LAUSR

To cause tumor regression by acting against cancer cells and inhibiting neovascularization in the tumor microenvironment, we constructed human serum albumin (HSA) 2-acetylpyridine-4,4-dimethyl-3-thiosemicarbazone-copper(II) [Cu(Ap44mT)]Cl and paclitaxel delivery systems to improve both therapeutic efficacy and targeting ability in vivo. X-ray crystallography and matrix-assisted laser desorption/ionization-time-of-flight mass spectra confirmed that [Cu(Ap44mT)]Cl complexed with HSA, whereas paclitaxel was tethered to the HSA complex by a linker sensitive to active matrix metalloproteinase 2 (MMP2) protein. Up to 78% of paclitaxel was released from HSA within 2 h owing to MMP2 protein cleavage. In addition, a large amount of Cu(Ap44mT) was released from HSA in pH 4.7 buffer. In vivo results revealed that 1) the tumor inhibitory rate of HSA conjugate and two-agent combination was 72.1% and 50.7%, respectively; 2) the inhibition rate of tumor angiogenesis of HSA conjugate (73.3%) was higher than that of the two-agent combination (52.4%); 3) the increased amount of Cu in the tumor treated by HSA conjugate was about 2-fold than that of in the tumor treated by two-agent combination. Obviously, the HSA conjugate not only possessed a stronger capacity to inhibit neovascularization and the growth of liver tumor but also improved the targeting ability compared to the combination of two agents alone.