Oral delivery of MOMIPP lipid nanoparticles for methuosis-induced cancer chemotherapy

Methuosis, a non-apoptotic pattern of cell death, triggers the accumulation of macropinosome-derived vacuoles in the cytoplasm. Through this novel mechanism, methuosis inducers possess great potential in fighting apoptosis-resistant cancer cells and offer a promising alternative for cancer treatment. However, the potent methuosis inducer, 3-(5-methoxy, 2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one (MOMIPP), faces an intractable issue of insolubility in most solvents, hindering in vivo dosing and compromising the validation of its antitumor efficacy. Few strategies have been developed to effectively deliver MOMIPP and achieve robust in vivo tumor inhibition since its first report in 2012. Here, a MOMIPP self-emulsifying drug delivery system (MOMIPP-SEDDS) was developed to substantially improve its oral bioavailability and achieve a favorable antitumor effect in a mouse xenograft tumor model. Our findings demonstrated that the MOMIPP-SEDDS was internalized into Caco-2 cells via the lipid raft/caveolae pathway and exhibited enhanced absorption in both cell monolayers and everted gut sacs. Compared with MOMIPP suspensions, MOMIPP-SEDDS showed a 13.3-fold increase in peak concentration and increased relative bioavailability by 19.98 times. By inducing methuosis, MOMIPP-SEDDS successfully retarded tumor progression in a subcutaneous HeLa mouse tumor model. Additionally, transmission electron microscopy (TEM) images of the tumor sections evidenced the occurrence of methuosis in the MOMIPP-SEDDS treatment group. This MOMIPP-SEDDS emerges as a promising lipid nanoparticle platform and high translational medicine for the oral delivery of MOMIPP to exert methuosis-induced tumor suppression for cancer treatment.