Abstract 4012: Visualization of EPR effect and active targeting by using microscopic mass spectrometry

Abstract

Abstract Microscopic mass spectrometry (MMS), in which a microscope is coupled with an atmospheric pressure matrix-assisted laser desorption/ionization (MALDI) and quadruple ion trap time-of-flight (TOF) analyzer has been developed for the investigation of the distribution of various molecules including drugs. The matrix-coated drug sample is ionized and then separated on the basis of its mass-to-charge ratio (m/z). Images were acquired from imaging mass spectrometry (IMS) or tandem mass spectrometry (MS/MS) data. Recently, pharmacokinetic (PK) and pharmacodynamic (PD) studies have become important to evaluate the efficacy and toxicity of the drugs. In these analyses, tissue homogenates are generally used for the quantification by high-performance liquid chromatography (HPLC) or liquid chromatography mass spectrometry (LC-MS). However, they lack the information regarding the drug distribution in a specific anatomical area. The information of the drug distribution would allow us to optimize the drug design enabling more efficient drug delivery. (1) We studied the tissue distribution of paclitaxel (PTX) and its micellar formulation (NK105) using a MMS. NK105 showed much stronger antitumor effects on a human pancreatic cancer BxPC3 xenograft than PTX. In the drug imaging, we demonstrated that NK105 delivered more PTX to the whole tumor tissue. In the mouse model, PTX caused the peripheral neurotoxicity but NK105 did not. Multiple high drug-signal areas surrounding and inside the caudal nerve were observed in the case of PTX, whereas the signals after NK105 administration were quite low. (2) The tissue distribution and controlled drug release of ADC (antibody-drug conjugate) consisting of a tissue factor specific antibody (TF) linked to the anticancer agent monomethyl auristatin E (MMAE) was evaluated in comparison with control-ADC (control antibody-MMAE conjugation). TF-ADC showed stronger antitumor effect on BxPC3 xenograft than control-ADC. We then established the selective detection method of MMAE for distinguishing free MMAE and its conjugated form. The released MMAE signal detected following the accumulation of TF-ADC was greatest 24 h after the administration, compared with the control-ADC at the same time (P<0.01). In summary, we succeeded in visualizing (1) the EPR (Enhanced permeability and retention) effect and (2) active targeting using MMS. The data obtained will facilitate more efficient drug development in the preclinical setting. Citation Format: Masahiro Yasunaga, Masaru Furuta, Koretsugu Ogata, Yuki Fujiwara, Yoshikatsu Koga, Yasuhiro Matsumura. Visualization of EPR effect and active targeting by using microscopic mass spectrometry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4012. doi:10.1158/1538-7445.AM2017-4012