Systemic administration of polymeric nanoparticle-encapsulated curcumin (NanoCurc™) blocks tumor growth and metastases in preclinical models of pancreatic cancer

摘要

Curcumin or diferuloylmethane is a yellow polyphenol extracted from the rhizome of turmeric (Curcuma longa). A large volume of published reports (numbering in several 100s) has established the anti-cancer and chemopreventative properties of curcumin in preclinical models of every known major cancer type. Nevertheless, the clinical translation of curcumin has been significantly hampered due to its poor systemic bioavailability, which mandates that patients consume up to 8-10 grams of the free drug orally each day, in order for detectable levels in the circulation. We have engineered a polymeric nanoparticle encapsulated curcumin formulation (NanoCurc™), which demonstrates remarkably higher systemic bioavailability in plasma and tissues compared to free curcumin upon parenteral administration. In xenograft models of human pancreatic cancer established in athymic mice, administration of parenteral NanoCurc™ significantly inhibits primary tumor growth in both subcutaneous and orthotopic settings. The combination of parenteral NanoCurc™ with gemcitabine results in enhanced tumor growth inhibition versus either single agent, suggesting an additive therapeutic influence in vivo. Furthermore, this combination completely abrogates systemic metastases in orthotopic pancreatic cancer xenograft models. Tumor growth inhibition is accompanied by significant reduction in activation of nuclear factor κ B (NFκB), as well as significant reduction in expression of matrix metalloproteinase MMP-9 and cyclin D1, in xenografts treated with NanoCurc™ and gemcitabine. NanoCurc™ is a promising new formulation that is able to overcome a major impediment for the clinical translation of curcumin to cancer patients by improving systemic bioavailability, and by extension, therapeutic efficacy.