Synthesis, Metal‐Exchange, and Hyaluronate Functionalization of a Cationic Gallium‐Based Thiosemicarbazone Anticancer Drug

We herein demonstrate that the thiosemicarbazone (TSC) ligand N'-(di(pyridin-2-yl)methylene)-4-(thiazol-2-yl)piperazine-1-carbothiohydrazide (HL) can coordinate with Ga3+ to give the cationic complex of [Ga(L)2]NO3 featuring an the octahedral Ga(III) center. [Ga(L)2]NO3 may undergo metathesis with both Fe2+ and Fe3+ and result in the formation of respective Fe2+- and Fe3+ complex. Meanwhile, [Ga(L)2]NO3 is also susceptible to anion exchange with solidum hyaluronate (NaA) to produce the nanoformulation of [Ga(L)2]A with boosted aqueous solubility and cell targetability. [Ga(L)2]A demonstrated remarkable in vitro cytotoxicity against NCI-H82 and A549 (lung cancer), as well as KYSE-510 and Te-1 (esophageal cancer) cell lines, featuring half maximal inhibitory concentration (IC50) values in the range of 0.102 − 2.616 μmol L−1. This work highlights the potential of using non-toxic and biocompatible Ga3+ as the central ion to prepare TSC-based nanomedicines for combating cancer.