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Highly Sensitive Hill-Type Small-Molecule pH Probe That Recognizes the Reversed pH Gradient of Cancer Cells

Author:
Luo, Xiao, Yang, Haotian, Wang, Haolu, Ye, Zhiwei, Zhou, Zhongneng, Gu, Luyan, Chen, Jinquan, Xiao, Yi, Liang, Xiaowen, Qian, Xuhong, Yang, Youjun
Source:
Analytical chemistry 2018 v.90 no.9 pp. 5803-5809
ISSN:
1520-6882
Subject:
biopsy, cell membranes, guidelines, histopathology, membrane permeability, neoplasm cells, neoplasms, pH
Abstract:
A hallmark of cancer cells is a reversed transmembrane pH gradient, which could be exploited for robust and convenient intraoperative histopathological analysis. However, pathologically relevant pH changes are not significant enough for sensitive detection by conventional Henderson–Hasselbalch-type pH probes, exhibiting an acid–base transition width of 2 pH units. This challenge could potentially be addressed by a pH probe with a reduced acid–base transition width (i.e., Hill-type probe), appropriate pKₐ, and membrane permeability. Yet, a guideline to allow rational design of such small-molecule Hill-type pH probes is still lacking. We have devised a novel molecular mechanism, enabled sequential protonation with high positive homotropic cooperativity, and synthesized small-molecule pH probes (PHX1–3) with acid–base transition ranges of ca. 1 pH unit. Notably, PHX2 has a pKₐ of 6.9, matching the extracellular pH of cancer cells. Also, PHX2 is readily permeable to cell membrane and allowed direct mapping of both intra- and extracellular pH, hence the transmembrane pH gradient. PHX2 was successfully used for rapid and high-contrast distinction of fresh unprocessed biopsies of cancer cells from normal cells and therefore has broad potentials for intraoperative analysis of cancer surgery.
Agid:
5986397