Small flexible structure for targeted delivery of therapeutic and imaging moieties in precision medicine.

The goals of precision medicine are to link diagnostic and therapeutic agents, improve clinical outcomes, and minimize side effects. We present a simple, small, flexible three-armed core structure that can be conjugated to targeting, imaging, and therapeutic moieties. The targeting molecule can be a peptide, protein, or chemical compound. The diagnostic reporter can be optical and/or nuclear in nature, and can be replaced by chemo- and/or radiotherapeutic compounds for treatment using a single targeting molecule. Imaging components can be used to detect disease biomarkers, monitor treatment response, and guide surgery in real-time to create a tumor-free margin. Isotope impurity can be exploited to visualize whole-body distribution of therapeutic agents. The one-to-one ratio of targeting component to therapeutic agents facilitates dose calculation. The simple synthesis and flexible, modular nature of the agent facilitate high-purity, large-scale production. The core capacity to "seek, treat, and see" may advance precision medicine in the future.

CXCR4-targeted near-infrared imaging allows detection of orthotopic and metastatic human osteosarcoma in a mouse model.

CXCR4 is expressed at primary and metastatic sites of osteosarcoma. We developed a novel CXCR4-targeted near-infrared (NIR) fluorescent imaging agent (referred to as CXCR4-IR-783). The binding to representative osteosarcoma cells (F5M2 and F4 for high- and low- CXCR4 expression) was examined. CXCR4-IR-783 fluorescence was also examined in a mouse xenograft model of human osteosarcoma using NIR fluorescence microscopy and a Kodak in-vivo multispectral system. Pulmonary metastases in mice bearing osteosarcoma xenografts were detected by micro CT, (18)F-PET scan and NIR imaging scan. Briefly, the binding of CXCR4-IR-783 was significantly higher in F5M2 than in F4 cells. Intense NIR fluorescence signals were detected in osteosarcoma xenografts, with signal/background ratio at 4.87 in mice bearing the F5M2 cell. At 4 weeks after F5M2 cell inoculation, metastatic lesions in the lungs were detectable using CXCR4-IR-783 and micro-CT scan, but not with (18)F-FDG PET scan. In conclusion, CXCR4-IR-783 is a promising tool for detection of high CXCR4-expressing osteosarcoma, and particularly for its metastatic lesions.

Combination of individualized local control and target-specific agent to improve unresectable liver cancer managements: a matched case-control study.

Management of late-stage hepatocellular carcinoma is difficult. A direct comparison of clinical data is needed in order to demonstrate the survival benefits of different therapies. We directly compared various therapies in a retrospective matched case-control study. A total of 79 patients with unresectable tumors greater than 10 cm in size were included in the study between 2008 and 2012. Thirty-five patients were treated with transarterial chemoembolization for local control, 20 were treated with sorafenib systemic chemotherapy, and 24 received combination treatment. The total follow-up time after initial therapy was 4.5 years. Survival time after treatment was significantly longer in the combination therapy group (P < 0.0001). The median survival times for combination, local control, and systemic chemotherapy were 15 (12-21), 10 (9-13), and 3.5 (2.5-9.0) months (95 % confidence interval), respectively. The hazard ratios for local control and systemic chemotherapy were 1.985 and 5.102, respectively, with combination treatment as the reference. There was no observed difference in combination therapy from the side effects of the individual therapies. In conclusion, the limited availability of therapeutic options for late-stage liver cancer necessitates reliance on multidisciplinary personalized medicine approaches with target-specific medications to increase survival time. Combining individualized local control therapy and drugs that target specific disease markers provides more benefits to patients.

Multi-modality imaging to determine the cellular heterogeneity of nasopharyngeal carcinoma components.

Nasopharyngeal carcinoma (NPC) is an endemic public health problem in South and Southeast Asian countries. The disease components at the molecular level are unclear and need exploration for the development of future individualized molecular medicine. The purpose of this study was to test the feasibility of target-specific agents to detect different components of NPC. The binding capability of human NPC cell lines was determined by incubation with either agents that specifically target the metabolic status, host cytokines, and stroma. Mice bearing human NPC xenografts were injected with the same test agents plus a clinical molecular imaging agent (18F-fluorodeoxyglucose) and computer tomography (CT) contrast agent. In vitro cell studies have demonstrated that target-specific agents bind to NPC cells with significantly higher signal intensities. Those agents not only bound to the cell membrane but also penetrated into the cytosol and cell nuclei. In vivo imaging demonstrated that the human NPC xenografts revealed high glucose uptake and a profound vasculature in the tumor. All agents were bound to the tumor regions with a high tumor-to-muscle ratio. Finally, all imaging data were validated by histopathological results. Multiple, target-specific agents determine the dynamic and heterogeneous components of NPC at the molecular level.