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Platinum compounds for high-resolution in vivo cancer imaging.

ABSTRACT: Platinum(II) compounds, principally cisplatin and carboplatin, are commonly used front-line cancer therapeutics. Despite their widespread use and continued interest in the development of new derivatives, including nanoformulations with improved properties, it has been difficult to visualize platinum compounds in live subjects, in real time, and with subcellular resolution. Here, we present four novel cisplatin- and carboplatin-derived fluorescent imaging compounds for quantitative intravital cancer imaging. We conjugated 4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-daiza-s-indacene (BODIPY) to Pt(II) complexes to generate derivatives with robust in vivo fluorescence and retained DNA-damaging and cytotoxic properties. We successfully applied these compounds to image pharmacokinetics and tumor uptake in a xenograft cancer mouse model. By using a genetic reporter of single-cell DNA damage for in vivo imaging, Pt drug accumulation and resultant DNA damage could be monitored in individual tumor cells, at subcellular resolution, and in real time in a live animal model of cancer. These derivatives represent promising imaging tools that will be useful in understanding further the distribution and interactions of platinum within tumors.

SUBMITTER: Miller MA

PROVIDER: S-EPMC4037345 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Platinum compounds for high-resolution in vivo cancer imaging.

Miller Miles A MA Askevold Bjorn B Yang Katherine S KS Kohler Rainer H RH Weissleder Ralph R

ChemMedChem 20140206 6

Platinum(II) compounds, principally cisplatin and carboplatin, are commonly used front-line cancer therapeutics. Despite their widespread use and continued interest in the development of new derivatives, including nanoformulations with improved properties, it has been difficult to visualize platinum compounds in live subjects, in real time, and with subcellular resolution. Here, we present four novel cisplatin- and carboplatin-derived fluorescent imaging compounds for quantitative intravital can ...[more]

PMID: 24504646

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Project description:Importance:Targeting the early pathogenic steps in Stargardt disease type 1 (STGD1) is critical to advance our understanding of this condition and to develop potential therapies. Lipofuscin precursors may accumulate within photoreceptors, leading to photoreceptor damage and preceding retinal pigment epithelial (RPE) cell death. Fluorescence adaptive optics scanning light ophthalmoscopy can provide autofluorescence (AF) images in vivo with microscopic resolution to elucidate the cellular origin of AF abnormalities in STGD1. Objective:To study the spatial distribution of photoreceptor, RPE, and AF abnormalities in patients with STGD1 at a cellular level. Design, Setting, and Participants:Cross-sectional study using fluorescence adaptive optics scanning light ophthalmoscopy to compare the cones, rods, and RPE cells between 3 patients with STGD1 and 1 control individual. Imaging sessions were conducted at the University of Rochester. Further image analyses were performed at Beijing Tongren Eye Center and the University of Pittsburgh. Data were collected from August 2015 to February 2016, and analysis began in March 2016. Main Outcomes and Measures:Structural appearance of cones, rods, and AF structures at different retinal locations. Results:Two women and 1 man with macular atrophy phenotype of STGD1 and visual acuity loss ranging from 20/30 to 20/150 and 1 woman without STGD1 with 20/20 visual acuity were analyzed. Cone and rod spacing was increased in all 3 patients at all locations where photoreceptors were detectable; most cones had a dark appearance. Autofluorescence was low contrast but contained structures consistent with RPE cells in the periphery. In the transition zone peripheral to the foveal atrophic lesion, the structural pattern of AF was more consistent with photoreceptors than RPE cells. The microscopic AF was disrupted within areas of clinically detectable atrophy. Conclusions and Relevance:Adaptive optics high-resolution images of cones, rods, and RPE cells at the leading disease front of STGD1 macular atrophy show an AF pattern that appears to colocalize with photoreceptors or may result from a combination of AF signals from both RPE cells and photoreceptors. This in vivo observation is consistent with histologic reports of fluorescence arising from photoreceptors in STGD1. The detection of bisretinoid accumulation in the photoreceptors may represent an early pathologic step in STGD1 and can provide an in vivo imaging tool to act as a biomarker of disease progression.

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Platinum compounds for high-resolution in vivo cancer imaging.

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Platinum compounds for high-resolution in vivo cancer imaging.

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