4 years ago

High-Contrast Fluorescence Detection of Metastatic Breast Cancer Including Bone and Liver Micrometastases via Size-Controlled pH-Activatable Water-Soluble Probes

High-Contrast Fluorescence Detection of Metastatic Breast Cancer Including Bone and Liver Micrometastases via Size-Controlled pH-Activatable Water-Soluble Probes
Daniel J. Siegwart, Gino Occhialini, Yihong Wan, Yunfeng Yan, Hao Zuo, Kejin Zhou, Hu Xiong
Breast cancer metastasis is the major cause of cancer death in women worldwide. Early detection would save many lives, but current fluorescence imaging probes are limited in their detection ability, particularly of bone and liver micrometastases. Herein, probes that are capable of imaging tiny (<1 mm) micrometastases in the liver, lung, pancreas, kidneys, and bone, that have disseminated from the primary site, are reported. The influence of the poly(ethylene glycol) (PEG) chain length on the performance of water-soluble, pH-responsive, near-infrared 4,4′-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) probes is systematically investigated to demonstrate that PEG tuning can provide control over micrometastasis tracking with high tumor-to-background contrast (up to 12/1). Optimized probes can effectively visualize tumor boundaries and successfully detect micrometastases with diameters <1 mm. The bone-metastasis-targeting ability of these probes is further enhanced by covalent functionalization with bisphosphonate. This improved detection of both bone and liver micrometastases (<2 mm) with excellent tumor-to-normal contrast (5.2/1). A versatile method is thus introduced to directly synthesize modular water-soluble probes with broad potential utility. Through a single intravenous injection, these materials can image micrometastases in multiple organs with spatiotemporal resolution. They thus hold promise for metastasis diagnosis, image-guided surgery, and theranostic PEGylated drug therapies. Size-controlled pH activatable probes can universally detect both primary tumor and breast cancer metastases in the liver, lung, pancreas, and kidneys. Covalent functionalization with bisphosphonate successfully enhances bone metastasis imaging and simultaneously illuminates micrometastases in the liver with high signal-to-noise ratio.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/adma.201700131

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