Self-assembled paclitaxel-loaded spermidine-geranic acid ionic liquid nanoaggregates: preparation, enhanced cellular uptake, and antitumor efficacy.

Paclitaxel (PTX) is a potent anticancer drug whose efficacy is limited by poor solubility and severe side effects. This study developed a self-assembled nanoaggregate system based on a novel spermidine-geranic acid ionic liquid ([Spd][Ger] IL) for PTX delivery. The synthesized [Spd][Ger] IL exhibited a low apparent critical aggregation concentration (0.33 mg/mL), and molecular dynamics simulation confirmed its spontaneous self-assembly in water. PTX was efficiently incorporated into [Spd][Ger] nanoaggregates, affording a stable formulation with an encapsulation efficiency of 89.6%, a drug loading of 8.3%, and an average particle size of 171.8 nm. PTX@[Spd][Ger] showed sustained and pH-responsive release, with cumulative PTX release of 73.66% at pH 6.5 and 61.60% at pH 7.4 after 72 h. In vitro, PTX@[Spd][Ger] reduced the IC50 from 2.25 to 0.60 μg/mL in MCF-7 cells and from 4.33 to 1.24 μg/mL in 4 T1 cells after incubation for 24 h, which was attributed to the higher cellular uptake of [Spd][Ger] nanoaggregates. In a 4 T1 orthotopic mouse model, PTX@[Spd][Ger] produced tumor suppression comparable to Taxol® with markedly improved systemic tolerability. These results indicate that [Spd][Ger]-based nanoaggregates provide an effective and safer platform for water-insoluble drug delivery such as PTX.