Rhodamine Esters As Fluorescent Tumor Painting Agents For Glioblastoma
CANCER RESEARCH(2016)
Abstract
Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LAGBM remains one of the most difficult cancers to treat. Despite surgery, radiation and chemotherapy, tumors invariably recur. There is a strong correlation between extend of resection and subsequent time to recurrence and ultimate patient survival. A key challenge for the neurosurgeon is to minimize removal normal brain tissue whilst being as aggressive as possible with regards of removal of tumor tissue. Defining tumor boundary during surgery remains challenging. Fluorescent dyes such as 5- Aminolevulinic acid, have been studied as aids for tumor delineation but have failed to gain widespread acceptance in clinical practice. It has long been known that a substantial number of cancers, including Glioblastoma, exhibit a hyperpolarization of the plasma and mitochondrial membrane potential. This hyperpolarization is manifest by increased retention of lipophilic cationic dyes (Nernstian probes), such as the SPECT-CT probes 99Tc-Sestamibi and 99Tc-Tetrofosmin in both glioma cells in culture and primary tumors. We synthesized a series of ester derivatives of Rhodamine B with high fluorescence quantum yield in the red spectrum and a very favorable biological safety profile. Utilizing a series of intracranial xenografted glioblastoma pre-clinical mouse models, we show that a single I.V. injection of 1 mg/kg fluoroethylrhodamine ester (RhoFe) results in dramatic selective fluorescence in tumor but not surrounding normal brain tissue. This was observed even in tumors with minimal breakdown of the blood brain barrier, as determined by T1-contrast enhancing agents. RhoFe-tumor-selective fluorescence can remain visible up to 72 hours after injection. Similar results were obtained with Tetramethylrhodamine ester (TMRE) and rhodamine 123 (Rho123), but unlike RhoFe, TMRE proved highly toxic, while Rho123 fluorescence was both weaker and in the green spectrum, accompanied by higher endogenous auto-fluorescence. While well tolerated in vivo, RhoFe shows strong photoxicity in cell culture, suggesting potential as a photodynamic therapy agent. Taken together, these data suggest that RhoFe may be a promising tumor painting agent, with potential utility in fluorescence guided surgery as well as photodynamic therapy.Citation Format: Yu-Hsi Lin, Steven Millward, Seth Gammon, Nikunj Satani, Naima Hammoudi, Joshua Philip Gray, Lindsay E. Kelderhouse, Argentina Ornelas, Haley Schroeder, Florian L. Muller. Rhodamine esters as fluorescent tumor painting agents for glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4242.
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Key words
rhodamine esters,fluorescent tumor,painting
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