Intraductal administration of a polymeric nanoparticle formulation of curcumin (NanoCurc) significantly attenuates incidence of mammary tumors in a rodent chemical carcinogenesis model: Implications for breast cancer chemoprevention in at-risk populations

摘要

Multiple lines of evidence support a role for curcumin in cancer chemoprevention. Nonetheless, despite its reported efficacy and safety profile, clinical translation of curcumin has been hampered by low oral bioavailability, requiring infeasible ‘mega’ doses for achieving detectable tissue levels. We have engineered a polymeric nanoparticle encapsulated formulation of curcumin (NanoCurc) to harness its full therapeutic potential. In the current study, we assessed the chemoprevention efficacy of NanoCurc administered via direct intraductal (i.duc) injection in a chemical carcinogen-induced rodent mammary cancer model. Specifically, Sprague–Dawley rats exposed to systemic N-methyl-N-nitrosourea were randomized to receive either oral free curcumin at a previously reported ‘mega’ dose (200mg/kg) or by direct i.duc injection of free curcumin or NanoCurc, respectively, each delivering 168 µg equivalent of curcumin per rodent teat (a ~20-fold lower dose per animal compared to oral administration). All three chemoprevention modalities resulted in significantly lower mammary tumor incidence compared with control rats; however, there was no significant difference in cancer incidence between the oral dosing and either i.duc arms. On the other hand, mean tumor size, was significantly smaller in the i.duc NanoCurc cohort compared with i.duc free curcumin (P 0.0001), suggesting the possibility of better resectability for ‘breakthrough’ cancers. Reduction in cancer incidence was associated with significant decrease in nuclear factor -κB activation in the NanoCurc treated mammary epithelium explants, compared to either control or oral curcumin-administered rats. Our studies confirm the potential for i.duc NanoCurc as an alternative to the oral route for breast cancer chemoprevention in high-risk cohorts.