Targeted Delivery Ursolic Acid To Brain-metastasis Melanoma By PLGA Core-shell Nanoparticles

Brain tumor is one of leading reason causing death. Despite the many advances have been made, the survival after treatment still is poor. In the course of screening new natural products for inhibition of brain-metastasis melanoma, we found that ursolic acid (UA) showed the potent inhibition activity against melanoma cells with low toxicity in vivo. However, the anti-cancer activity of UA in vivo in mice was found to be limited in the xenograft models including solid-tumor model or metastasis cancer model. In this work, therefore, we developed a new UA-loaded Poly(lactic-co-glycolic acid) (PLGA) nanoparticles for targeting brain-metastasis melanoma. The free UA was first encapsulated into PLGA emulsion by simple emulsion solvent evaporation method to form the UA-loaded PLGA nanoparticles. Then UA-loaded PLGA nanoparticles was coated with chitosan (CS). And end, the surface of the obtain amino group was further to linked with a hyaluronic acid (HA), an anionic, nonsulfated glycosaminoglycan with high affinity to cell receptors including CD44 on the melanoma. As vitro experiments shown, the UA-loaded PLGA nanomedicine coated with HA through the interaction between CD44 receptor and HA ligand showed high affinity to melanoma and inhibited the growth of B16 cells. As vivo experiments shown, comparation of free UA and nanomedicine without HA,HA coated UA loaded PLGA nanomedicne had the stronger inhibiton vibility of growth of brain-metastasis melanoma and prolonged the survival of brain-metastasis melanoma model. Mechanically, further experimental confirmed that the nanomedicine deliveried UA into the melanoma cells and resulted in ROS accumulation, MMP decreasion, AIF translocation and cell-cycle arrest and following apoptotic cell death. In conclusion, the UA-loaded PLGA core-shell nanomedicine coated with CS-HA might present a promising intracerebral drug delivery system to target brain-metastasis melanoma.