Tumor Microenvironment-Responsive Lipid Nanoparticle for Blocking Mitosis and Reducing Drug Resistance in NSCLC

Blocking
mitosis is a promising strategy to induce tumor cell death.
However, AMPK- and PFKFB3-mediated glycolysis can maintain ATP supply
and help tumor cells overcome antimitotic drugs. Inhibiting glycolysis
provides an opportunity to decrease the resistance of tumor cells
to antimitotic drugs. Meanwhile, increased glutathione (GSH) expression
in cancer cells due to glycolysis becomes a target for developing
microenvironment-responsive drugs. Herein, a novel cationic lipid
with disulfide bonds in hydrophobic tails was synthesized and used
to prepare a GSH-triggered lipid nanoparticle named 2-DG@SLNP(siR)
encapsulating both Plk1 siRNA and 2-deoxyglucose (2-DG) for blocking
mitosis and reducing drug resistance of nonsmall cell lung cancer
(NSCLC) cells in vivo. Experimental results showed that the NSCLC
cell cycle was arrested at the G2/M phase by Plk1 siRNA and glycolysis
was effectively inhibited by 2-DG, demonstrating the potential of
2-DG@SLNP(siR) as an efficient platform for blocking mitosis and reducing
drug resistance of cancer cells.