MALEIC ANHYDRIDE PROTON SPONGE AND ITS DERIVATIVES TOWARD MALDI-MSI BASED BRAIN TUMOR DIAGNOSIS

摘要

The diagnosis of malignant glioma, one of most aggressive brain tumor, is still a challenge in the biomedical and surgical imaging procedures. An emerging cancer hallmark is the reprogramming metabolism where the energy metabolism is adjusted to enhance the energy supply and therefore the biosynthetic pathways for the uncontrolled cell growth. The main metabolic phenotypes in a tumor cell are an overproduction of lactate, so called Warburg effect, and several mutations of mitochondrial enzymes. Due to this, an alteration of cellular metabolism occurs causing the cancer progression [1]. Imaging of cancer metabolism is an optimal diagnostic tool for an accurate glioma classification and localization of tumor in surgical biopsies. In this regard, Matrix Assisted Laser Desorption Ionization Mass Spectrometry Imaging (MALDI-MSI), a multi-component imaging technique able to detect and localize onto the tissue many compounds at the same run, could perform a visualization of the cancer metabolism directly on the glioma tissue. Unfortunately the detection of metabolites is still challenge because of low concentrations, matrix interference and fragmentations phenomena. It is known that the chemistry of matrix serves fundamental functions in desorption and ionization. For this reason the search for new MALDI matrices is required and then improve the limit detection of metabolites without any matrix background. For the first time, the 1,8bis(dimethylamino)naphthalene (DMAN) or Proton Sponge was used in MALDI-MS for the detection of small weak acidic compounds with any matrix interference [2]. Unfortunately it was observed that DMAN is vacuum stable and then not suitable for the long-time MALDI-MSI procedures. Indeed in order to increase the vacuum stability the DMAN was structural modified generating two derivatives 1,8-Di(piperidinyl)-naphthalene (DPN) [3] and 3-(4,5-bis(dimethylamino)napthalen-1-yl)furan-2,5-dione (4-maleicoanhydrido proton sponge or MAPS) [4],[5]. Regarding the para-substituted derivative MAPS, it was shown that this novel MALDI-MSI matrix is able to detect and localize compounds as small as chloride directly onto glioma tissues [6]. This work wants to show the potentiality of the MAPS as MALDI-MSI matrix in the discovery of novel biomarker candidates in the glioma diagnosis and as synthetic precursor of a new proton sponge based matrices generation.