Curcumin-Loaded Nanoparticles Impair the Pro-Tumor Activity of Acid-Stressed MSC in an In Vitro Model of Osteosarcoma.

In the tumor microenvironment, mesenchymal stromal cells (MSCs) are key modulators of cancer cell behavior in response to several stimuli. Intratumoral acidosis is a metabolic trait of fast-growing tumors that can induce a pro-tumorigenic phenotype in MSCs through the activation of the NF-κB-mediated inflammatory pathway, driving tumor clonogenicity, invasion, and chemoresistance. Recent studies have indicated that curcumin, a natural ingredient extracted from Curcuma longa, acts as an NF-κB inhibitor with anti-inflammatory properties. In this work, highly proliferating osteosarcoma cells were used to study the ability of curcumin to reduce the supportive effect of MSCs when stimulated by acidosis. Due to the poor solubility of curcumin in biological fluids, we used spherical polymeric nanoparticles as carriers (SPN-curc) to optimize its uptake by MSCs. We showed that SPN-curc inhibited the release of inflammatory cytokines (IL6 and IL8) by acidity-stimulated MSCs at a higher extent than by free curcumin. SPN-curc treatment was also successful in blocking tumor stemness, migration, and invasion that were driven by the secretome of acid-stressed MSCs. Overall, these data encourage the use of lipid-polymeric nanoparticles encapsulating NF-κB inhibitors such as curcumin to treat cancers whose progression is stimulated by an activated mesenchymal stroma.