Vatalanib succinate

Exosomes as a unique drug delivery system provide a new choice for tumor therapy. However, the in vitro functionalization of exosomes and the process of circulating drug delivery can easily cause exosome degradation and drug loss, thus reducing the efficiency of drug delivery. In this work, based on the endocyto-fusion-exocytosis pathway of exosome formation, a multifunctional hyaluronic acid nanogel loaded with the antiangiogenic drug vatalanib and the near-infrared photothermal agent indocyanine green (ICG) was designed. Lysosome escape and photothermal therapy were combined to promote exosome production. Hyaluronic acid nanogels were endocytosed by tumor cells with CD44 mediation, forming intracellular vesicle-coated nanogels, which were subsequently degraded by hyaluronidase with high expression in tumor cells. Anti-angiogenic signals in intracellular vesicles were then delivered to vascular endothelial cells by exosomes through membrane fusion and exocytosis, which inhibited tumor angiogenesis to prevent tumor proliferation and metastasis. Cell experiments and tumor models demonstrate that our therapeutic strategy can achieve effective tumor inhibition.

In our attempts to improve pharmacokinetics and pharmacodynamics characters of vatalanib, four strategies of the drug design were applied to design and synthesis new quinoxaline based vatalanib analogs.Antiproliferative activities of the synthesized compounds were investigated against two tumor cell lines (HepG2 and HCT-116) using vatalanib as a pos. control.The new candidates showed promising anticancer activity against two tested cancer cell lines with IC₅₀ values ranging from 6.04 ± 0.19 to 100.15 ± 3.26 μM, in particular compounds 11b and 11c which were more potent than vatalanib.The most potent was the 4-benzoylquinoxaline derivative 11b (IC₅₀ = 6.04 ± 0.19 μM and 15.58 ± 0.58 μM) compared to vatalanib (IC₅₀ of 25.27 ± 0.84 μM and 43.91 ± 1.64 μM) against HepG2 and HCT116, resp.The selectivity indexes of 11b were found to be approx. 14 and 5 towards HepG2 and HCT116, resp.While vatalanib showed selectivity indexes of about 5 and 3 towards HepG2 and HCT116, resp.The most promising compound 11b was further investigated in HepG-2 cells for its apoptotic effect, cell cycle arrest and in vitro VEGFR-2 inhibitory activity as the main mechanisms of cell death.It was found that 11b can induce apoptosis and arrest the cell cycle at the at G1 phase in addition to, compound 11b showed effective inhibition of VEGFR-2 with IC₅₀ of 0.918 ± 0.033 μM compared to vatalanib (IC₅₀ of 0.265 ± 0.009 μM).Deep computational studies were created for the designed compounds including mol. docking, physicochem. properties, profiling pharmacokinetics, ADMET studies, and toxicity predictions to evaluate the prospective drug candidates.The results of the docking study were consistent with biol. testing, furthermore, in silico ADMET study revealed the superior pharmacokinetics characters of the new candidates over vatalanib.So, the current work suggests that the 4-benzoylquinoxaline-1-yl-acetamide derivatives, especially 11b, can serve as lead mols. for development of new effective anticancer drugs.