Examining and improving the chemopreventive efficacy of curcumin

Abstract

Curcumin, a polyphenol extracted from turmeric, has shown chemopreventive and chemotherapeutic effects against cancer. However, curcumin suffers from poor bioavailability, which limits its clinical use. We hypothesized that using novel microparticle and SMEDDS formulations will improve the pharmacokinetics and therapeutic efficacy of curcumin. Initial studies examined the anticancer efficacy of curcumin loaded poly(lactide-co-glycolic acid) (PLGA) microparticles in a transgenic mouse model of human epidermal growth factor receptor-2 (HER-2) cancer, Balb-neuT. HER-2 is overexpressed in 30% of breast cancer cases and is associated with poor prognosis and high incidence of metastasis. Curcumin microparticles delayed tumor appearance by 2-3 weeks and were associated with a decrease in VEGF protein levels and CD-31+ microvasculature compared to empty microparticles. However, when compared to saline controls, blank microparticles appeared to accelerate tumorigenesis. Blank PLGA microparticles were shown to activate NF-kB signaling, indicating systemic inflammation after injection. The delay in tumorigenesis with curcumin-loaded microparticles was likely attributed to the anti-inflammatory effects of curcumin. Future studies will examine the systemic effects of blank PLGA microparticles as well as explore other polymers for curcumin microparticle delivery. A self microemulsifying drug delivery system (SMEDDS) was examined for oral delivery of curcumin. The SMEDDS formulation solubilized curcumin at high concentrations (~45 mg/mL). However, administering curcumin in the SMEDDS formulation did not increase curcumin bioavailability but increased gut absorption, evident by increased plasma curcumin glucuronide levels. We hypothesized that oral bioavailability of curcumin could be enhanced by increasing its absorption and decreasing metabolic clearance simultaneously. Microsomal studies showed that silibinin and quercetin inhibited curcumin glucuronidation in vitro. Piperine, which was shown to improve curcumin bioavailability previously, silibinin and quercetin were administered with curcumin in vivo. Coadministration of curcumin and piperine showed high variability after dosing. Addition of silibinin significantly improved curcumin bioavailability (3.5 fold) compared to curcumin alone. Future studies should examine the chemopreventive potential of curcumin and silibinin for HER-2+ breast cancer.