Metastasis is a multistep biological process regulated by multiple signaling pathways. The integrity of the Golgi apparatus plays an important role in these signaling pathways. Inspired by the mechanism and our previous finding about accumulation of chondroitin sulfate in Golgi apparatus in hepatic stellate cells, we developed a Golgi apparatus-targeting prodrug nanoparticle system by synthesizing retinoic acid (RA)-conjugated chondroitin sulfate (CS) (CS-RA). The prodrug nanoparticles appeared to accumulate in the Golgi apparatus in cancer cells and realized RA release under an acidic environment. We confirmed that CS-RA exhibited successful inhibition of multiple metastasis-associated proteins expression in vitro and in vivo by disruption of the Golgi apparatus structure. Following loading with paclitaxel (PTX), the CS-RA based nanoformulation (PTX-CS-RA) inhibited migration, invasion, and angiogenesis in vitro and suppressed tumor growth and metastasis in 4T1-Luc bearing mice. This multistep targeted nanoparticle system potentially enhanced the effect of antimetastasis combined with chemotherapy.
Keywords: Golgi apparatus; chondroitin sulfate; combination therapy; drug delivery; metastasis; metastasis-associated proteins; prodrug; self-assembly.