Toxicity Reduction and Efficacy Promotion of Doxorubicin in the Treatment of Breast Tumors Assisted by Enhanced Oral Absorption of Curcumin-Loaded Lipid-Polyester Mixed Nanoparticles

Curcumin (CUR), a polyphenol derived from turmeric, exhibits anticancer and anti-inflammatory properties. However, it has poor water solubility, stability, and oral bioavailability. To overcome these limitations, lipid-polyester mixed nanoparticles (NPs) embedded in enteric polymer-EudragitL100-55(Eu) were formulated (CUR-NPs-Eu). NPs composed of mPEG-b-PCL have a hybrid core made up of middle chain triglyceride (MCT) and poly(epsilon-caprolactone) (PCL) for enhancing drug loading. The CUR-NPs with MCT content of 10% had a particle size of 121.2 +/- 16.8 nm, zeta potential of -16.25 +/- 1.38 mV, drug loading of 9.8%, and encapsulation efficiency of 87.4%. The transport of the CUR-NPs-Eu across Caco-2 monolayers is enhanced compared with CUR alone (1.98 +/- 0.94 x 10(-6) of curcumin versus 55.43 +/- 6.06 x 10(-6) cm/s of curcumin-loaded NPs) because of the non-disassociated nanostructure during absorption. The absolute bioavailability of CUR-NPs-Eu was 7.14%, which was drastically improved from 1.08% of the CUR suspension (CUR-Sus). Therefore, in the xenograft 4T1 tumor-bearing mice, increased drug accumulation in heart and tumor was noticed because of enhanced oral bioavailability of CUR. The chemosensitizing effect of CUR was attributed to its NF-kappa B reduction effect (148 +/- 11.83 of DOX alone versus 104 +/- 8.71 of combined therapy, ng/g tissue). The cardioprotective effect of CUR was associated with maintenance of cardiac antioxidant enzyme activity and down-regulation of NF-kappa B. This study provided a partial illustration of the mechanisms of chemosensitizing and cardioprotective effects of CUR utilizing the oral availability promotion effect brought by the NPs-Eu formulation. And these results further demonstrated that the capability of this NPs-Eu system in oral delivery of poorly soluble and poorly permeable drugs.