MALDI Matrices for the Analysis of Low Molecular Weight Compounds: Rational Design, Challenges and Perspectives

Abstract

The analysis of low molecular weight (LMW) compounds is of great interest to detect small pharmaceutical drugs rapidly and sensitively, or to trace and understand metabolic pathways. Matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) plays a central role in the analysis of high molecular weight (bio)molecules. However, its application for LMW compounds is restricted by spectral interferences in the low m/z region, which are produced by conventional organic matrices. Several strategies regarding sample preparation have been investigated to overcome this problem. A different rationale is centred on developing new matrices which not only meet the fundamental requirements of good absorption and high ionization efficiency, but are also vacuum stable and "MALDI silent", i. e., do not give matrix-related signals in the LMW area. This review gives an overview on the rational design strategies used to develop matrix systems for the analysis of LMW compounds, focusing on (i) the modification of well-known matrices, (ii) the search for high molecular weight matrices, (iii) the development of binary, hybrid and nanomaterial-based matrices, (iv) the advance of reactive matrices and (v) the progress made regarding matrices for negative or dual polarity mode.

Keywords: LMW compounds; MALDI MS; MSI; matrix.

Figure 1

Rational design strategies and their corresponding advantages.[ ⁴¹ , ⁵⁰ , ⁵² , ¹²⁶ ]

Figure 2

Top: Embedding DHB in a polysiloxane backbone to form a sol‐gel structure. ^[50] Middle: Introducing vinyl groups to DHB to obtain polyethylene‐based P(VDHB) by radical polymerization. Bottom: Introducing vinyl groups to Harmine to obtain polyethylene‐based P(VHarmine) by radical polymerization. ^[52]

Figure 3

Top: molecular structures of conjugated polymer PNDI(T2), PII(T2), PTQ1, P3DDT and P9OFl ^[19] Bottom: Ion images of selected mass channels acquired by MALDI MSI of a coronal rat brain section in negative mode and by using P3DDT as matrix. The distributions of the ionic species are visualized as heat maps. Ionic species (m/z) from top left to bottom right: 113.1 Da (±0.3 Da); 124.0 Da (±0.2 Da); 210.9 Da (±0.3 Da); 309.5 Da (±0.3 Da); 384.7 Da (±0.3 Da); 904.7 Da (±0.3 Da). ^[19]

Figure 4

Top: FMP as a reactive matrix to detect analytes with hydroxy groups. ^[97] Bottom: Derivatization of epinephrine with the reactive matrix 4‐(N‐methyl)pyridinium boronic acid. ^[98]

Figure 5

Structures of DAN and some archetypal proton sponge matrices. DAN: 1,5‐Diaminonaphthalene; ^[124] DMAN: 1,8‐Bis (dimethylamino) naphthalene; ^[69] DPN: 1,8‐Di(piperidinyl)naphthalene; ^[121] MAPS: 3‐(4,5‐Bis (dimethylamino)napthalen‐1‐yl)furan‐2,5‐dione; ^[122] TMGN: 1,8‐Bis(tetramethyl‐guanidino)naphthalene. ^[123]