Cinnamaldehyde /naringin co-loaded into lactoferrin/ casienate-coated zein nanoparticles as a gastric resistance oral carrier for mitigating doxorubicin-induced hepatotoxicity

Doxorubicin (DOX) is a potent anticancer drug with severe toxic side effects on vital organs. The main mechanism of DOX's toxicity includes overproduction of reactive oxygen species (ROS) causing extensive oxidative stress. In order to minimize DOX-induced hepatotoxicity, cinnamaldehyde (CNM) and naringin (NAR) were coencapsulated into zein nanoparticles (NPs). Afterwards, the dual-loaded NPs were dual-coated with lactoferrin (LF) and sodium casieate (NaCAS) in order to resist the gastric acidity upon oral administration. CNM/NARloaded LF/NaCAS-coated zein NPs exhibited a double coated spherical shape with particle size of 268.5 +/- 6.4 nm, zeta potential of -12 +/- 1.1 mV, and EE% of 79.54 +/- 4.3 for CNM and 73.61 +/- 2.9 % for NAR. Moreover, dual drug-loaded LF/NaCAS-coated zein NPs demonstrated slow release of CNM and NAR in simulated gastric fluid (SGF) compared to NaCAS-coated NPs, free CNM and free NAR, resulting in enhanced bioavailability. In addition, the prepared formulation showed good physical stability and hemocompatibility. More importantly, when this formulation was orally administrated to DOX oxidative stress-induced mice, they showed improved liver architecture with reduced inflammation and better antioxidant potential with no signs of toxicity, suggesting a reduction in ROS-mediated damage. In conclusion, CNM/NAR-loaded LF/NaCAS-coated zein NPs might be administrated orally in patients receiving DOX as a natural supplement to reduce the detrimental effects of this potent cytotoxic drug.