Quantitative analysis of drug distribution in heterogeneous tissues using dual‐stacking capillary electrophoresis–mass spectrometry

• DOI: 10.1111/bph.15988
• Publication Date: 2022-11-15T09:04:41Z
• Authors: Shigehiro Koganemaru; Takayuki Kawai; Hirobumi Fuchigami; Naoyuki Maeda; Kumiko Koyama; Yasutoshi Kuboki; Toru Mukohara; Toshihiko Doi; Masahiro Yasunaga
• Keywords: 0301 basic medicine; 03 medical and health sciences; Neoplasms; Humans; Electrophoresis, Capillary; Mass Spectrometry; Micelles; 3. Good health

Intratumour heterogeneity frequently leads to drug resistance, which is a major issue in discovery. Drug distribution one of the key factors for elucidating resistance mechanism; however, quantitative and regional measurement challenging. Here, we developed novel ultra-sensitive analytical method applied it HER3-targeting antibody-drug conjugate patritumab deruxtecan (HER3-DXd), aiming explore its payload (DXd) within heterogeneous tissues.The named LDMS-CE-MS, capillary electrophoresis-mass spectrometry (CE-MS) coupled with sample preconcentration/separation called "large-volume dual-sample stacking by micelle collapse sweeping (LDMS)". First, performance LDMS-CE-MS DXd detection was evaluated. Subsequently, evaluated bystander effect HER3-DXd, where tumour tissues were excised from xenograft models clinical specimens after administration HER3-DXd. HER3-high expression, adjacent, HER3-low expression regions then sampled laser microdissection quantify released DXd.LDMS concentrated 1000-fold separated hydrophilic bio-matrix through continuous capture release charged micelles, allowing quantification at sub-attomole-level. concentrations decreased order antigen-high > adjacent antigen-low model, whereas specimens, had approximately same concentration. These distributions represent effect.Our successfully visualized attomole-level specimens. This new platform opens era pharmacokinetic analysis, facilitating discovery development.