Here, we demonstrate that a simple nanoparticle can be used as a contrast agent for biomedical imaging in six different modalities. Near infrared (NIR) fluorescence (FL), NIR-to-NIR upconversion (UC) luminescence, photoacoustic (PA) imaging, Cerenkov luminescence (CL), X-ray computed tomography (CT) and positron emission tomography (PET) were compared in phantom studies and then used for lymphatic mapping in mice. The nanoparticle is self-assembled from just two active imaging components: porphyrin-phospholipid, which coats a core-shell upconversion nanosphere. The porphyrin-phospholipid provides strong absorption for PA, allows for self-assembly-responsive FL, and enables seamless post-labeling with 64Cu for PET and CL. The core-shell provides UC that is not quenched by the porphyrin coating as well as electron density for CT.

There is a growing demand for long-term in vivo stem cell imaging for assessing cell therapy techniques and guiding therapeutic decisions. This work develops the production of 52Mn and establishes proof of concept for the use of divalent metal transporter 1 (DMT1) as a positron emission tomography (PET) and magnetic resonance imaging (MRI) reporter gene for stem cell tracking in the rat brain. 52Mn was produced via proton irradiation of a natural chromium target. In a comparison of two 52Mn separation methods, solvent-solvent extraction was preferred over ion exchange chromatography because of reduced chromium impurities and higher 52Mn recovery. In vitro uptake of Mn-based PET and MRI contrast agents (52Mn2+ and Mn2+, respectively) was enhanced in DMT1 over-expressing human neural progenitor cells (hNPC-DMT1) compared to wild-type control cells (hNPC-WT). After cell transplantation in the rat striatum, increased uptake of Mn-based contrast agents in grafted hNPC-DMT1 was detected in in vivo manganese-enhanced MRI (MEMRI) and ex vivo PET and autoradiography. These initial studies indicate that this approach holds promise for dual-modality PET/MR tracking of transplanted stem cells in the central nervous system and prompt further investigation into the clinical applicability of this technique.

Actively targeted theranostic nanomedicine may be the key for future personalized cancer management. Although numerous types of theranostic nanoparticles have been developed in the past decade for cancer treatment, challenges still exist in the engineering of biocompatible theranostic nanoparticles with highly specific in vivo tumor targeting capabilities. Here, we report the design, synthesis, surface engineering, and in vivo active vasculature targeting of a new category of theranostic nanoparticle for future cancer management. Water-soluble photothermally sensitive copper sulfide nanoparticles were encapsulated in biocompatible mesoporous silica shells, followed by multistep surface engineering to form the final theranostic nanoparticles. Systematic in vitro targeting, an in vivo long-term toxicity study, photothermal ablation evaluation, in vivo vasculature targeted imaging, biodistribution and histology studies were performed to fully explore the potential of as-developed new theranostic nanoparticles.

Pembrolizumab is a humanized monoclonal antibody targeting programmed cell death protein 1 (PD-1) found on T and pro-B cells. Pembrolizumab prevents PD-1 ligation by both PD-L1 and PD-L2, preventing the immune dysregulation that otherwise occurs when T cells encounter cells expressing these ligands. Clinically, PD-1 blockade elicits potent anti-tumor immune responses and antibodies blocking PD-1 ligation, including pembrolizumab, have recently received federal drug administration approval for the treatment of advanced melanoma, renal cell cancer, and non-small cell lung cancer. Methods In this study, we evaluated the pharmacokinetics, biodistribution, and dosimetry of pembrolizumab in vivo, accomplished through radiolabeling with positron emitter zirconium-89 (89Zr). Positron emission tomography (PET) imaging was utilized to evaluate the whole-body distribution of 89Zr-Df-Pembrolizumab in two rodent models (mice and rats). Data obtained from PET scans and biodistribution studies were extrapolated to humans to estimate the dosimetry of the tracer. As a proof-of-concept, the biodistribution of 89Zr-Df-Pembrolizumab is further investigated in a humanized murine model. Results The tracer remained stable in blood circulation throughout the study and accumulated the greatest in liver and spleen tissues. Both mice and rats showed similar biodistribution and pharmacokinetics of 89Zr-Df-Pembrolizumab. In the humanized mouse model, T-cell infiltration into the salivary and lacrimal glands could be successfully visualized. Conclusion These data will augment our understanding of the pharmacokinetics and biodistribution of radiolabeled pembrolizumab in vivo, while providing detailed dosimetry data that may lead to better dosing strategies in the future. These findings further demonstrate the utility of noninvasive in vivo PET imaging to dynamically track T-cell checkpoint receptor expression and localization in a humanized mouse model.

52Mn (t1/2 = 5.59 d, β+ = 29.6%, Eβave = 0.24 MeV) shows promise in positron emission tomography (PET) and in dual-modality manganese-enhanced magnetic resonance imaging (MEMRI) applications including neural tractography, stem cell tracking, and biological toxicity studies. The extension to bioconjugate application requires high-specific-activity 52Mn in a state suitable for macromolecule labeling. To that end a 52Mn production, purification, and labeling system is presented, and its applicability in preclinical, macromolecule PET is shown using the conjugate 52Mn-DOTA-TRC105. 52Mn is produced by 60 μA, 16 MeV proton irradiation of natural chromium metal pressed into a silver disc support. Radiochemical separation proceeds by strong anion exchange chromatography of the dissolved Cr target, employing a semiorganic mobile phase, 97:3 (v:v) ethanol:HCl (11 M, aqueous). The method is 62 ± 14% efficient (n = 7) in 52Mn recovery, leading to a separation factor from Cr of (1.6 ± 1.0) × 106 (n = 4), and an average effective specific activity of 0.8 GBq/μmol (n = 4) in titration against DOTA. 52Mn-DOTA-TRC105 conjugation and labeling demonstrate the potential for chelation applications. In vivo images acquired using PET/CT in mice bearing 4T1 xenograft tumors are presented. Peak tumor uptake is 18.7 ± 2.7%ID/g at 24 h post injection and ex vivo 52Mn biodistribution validates the in vivo PET data. Free 52Mn2+ (as chloride or acetate) is used as a control in additional mice to evaluate the nontargeted biodistribution in the tumor model.

MR image-guided radiotherapy has the potential to improve patient care, but integration of an MRI scanner with a linear accelerator adds complexity to the commissioning process. This work describes a single institution experience of commissioning an Elekta Unity MR-linac, including mechanical testing, MRI scanner commissioning, and dosimetric validation. Mechanical testing included multileaf collimator (MLC) positional accuracy, measurement of radiation isocenter diameter, and MR-to-MV coincidence. Key MRI tests included magnetic field homogeneity, geometric accuracy, image quality, and the accuracy of navigator-triggered imaging for motion management. Dosimetric validation consisted of comparison between measured and calculated PDDs and profiles, IMRT measurements, and end-to-end testing. Multileaf collimator positional accuracy was within 1.0 mm, the measured radiation isocenter walkout was 0.20 mm, and the coincidence between MR and MV isocenter was 1.06 mm, which is accounted for in the treatment planning system (TPS). For a 350mm-diameter spherical volume, the peak-to-peak deviation of the magnetic field homogeneity was 4.44 ppm and the geometric distortion was 0.8 mm. All image quality metrics were within ACR recommendations. Navigator-triggered images showed a maximum deviation of 0.42, 0.75, and 3.0 mm in the target centroid location compared to the stationary target for a 20 mm motion at 10, 15, and 20 breaths per minute, respectively. TPS-calculated PDDs and profiles showed excellent agreement with measurement. The gamma passing rate for IMRT plans was 98.4 ± 1.1% (3%/ 2 mm) and end-to-end testing of adapted plans showed agreement within 0.4% between ion-chamber measurement and TPS calculation. All credentialing criteria were satisfied in an independent end-to-end test using an IROC MRgRT phantom.

Given the highly heterogeneous character of brain malignancies and the associated implication for its proper diagnosis and treatment, finding biomarkers that better characterize this disease from a molecular standpoint is imperative. In this study, we evaluated CD146 as a potential molecular target for diagnosis and targeted therapy of glioblastoma multiforme (GBM), the most common and lethal brain malignancy. YY146, an anti-CD146 monoclonal antibody, was generated and radiolabeled for noninvasive positron-emission tomography (PET) imaging of orthotopic GBM models. 64Cu-labeled YY146 preferentially accumulated in the tumors of mice bearing U87MG xenografts, which allowed the acquisition of high-contrast PET images of small tumor nodules (∼2 mm). Additionally, we found that tumor uptake correlated with the levels of CD146 expression in a highly specific manner. We also explored the potential therapeutic effects of YY146 on the cancer stem cell (CSC) and epithelial-to-mesenchymal (EMT) properties of U87MG cells, demonstrating that YY146 can mitigate those aggressive phenotypes. Using YY146 as the primary antibody, we performed histological studies of World Health Organization (WHO) grades I through IV primary gliomas. The positive correlation found between CD146-positive staining and high tumor grade (χ2 = 9.028; P = 0.029) concurred with the GBM data available in The Cancer Genome Atlas (TCGA) and validated the clinical value of YY146. In addition, we demonstrate that YY146 can be used to detect CD146 in various cancer cell lines and human resected tumor tissues of multiple other tumor types (gastric, ovarian, liver, and lung), indicating a broad applicability of YY146 in solid tumors.

Multifunctional zinc oxide (ZnO) nanoparticles (NPs) with well-integrated multimodality imaging capacities have generated increasing research interest in the last decade. However, limited progress has been made in developing ZnO NP-based multimodality tumor-imaging agents. Here we developed novel red fluorescent ZnO NPs and described the successful conjugation of 64Cu (t1/2 = 12.7 h) and TRC105, a chimeric monoclonal antibody against CD105, to these ZnO NPs via well-developed surface engineering procedures. The produced dual-modality ZnO NPs were readily applicable for positron emission tomography (PET) imaging and fluorescence imaging of the tumor vasculature. Their pharmacokinetics and tumor-targeting efficacy/specificity in mice bearing murine breast 4T1 tumor were thoroughly investigated. ZnO NPs with dual-modality imaging properties can serve as an attractive candidate for future cancer theranostics.