Sigma receptor-mediated targeted delivery of anti-angiogenic multifunctional nanodrugs for combination tumor therapy

The potential of low molecular weight heparin (LMWH) in anti-angiogenic therapy has been tempered by poor in vivo delivery to the tumor cell and potentially harmful side effects, such as the risk of bleeding due to heparin's anticoagulant activity . In order to overcome these limitations and further improve the therapeutic effect of LMWH, we designed a novel combination nanosystem of LMWH and ursolic acid (UA), which is also an angiogenesis inhibitor for tumor therapy. In this system, an amphiphilic LMWH-UA (LHU) conjugate was synthesized and self-assembled into core/shell nanodrugs with combined anti-angiogenic activity and significantly reduced anticoagulant activity. Furthermore, DSPE-PEG-AA-modified LHU nanodrugs (A-LHU) were developed to facilitate the delivery of nanodrugs to the tumor. The anti-angiogenic activity of A-LHU was investigated both in vitro and in vivo . It was found that A-LHU significantly inhibited the tubular formation of human umbilical vein endothelial cells (HUVECs) (p   <   0.01) and the angiogenesis induced by basic fibroblast growth factor (bFGF) in a Matrigel plug assay (p   <   0.001). More importantly, A-LHU displayed significant inhibition on the tumor growth in B16F10-bearing mice in vivo . The level of CD31 and p-VEGFR-2 expression has demonstrated that the excellent efficacy of antitumor was associated with a decrease in angiogenesis. In conclusion, A-LHU nanodrugs are a promising multifunctional antitumor drug delivery system.