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The ability to effectively assess tumor margins for brain tumor resection is a crucial factor in determining outcome in patients with brain tumors. Moritz Kircher and colleagues have developed a gold-silica nanoparticle that provides a triple-mode imaging capability of magnetic resonance, photoacoustic and Raman imaging, capitalizing on the complementary strengths of each modality for noninvasively delineating brain tumor margins both preoperatively and intraoperatively. The approach was tested in several mouse models, including one that recapitulates the infiltrating growth pattern of human gliomas. The difficulty in delineating brain tumor margins is a major obstacle in the path toward better outcomes for patients with brain tumors. Current imaging methods are often limited by inadequate sensitivity, specificity and spatial resolution. Here we show that a unique triple-modality magnetic resonance imaging–photoacoustic imaging–Raman imaging nanoparticle (termed here MPR nanoparticle) can accurately help delineate the margins of brain tumors in living mice both preoperatively and intraoperatively. The MPRs were detected by all three modalities with at least a picomolar sensitivity both in vitro and in living mice. Intravenous injection of MPRs into glioblastoma-bearing mice led to MPR accumulation and retention by the tumors, with no MPR accumulation in the surrounding healthy tissue, allowing for a noninvasive tumor delineation using all three modalities through the intact skull. Raman imaging allowed for guidance of intraoperative tumor resection, and a histological correlation validated that Raman imaging was accurately delineating the brain tumor margins. This new triple-modality–nanoparticle approach has promise for enabling more accurate brain tumor imaging and resection.

Antibodies (Abs) and their fragments can be labeled with PET radioisotope (immunoPET) for in vivo diagnostic imaging. Compared to the conventional FDG-PET, immunoPET can be designed to target in vivo cancer-specific antigen expression levels for various tumors and metastasis, which makes immunoPET (iPET) a powerful technique for molecular imaging and therapy monitoring. However, achieving the optimal dose to minimize radioisotope toxicity without compromising the visualization of the smallest tumor is challenging. To find an ultra-minimal tracer dose, we have developed a novel iPET with an intact rituximab Ab labeled with 64 Cu to image human CD20 (hCD20) in a transgenic mouse model for non-Hodgkin’s lymphoma (NHL) imaging. Using phantom and in vivo mouse models, we optimized the minimal dose that can be administered in a mouse using a high-specific iPET tracer prepared from 64 Cu-rituximab. A phantom study was used to characterize the scanner capability and limit for imaging using low doses. An ultra-minimal dose administered in a mouse model showed good image quality with high signal-to-noise ratio without compromising quantitative accuracy. The phantom study with below 50 μCi dose level indicated a slight increase in variability due to reduced dose specifically for target regions with lower uptakes (<3:1 ratio) relative to the background. In vivo study performed with four groups of mice ( n = 3), each group injected with ~90, ~50, ~25, and ~10 μCi showed a linear increase of tracer uptake measured as percentage injected dose per gram (%ID/g). This tracer has shown high specific uptake in the spleen, where most B-cells are engineered to express hCD20. The study demonstrated that the lowest dose threshold limit for 64 Cu-antibody-based iPET was about 25 μCi while achieving a high-quality image and quantitative accuracy.

The immune checkpoint programmed death 1 receptor (PD-1) expressed on some tumor-infiltrating lymphocytes, and its ligand (PD-L1) expressed on tumor cells, enable cancers to evade the immune system. Blocking PD-1 with the monoclonal antibody pembrolizumab is a promising immunotherapy strategy. Thus, noninvasively quantifying the presence of PD-1 expression in the tumor microenvironment prior to initiation of immune checkpoint blockade may identify the patients likely to respond to therapy. We have developed a 64 Cu-pembrolizumab radiotracer and evaluated human dosimetry. The tracer was utilized to image hPD-1 levels in two subcutaneous mouse models: (a) 293 T/hPD-1 cells xenografted into NOD-scid IL-2Rγnull mice (NSG/293 T/hPD-1) and (b) human peripheral blood mononuclear cells engrafted into NSG bearing A375 human melanoma tumors (hNSG/A375). In each mouse model two cohorts were evaluated (hPD-1 blockade with pembrolizumab [blk] and non-blocked [nblk]), for a total of four groups (n = 3–5/group). The xenograft-to-muscle ratio in the NSG/293 T/hPD-1 model at 24 h was significantly increased in the nblk group (7.0 ± 0.5) compared to the blk group (3.4 ± 0.9), p = 0.01. The radiotracer dosimetry evaluation (PET/CT ROI-based and ex vivo ) in the hNSG/A375 model revealed the highest radiation burden to the liver. In summary, we validated the 64 Cu-pembrolizumab tracer’s specific hPD-1 receptor targeting and predicted human dosimetry.

Purpose Glioblastoma (GBM), a lethal primary adult malignancy, is difficult to treat because of the restrictive nature of the blood–brain barrier (BBB), blood-tumor barrier (BTB), and the immunosuppressive tumor microenvironment (TME). Since pulsed focused ultrasound (pFUS) is currently used to improve therapeutic deliveries across these barriers, this study aims to characterize the impact of pFUS on the TME proteomics upon opening the BBB and BTB. Methods We utilized MRI-guided, pFUS with ultrasound contrast microbubbles (termed ‘pFUS’ herein) to selectively and transiently open the BBB and BTB investigating proteomic modifications in the TME. Utilizing an orthotopically-allografted mouse GL26 GBM model (Ccr2RFP/wt − Cx3cr1GFP/wt), pFUS’s effect on glioma proteomics was evaluated using a Luminex 48-plex assay. Results pFUS treated tumors exhibited increases in pro-inflammatory cytokines, chemokines, and trophic factors (CCTFs). Proteomic changes in tumors tend to peak at 24 h after single pFUS session (1x), with levels then plateauing or declining over the subsequent 24 h. Tumors receiving three pFUS sessions (3x) showed elevated CCTFs levels peaking as early as 6 h after the third session. Conclusions pFUS together with microbubbles induces a sterile inflammatory response in the TME of a mouse GBM tumor. Moreover, this proinflammatory shift can be sustained and perhaps primed for more rapid responses upon multiple sessions of pFUS. These findings raise the intriguing potential that pFUS-induced BBB and BTB opening may not only be effective in facilitating the therapeutic agent delivery, but also be harnessed to modify the TME to assist immunotherapies in overcoming immune evasion in GBM.

Cerenkov luminescence imaging (CLI) is commonly performed using two-dimensional (2-D) conventional optical imaging systems for its cost-effective solution. However, quantification of CLI comparable to conventional three-dimensional positron emission tomography (PET) is challenging using these systems due to both the high attenuation of Cerenkov radiation (CR) on mouse tissue and nonexisting depth resolution of CLI using 2-D imaging systems (2-D CLI). In this study, we developed a model that estimates effective tissue attenuation coefficient and corrects the tissue attenuation of CLI signal intensity independent of tissue depth and size. To evaluate this model, we used several thin slices of ham as a phantom and placed a radionuclide (89Zr and 64Cu) inside the phantom at different tissue depths and sizes (2, 7, and 12 mm). We performed 2-D CLI and MicroPET/CT (Combined small animal PET and Computed Tomography (CT)) imaging of the phantom and in vivo mouse model after administration of 89Zr tracer. Estimates of the effective tissue attenuation coefficient (μeff) for 89Zr and 64Cu were ∼2.4 and ∼2.6 cm−1, respectively. The computed unit conversion factor to %ID/g from 2-D CLI signal was 2.74 × 10−3 μCi/radiance estimated from phantom study. After applying tissue attenuation correction and unit conversion to the in vivo animal study, an average quantification difference of 10% for spleen and 35% for liver was obtained compared to PET measurements. The proposed model provides comparable quantification accuracy to standard PET system independent of deep tissue CLI signal attenuation.

Antibodies (Abs) and their fragments can be labeled with PET radioisotope (immunoPET) for diagnostic imaging. Compared to the conventional FDG-PET, immunoPET can be designed to target cancer-specific antigen expression levels for various tumors and metastasis, which makes immunoPET (iPET) a powerful technique for molecular imaging and therapy monitoring. However, achieving the optimal dose to minimize radioisotope toxicity without compromising the visualization of the smallest tumor is challenging. To find an ultra-minimal tracer dose, we have developed a novel iPET with an intact rituximab Ab labeled with Cu to image human CD20 (hCD20) in a transgenic mouse model for non-Hodgkin's lymphoma (NHL) imaging. Using phantom and mouse models, we optimized the minimal dose that can be administered in a mouse using a high-specific iPET tracer prepared from Cu-rituximab. A phantom study was used to characterize the scanner capability and limit for imaging using low doses. An ultra-minimal dose administered in a mouse model showed good image quality with high signal-to-noise ratio without compromising quantitative accuracy. The phantom study with below 50 μCi dose level indicated a slight increase in variability due to reduced dose specifically for target regions with lower uptakes (<3:1 ratio) relative to the background. study performed with four groups of mice ( = 3), each group injected with ~90, ~50, ~25, and ~10 μCi showed a linear increase of tracer uptake measured as percentage injected dose per gram (%ID/g). This tracer has shown high specific uptake in the spleen, where most B-cells are engineered to express hCD20. The study demonstrated that the lowest dose threshold limit for Cu-antibody-based iPET was about 25 μCi while achieving a high-quality image and quantitative accuracy.

Targeting CD47 with monoclonal antibody (mAb) therapy activates tumor-associated macrophages (TAMs). Quantitative imaging methods are important for identifying responders to this novel immunotherapy. The purpose of our study was to investigate whether the metabolic activity of osteosarcomas on 18F-FDG PET/CT changes after CD47 mAb treatment. Twenty female BALB/c mice with intratibial murine K7M2 osteosarcomas, twenty female NOD scid gamma (NSG) mice with intratibial human 143B tumors, and twenty male NSG mice with intratibial human MG63.3 tumors were treated with either phosphate-buffered saline (PBS) or murine/human CD47 mAb (n = 10 per arm) and underwent either 18F-FDG PET/CT or ferumoxytol-enhanced MRI (n = 5 per group). Differences in tumor metabolic activity (%ID/g max), tumor T2* relaxation times, TAM (%F4/80), and M1 macrophage polarization (%CD80+) between PBS and CD47 mAb-treated mice were estimated from linear regression. The tumor %ID/g max of CD47 mAb-treated K7M2 tumors (6.58 ± 2.42) was not significantly different compared to PBS-treated K7M2 tumors (8.04 ± 2.91; p = 0.17). Similarly, the tumor %ID/g max of CD47 mAb-treated 143B tumors (9.12 ± 1.68) and MG63.3 tumors (5.44 ± 1.99) were not significantly different compared to PBS-treated 143B tumors (9.38 ± 2.32; p = 0.32 ) and MG63.3 tumors (6.02 ± 0.63, p = 0.79 ). By comparison, K7M2 tumors, 143B tumors, and MG63.3 tumors all demonstrated significantly shorter T2* relaxation times after CD47 mAb treatment compared to PBS treatment (all p < 0.001). All tumors exhibited significantly higher TAM (%F4/80+) and M1 macrophage polarization (%CD80+) after CD47 mAb treatment compared to PBS treatment (all p < 0.05). The metabolic activity of osteosarcomas on 18F-FDG PET/CT does not show significant changes after CD47 mAb treatment. This lowers the risk of observing pseudoprogression and misinterpreting drug-induced inflammation, simplifying routine clinical scan interpretation.Targeting CD47 with monoclonal antibody (mAb) therapy activates tumor-associated macrophages (TAMs). Quantitative imaging methods are important for identifying responders to this novel immunotherapy. The purpose of our study was to investigate whether the metabolic activity of osteosarcomas on 18F-FDG PET/CT changes after CD47 mAb treatment. Twenty female BALB/c mice with intratibial murine K7M2 osteosarcomas, twenty female NOD scid gamma (NSG) mice with intratibial human 143B tumors, and twenty male NSG mice with intratibial human MG63.3 tumors were treated with either phosphate-buffered saline (PBS) or murine/human CD47 mAb (n = 10 per arm) and underwent either 18F-FDG PET/CT or ferumoxytol-enhanced MRI (n = 5 per group). Differences in tumor metabolic activity (%ID/g max), tumor T2* relaxation times, TAM (%F4/80), and M1 macrophage polarization (%CD80+) between PBS and CD47 mAb-treated mice were estimated from linear regression. The tumor %ID/g max of CD47 mAb-treated K7M2 tumors (6.58 ± 2.42) was not significantly different compared to PBS-treated K7M2 tumors (8.04 ± 2.91; p = 0.17). Similarly, the tumor %ID/g max of CD47 mAb-treated 143B tumors (9.12 ± 1.68) and MG63.3 tumors (5.44 ± 1.99) were not significantly different compared to PBS-treated 143B tumors (9.38 ± 2.32; p = 0.32 ) and MG63.3 tumors (6.02 ± 0.63, p = 0.79 ). By comparison, K7M2 tumors, 143B tumors, and MG63.3 tumors all demonstrated significantly shorter T2* relaxation times after CD47 mAb treatment compared to PBS treatment (all p < 0.001). All tumors exhibited significantly higher TAM (%F4/80+) and M1 macrophage polarization (%CD80+) after CD47 mAb treatment compared to PBS treatment (all p < 0.05). The metabolic activity of osteosarcomas on 18F-FDG PET/CT does not show significant changes after CD47 mAb treatment. This lowers the risk of observing pseudoprogression and misinterpreting drug-induced inflammation, simplifying routine clinical scan interpretation.

Resistance to androgen deprivation therapy, or castration-resistant prostate cancer (CRPC), is often accompanied by metastasis and is currently the ultimate cause of prostate cancer-associated deaths in men. Recently, secondary hormonal therapies have led to an increase of neuroendocrine prostate cancer (NEPC), a highly aggressive variant of CRPC. Here, we identify that high levels of cell surface receptor Trop2 are predictive of recurrence of localized prostate cancer. Moreover, Trop2 is significantly elevated in CRPC and NEPC, drives prostate cancer growth, and induces neuroendocrine phenotype. Overexpression of Trop2 induces tumor growth and metastasis while loss of Trop2 suppresses these abilities in vivo. Trop2-driven NEPC displays a significant up-regulation of PARP1, and PARP inhibitors significantly delay tumor growth and metastatic colonization and reverse neuroendocrine features in Trop2-driven NEPC. Our findings establish Trop2 as a driver and therapeutic target for metastatic prostate cancer with neuroendocrine phenotype and suggest that high Trop2 levels could identify cancers that are sensitive to Trop2-targeting therapies and PARP1 inhibition.

Advances in precision molecular imaging promise to transform our ability to detect, diagnose and treat disease. Here, we describe the engineering and validation of a new cystine knot peptide (knottin) that selectively recognizes human integrin αvβ 6 with single-digit nanomolar affinity. We solve its 3D structure by NMR and x-ray crystallography and validate leads with 3 different radiolabels in pre-clinical models of cancer. We evaluate the lead tracer’s safety, biodistribution and pharmacokinetics in healthy human volunteers, and show its ability to detect multiple cancers (pancreatic, cervical and lung) in patients at two study locations. Additionally, we demonstrate that the knottin PET tracers can also detect fibrotic lung disease in idiopathic pulmonary fibrosis patients. Our results indicate that these cystine knot PET tracers may have potential utility in multiple disease states that are associated with upregulation of integrin α v β 6 . Knottin is a cystine knot peptide. Here, the authors develop a knottin-based tracer for positron emission tomography and demonstrate its ability to detect cancer and idiopathic pulmonary fibrosis through selective binding to integrin αvβ 6 .

Targeting CD47 with monoclonal antibody (mAb) therapy activates tumor-associated macrophages (TAMs). Quantitative imaging methods are important for identifying responders to this novel immunotherapy. The purpose of our study was to investigate whether the metabolic activity of osteosarcomas on F-FDG PET/CT changes after CD47 mAb treatment. Twenty female BALB/c mice with intratibial murine K7M2 osteosarcomas, twenty female NOD scid gamma (NSG) mice with intratibial human 143B tumors, and twenty male NSG mice with intratibial human MG63.3 tumors were treated with either phosphate-buffered saline (PBS) or murine/human CD47 mAb (n = 10 per arm) and underwent either F-FDG PET/CT or ferumoxytol-enhanced MRI (n = 5 per group). Differences in tumor metabolic activity (%ID/g max), tumor T2* relaxation times, TAM (%F4/80), and M1 macrophage polarization (%CD80 ) between PBS and CD47 mAb-treated mice were estimated from linear regression. The tumor %ID/g max of CD47 mAb-treated K7M2 tumors (6.58 ± 2.42) was not significantly different compared to PBS-treated K7M2 tumors (8.04 ± 2.91; p = 0.17). Similarly, the tumor %ID/g max of CD47 mAb-treated 143B tumors (9.12 ± 1.68) and MG63.3 tumors (5.44 ± 1.99) were not significantly different compared to PBS-treated 143B tumors (9.38 ±  2.32; p = 0.32 ) and MG63.3 tumors (6.02 ±  0.63, p = 0.79 ). By comparison, K7M2 tumors, 143B tumors, and MG63.3 tumors all demonstrated significantly shorter T2* relaxation times after CD47 mAb treatment compared to PBS treatment (all p < 0.001). All tumors exhibited significantly higher TAM (%F4/80 ) and M1 macrophage polarization (%CD80 ) after CD47 mAb treatment compared to PBS treatment (all p < 0.05). The metabolic activity of osteosarcomas on F-FDG PET/CT does not show significant changes after CD47 mAb treatment. This lowers the risk of observing pseudoprogression and misinterpreting drug-induced inflammation, simplifying routine clinical scan interpretation.