The significance of microscopic mass spectrometry with high resolution in the visualisation of drug distribution

Abstract

The visualisation and quantitative analysis of the native drug distribution in a pre-clinical or clinical setting are desirable for evaluating drug effects and optimising drug design. Here, using matrix-assisted laser desorption ionisation imaging mass spectrometry (MALDI-IMS) with enhanced resolution and sensitivity, we compared the distribution of a paclitaxel (PTX)-incorporating micelle (NK105) with that of PTX alone after injection into tumour-bearing mice. We demonstrated optically and quantitatively that NK105 delivered more PTX to the tumour, including the centre of the tumour, while delivering less PTX to normal neural tissue, compared with injection with PTX alone. NK105 treatment yielded a greater antitumour effect and less neural toxicity in mice than did PTX treatment. The use of high-resolution MALDI-IMS may be an innovative approach for pharmacological evaluation and drug design support.A dvances in our understanding of cancer at the cellular and molecular levels have promoted the development of new drugs 1,2 . Pharmacokinetic (PK) and pharmacodynamic (PD) studies are very important to evaluate the efficacy and toxicity of new drugs as well as to optimise drug design. For these purposes, tissue homogenate samples are generally analysed by high-performance liquid chromatography (HPLC) or liquid chromatography mass spectrometry (LC-MS) 3 . For the development of anticancer drugs (ACAs), including molecular targeting agents, precise chemical modulation is needed because the small differences between cancer cells and their host cells creates a narrow therapeutic window. In addition, clinical human cancer tissues generally exhibit abundant and versatile stroma, which is the result of the process of tumour cell invasion into tumour vessels, haemorrhage, fibrin clot formation, and replacement with collagen tissues and non-malignant stromal cells. Therefore, it is very important to consider the delivery of ACAs to cancer tissues and their distribution to target cancer cells within this heterogeneous tumour microenvironment. Furthermore, the drug distribution within normal tissues, particularly vital organs, should also be evaluated because ACAs frequently cause adverse effects 4 . A large body of clinical evidence has revealed that neoadjuvant chemotherapy is useful for a variety of solid tumours. The tissue excised during surgery or endoscopic biopsy can be used to investigate drug distribution 5,6 . Thus, a convenient method for evaluating the distribution of clinically used native (non-radiolabeled or non-chemically modified) drugs is urgently required.Matrix-assisted laser desorption ionisation imaging mass spectrometry (MALDI-IMS) has been developed for the investigation of the distribution of molecules such as small peptides, drugs, and their metabolites 7-12 . Moreover, MALDI-IMS can be used to evaluate numerous molecules in a single measurement without a specialised probe [7][8][9][10][11][12] . Therefore, this method enables the observation of a drug directly within tissue with the distinction bet...

Drug compound characterization by mass spectrometry imaging in cancer tissue

“…Recently, high resolution MSI provided a significant advantage of autoradiography from the aspect of the drug metabolites (Fehniger et al 2011;Jirasko et al 2014;Liu et al 2013;Buck et al 2015) and demonstrated the distribution of a confirmed drug metabolite that possibly lead to the drug toxicity (Török et al 2015). The technology is today making important contributions in fields such as PK screening (Castellino et al 2013), novel pro-drug concepts (Nilsson et al 2010;Fehniger et al 2011), drug delivery systems (DDS) by micellar nanoparticle formulation (Swales et al 2014), biomarkers for PD (Yasunaga et al 2013;Shariatgorji et al 2014;Cobice et al 2013) as well as proteomics (Goto et al 2014;Ye et al 2014). MSI ultimately leads to a better understanding of ADME, PK/PD and TK/TD.…”

Small molecule-sensing strategy and techniques for understanding the functionality of green tea

“…5) To overcome the limitation of the 1,5-DAN-MALDI-MSI technique and to ensure its practical use, further improvement of its detection sensitivity, such as employing a targeted selective reaction monitoring mode (SRM) approach using a triple quadrupole system (QqQ), 89) application of a Fourier transform ion cyclotron resonance-MS (FT-ICR-MS) instrument capable of accumulating continuously selected ions, 90) and on-tissue chemical derivatization approaches to increase the ionization efficiency 91,92) as well as the improvement of MALDI efficiency based on matrix choice and development, may be required. Additionally, other studies including kinetic histochemistry, 80,84,93) microscopic analysis with high-spatial resolution, [94][95][96] 3D imaging, [97][98][99] , and distribution of other metabolites 86,99) will be required to unravel both the biological consequences of biotransformation of the dietary polyphenol and its mechanism (s) of action. …”

The Drug Discovery by NanoMedicine and its Clinical Experience

“…In the study using matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS), significant levels of PTX, even in the core of the tumor tissue, were observed following NK105 administration, and the NK105 was retained for a long period of time ( Fig. 6A) (56). Low molecular weight (LMW) ACAs, including molecular targeting agents, can easily extravasate from normal blood vessels and cause various adverse effects.…”