Human Serum Albumin-Based Dual-Agent Delivery Systems for Combination Therapy: Acting against Cancer Cells and Inhibiting Neovascularization in the Tumor Microenvironment

摘要

To cause tumor regression by acting against cancer cells and inhibiting neovascularization in the tumor microenvironment, we constructed human serum albumin (HSA)-based delivery systems of 2-acetylpyridine-4,4-dimethyl-3-thiosemicarbazone-copper(II) [Cu(Ap44mT)]Cl and paclitaxel to improve both the therapeutic efficacy and the 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 the 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 a pH 4.7 buffer. In vivo results revealed the following: (1) the tumor inhibitory rates of the HSA conjugate and the two-agent combination were 72.1 and 50.7%, respectively; (2) the inhibition rate of tumor angiogenesis of the 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 with the HSA conjugate was about 2-fold that in the tumor treated with the two-agent combination. Obviously, the HSA conjugate not only possessed a stronger capacity to inhibit neovascularization and the growth of liver tumors but also improved the targeting ability compared to the combination of the two agents alone.