Radioactive ^(198)Au-Doped Nanostructures with Different Shapes for In Vivo Analyses of Their Biodistribution, Tumor Uptake, and Intratumoral Distribution

With Au nanocages as an example, we recently demonstrated that radioactive ^(198)Au could be incorporated into the crystal lattice of Au nanostructures for simple and reliable quantification of their in vivo biodistribution by measuring the γ radiation from ^(198)Au decay and for optical imaging by detecting the Cerenkov radiation. Here we extend the capability of this strategy to synthesize radioactive ^(198)Au nanostructures with a similar size but different shapes and then compare their biodistribution, tumor uptake, and intratumoral distribution using a murine EMT6 breast cancer model. Specifically, we investigated Au nanospheres, nanodisks, nanorods, and cubic nanocages. After PEGylation, an aqueous suspension of the radioactive Au nanostructures was injected into a tumor-bearing mouse intravenously, and their biodistribution was measured from the γ radiation while their tumor uptake was directly imaged using the Cerenkov radiation. Significantly higher tumor uptake was observed for the Au nanospheres and nanodisks relative to the Au nanorods and nanocages at 24 h postinjection. Furthermore, autoradiographic imaging was performed on thin slices of the tumor after excision to resolve the intratumoral distributions of the nanostructures. While both the Au nanospheres and nanodisks were only observed on the surfaces of the tumors, the Au nanorods and nanocages were distributed throughout the tumors

Radioactive ^(198)Au-Doped Nanostructures with Different Shapes for In Vivo Analyses of Their Biodistribution, Tumor Uptake, and Intratumoral Distribution

With Au nanocages as an example, we recently demonstrated that radioactive ^(198)Au could be incorporated into the crystal lattice of Au nanostructures for simple and reliable quantification of their in vivo biodistribution by measuring the γ radiation from ^(198)Au decay and for optical imaging by detecting the Cerenkov radiation. Here we extend the capability of this strategy to synthesize radioactive ^(198)Au nanostructures with a similar size but different shapes and then compare their biodistribution, tumor uptake, and intratumoral distribution using a murine EMT6 breast cancer model. Specifically, we investigated Au nanospheres, nanodisks, nanorods, and cubic nanocages. After PEGylation, an aqueous suspension of the radioactive Au nanostructures was injected into a tumor-bearing mouse intravenously, and their biodistribution was measured from the γ radiation while their tumor uptake was directly imaged using the Cerenkov radiation. Significantly higher tumor uptake was observed for the Au nanospheres and nanodisks relative to the Au nanorods and nanocages at 24 h postinjection. Furthermore, autoradiographic imaging was performed on thin slices of the tumor after excision to resolve the intratumoral distributions of the nanostructures. While both the Au nanospheres and nanodisks were only observed on the surfaces of the tumors, the Au nanorods and nanocages were distributed throughout the tumors

Comparison Study of Gold Nanohexapods, Nanorods, and Nanocages for Photothermal Cancer Treatment

Gold nanohexapods represent a novel class of optically tunable nanostructures consisting of an octahedral core and six arms grown on its vertices. By controlling the length of the arms, their localized surface plasmon resonance peaks could be tuned from the visible to the near-infrared region for deep penetration of light into soft tissues. Herein we compare the in vitro and in vivo capabilities of Au nanohexapods as photothermal transducers for theranostic applications by benchmarking against those of Au nanorods and nanocages. While all these Au nanostructures could absorb and convert near-infrared light into heat, Au nanohexapods exhibited the highest cellular uptake and the lowest cytotoxicity in vitro for both the as-prepared and PEGylated nanostructures. In vivo pharmacokinetic studies showed that the PEGylated Au nanohexapods had significant blood circulation and tumor accumulation in a mouse breast cancer model. Following photothermal treatment, substantial heat was produced in situ and the tumor metabolism was greatly reduced for all these Au nanostructures, as determined with ^(18)F-flourodeoxyglucose positron emission tomography/computed tomography (^(18)F-FDG PET/CT). Combined together, we can conclude that Au nanohexapods are promising candidates for cancer theranostics in terms of both photothermal destruction and contrast-enhanced diagnosis

PET/CT Imaging of Chemokine Receptors in Inflammatory Atherosclerosis Using Targeted Nanoparticles

Atherosclerosis is inherently an inflammatory process that is strongly affected by the chemokine/chemokine receptors axes regulating the trafficking of inflammatory cells at all stages of the disease. Of the chemokine receptor family, some specifically up-regulated on macrophages play a critical role in plaque development and may have the potential to track plaque progression. However, the diagnostic potential of these chemokine receptors has not been fully realized. Based on our previous work using a broad-spectrum peptide antagonist imaging 8 chemokine receptors together, the purpose of this study was to develop a targeted nanoparticle for sensitive and specific detection of these chemokine receptors in both a mouse vascular injury model and a spontaneously developed mouse atherosclerosis model. METHODS: The viral macrophage inflammatory protein-II (vMIP-II) was conjugated to a biocompatible poly(methyl methacrylate)-core/polyethylene glycol-shell amphiphilic comb-like nanoparticle through controlled conjugation and polymerization before radiolabeling with (64)Cu for PET imaging in an apolipoprotein E–deficient (ApoE(-/-)) mouse vascular injury model and a spontaneous ApoE(-/-) mouse atherosclerosis model. Histology, immunohistochemistry, and real-time reverse transcription polymerase chain reaction (RT-PCR) were performed to assess the plaque progression and up-regulation of chemokine receptors. RESULTS: The chemokine receptors targeted (64)Cu-vMIP-II-Comb showed extended blood retention and improved biodistribution. PET imaging showed specific tracer accumulation at plaques in ApoE(-/-) mice, confirmed by competitive receptor blocking studies and assessment in wild-type mice. Histopathological characterization showed the progression of plaque including size and macrophage population, corresponding to the elevated concentration of chemokine receptors and more importantly increased PET signals. CONCLUSION: This work provides a useful nanoplatform for sensitive and specific detection of chemokine receptors to assess plaque progression in mouse atherosclerosis models

PET/CT Imaging of Chemokine Receptor CCR5 in Vascular Injury Model Using Targeted Nanoparticle

Inflammation plays important roles at all stages of atherosclerosis. Chemokine systems have major effects on the initiation and progression of atherosclerosis by controlling the trafficking of inflammatory cells in vivo through interaction with their receptors. Chemokine receptor 5 (CCR5) has been reported to be an active participant in the late stage of atherosclerosis and has the potential as a prognostic biomarker for plaque stability. However, its diagnostic potential has not yet been explored. The purpose of this study was to develop a targeted nanoparticle for sensitive and specific PET/CT imaging of the CCR5 receptor in an apolipoprotein E knock-out (ApoE(−/−)) mouse vascular injury model. METHODS: The D-Ala1-peptide T-amide (DAPTA) peptide was selected as a targeting ligand for the CCR5 receptor. Through controlled conjugation and polymerization, a biocompatible poly(methyl methacrylate)-core/polyethylene glycol-shell amphiphilic comblike nanoparticle was prepared and labeled with (64)Cu for CCR5 imaging in the ApoE(−/−) wire-injury model. Immunohistochemistry, histology, and real-time reverse transcription polymerase chain reaction (RT-PCR) were performed to assess the disease progression and upregulation of CCR5 receptor. RESULTS: The (64)Cu-DOTA-DAPTA tracer showed specific PET imaging of CCR5 in the ApoE(−/−) mice. The targeted (64)Cu-DOTA-DAPTA-comb nanoparticles showed extended blood signal and optimized biodistribution. The tracer uptake analysis showed significantly higher accumulations at the injury lesions than those acquired from the sham-operated sites. The competitive PET receptor blocking studies confirmed the CCR5 receptor–specific uptake. The assessment of (64)Cu-DOTA-DAPTA-comb in C57BL/6 mice and (64)Cu-DOTA-comb in ApoE(−/−) mice verified low nonspecific nanoparticle uptake. Histology, immunohistochemistry, and RT-PCR analyses verified the upregulation of CCR5 in the progressive atherosclerosis model. CONCLUSION: This work provides a nanoplatform for sensitive and specific detection of CCR5’s physiologic functions in an animal atherosclerosis model

PET/CT Imaging of Chemokine Receptor CCR5 in Vascular Injury Model Using Targeted Nanoparticle

UnlabelledInflammation plays important roles at all stages of atherosclerosis. Chemokine systems have major effects on the initiation and progression of atherosclerosis by controlling the trafficking of inflammatory cells in vivo through interaction with their receptors. Chemokine receptor 5 (CCR5) has been reported to be an active participant in the late stage of atherosclerosis and has the potential as a prognostic biomarker for plaque stability. However, its diagnostic potential has not yet been explored. The purpose of this study was to develop a targeted nanoparticle for sensitive and specific PET/CT imaging of the CCR5 receptor in an apolipoprotein E knock-out (ApoE(-/-)) mouse vascular injury model.MethodsThe D-Ala1-peptide T-amide (DAPTA) peptide was selected as a targeting ligand for the CCR5 receptor. Through controlled conjugation and polymerization, a biocompatible poly(methyl methacrylate)-core/polyethylene glycol-shell amphiphilic comblike nanoparticle was prepared and labeled with (64)Cu for CCR5 imaging in the ApoE(-/-) wire-injury model. Immunohistochemistry, histology, and real-time reverse transcription polymerase chain reaction (RT-PCR) were performed to assess the disease progression and upregulation of CCR5 receptor.ResultsThe (64)Cu-DOTA-DAPTA tracer showed specific PET imaging of CCR5 in the ApoE(-/-) mice. The targeted (64)Cu-DOTA-DAPTA-comb nanoparticles showed extended blood signal and optimized biodistribution. The tracer uptake analysis showed significantly higher accumulations at the injury lesions than those acquired from the sham-operated sites. The competitive PET receptor blocking studies confirmed the CCR5 receptor-specific uptake. The assessment of (64)Cu-DOTA-DAPTA-comb in C57BL/6 mice and (64)Cu-DOTA-comb in ApoE(-/-) mice verified low nonspecific nanoparticle uptake. Histology, immunohistochemistry, and RT-PCR analyses verified the upregulation of CCR5 in the progressive atherosclerosis model.ConclusionThis work provides a nanoplatform for sensitive and specific detection of CCR5's physiologic functions in an animal atherosclerosis model

Folate Receptor α‑Targeted 89Zr-M9346A Immuno-PET for Image-Guided Intervention with Mirvetuximab Soravtansine in Triple-Negative Breast Cancer

Folate receptor α (FRα) is a well-studied tumor biomarker highly expressed in many epithelial tumors such as breast, ovarian, and lung cancers. Mirvetuximab soravtansine (IMGN853) is the antibody–drug conjugate of FRα-binding humanized monoclonal antibody M9346A and cytotoxic maytansinoid drug DM4. IMGN853 is currently being evaluated in multiple clinical trials, in which the immunohistochemical evaluation of an archival tumor or biopsy specimen is used for patient screening. However, limited tissue collection may lead to inaccurate diagnosis due to tumor heterogeneity. Herein, we developed a zirconium-89 (89Zr)-radiolabeled M9346A (89Zr-M9346A) as an immuno-positron emission tomography (immuno-PET) radiotracer to evaluate FRα expression in triple-negative breast cancer (TNBC) patients, providing a novel means to guide intervention with therapeutic IMGN853. In this study, we verified the binding specificity and immunoreactivity of 89Zr-M9346A by in vitro studies in FRαhigh cells (HeLa) and FRαlow cells (OVCAR-3). In vivo PET/computed tomography (PET/CT) imaging in HeLa xenografts and TNBC patient-derived xenograft (PDX) mouse models with various levels of FRα expression demonstrated its targeting specificity and sensitivity. Following PET imaging, the treatment efficiencies of IMGN853, pemetrexed, IMGN853 + pemetrexed, paclitaxel, and saline were assessed in FRαhigh and FRαlow TNBC PDX models. The correlation between 89Zr-M9346A tumor uptake and treatment response using IMGN853 in FRαhigh TNBC PDX model suggested the potential of 89Zr-M9346A PET as a noninvasive tool to prescreen patients based on the in vivo PET imaging for IMGN853-targeted treatment