MR CA for UHF brain imaging.