Enhancing Anti-Tumorigenic Efficacy of Eugenol in Human Colon Cancer Cells Using Enzyme-Responsive Nanoparticles

SIMPLE SUMMARY: The migratory and invasive pathways that evolve in the early stage of colorectal cancer (CRC) are crucial in developing the metastatic cascade and drug resistance. Natural plant-based compounds and their active secondary metabolites selectively target several oncogenic and oncosuppressive signaling pathways. The anticancer mechanisms medicated by plant-based compounds can circumvent the associated side effects observed with chemotherapeutic agents. This study has developed a new potential anticancer therapeutic: casein-coated nanoparticles (NPs) encapsulating eugenol (EUG), a potent anti-metastatic molecule. The active form of matrix metalloproteinases (MMPs) predominantly releases at the leading edges of migrating tumor cells and can locally digest the “gatekeeping” casein coat of the EUG-carrying NPs and expose CRC cells to a high local concentration of EUG. Therefore, the targeted delivery of EUG by a “smart” nanoparticle can significantly improve its therapeutic index and minimize side effects on normal cells. ABSTRACT: This study is focused on the selective delivery and release of the plant-based anticancer compound eugenol (EUG) in colorectal cancer cells (CRC). EUG is an apoptotic and anti-growth compound in diverse malignant tumors, including CRC. However, EUG’s rapid metabolization, excretion, and side effects on normal cells at higher dosages are major limitations of its therapeutic potential. To address this problem, we developed a “smart” enzyme-responsive nanoparticle (eNP) loaded with EUG that exposes tumors to a high level of the drug while keeping its concentration low among healthy cells. We demonstrated that EUG induces apoptosis in CRC cells irrespective of their grades in a dose- and time-dependent manner. EUG significantly decreases cancer cell migration, invasion, and the population of colon cancer stem cells, which are key players in tumor metastasis and drug resistance. The “smart” eNPs–EUG show a high affinity to cancer cells with rapid internalization with no affinity toward normal colon epithelial cells. NPs–EUG enhanced the therapeutic efficacy of EUG measured by a cell viability assay and showed no toxicity effect on normal cells. The development of eNPs–EUG is a promising strategy for innovative anti-metastatic therapeutics.