Developing a Gallium(III) Agent Based on the Properties of the Tumor Microenvironment and Lactoferrin: Achieving Two-Agent Co-delivery and Multi-targeted Combination Therapy of Cancer

To develop a next-generation anticancer metal-based drug,
realize
the multi-targeted combination therapy of protein drug and metal-based
drug for cancer, solve their co-delivery challenges, and improve their
in vivo targeting ability, we proposed to develop a multi-targeted
anticancer metal-based agent exploiting the properties of the tumor
microenvironment (TME) and of lactoferrin (LF). To this end, we optimized
a series of gallium (Ga, III) isopropyl-2-pyridyl-ketone thiosemicarbazone
compounds to obtain a Ga compound (C4) with remarkable cytotoxicity
and then constructed a new LF-C4 nanoparticle (LF-C4 NP) delivery
system. In vivo studies showed that LF-C4 NPs not only had a greater
capacity for inhibiting tumor growth than LF or C4 alone but also
solved the co-delivery problems of LF and C4 and improved their targeting
ability. Furthermore, free C4 and LF-C4 NPs inhibited tumor growth
through multiple synergistic actions on the TME: killing cancer cell,
inhibiting tumor angiogenesis, and activating immune system.