Neutral/negatively charged nanoparticles are beneficial to reduce
plasma protein adsorption and prolong their blood circulation time, while positively charged nanoparticles easily transverse the blood vessel endothelium into a
tumor and easily penetrate the depth of the
tumor via transcytosis. Γ-
Glutamyl transpeptidase (GGT) is overexpressed on the external surface of endothelial cells of
tumor blood vessels and metabolically active
tumor cells. Nanocarriers modified by molecules containing γ-glutamyl moieties (such as
glutathione, G-SH) can maintain a neutral/negative charge in the blood, as well as can be easily hydrolyzed by the GGT
enzymes to expose the cationic surface at the
tumor site, thus achieving good
tumor accumulation via charge reversal. In this study, DSPE-PEG2000-GSH (DPG) was synthesized and used as a stabilizer to generate
paclitaxel (PTX) nanosuspensions for the treatment of Hela
cervical cancer (GGT-positive). The obtained drug-delivery system (PTX-DPG nanoparticles) was 164.6 ± 3.1 nm in diameter with a zeta potential of -9.85 ± 1.03 mV and a high
drug-loaded content of 41.45 ± 0.7%. PTX-DPG NPs maintained their negative surface charge in a low concentration of GGT
enzyme (0.05 U/mL), whereas they showed a significant charge-reversal property in the high-concentration
solution of GGT
enzyme (10 U/mL). After
intravenous administration, PTX-DPG NPs mainly accumulated more in the
tumor than in the liver, achieved good
tumor-targetability, and significantly improved anti-
tumor efficacy (68.48% vs. 24.07%,
tumor inhibition rate, p < 0.05 in contrast to free PTX). This kind of GGT-triggered charge-reversal nanoparticle is promising to be a novel anti-
tumor agent for the effective treatment of such GGT-positive
cancers as
cervical cancer.