Gadolinium Neutron Capture Therapy Research Articles

DNA-damage RBE assessment for combined boron and gadolinium neutron capture therapy.

Neutron capture therapy (NCT) by 10B and 157Gd agents is a unique irradiation-based method which can be used to treat brain tumors. Current study aims to quantitatively evaluate the relative biological effectiveness (RBE) and dose distributions during the combined BNCT and GdNCT modalities through a hybrid Monte Carlo (MC) simulation approach. Snyder head phantom as well as a cubic hypothetical tumor was at first modeled by Geant4 MC Code. Then, the energy spectra and dose distribution relevant to the released secondary particles during the combined Gd/BNCT were scored for different concentrations of 157Gd and 10B inside tumor volume. Finally, the scored energy spectra were imported to the MCDS code to estimate both RBESSB and RBEDSB values for different 157Gd concentrations. The results showed that combined Gd/BNCT increases the fluence-averaged RBESSB values by about 1.7 times when 157Gd concentration increments from 0 to 2000µg/g for both considered cell oxygen levels (pO2=10% and 100%). Besides, a reduction of about 26% was found for fluence-averaged RBEDSB values with an increment of 157Gd concentration in tumor volume. From the results, it can be concluded that combined Gd/BNCT technique can improve tumor coverage with higher dose levels but in the expense of RBEDSB reduction which can affect the clinical efficacy of the NCT technique.

Assessing DNA damage and relative biological effectiveness of the secondary electrons in gadolinium neutron capture therapy using an adapted Geant4-DNA

The aim of this study is to assess the impact of internal conversion (IC) and Auger electrons released during gadolinium neutron capture therapy (157GdNCT) on the amount of DNA damage induced and the relative biological effectiveness (RBE) across varying cellular structures and types. We developed cell models that featured simplified chromosome geometries with diverse shapes and base pair densities, utilizing the Geant4-DNA package. The RBE values of these secondary electrons were determined based on the DNA double-strand breaks (DNA-DSBs) endpoint. The findings revealed that the more the distribution of gadolinium is concentrated in the nucleus, the greater the degree of DNA damage. In the cytoplasm, the influence of secondary electrons on DNA damage were not related to cell shape. However, when the secondary electrons were distributed in the nuclear membrane, the RBE of the secondary electrons was affected by the cell shape. When there is a greater difference in base pair density, more pronounced discrepancies in the yield of DSBs are evident. As the base pair density decreased, the yield of DSBs increased. Furthermore, the yield of DSBs exceeded 8.63 ± 0.33 DSBs/Gy/Gbp under different influencing factors. The RBE range of IC electrons and Auger electrons released from 157GdNCT based on DNA-DSBs endpoints was found to be between 0.8 and 1.6.

Self-Folding Macromolecular Drug Carrier for Cancer Imaging and Therapy.

Nano-sized contrast agents (NCAs) hold potential for highly specific tumor contrast enhancement during magnetic resonance imaging. Given the quantity of contrast agents loaded into a single nano-carrier and the anticipated relaxation effects, the current molecular design approaches its limits. In this study, a novel molecular mechanism to augment the relaxation of NCAs is introduced and demonstrated. NCA formation is driven by the intramolecular self-folding of a single polymer chain that possesses systematically arranged hydrophilic and hydrophobic segments in water. Utilizing this self-folding molecular design, the relaxivity value can be elevated with minimal loading of gadolinium complexes, enabling sharp tumor imaging. Furthermore, the study reveals that this NCA can selectively accumulate into tumor tissues, offering effective anti-tumor results through gadolinium neutron capture therapy. The efficacy and versatility of this self-folding molecular design underscore its promise for cancer diagnosis and treatment.

Impact of gadolinium concentration and cell oxygen levels on radiobiological characteristics of gadolinium neutron capture therapy technique in brain tumor treatment.

Neutron capture therapy (NCT) with various concentrations of gadolinium (157Gd) is one of the treatment modalities for glioblastoma (GBM) tumors. Current study aims to evaluate how variations of 157Gd concentration and cell oxygen levels can affect the relative biological effectiveness (RBE) of gadolinium neutron capture therapy (GdNCT) technique through a hybrid Monte Carlo (MC) simulation approach. At first, Snyder phantom including a spherical tumor was simulated by Geant4 MC code and relevant energy electron spectra to different 157Gd concentrations including 100, 250, 500, and 1000 ppm were calculated following the neutron irradiation of simulated phantom. Scored energy electron spectra were then imported to Monte Carlo damage simulation (MCDS) code to estimate RBE values (both RBESSB and RBEDSB) at different gadolinium concentrations and oxygen levels from 10 to 100%. The results indicate that variations of 157Gd can affect the energy spectrum of released secondary electrons including Auger electrons. Variation of gadolinium concentration from 100 to 1000 ppm in tumor region can change RBESSB and RBEDSB values by about 0.1% and 0.5%, respectively. Besides, maximum variations of 4.3% and 2% were calculated for RBEDSB and RBESSB when cell oxygen level changed from 10 to 100%. From the results, variations of considered gadolinium and oxygen concentrations during GdNCT can influence RBE values. Nevertheless, due to the not remarkable changes in the intensity of Auger electrons, a slight difference in RBE values would be expected at various 157Gd concentrations, although considerable RBE changes were calculated relevant to the oxygen alternations inside tumor tissue.

Development of a Gadolinium-Boron-Conjugated Albumin for MRI-Guided Neutron Capture Therapy.

Noninvasive monitoring of boron agent biodistribution is required in advance of neutron capture therapy. In this study, we developed a gadolinium-boron-conjugated albumin (Gd-MID-BSA) for MRI-guided neutron capture therapy. Gd-MID-BSA was prepared by labeling bovine serum albumin with a maleimide-functionalized gadolinium complex and a maleimide-functionalized closo-dodecaborate orthogonally. The accumulation of Gd-MID-BSA in tumors in CT26 tumor-bearing mice reached a maximum at 24 h after the injection, as confirmed by T1-based MRI and biodistribution analysis using inductively coupled plasma optical emission spectrometry. The concentrations of boron and gadolinium in the tumors exceeded the thresholds required for boron neutron capture therapy (BNCT) and gadolinium neutron capture therapy (GdNCT), respectively. The boron concentration ratios of tumor to blood and tumor to normal tissues satisfied the clinical criteria, indicating the reduction of undesired nuclear reactions of endogenous nuclei. The molar ratio of boron to gadolinium in the tumor was close to that of Gd-MID-BSA, demonstrating that the accumulation of Gd-MID-BSA in the tumor can be evaluated by MRI. Thermal neutron irradiation with Gd-MID-BSA resulted in significant suppression of tumor growth compared to the group injected with a boron-conjugated albumin without gadolinium (MID-BSA). The neutron irradiation with Gd-MID-BSA did not cause apparent side effects. These results demonstrate that the conjugation of gadolinium and boron within the albumin molecule offers a novel strategy for enhancing the therapeutic effect of BNCT and the potential of MRI-guided neutron capture therapy as a promising treatment for malignant tumors.

Gadolinium Neutron Capture Therapy for Cats and Dogs with Spontaneous Tumors Using Gd-DTPA

We conducted a clinical veterinary study on neutron capture therapy (NCT) at a neutron-producing accelerator with seven incurable pets with spontaneous tumors and gadolinium as a neutron capture agent (gadolinium neutron capture therapy, or GdNCT). Gadolinium-containing dimeglumine gadopentetate, or Gd-DTPA (Magnevist®, 0.6 mL/kg b.w.), was used. We observed mild and reversible toxicity related to the treatment. However, no significant tumor regression in response to the treatment was observed. In most cases, there was continued tumor growth. Overall clinical improvement after treatment was only temporary. The use of Gd-DTPA for NCT had no significant effects on the life expectancy and quality of life of animals with spontaneous tumors. Further experiments using more advanced gadolinium compounds are needed to improve the effect of GdNCT so that it can become an alternative to boron neutron capture therapy. Such studies are also necessary for further NCT implementation in clinical practice as well as in veterinary medicine.

Stem cell–nanomedicine system as a theranostic bio-gadolinium agent for targeted neutron capture cancer therapy

The potential clinical application of gadolinium-neutron capture therapy (Gd-NCT) for glioblastoma multiforme (GBM) treatment has been compromised by the fast clearance and nonspecific biodistribution of gadolinium-based agents. We have developed a stem cell–nanoparticle system (SNS) to actively target GBM for advanced Gd-NCT by magnetizing umbilical cord mesenchymal stem cells (UMSCs) using gadodiamide-concealed magnetic nanoparticles (Gd-FPFNP). Nanoformulated gadodiamide shielded by a dense surface composed of fucoidan and polyvinyl alcohol demonstrates enhanced cellular association and biocompatibility in UMSCs. The SNS preserves the ability of UMSCs to actively penetrate the blood brain barrier and home to GBM and, when magnetically navigates by an external magnetic field, an 8-fold increase in tumor-to-blood ratio is achieved compared with clinical data. In an orthotopic GBM-bearing rat model, using a single dose of irradiation and an ultra-low gadolinium dose (200 μg kg−1), SNS significantly attenuates GBM progression without inducing safety issues, prolonging median survival 2.5-fold compared to free gadodiamide. The SNS is a cell-based delivery system that integrates the strengths of cell therapy and nanotechnology, which provides an alternative strategy for the treatment of brain diseases.

In vivo evaluation of the effects of combined boron and gadolinium neutron capture therapy in mouse models

While boron neutron capture therapy (BNCT) depends primarily on the short flight range of the alpha particles emitted by the boron neutron capture reaction, gadolinium neutron capture therapy (GdNCT) mainly relies on gamma rays and Auger electrons released by the gadolinium neutron capture reaction. BNCT and GdNCT can be complementary in tumor therapy. Here, we studied the combined effects of BNCT and GdNCT when boron and gadolinium compounds were co-injected, followed by thermal neutron irradiation, and compared these effects with those of the single therapies. In cytotoxicity studies, some additive effects (32‒43%) were observed when CT26 cells were treated with both boron- and gadolinium-encapsulated PEGylated liposomes (B- and Gd-liposomes) compared to the single treatments. The tumor-suppressive effect was greater when BNCT was followed by GdNCT at an interval of 10 days rather than vice versa. However, tumor suppression with co-injection of B- and Gd-liposomes into tumor-bearing mice followed by neutron beam irradiation was comparable to that observed with Gd-liposome-only treatment but lower than B-liposome-only injection. No additive effect was observed with the combination of BNCT and GdNCT, which could be due to the shielding effect of gadolinium against thermal neutrons because of its overwhelmingly large thermal neutron cross section.

Gadolinium Neutron Capture Therapy (GdNCT) Agents from Molecular to Nano: Current Status and Perspectives.

157Gd (natural abundance = 15.7%) has the highest thermal neutron capture cross section (σ) of 254,000 barns (1 barn = 10–28 m2) among stable (nonradioactive) isotopes in the periodic table. Another stable isotope, 155Gd (natural abundance = 14.8%), also has a high σ value of 60,700 barns. These σ values are higher than that of 10B (3840 barns, natural abundance = 19.9%), which is currently used as a neutron-absorbing isotope for boron neutron capture therapy agents. Energetic particles such as electrons and γ-rays emitted from Gd-isotopes after neutron beam absorption kill cancer cells by damaging DNAs inside cancer-cell nuclei without damaging normal cells if Gd-chemicals are positioned in cancer cells. To date, various Gd-chemicals such as commercial Gd-chelates used as magnetic resonance imaging contrast agents, modified Gd-chelates, nanocomposites containing Gd-chelates, fullerenes containing Gd, and solid-state Gd-nanoparticles have been investigated as gadolinium neutron capture therapy (GdNCT) agents. All GdNCT agents had exhibited cancer-cell killing effects, and the degree of the effects depended on the GdNCT agents used. This confirms that GdNCT is a promising cancer therapeutic technique. However, the commercial Gd-chelates were observed to be inadequate in clinical use because of their low accumulation in cancer cells due to their extracellular and noncancer targeting properties and rapid excretion. The other GdNCT agents exhibited higher accumulation in cancer cells, compared to Gd-chelates; consequently, they demonstrated higher cancer-cell killing effects. However, they still displayed limitations such as poor specificity to cancer cells. Therefore, continuous efforts should be made to synthesize GdNCT agents suitable in clinical applications. Herein, the principle of GdNCT, current status of GdNCT agents, and general design strategy for GdNCT agents in clinical use are discussed and reviewed.

Studying the Accumulation of Gadolinium in Human Brain Glioma for Gadolinium-Neutron Capture Therapy

Studying the Accumulation of Gadolinium in Human Brain Glioma for Gadolinium-Neutron Capture Therapy

Gadolinium delivery agents for neutron capture therapy

<p indent=0mm>Neutron capture therapy (NCT) is a binary form of radiation therapy that combines neutron irradiation with a tumor targeting agent labeled with a stable isotope having a high thermal neutron capture cross section and yielding charged particle reaction products after neutron capture. At present, NCT has largely, but not exclusively, focused on the use of boron-10 as the target nuclide. Gadolinium neutron capture therapy (Gd-NCT) is an alternative and supplementary method of boron neutron capture therapy (BNCT). Gd-157, which has the largest cross-section (254000 barn) of thermal neutrons of all stable isotopes, is the most effective isotope in terms of neutron capture. The Gd neutron capture reaction, ¹⁵⁷Gd(n, γ)¹⁵⁸Gd, provokes complicated nuclear decay transitions that generate low linear energy transfer (LET) gamma photons and the emission of high LET conversion electrons and Auger electrons. Therefore, Gd is considered to be highly suitable for the absorption of thermal neutrons in the NCT reaction. Another advantage of Gd-NCT is Gd³⁺ has a longer retention time and can thus be tracked by means of magnetic resonance imaging (MRI) methods. Currently, Gd(III) based MRI contrast agents are most commonly used in clinical practice. However, due to lack of appropriate tumor-selective Gd agents, the Gd-NCT concept has not yet been clinically tested. For a successful neutron capture therapy, a target nuclide delivery system with high therapeutic efficiency and low adverse effects is crucial. Three major classes Gd delivery agents have been developed so far, small molecule chelates of Gd, nano- delivery agents, and Gd-B dual delivery agents. In the first trial of Gd-NCT, commercially available MRI contrast agents composed of Gd-chelating compounds were used as Gd delivery agents. However, due to the insufficient number of tumor cell nuclei incorporating Gd, efficacy of small molecule chelates of Gd as Gd-NCT delivery agents is generally low. In recent years, with the rapid development of nanotechnology, nanomaterials have been widely employed as carriers for cancer theranostics. A variety of Gd-based nanomaterials have been developed for pre-clinical trials of NCT. Majority of them are constructed by incorporating commercially available MRI contrast agents in biocompatible nanomaterials (liposomes, albumin, and micelles), or employing Gd based nanoparticles with their unique physiochemical properties. While nano-Gd delivery agents have proved to be a promising strategy in Gd-NCT, it is also possible to integrate of both Gd and B in one delivery agent. The design of many Gd-NCT agents to date has focused on combined BNCT and Gd-NCT agents in order to maximise cytotoxicity from the combined effects or to use the B component for NCT and the Gd component as a MRI imaging agent. This paper highlights the recent advances in Gd selective and efficient delivery methods and the preclinical outcome of Gd-NCT, both advantages and disadvantages of various Gd delivery agents were addressed. Finally, we offered our perspectives on the challenges and future development of Gd delivery agents for Gd-NCT.

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.

In vivo evaluation of PEGylated-liposome encapsulating gadolinium complexes for gadolinium neutron capture therapy

Gadolinium neutron capture therapy (GdNCT) is a form of binary radiotherapy. It utilizes nuclear reactions that occur when gadolinium-157 is irradiated with thermal neutrons, producing high-energy γ-rays and Auger electrons. Herein, we evaluate the potential of GdNCT for cancer treatment using PEGylated liposome incorporated with an FDA-approved MRI contrast agent. The clinical gadolinium complex (Gadovist®) was successfully encapsulated inside the aqueous core of PEGylated liposomes by repeated freeze and thaw cycling. At a concentration of 152 μM Gd, the Gd-liposome showed high cytotoxicity upon thermal-neutron irradiation. In animal experiments, when a CT26 tumor model was administered with Gd-liposomes (19 mg 157Gd per kg) followed by 20-min irradiation of thermal neutron at a flux of 1.94 × 104 cm−2 s−1, tumor growth was suppressed by 43%, compared to that in the control group, on the 23rd day of post-irradiation. After two-cycle GdNCT treatment at a 10-day interval, tumor growth was more efficiently retarded. On the 31st day after irradiation, the weight of the excised tumor in the GdNCT group (38 mg 157Gd per kg per injection) was only 30% of that of the control group. These results demonstrate the potential of GdNCT using PEGylated liposomes containing MRI contrast agents in cancer treatment.

Radiobiological impact of gadolinium neutron capture from proton therapy and alternative neutron sources using TOPAS-nBio.

A multi-scale investigation of the biological properties of gadolinium neutron capture (GdNC) therapy with applications in particle therapy is conducted using the TOPAS Monte Carlo (MC) simulation code. The simulation results are used to quantify the amount of gadolinium dose enhancement produced as a result of the secondary neutron production from proton therapy scaled by measured data. MC modeling was performed using the radiobiology extension TOol for PArticle Simulation TOPAS-nBio MC simulation code to study the radiobiological effects produced from GdNC on a segment of DNA, a spherical cellular model, and from the modeling of previous experimental measurements. The average RBE values were calculated from two methods, microdosimetric kinematic (MK) and biological weighting r(y) within a 2nm DNA segment for GdNC. The single-strand breaks (SSBs) and double-strand breaks (DSBs) were calculated from within the nucleus of a 20µm diameter, spherical cell model. From a previous experimental proton therapy measurement using a spread-out Bragg peak (SOBP) of 4.5-9.5cm and a delivered absorbed dose of 10.4Gy, the amount of Gd neutron captures was calculated and used to quantify the amount of GdNC absolute dose from particle therapy. The average RBE from microdosimetric kinematic and biological weighting was 1.35, and 1.70 for a 10% cell survival on HSG cell-line and weighting function data from early intestinal tolerance of mice. From a central isotropic GdNC source, the energy deposition is found to decrease from roughly 2.7eV per capture down to approximately 0.01eV per capture, a drop of two orders of magnitude within 50nm. This result suggests that Gd needs to be close to the DNA (within 10-20nm) in order for neutron capture to induce a significant dose enhancement due to the short-range electrons emitted after Gd neutron capture. Within a spherical cell model, the SSBs, and DSBs were determined to be 39 and 1.5 per neutron capture, respectively. From the total neutron captures produced from an experimental proton therapy measurement on a 3000 PPM Gd solution, an insignificant absolute Gd dose enhancement was quantified to be 5.4×10-6 Gy per Gy of administered proton dose. From this study and literature review, the production of secondary thermal neutrons from proton therapy is determined to be a limiting factor and unlikely to produce a clinically useful dose enhancement for secondary neutron capture therapy. Moreover, alternative neutron sources, such as, a compact deuterium-tritium (D-T) neutron generator, a "high yield" deuterium-deuterium (D-D) generator, or an industrial strength (100mg) 252 Cf source were investigated, with the 252 Cf source the most likely to be capable of producing enough neutrons for 1Gy of localized GdNC absolute dose within a reasonable treatment time.

Experimental Proof of Gadolinium Neutron Capture Therapy Antitumor Efficacy

Neutron capture therapy (NCT) is a promising method of curing cancer, which uses stable isotopes with large thermal neutron capture cross section value (a) to provide selective damage of a tumor. Boron isotope 10 B (a = 3880 barn) is the most know and most widely used in NCT isotope. Gadolinium isotope 157Gd has even larger thermal neutron capture cross section value ( σ = 254 000 barn) than 10 B, but secondary radiation emitted by this isotope as the results of neutron capture nuclear reaction is absorbed by tumor tissues less effectively than for 10 B. The purpose of this research was to study gadolinium neutron capture therapy efficacy in curing spontaneous tumors. 13 dogs diagnosed with oral cavity spontaneous melanoma were studied. MRI contrast drug Dipentast® was used as a gadolinium containing substance. The drug was injected directly into the tumor immediately before neutron irradiation. The administered dose of the drug was 10 mg of gadolinium per 1 cm 3 of tumor. The irradiation was made with thermal neutron beam with neutron flux 7x10 8 n/cm 2 s and 3-6 cm diameter. The duration of irradiation was 70 minutes. As the results of the therapy complete tumor regression was achieved in 46 % of animals. Recurrence free period was 106.0±7.5 days for 66.7 % of dogs with complete tumor regression and more than 150 days for 16.7 %.

Enhanced MRI‐Guided Gadolinium (III) Neutron Capture Therapy by Polymeric Nanocarriers Promoting Tumor Accumulation and Intracellular Delivery

AbstractGadolinium(III) (Gd(III)) chelates are promising compounds for developing MRI‐guided neutron capture therapies (NCT). However, despite their success as MRI contrast agents (CAs), current Gd(III) chelates do not present appropriate accumulation in tumors for effective NCT. To overcome this limitation, we developed a series of biocompatible polymeric nanocarriers conjugating Gd(III)‐chelates, i. e. Gd‐DOTA, as NCT agents with high MRI sensitivity and tumor delivery. These polymers were based on poly(aspartic acid) (P(Asp)) and were modified with poly(ethylene glycol) (PEG) chains having different molecular weight (Mw) for controlling stability and pharmacokinetics. The T1 relaxivity of the Gd‐DOTA conjugated polymers increased 2‐fold compared to that of clinically used Gd(III) CAs. In vivo, the PEG‐modified polymers promoted the accumulation in tumor tissues, enhancing the MRI contrast of tumors. After neutron irradiation, the nanocarriers effectively suppressed the tumor growth, particularly the PEG‐P(Asp‐Gd‐DOTA) with shorter PEG chain, which promoted higher intracellular delivery, supporting their potential as NCT agents.

Dose Analysis of Gadolinium Neutron Capture Therapy (GdNCT) on Cancer Using SHIELD-HIT12A

This research aimed to determine the dose of radiation received in cancer therapy for each decay of Gadolinium atomic nuclei with isotope 157 (157Gd) in Gadolinium Neutron Capture Therapy using the SHIELD-HIT12A program. Knowing the amount of dose given to cancer tissue should aid in minimizing the damage that could occur in the healthy tissue around the cancer tissue, effectively killing only the cancer cells. The simulation employed in this research used the SHIELD-HIT12A program by providing input on beam.dat, mat.dat, detect.dat, and geo.dat files. The output data from the program comprised the value of recoil energy lost (energy absorbed into the target materials) for each of the 157Gd atomic nuclei, which was then processed by the dose determination equation to determine the dose given by the 157Gd nucleus to soft tissue. Based on the results, the amount of the dose given by each atomic nucleus 157Gd to soft tissue was 5.44 × 1011 Gy/decay.

Image-Guided Neutron Capture Therapy Using the Gd-DO3A-BTA Complex as a New Combinatorial Treatment Approach.

Gadolinium-neutron capture therapy (Gd-NCT) is based on the nuclear capture reaction that occurs when 157Gd is irradiated with low energy thermal neutrons to primarily produce gamma photons. Herein, we investigated the effect of neutron capture therapy (NCT) using a small molecular gadolinium complex, Gd-DO3A-benzothiazole (Gd-DO3A-BTA), which could be a good candidate for use as an NCT drug due to its ability to enter the intracellular nuclei of tumor cells. Furthermore, MRI images of Gd-DO3A-BTA showed a clear signal enhancement in the tumor, and the images also played a key role in planning NCT by providing accurate information on the in vivo uptake time and duration of Gd-DO3A-BTA. We injected Gd-DO3A-BTA into MDA-MB-231 breast tumor-bearing mice and irradiated the tumors with cyclotron neutrons at the maximum accumulation time (postinjection 6 h); then, we observed the size of the growing tumor for 60 days. Gd-DO3A-BTA showed good therapeutic effects of chemo-Gd-NCT for the in vivo tumor models. Simultaneously, the Gd-DO3A-BTA groups ([Gd-DO3A-BTA(+), NCT(+)]) showed a significant reduction in tumor size (p < 0.05), and the inhibitory effect on tumor growth was exhibited in the following order: [Gd-DO3A-BTA(+), NCT(+)] > [Gd-DO3A-BTA(+), NCT(−)] > [Gd-DO3A-BTA(−), NCT(+)] > [Gd-DO3A-BTA(−), NCT(−)]. On day 60, the [Gd-DO3A-BTA(+), NCT(+)] and [Gd-DO3A-BTA(−), NCT(−)] groups exhibited an approximately 4.5-fold difference in tumor size. Immunohistochemistry studies demonstrated that new combinational therapy with chemo-Gd-NCT could treat breast cancer by both the inhibition of tumor cell proliferation and induction of apoptosis-related proteins, with in vivo tumor monitoring by MRI.

Cyclic RGD‐Coated Ultrasmall Gd2O3 Nanoparticles as Tumor‐Targeting Positive Magnetic Resonance Imaging Contrast Agents

The excellent theranostic properties of gadolinium oxide (Gd2O3) nanoparticles (GNPs) make them very useful as high‐performance positive magnetic resonance imaging (T1 MRI) contrast agents, X‐ray computed tomography (CT) contrast agents, and gadolinium neutron capture therapy (GdNCT) agents in tumor targeting. Among these applications, tumor‐targeting T1 MRI is investigated in this study. To this end, we employ cyclic RGDs (cRGDs; cyclic Arg–Gly–Asp peptides) as tumor‐targeting ligands to coat ultrasmall GNPs (particle diameter = 1.0–2.5 nm). Five types of commercial cRGDs are used in the coating. The cRGD‐coated GNPs (cRGD‐GNPs) are prepared through one‐pot syntheses. They exhibit longitudinal water‐proton relaxivity (r1) values of 10.0–18.7 s–1 mm–1, with r2/r1 ratios of 1.4–1.7 (r2 = transverse water‐proton relaxivity), which are 3–5 times higher than those of commercial Gd chelates. The in vivo tumor targeting of the cRGD‐GNPs is demonstrated by taking T1 MR images in a model mouse with a liver tumor using one of the five cRGD‐GNP sample solutions prepared. Approximately threefold contrast enhancements are observed in the T1 MR images in the tumor region of the liver than in the normal part of the liver, following intravenous administration of the solution. These results demonstrate that cRGD‐GNPs are potential tumor‐targeting T1 MRI contrast agents.

Magnetic resonance imaging, gadolinium neutron capture therapy, and tumor cell detection using ultrasmall Gd2O3 nanoparticles coated with polyacrylic acid-rhodamine B as a multifunctional tumor theragnostic agent

Monodisperse and ultrasmall gadolinium oxide (Gd2O3) nanoparticle colloids (davg = 1.5 nm) (nanoparticle colloid = nanoparticle coated with hydrophilic ligand) were synthesized and their performance as a multifunctional tumor theragnostic agent was investigated. The aqueous ultrasmall nanoparticle colloidal suspension was stable and non-toxic owing to hydrophilic polyacrylic acid (PAA) coating that was partly conjugated with rhodamine B (Rho) for an additional functionalization (mole ratio of PAA : Rho = 5 : 1). First, the ultrasmall nanoparticle colloids performed well as a powerful T1 magnetic resonance imaging (MRI) contrast agent: they exhibited a very high longitudinal water proton relaxivity (r1) of 22.6 s−1 mM−1 (r2/r1 = 1.3, r2 = transverse water proton relaxivity), which was ∼6 times higher than those of commercial Gd-chelates, and high positive contrast enhancements in T1 MR images in a nude mouse after intravenous administration. Second, the ultrasmall nanoparticle colloids were applied to gadolinium neutron capture therapy (GdNCT) in vitro and exhibited a significant U87MG tumor cell death (28.1% net value) after thermal neutron beam irradiation, which was 1.75 times higher than that obtained using commercial Gadovist. Third, the ultrasmall nanoparticle colloids exhibited stronger fluorescent intensities in tumor cells than in normal cells owing to conjugated Rho, proving their pH-sensitive fluorescent tumor cell detection ability. All these results together demonstrate that ultrasmall Gd2O3 nanoparticle colloids are the potential multifunctional tumor theragnostic agent.