Non invasive individual monitoring of tumor response to anti-cancer treatments : early detection of radio- and chemo-induced cell death by magnetic resonance imaging
(2010)
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- (en) The improvement in cancer survival in the last decades reflects progresses in early diagnosing and treatments. However it still lacks early evaluation of treatment outcome since it can take several weeks to predict tumor response to treatment, which is usually based on morphological imaging of tumor shrinkage. Therefore will the development of specifically targeted contrast agents have a great impact on the individual assessment of treatment outcome. Patients’ lifetime and quality of life could be improved by novel approaches for detection of treatment response in tumors. The aim of the study was to develop a new molecular marker for non invasive diagnosis and monitoring of cell death in order to evaluate the efficacy of anti-cancer treatments in vivo. The phosphatidylserine-targeted peptide E3, isolated by phage-display, was coupled to pegylated ultrasmall particles of iron oxide (USPIO). USPIO particles are used as negative contrast agent for magnetic resonance imaging (MRI) due to strong T2 and T2* effects and besides this method they can also be quantitatively detected by electron paramagnetic resonance (EPR). Transplantable liver tumors (TLT) were implanted in the gastrocnemius muscle of NMRI mice and tumor cell death was induced by x-ray irradiation. Accumulation of the intravenously administered USPIO-E3 particles in treated and untreated TLT tumors was compared to the accumulation of control particles (ungrafted USPIO and USPIO grafted to a scrambled peptide) ex vivo by X- band EPR, and in vivo by L-band EPR and by T2-weighted MRI. Tumor levels of necrosis and apoptosis were assessed by histology. MRI and X-band EPR were also used to compare accumulation of USPIO-E3 in 3 different tumor models presenting different degrees of radiosensitivity (fibrosarcoma FsaII is less sensitive than hepatocarcinoma TLT which is less sensitive than lymphoma EL4). Different chemotherapeutic agents (cyclophosphamide, 5-fluorouracil and etoposide) were also used to induce different levels of cell death in TLT tumors. Results obtained by T2-weighted and diffusion-weighted MRI, 1H-MR spectroscopy and X-band EPR permit to compare the different techniques. Results: In irradiated tumors was greater accumulation of targeted USPIO particles compared to control particles or compared to accumulation of targeted particles in untreated tissues. The ability of this new biomarker to distinguish between different levels of tumor cell death could be shown using 3 different tumor models and also when using cytotoxic agents presenting different treatment efficiencies. Conclusion: The major finding of the present investigation is that functionalization of the surface of iron oxide particles with the E3 hexapeptide allows the sensitive detection and mapping of tumor cell death after cytotoxic treatment. This molecular targeted system should be further evaluated as a potential biomarker of tumor response to treatment. This work illustrates the need for multi-modal imaging in assessing tumor response to treatment to compensate for individual limitations.
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Radermacher, K. (2010). Non invasive individual monitoring of tumor response to anti-cancer treatments : early detection of radio- and chemo-induced cell death by magnetic resonance imaging. https://hdl.handle.net/2078.5/131108