Browsing by Author "Karathanasis, Efstathios"

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    A comparative analysis of EGFR-targeting antibodies for gold nanoparticle CT imaging of lung cancer.
    (PloS one, 2018-01) Ashton, Jeffrey R; Gottlin, Elizabeth B; Patz, Edward F; West, Jennifer L; Badea, Cristian T
    Computed tomography (CT) is the standard imaging test used for the screening and assessment of suspected lung cancer, but distinguishing malignant from benign nodules by CT is an ongoing challenge. Consequently, a large number of avoidable invasive procedures are performed on patients with benign nodules in order to exclude malignancy. Improving cancer discrimination by non-invasive imaging could reduce the need for invasive diagnostics. In this work we focus on developing a gold nanoparticle contrast agent that targets the epidermal growth factor receptor (EGFR), which is expressed on the cell surface of most lung adenocarcinomas. Three different contrast agents were compared for their tumor targeting effectiveness: non-targeted nanoparticles, nanoparticles conjugated with full-sized anti-EGFR antibodies (cetuximab), and nanoparticles conjugated with a single-domain llama-derived anti-EGFR antibody, which is smaller than the cetuximab, but has a lower binding affinity. Nanoparticle targeting effectiveness was evaluated in vitro by EGFR-binding assays and in cell culture with A431 cells, which highly express EGFR. In vivo CT imaging performance was evaluated in both C57BL/6 mice and in nude mice with A431 subcutaneous tumors. The cetuximab nanoparticles had a significantly shorter blood residence time than either the non-targeted or the single-domain antibody nanoparticles. All of the nanoparticle contrast agents demonstrated tumor accumulation; however, the cetuximab-targeted group had significantly higher tumor gold accumulation than the other two groups, which were statistically indistinguishable from one another. In this study we found that the relative binding affinity of the targeting ligands had more of an effect on tumor accumulation than the circulation half life of the nanoparticles. This study provides useful insight into targeted nanoparticle design and demonstrates that nanoparticle contrast agents can be used to detect tumor receptor overexpression. Combining receptor status data with traditional imaging characteristics has the potential for better differentiation of malignant lung tumors from benign lesions.
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    The impact of respiratory gating on improving volume measurement of murine lung tumors in micro-CT imaging.
    (PloS one, 2020-01) Blocker, SJ; Holbrook, MD; Mowery, YM; Sullivan, DC; Badea, CT
    Small animal imaging has become essential in evaluating new cancer therapies as they are translated from the preclinical to clinical domain. However, preclinical imaging faces unique challenges that emphasize the gap between mouse and man. One example is the difference in breathing patterns and breath-holding ability, which can dramatically affect tumor burden assessment in lung tissue. As part of a co-clinical trial studying immunotherapy and radiotherapy in sarcomas, we are using micro-CT of the lungs to detect and measure metastases as a metric of disease progression. To effectively utilize metastatic disease detection as a metric of progression, we have addressed the impact of respiratory gating during micro-CT acquisition on improving lung tumor detection and volume quantitation. Accuracy and precision of lung tumor measurements with and without respiratory gating were studied by performing experiments with in vivo images, simulations, and a pocket phantom. When performing test-retest studies in vivo, the variance in volume calculations was 5.9% in gated images and 15.8% in non-gated images, compared to 2.9% in post-mortem images. Sensitivity of detection was examined in images with simulated tumors, demonstrating that reliable sensitivity (true positive rate (TPR) ≥ 90%) was achievable down to 1.0 mm3 lesions with respiratory gating, but was limited to ≥ 8.0 mm3 in non-gated images. Finally, a clinically-inspired "pocket phantom" was used during in vivo mouse scanning to aid in refining and assessing the gating protocols. Application of respiratory gating techniques reduced variance of repeated volume measurements and significantly improved the accuracy of tumor volume quantitation in vivo.