Gadolinium-based Nanoparticles Research Articles

NANO-GBM trial of AGuIX nanoparticles with radiotherapy and temozolomide in the treatment of newly diagnosed Glioblastoma: Phase 1b outcomes and MRI-based biodistribution

BackgroundIn glioblastoma (GBM), tumor progression occurs mainly within the irradiated tumor volume. To address this challenge, a radiosensitization strategy with intravenous gadolinium-based theranostic nanoparticles (AGuIX) is being explored in the NANO-GBM phase1b/2R trial (NCT04881032). Here, we present the results of the phase 1b part, which is the first-in-human use of these nanoparticles with radiotherapy and chemotherapy for the treatment of newly diagnosed GBM. Material and MethodsEligible patients were aged 18 to 75 years with newly diagnosed and histologically confirmed GBM, with incomplete resection (biopsy or partial surgery). The phase 1b part was a dose escalation approach (Time-to-event Continuous Reassessment Method) with three dose levels: 50, 75, and 100 mg/kg. Patients were treated with RT (60 Gy), and concomitant and adjuvant TMZ, and 4 injections of AGuIX (D-3/-7, D1, D8, and D15). Dose-limiting-toxicity (DLT) was defined as any grade 3–4 adverse event (CTCAE v5.0), excluding alopecia, nausea, and rapidly controlled vomiting. Pharmacokinetic (PK), and biodistribution based on MRI were evaluated. ResultsBetween March 2022 and March 2023, eight patients were enrolled: 1 at 50 mg/kg, 1 at 75 mg/kg, and 6 at 100 mg/kg. All patients received the four AGuIX injections. Only one patient experienced a DLT (at 100 mg/kg): a grade 3 lymphopenia (related to TMZ). The RP2D of AGuIX was determined as 100 mg/kg. AGuIX mean AUC increased with dose. Regions of GBM with moderate (36–123 µM), and high (123–291 µM) or very high (>291 µM) AGuIX concentrations accounted in average for 38.7 and 26.8 %, respectively. ConclusionThese results confirm the lack of AGuIX-related toxicity and the widespread dispersion of nanoparticles throughout GBM. This supports progression to the randomized phase 2 part, utilizing an RP2D of AGuIX of 100 mg/kg (4 injections).

Theragnostic Gadolinium-Based Nanoparticles Safely Augment X-ray Radiation Effects in Patients with Cervical Cancer.

Activated guided irradiation by X-ray (AGuIX) nanoparticles are gadolinium-based agents that have the dual benefit of mimicking the effects of a magnetic resonance imaging (MRI) contrast agent used in a clinical routine and enhancing the radiotherapeutic activity of conventional X-rays (for cancer treatment). This "theragnostic" action is explained on the one hand by the paramagnetic properties of gadolinium and on the other hand by the generation of high densities of secondary radiation following the interaction of ionizing radiation and high-Z atoms, which leads to enhanced radiation dose deposits within the tumors where the nanoparticles accumulate. Here, we report the results of a phase I trial that aimed to assess the safety and determine the optimal dose of AGuIX nanoparticles in combination with chemoradiation and brachytherapy in patients with locally advanced cervical cancer. AGuIX nanoparticles were administered intravenously and appropriately accumulated within tumors on a dose-dependent manner, as assessed by T1-weighted MRI, with a rapid urinary clearance of uncaught nanoparticles. We show that the observed tumor accumulation of the compounds can support precise delineation of functional target volumes at the time of brachytherapy based on gadolinium enhancement. AGuIX nanoparticles combined with chemoradiation appeared well tolerated among the 12 patients treated, with no dose-limiting toxicity observed. Treatment yielded excellent local control, with all patients achieving complete remission of the primary tumor. One patient had a distant tumor recurrence. These results demonstrate the clinical feasibility of using theranostic nanoparticles to augment the accuracy of MRI-based treatments while focally enhancing the radiation activity in tumors.

Amorphous Albumin Gadolinium-Based Nanoparticles for Ultrahigh-Resolution Magnetic Resonance Angiography.

Magnetic resonance angiography (MRA) contrast agents are extensively utilized in clinical practice due to their capability of improving the image resolution and sensitivity. However, the clinically approved MRA contrast agents have the disadvantages of a limited acquisition time window and high dose administration for effective imaging. Herein, albumin-coated gadolinium-based nanoparticles (BSA-Gd) were meticulously developed for in vivo ultrahigh-resolution MRA. Compared to Gd-DTPA, BSA-Gd exhibits a significantly higher longitudinal relaxivity (r1 = 76.7 mM-1 s-1), nearly 16-fold greater than that of Gd-DTPA, and an extended blood circulation time (t1/2 = 40 min), enabling a dramatically enhanced high-resolution imaging of microvessels (sub-200 μm) and low dose imaging (about 1/16 that of Gd-DTPA). Furthermore, the clinically significant fine vessels were successfully mapped in large mammals, including a circle of Willis, kidney and liver vascular branches, tumor vessels, and differentiated arteries from veins using dynamic contrast-enhanced MRA BSA-Gd, and have superior imaging capability and biocompatibility, and their clinical applications hold substantial promise.

Effect of gamma irradiation on the size of cellulose nanocrystals with polyethylene glycol and sodium hydroxide/Gd2O3 nanocomposite as contrast agent in magnetic resonance imaging (MRI)

The attractive properties of gadolinium-based nanoparticles as a positive contrast agent for magnetic resonance imaging (MRI) have piqued the interest of both researchers and clinicians. Nonetheless, due to the biotoxicity of gadolinium (III) ions' free radicals, there is a need to address this issue. Therefore, this research aimed to develop a biocompatible, dispersible, stable, hydrophilic, and less toxic cellulose nanocrystals/gadolinium oxide nanocomposite as contrast agent properties for MRI purposes. This study aimed to synthesize gadolinium oxide nanoparticles coated with cellulose nanocrystals with polyethylene glycol and sodium hydroxide (CNCs-PEG/NaOH)/Gd2O3 using the gamma irradiation method to reduce the particle size. The results showed that using a gamma irradiation dose of 10 kGy, quasi-spherical morphology with a size of approximately 5.5 ± 0.65 nm could be produced. Furthermore, the cytocompatibility of (CNCs-PEG/NaOH)/Gd2O3 nanocomposite synthesized was assessed through MTT assay tests on Hep G2 cells, which demonstrated good cytocompatibility without any cytotoxic effects within a concentration range of (10 μg/mL −150 μg/mL) and had sufficient cellular uptake. Moreover, the T1-weighted MRI of (CNCs-PEG/NaOH)/Gd2O3 nanocomposite revealed promising results as a positive contrast agent. It is envisaged that the gamma irradiation method is promising in synthesizing (CNCs-PEG/NaOH)/Gd2O3 nanocomposite with nanoscale for different applications, especially in the radiotherapy field.

Potential of Gd-based nanocomposites (GdFeO3) as photocatalysts for the degradation of organic pollutants: a review

Abstract Gadolinium-based photocatalysts have gained interest in the past few years for their exceptional qualities and are currently being explored as potential photocatalysts for the degradation of organic pollutants and environment restoration. This review paper presents an in-depth examination of the photo-catalytic capabilities of Gadolinium-based nanoparticles (Gd-NPs) and their wide range of applications in the treatment of wastewater and other pollutants. The production processes, optimization variables, modifying procedures, diverse applications, and anti-stokes-up transformation features of Gd-NPs (GdFeO3) have been discussed. Furthermore, it also intends to better understand the redox properties, charge transport, bandgap tenability, blemish management and harmful effects of Gd photocatalysts. The disadvantages of Gadolinium-based small particles remained reviewed and addressed with modified approaches. These findings of literature suggest that Gd-NPs, nano-composite material/heterojunctions, or upconversion nanomaterials are being intensively reported in literature as photocatalytic materials. As a whole, this study offers light on current breakthroughs in Gd-based nanomaterials in regard to their uses in pollution elimination, and to control over environmental pollution and toxicity.

Gadolinium-Based Nanoparticles Sensitize Ovarian Peritoneal Carcinomatosis to Targeted Radionuclide Therapy.

Ovarian cancer (OC) is the most lethal gynecologic malignancy (5-y overall survival rate, 46%). OC is generally detected when it has already spread to the peritoneal cavity (peritoneal carcinomatosis). This study investigated whether gadolinium-based nanoparticles (Gd-NPs) increase the efficacy of targeted radionuclide therapy using [177Lu]Lu-DOTA-trastuzumab (an antibody against human epidermal growth factor receptor 2). Gd-NPs have radiosensitizing effects in conventional external-beam radiotherapy and have been tested in clinical phase II trials. Methods: First, the optimal activity of [177Lu]Lu-DOTA-trastuzumab (10, 5, or 2.5 MBq) combined or not with 10 mg of Gd-NPs (single injection) was investigated in athymic mice bearing intraperitoneal OC cell (human epidermal growth factor receptor 2-positive) tumor xenografts. Next, the therapeutic efficacy and toxicity of 5 MBq of [177Lu]Lu-DOTA-trastuzumab with Gd-NPs (3 administration regimens) were evaluated. NaCl, trastuzumab plus Gd-NPs, and [177Lu]Lu-DOTA-trastuzumab alone were used as controls. Biodistribution and dosimetry were determined, and Monte Carlo simulation of energy deposits was performed. Lastly, Gd-NPs' subcellular localization and uptake, and the cytotoxic effects of the combination, were investigated in 3 cancer cell lines to obtain insights into the involved mechanisms. Results: The optimal [177Lu]Lu-DOTA-trastuzumab activity when combined with Gd-NPs was 5 MBq. Moreover, compared with [177Lu]Lu-DOTA-trastuzumab alone, the strongest therapeutic efficacy (tumor mass reduction) was obtained with 2 injections of 5 mg of Gd-NPs/d (separated by 6 h) at 24 and 72 h after injection of 5 MBq of [177Lu]Lu-DOTA-trastuzumab. In vitro experiments showed that Gd-NPs colocalized with lysosomes and that their radiosensitizing effect was mediated by oxidative stress and inhibited by deferiprone, an iron chelator. Exposure of Gd-NPs to 177Lu increased the Auger electron yield but not the absorbed dose. Conclusion: Targeted radionuclide therapy can be combined with Gd-NPs to increase the therapeutic effect and reduce the injected activities. As Gd-NPs are already used in the clinic, this combination could be a new therapeutic approach for patients with ovarian peritoneal carcinomatosis.

Evaluation of physicochemical and biocompatibility characteristics of gadolinium oxide nanoparticles as magnetic resonance imaging contrast agents

The attractive properties of gadolinium-based nanoparticles as a positive contrast agent for magnetic resonance imaging (MRI) have piqued the interest of both researchers and clinicians. Nonetheless, due to the biotoxicity of gadolinium (III) ions' free radicals, there is a need to address this issue. Therefore, this research aimed to develop and evaluate of physicochemical and biocompatibility characteristics of gadolinium oxide nanoparticles (Gd2O3-NPs) as MRI contrast agents. Whereby, the Gd2O3-NPs were synthesized via sol-gel method at various annealing temperatures of (500 °C−1100 °C). The results showed that the Gd2O3-NPs annealed at a temperature of 1000 °C exhibited prominent physicochemical properties in comparison to other annealing temperatures such as high saturation magnetization, colloidal stability with a highly positive surface charge, high crystallinity percentage, high weight percentage of gadolinium Gd and small energy band gap of 4 eV. Moreover, during the heating process, the complete decomposition of gadolinium hydroxide (Gd(OH)3) resulted in a significant increase in signal intensity in T1-weighted MRI images. The enhanced signal intensity in MRI is caused by structural changes in tissues or the contrast agent, which affect their interaction with the magnetic field, leading to the increased signal due to molecular conformation, aggregation, and mobility influencing T1 relaxation properties. Furthermore, the biocompatibility of Gd2O3-NPs synthesized at 1000 °C was assessed through MTT assay tests on Hep G2 cells, which demonstrated good biocompatibility without any cytotoxic effects. The sol-gel technique shows promise in synthesizing Gd2O3-NPs with remarkable properties for various applications, including MRI contrast agents, by controlling annealing temperature.

Biological modeling of gadolinium-based nanoparticles radio-enhancement for kilovoltage photons: a Monte Carlo study

BackgroundGadolinium-based nanoparticles (GdNPs) are clinically used agents to increase the radiosensitivity of tumor cells. However, studies on the mechanisms and biological modeling of GdNP radio-enhancement are still preliminary. This study aims to investigate the mechanism of radio-enhancement of GdNPs for kilovoltage photons using Monte Carlo (MC) simulations, and to establish local effect model (LEM)-based biological model of GdNP radiosensitization.MethodsThe spectrum and yield of secondary electrons and dose enhancement around a single GdNP and clustered GdNPs were calculated in a water cube phantom by MC track-structure simulations using TOPAS code. We constructed a partial shell-like cell geometry model of pancreatic cancer cell based on transmission electron microscope (TEM) observations. LEM-based biological modeling of GdNP radiosensitization was established based on the MC-calculated nano-scale dose distributions in the cell model to predict the cell surviving fractions after irradiation.ResultsThe yield of secondary electrons for GdNP was 0.16% of the yield for gold nanoparticle (GNP), whereas the average electron energy was 12% higher. The majority of the dose enhancement came from the contribution of Auger electrons. GdNP clusters had a larger range and extent of dose enhancement than single GdNPs, although GdNP clustering reduced radial dose per interacting photon significantly. For the dose range between 0 and 8 Gy, the surviving fraction predicted using LEM-based biological model laid within one standard deviation of the published experimental results, and the deviations between them were all within 25%.ConclusionsThe mechanism of radio-enhancement of GdNPs for kilovoltage photons was investigated using MC simulations. The prediction results of the established LEM-based biological model for GdNP radiosensitization showed good agreement with published experimental results, although the deviation of simulation parameters can lead to large disparity in the results. To our knowledge, this was the first LEM-based biological model for GdNP radiosensitization.

Gadolinium-Bisphosphonate Nanoparticle-Based Low-Dose Radioimmunotherapy for Osteosarcoma.

Osteosarcoma is a malignant osteogenic tumor with a high metastatic rate commonly occurring in adolescents. Although radiotherapy is applied to treat unresectable osteosarcoma with radiation resistance, a high dose of radiotherapy is required, which may weaken the immune microenvironment. Therefore, there is an urgent need to develop novel agents to maximize the radiotherapeutic effects by eliciting immune activation effects. In this study, we synthesized therapeutic gadolinium-based metal-bisphosphonate nanoparticles (NPs) for osteosarcoma treatment that can be combined with radiotherapy. The gadolinium ion (Gd) was chelated with zoledronic acid (Zol), a commonly used drug to prevent/treat osteoporosis or bone metastases from advanced cancers, and stabilized by ovalbumin (OVA) to produce OVA-GdZol NPs. OVA-GdZol NPs were internalized into K7M2 osteosarcoma cells, showing a high sensitization effect under X-ray irradiation. Cell pretreatment of OVA-GdZol NPs significantly enhanced the radiation therapeutic effect in vitro by reducing the cell colonies and increased the signal of γH2AX-positive cells. More importantly, OVA-GdZol NPs promoted the maturation of bone marrow-derived dendritic cells (BMDCs) and M1 polarization of macrophages. The inhibitory effect on K7M2 osteosarcoma of OVA-GdZol NPs and X-ray radiation was evident, indicated by a significantly reduced tumor volume, high survival rate, and decreased lung metastasis. Meanwhile, both innate and adaptive immune systems were activated to exert a strong antitumor effect. The above results highly suggest that OVA-GdZol NPs serve as both radiosensitizers and immune adjuvants, suitable for the sequential combination of vaccination and radiotherapy.

Gadolinium-based ultra-small nanoparticles augment radiotherapy-induced T-cell response to synergize with checkpoint blockade immunotherapy.

Radiotherapy suffers from its high-dose radiation-induced systemic toxicity and radioresistance caused by the immunosuppressive tumor microenvironment. Immunotherapy using checkpoint blocking in solid tumors shows limited anticancer efficacy due to insufficient T-cell infiltration and inadequate systemic immune responses. Activation and guiding of irradiation by X-ray (AGuIX) nanoparticles with sizes below 5 nm have entered a phase III clinical trial as efficient radiosensitizers. This study aimed to develop a unique synergistic strategy based on AGuIX-mediated radiotherapy and immune checkpoint blockade to further improve the efficiency for B16 tumor therapy. AGuIX exacerbated radiation-induced DNA damage, cell cycle arrest, and apoptosis on B16 cells. More importantly, it could efficiently induce the immunogenic cell death of irradiated B16 tumor cells, and consequently trigger the maturation of dendritic cells and activation of systemic T-cell responses. Combining AGuIX-mediated radiotherapy with programmed cell death protein 1 blockade demonstrated excellent synergistic therapeutic effects in both bilateral and metastatic B16 tumor models, as indicated by a significant increase in the infiltration of effector CD8+ T cells and effective alleviation of the immunosuppressive tumor microenvironment. Our findings indicate that the synergy between radiosensitization and immunomodulation provides a new and powerful therapy regimen to achieve durable antitumor T-cell responses, which is promising for cancer treatment.

Abstract 2069: Targeting the DNA damage response in combination with high Z metal nanoparticle radiosensitizers in glioblastoma

Abstract Introduction: Glioblastoma (GBM) is a devastating disease with an extremely poor prognosis of approximately 11-15 months following standard-of-care treatments. There is a critical need for the development of clinical unmet need and a need for novel therapies in GBM. Combining novel drugs with radiotherapy has clear potential to considerably improve patient outcomes. Metal nanoparticles (NPs) and inhibitors of the DNA damage response (DDRIs) have been successfully translated to the clinical setting to benefit patients. In this study, we aimed to evaluate a novel multi-modal treatment in GBM by combining radiotherapy with metal NPs and DDRIs. Materials and methods: GBM cell models (U87 & U251) were screened with different NP formulations and sizes, including gadolinium-, iron- and gold-based NPs, to determine the most effective NP. Cells were transiently exposed to NPs for 1 or 24 hr prior to irradiation by x-rays and cell survival determined. IC50 values were determined for various DDRIs which specifically target PARP, ATR, ATM and DNA-PKcs. Clonogenic cell survival assays were conducted and cells treated with NP and DDRI combinations either 1 or 24 hr prior to irradiation to define the optimum schedule for drugging. Results and conclusions: We have demonstrated the radiosensitizing potential of Activation and Guidance of Irradiation by X-ray (AGuIX), a gadolinium-based NP, at low-moderate concentrations with the highest concentration tested (2mM) showing the greatest efficacy. A promising lack of cytotoxicity on both GBM cell models was observed. In contrast to AGuIX, U87 and U251 cell survival responses indicated a lack of dose dependency when exposed to varying concentrations of Superparamagnetic Iron Oxide Nanoparticles (SPIONs). Both cell models exhibited differential radiotherapy responses when exposed to ID10 and ID11, gold-based NPs with varying PEG chain lengths. Combination treatment with AGuIX and Olaparib resulted in differential efficacy between cell lines. A non-significant difference in cell survival was observed between differing treatment scheduling. Future work will explore several variations of NP and DDRI treatments in combination with irradiation by x-rays on GBM cell models. The future implications of this research are GBM patients would receive combination therapies tailored to the specific DNA mutations in their tumor. Citation Format: Brianna Kerr. Targeting the DNA damage response in combination with high Z metal nanoparticle radiosensitizers in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2069.

Development of an Antibody-Targeted Nanoparticle for Early Detection of Minimal Residual Disease in Multiple Myeloma

Development of methods for the early detection of minimal residual disease (MRD) is a central challenge to the effective treatment of patients with multiple myeloma (MM). The presence of MRD is directly linked to both the durations of treatment response as well as to long-term survival outcomes. Current diagnostic methods utilize serologic biomarkers and/or repeated bone marrow samplings that do not take into account the spatial heterogeneity of the tumor microenvironment; as such, they often lead to false negative results. Available diagnostic imaging agents are not designed to detect plasma-cell populations; they rely on passive tumor accumulation that hinders both their detection specificity and sensitivity.Here, we utilize ultra-small gadolinium-based nanoparticles (Gd-NPs) that are conjugated to monoclonal antibodies to enable magnetic resonance imaging of plasma cells in a murine model of MM. We demonstrate the first example of utilizing a non-invasive imaging agent to improve early detection of MRD after therapeutic administration.To develop a plasma-cell targeted MRI contrast agent that would improve early detection of MRD, we fabricated ultra-small, sub-5 nm Gd-NPs that were conjugated to monoclonal antibodies directed against different receptors on the surfaces of MM cells. We postulated that these ultra-small Gd-NPs would minimally affect antibody targeting upon conjugation and could achieve improved in vivo imaging of plasma cell populations. For targeting of MM cells, we selected antibodies against the signaling lymphocytic activation molecule-F7 (SLAMF7) and the B-cell maturation antigen (BCMA). Both antigens are almost exclusively present on the surfaces of malignant B-cells. To generate our MM-targeted imaging construct, the surfaces of our Gd-NPs were decorated with free N-hydroxysuccinimide (NHS) groups and were conjugated to NHS groups on the surface of anti-SLAMF7 and BCMA antibodies via a bissulfosuccinimidyl suberate crosslinker.An MRI study was undertaken to compare the efficiencies of the various nanoparticle constructs (Gd-NP, NP-SLAMF7, and NP-BCMA) to identify identical plasma cell burdens and as compared to the FDA-approved contrast agent MagnevistTM. Gd uptake in the spine and femurs of animals were visualized using a 7T MRI machine with a T1-GRE sequence. The specificity of each of the administered contrast agents to target MM cells was confirmed by animal sacrifice immediately after MRI; the femurs and vertebral tissues of each animal were harvested for histologic assessment after staining by H&E and by Prussian blue, which showed sheets of marrow-infiltrating plasma cells and which labeled Gd deposits, respectively. This quantification demonstrated the enhanced sensitivity of NP-SLAMF7 and NP-BCMA, as compared to the passive targeting agents Gd-NP and MagnevistTM, to detect plasma cell populations. As soon as 30 min after the intravenous injection of the nanoparticle-antibody complexes, animals that had been administered NP-SLAMF7 demonstrated an ~3.8-fold increase in the SNR for plasmacytomas in the spine while those that had received NP-BCMA exhibited a ~12-fold enhancement. Note that the NP-BCMA conjugate demonstrated better tumor uptake than NP-SLAMF7 (p= 0.0045, one-sided paired t-test), which was attributed to the greater numbers of surface BCMA antigens on MM cells as assessed on a per cellular basis.We subsequently evaluated their targeting efficiencies both in vitro and in vivo prior to performing a comparative study to determine their detection capabilities when compared to other clinically-available diagnosis, such as computed tomography scans and methods levels of serum lambda light-chains. Comparisons of AUC for the SNR detected by each modality and over the entire duration of the experiment further supported the superiority of the NP-BCMA for both early diagnostic of MM and MRD diagnostic.Selection of alternative cell surface targets may also enable detection of MRD in patients diagnosed with leukemia or other hematological malignancies. Ultra-small nanoparticle-antibody complexes are, thus, poised to impact both the diagnosis and treatment of MM. Their successful application may further afford insights into the fabrication of other targeted constructs that may help translate the full potential of nanomedicines to improve the care and survival of cancer patients. DisclosuresNo relevant conflicts of interest to declare.

Maltodextrin-Conjugated Gd-Based MRI Contrast Agents for Specific Diagnosis of Bacterial Infections.

Bacterial infections are one of the most serious health risks worldwide, and their rapid diagnosis remains a major challenge in clinic. To enhance the relaxivity and bacterial specificity of magnetic resonance imaging (MRI) contrast agents, here, a kind of gadolinium-based nanoparticles (NPs) of impressive biocompatibility is constructed as a contrast agent for maltodextrin-mediated bacteria-targeted diagnosis. To realize this, positively charged ultrasmall gadolinium oxide (Gd2O3, 2-3 nm) NPs are embedded in mesoporous silica NPs (MSN) with pore size around 6.38 nm. The resulting Gd2O3@MSN exhibits enhanced r1 value and T1-weighted MRI performance. Interestingly, upon conjugation of Gd2O3@MSN with maltodextrin to produce Gd2O3@MSN-Malt NPs, a remarkable decrease in internalization by osteosarcoma cells, alongside an increased adsorption toward E. coli and S. aureus, is achieved. It is therefore conceivable that the bacteria-targeted Gd2O3@MSN-Malt might be a promising MRI contrast agent for effective discrimination of bacterial infections from tumor.

Imaging and Characterization of Sustained Gadolinium Nanoparticle Release from Next Generation Radiotherapy Biomaterial.

Smart radiotherapy biomaterials (SRBs) present a new opportunity to enhance image-guided radiotherapy while replacing routinely used inert radiotherapy biomaterials like fiducials. In this study the potential of SRBs loaded with gadolinium-based nanoparticles (GdNPs) is investigated for magnetic resonance imaging (MRI) contrast. GdNP release from SRB is quantified and modelled for accurate prediction. SRBs were manufactured similar to fiducials, with a cylindrical shell consisting of poly(lactic-co-glycolic) acid (PLGA) and a core loaded with GdNPs. Magnetic resonance imaging (MRI) contrast was investigated at 7T in vitro (in agar) and in vivo in subcutaneous tumors grown with the LLC1 lung cancer cell line in C57/BL6 mice. GdNPs were quantified in-phantom and in tumor and their release was modelled by the Weibull distribution. Gd concentration was linearly fitted to the R1 relaxation rate with a detection limit of 0.004 mmol/L and high confidence level (R2 = 0.9843). GdNP loaded SRBs in tumor were clearly visible up to at least 14 days post-implantation. Signal decrease during this time showed GdNP release in vivo, which was calculated as 3.86 ± 0.34 µg GdNPs release into the tumor. This study demonstrates potential and feasibility for SRBs with MRI-contrast, and sensitive GdNP quantification and release from SRBs in a preclinical animal model. The feasibility of monitoring nanoparticle (NP) concentration during treatment, allowing dynamic quantitative treatment planning, is also discussed.

Enhanced MRI-guided radiotherapy with gadolinium-based nanoparticles: preclinical evaluation with an MRI-linac

BackgroundThe AGuIX® (NH TherAguix) nanoparticle has been developed to enhance radiotherapy treatment and provide strong MR contrast. These two properties have previously been investigated separately and progressed to clinical trial following a clinical workflow of separate MR imaging followed some time later by radiotherapy treatment. The recent development of MRI-linacs (combined Magnetic Resonance Imaging–linear accelerator systems enabling MRI-guided radiotherapy) opens up a new workflow where MR confirmation of nanoparticle uptake can be carried out at the time of treatment. A preclinical study was carried out to assess the suitability of a gadolinium-containing nanoparticle AGuIX® (NH TherAguix) for nano-enhanced image-guided radiotherapy on an MRI-linac.MethodsTreatments were carried out on F344 Fischer rats bearing a 9L glioma brain tumour. Animals received either: (A) no treatment; (B) injection of nanoparticles followed by MRI; (C) radiotherapy with MRI; or (D) injection of nanoparticles followed by radiotherapy with MRI. Pre-clinical irradiations were carried out on the 1.0 T, 6 MV in-line Australian MRI-linac. Imaging used a custom head coil specially designed to minimise interference from the radiotherapy beam. Anaesthetised rats were not restrained during treatment but were monitored with a cine-MRI sequence. Inductively Coupled Plasma Mass Spectrometry (ICP-MS) analysis was used to quantify residual gadolinium in the brain in normal and tumour tissue.ResultsA preclinical evaluation of nano-enhanced radiation treatment has been carried out on a 1.0 T MRI-linac, establishing a workflow on these novel systems. Extension of life when combining radiotherapy with nanoparticles was not statistically different from that for rats receiving radiotherapy only. However, there was no detrimental effect for animals receiving nanoparticles and radiation treatment in the magnetic field compared with control branches. Cine-MR imaging was sufficient to carry out monitoring of anaesthetised animals during treatment. AGuIX nanoparticles demonstrated good positive contrast on the MRI-linac system allowing confirmation of tumour extent and nanoparticle uptake at the time of treatment.ConclusionsNovel nano-enhanced radiotherapy with gadolinium-containing nanoparticles is ideally suited for implementation on an MRI-linac, allowing a workflow with time-of-treatment imaging. Live irradiations using this treatment workflow, carried out for the first time at the Australian MRI-linac, confirm the safety and feasibility of performing MRI-guided radiotherapy with AGuIX® nanoparticles. Follow-up studies are needed to demonstrate on an MRI-linac the radiation enhancement effects previously shown with conventional radiotherapy.

Nebulised Gadolinium-Based Nanoparticles for a Multimodal Approach: Quantitative and Qualitative Lung Distribution Using Magnetic Resonance and Scintigraphy Imaging in Isolated Ventilated Porcine Lungs.

PurposeThis study aims at determining lung distribution of gadolinium-based polysiloxane nanoparticles, AGuIX® (small rigid platform – SRP), as a potential theranostic approach by the pulmonary route.MethodsFirst, the aerodynamic size distribution and the aerosol output rate were thoroughly characterized. Then, a multimodal approach using magnetic resonance (MR) and gamma-camera (GC) imaging allows to assess the deposition of the aerosolised nanoparticles in the respiratory tract using isolated ventilated porcine lungs.ResultsThe SRP has proven to be radiolabelled by radioisotope with a good yield. Crude SRP or radiolabelled ones showed the same aerodynamic size distribution and output as a conventional molecular tracer, as sodium fluoride. With MR and GC imaging approaches, the nebulised dose represented about 50% of the initial dose of nanoparticles placed in the nebuliser. Results expressed as proportions of the deposited aerosol showed approximately a regional aerosol deposition of 50% of the deposited dose in the lungs and 50% in the upper airways. Each technique assessed a homogeneous pattern of deposited nanoparticles in Lungs. MR observed a strong signal enhancement with the SRP, similar to the one obtained with a commonly used MRI contrast agent, gadoterate meglumine.ConclusionAs a known theranostic approach by intravenous administration, SRP appeared to be easily aerosolised with a conventional nebuliser. The present work proves that pulmonary administration of SRP is feasible in a human-like model and allows multimodal imaging with MR and GC imaging. This work presents the proof of concept of SRP nebulisation and aims to generate preclinical data for the potential clinical transfer of SRP for pulmonary delivery.

Anti-MUC1-C Antibody–Conjugated Nanoparticles Potentiate the Efficacy of Fractionated Radiation Therapy

Heavy-metal chelators and inorganic nanoparticles (NPs) have been examined as potential radioenhancers to increase the efficacy of external beam radiation therapy for various cancers. Most of these agents have, unfortunately, displayed relatively poor pharmacokinetic properties, which limit the percentage of injected dose (%ID/g) that localizes to tumors and which shorten the window for effective radiation enhancement due to rapid tumor washout. To address these challenges, we sought to conjugate gadolinium-based ultrasmall (<5 nm) NPs to an antibody directed against the oncogenic MUC1-C subunit that is overexpressed on the surface of many different human cancer types. The binding of the anti-MUC1-C antibody 3D1 to MUC1-C on the surface of a cancer cell is associated with its internalization and, thereby, to effective intracellular delivery of the antibody-associated payload, promoting its effective tumor retention. As such, we examined whether systemically administered anti-MUC1-C antibody-conjugated, gadolinium-based NPs (anti-MUC1-C/NPs) could accumulate within cell-line xenograft models of MUC1-C-expressing (H460) lung and (E0771) breast cancers to improve the efficacy of radiation therapy (XRT). The %ID/g of anti-MUC1-C/NPs that accumulated within tumors was found to be similar to that of their unconjugated counterparts (6.6 ± 1.4 vs 5.9 ± 1.7 %ID/g, respectively). Importantly, the anti-MUC1-C/NPs demonstrated prolonged retention in invivo tumor microenvironments; as a result, the radiation boost was maintained during the course of fractionated therapy (3 × 5.2 Gy). We found that by administering anti-MUC1-C/NPs with XRT, it was possible to significantly augment tumor growth inhibition and to prolong the animals' overall survival (46.2 ± 3.1 days) compared with the administration of control NPs with XRT (31.1 ± 2.4 days) or with XRT alone (27.3 ± 1.6 days; P < .01, log-rank). These findings suggest that anti-MUC1-C/NPs could be used to enhance the effectiveness of radiation therapy and potentially to improve clinical outcomes.

Beta‐Amyloid Oligomers: Amyloid‐β Oligomer‐Targeted Gadolinium‐Based NIR/MR Dual‐Modal Theranostic Nanoprobe for Alzheimer's Disease (Adv. Funct. Mater. 16/2020)

In article number 1909529, Hung-Wing Li, Man Shing Wong, and co-workers develop amyloid-β (Aβ) oligomer-targeted gadolinium-based nanoparticles and demonstrate its utility in the visualization of Aβ content in an Alzheimer's disease mouse model in different age groups via in vivo near-infrared and magnetic resonance dual-modal imaging. Furthermore, the nanoparticle inhibits Aβ aggregation and attenuates reactive oxygen species generation, affording a smart theranostic nanoprobe.

Gadolinium-Based Nanoparticles Can Overcome the Radioresistance of Head and Neck Squamous Cell Carcinoma Through the Induction of Autophagy.

Radiation therapy is a mainstay in the therapeutic management of Head and Neck Squamous Cell Carcinoma (HNSCC). Despite significant progress in this field, radioresistance still accounts for most treatment failures. Gadolinium-based nanoparticles (GBNs) have shown great promises as radiosensitizers but the underlying sensitizing mechanism is still largely unknown with regards to the disparities obtained in in vitro studies. In this study, we show that a new formulation of GBNs, AGuIX®, can radiosensitize HNSCC after cell uptake and further accumulation in lysosomes. Although radiation alone triggered late apoptosis and mitochondrial impairment, the pre-treatment with GBNs led to complex DNA damage and a specific increase of autophagic cell death. In addition, a significant radio-enhancement effect was obtained after the pre-conditioning of cells with a glutathione inhibitor before GBNs treatment and radiation exposure. Overall, our results provide additional information on the radio-enhancing properties of GBNs in the management of radioresistant HNSCC.

Toxicity Mechanism of Gadolinium Oxide Nanoparticles and Gadolinium Ions in Human Breast Cancer Cells.

Due to the potential advantages of Gadolinium Nanoparticles (NPs) over gadolinium elements, gadolinium based NPs are currently being explored in the field of MRI. Either in elemental form or nanoparticulate form, gadolinium toxicity is believed to occur due to the deposition of gadolinium ion (designated as Gd3+ ion or simply G ion). There is a serious lack of literature on the mechanisms of toxicity caused by either gadolinium-based NPs or ions. Breast cancer tumors are often subjected to MRIs, therefore, human breast cancer (MCF-7) cells could serve as an appropriate in vitro model for the study of Gadolinium Oxide (GO) NP and G ion. Cytotoxicity and oxidative damage was determined by quantifying cell viability, cell membrane damage, and Reactive Oxygen Species (ROS). Intracellular Glutathione (GSH) was measured along with cellular Total Antioxidant Capacity (TAC). Autophagy was determined by using Monodansylcadaverine (MDC) and Lysotracker Red (LTR) dyes in tandem. Mitochondrial Membrane Potential (MMP) was measured by JC-1 fluorescence. Physicochemical properties of GO NPs were characterized by field emission transmission electron microscopy, X-ray diffraction, and energy dispersive spectrum. A time- and concentration-dependent toxicity and oxidative damage was observed due to GO NPs and G ions. Bax/Bcl2 ratios, FITC-7AAD double staining, and cell membrane blebbing in phase-contrast images all suggested different modes of cell death induced by NPs and ions. In summary, cell death induced by GO NPs with high aspect ratio favored apoptosis-independent cell death, whereas G ions favored apoptosis-dependent cell death.