Abstract
Quantitative screening for potential drug–protein binding is an essential step in developing novel metal-based anticancer drugs. ICP–MS approaches are at the core of this task; however, many applications lack in the capability of large-scale high-throughput screenings and proper validation. In this work, we critically discuss the analytical figures of merit and the potential method-based quantitative differences applying four different ICP–MS strategies to ex vivo drug–serum incubations. Two candidate drugs, more specifically, two Pt(IV) complexes with known differences of binding affinity towards serum proteins were selected. The study integrated centrifugal ultrafiltration followed by flow injection analysis, turbulent flow chromatography (TFC), and size exclusion chromatography (SEC), all combined with inductively coupled plasma-mass spectrometry (ICP–MS). As a novelty, for the first time, UHPLC SEC-ICP–MS was implemented to enable rapid protein separation to be performed within a few minutes at > 90% column recovery for protein adducts and small molecules.Graphical abstractQuantitative screening for potential drug–protein binding is an essential step in developingnovel metal-based anticancer drugs
Highlights
The development of metal-based anticancer drugs continues to be a topical research theme
Already in 1999 [24], size exclusion chromatography (SEC) combined with inductively coupled plasma-mass spectrometry (ICP–MS) emerged as essential tool for studying the interaction of metallodrugs and serum proteins and has seen numerous applications ever since in support of new drug design concepts
The UHPLC SEC-ICP–MS approach established in this work relied on the most advanced columns available on the market
Summary
The development of metal-based anticancer drugs continues to be a topical research theme. Already in 1999 [24], SEC combined with ICP–MS emerged as essential tool for studying the interaction of metallodrugs and serum proteins and has seen numerous applications ever since in support of new drug design concepts. Despite this success, the separation was considered a low-resolution, timeconsuming method. On-line protein removal by turbulent flow chromatography (TFC) was introduced in combination with ICP–MS for studying metal-based anticancer drugs and their protein binding. The separation and elution of the HMF and LMF were carried out by a two inert six-port
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