Inhibitory effects of brusatol delivered using glycosaminoglycan­placental chondroitin sulfate A­modified nanoparticles on the proliferation, migration and invasion of cancer cells.

ABSTRACT

Breakthroughs in cancer management result from the development of drugs that can be used for early diagnosis and effective treatment. Surgery, chemotherapy, radiotherapy and hormone therapy are the main anticancer therapies. However, traditional cancer chemotherapy is associated with serious systemic side effects. Nanoparticles (NPs) provide an effective solution for cancer treatment via the targeted delivery of drugs to cancer cells, while minimizing injury to normal cells. Glycosaminoglycan­placental chondroitin sulfate A (plCSA) is expressed in a number of tumor cells and trophoblasts. A plCSA­binding peptide (plCSA­BP) was isolated from malaria protein VAR2CSA, which can effectively promote the binding of lipid polymer NPs to tumor cells, thereby significantly enhancing the anticancer effect of encapsulated drugs. Brusatol is an important compound derived from Brucea javanica that exerts a multitude of biological effects, including inhibiting tumor cell growth, reducing the reproduction of malaria parasites, reducing inflammation and resisting virus invasion. In the present study, brusatol­loaded NPs (BNPs) or coumarin 6 NPs (CNPs), plCSA­BP and scrambled control peptide­bound BNPs or CNPs were prepared. Ovarian cancer cells (SKOV3), endometrial cancer cells (HEC­1­A) and lung cancer cells (A549) were treated with the NPs. The uptake of plCSA­CNPs by tumor cells was found to be markedly higher compared with that of other types of NPs. Further studies demonstrated that the plCSA­BNPs promoted the apoptosis of cancer cells more effectively and inhibited their proliferation, invasion and migration, accompanied by downregulation of matrix metalloproteinase (MMP)­2, MMP­9 and B­cell CLL/lymphoma 2 (BCL2) levels, but upregulation of BCL2­associated X protein BAX and cleaved caspase­3 levels. The results demonstrated the potential of brusatol delivered by plCSA­modified NPs as a chemotherapeutic agent for the targeted therapy of tumors by regulating the BCL2, BAX, cleaved caspase­3, MMP­2 and MMP­9 pathways, and indicated that it may be an effective and safe strategy for the treatment of various tumors.