Self-assembled nanomicelles for oral delivery of luteolin utilizing the intestinal lymphatic pathway to target pancreatic cancer.

ABSTRACT

Pancreatic cancer is one of the major cause of cancer-related deaths worldwide, and is mainly associated with carcinomas of the pancreatic tissue. Current therapies for treating pancreatic cancer have a major drawback related to their low bioavailability and non-specificity, which leads to low therapeutic efficacy and side effects. Luteolin (LUT) has been clinically used for treatment of various types of cancer, although its clinical use has declined owing to its low oral bioavailability. In this work, we prepared an effervescent-based nanocarrier (NG) that rapidly triggers an effervescent reaction and transforms into nanomicelles to modulate the oral bioavailability of the hydrophobic drug Luteolin (LUT). Furthermore, we performed tests to assess its in vitro epithelial cell permeability and cellular internalization on a Caco-2 monolayer. We also performed in vivo toxicity assessment using animal models. Further, we evaluated the nanocarrier system's in vivo efficacy in tumor xenograft pancreatic cancer models. We validated that being pH responsive, our effervescent carrier disassembles at intestinal pH and is absorbed through the intestinal lymphatic system (ILS) to further site-specifically invade the pancreatic cancer cells. Furthermore, the negative surface charge and particle size (450 ± 100 nm) of the nanomicelles helped to internalize LUT through the ILS. We observed that LUT-loaded nanomicelles have significant antipancreatic cancer efficacy by activating caspase-3 activity and downregulating VEGF-A, FAK, TNF-α, and Ki-67. Unlike other drug-delivery systems, we developed noninvasive nanocarrier system has the capability of transporting the hydrophobic drug LUT from the intestine to the tumor site by utilizing the ILS.