Abstract
Bone metastasis remains a challenge in cancer treatment. Here we show enzymatic responsive rigid-rod aromatics acting as the substrates of "undruggable" phosphatases to kill cancer cells in a mimetic bone microenvironment. By phosphorylation and conjugating nitrobenzoxadiazole (NBD) to hydroxybiphenylcarboxylate (BP), we obtained pBP-NBD (
) as a substrate of both acid and alkaline phosphatases.
effectively kills both metastatic castration-resistant prostate cancer cells (mCRPCs) and osteoblast mimic cells in their coculture.
enters Saos2 almost instantly to target the endoplasmic reticulum (ER) of the cells. Co-culturing with Saos2 cells boosts the cellular uptake of
by mCRPCs. Cryo-EM reveals the nanotube structures of both
(2.4 Å resolution, pH 5.6) and
(2.2 Å resolution, pH 7.4). The helical packing of both nanotubes is identical, held together by strong pi-stacking interactions. Besides reporting the atomistic structure of nanotubes formed by the assembly of rigid-rod aromatics, this work expands the pool of molecules for designing EISA substrates that selectively target TME.