TPGS incorporated solanesol-paclitaxel prodrug nanoparticles for synergic therapy of cancer.

Paclitaxel (PTX) chemotherapy is severely limited by poor aqueous solubility, off-target toxicity, and P-glycoprotein-mediated multidrug resistance (MDR). Herein, we report a redox-responsive prodrug nanosystem, SOL-SS-PTX, constructed by conjugating PTX to the bioactive natural polyisoprenoid solanesol (SOL) via a disulfide bond. Unlike conventional polymer- or lipid-based carriers, SOL simultaneously serves as the hydrophobic self-assembly driver and a pharmacologically active co-agent, enabling synergistic antitumor activity. The prodrug spontaneously self-assembles into uniform nanoparticles with an ultra-high drug loading of approximately 50% (w/w). D-α-Tocopheryl polyethylene glycol succinate (TPGS) is further incorporated to enhance stability and reverse MDR via P-gp inhibition. In a reductive tumor-mimetic environment, cumulative PTX release exceeded 80% within 48 h, while less than 10% PTX leakage occurred physiological conditions. In vitro, SOL-SS-PTX/50%TPGS exhibited potent cytotoxicity against both sensitive (A549, HepG-2) and resistant (A549/MDR) cells, achieving a reversal resistance index (RRI) higher than that of the ester-linked control (2.75 fold). In H22 xenograft-bearing mice, the nanoformulation achieved a 69.7% tumor growth inhibition rate with no observable organ toxicity. This work establishes SOL-SS-PTX as a high-drug-loading, stimulus-responsive prodrug platform that synergistically integrates natural product pharmacology, redox-triggered release, and MDR reversal for drug-resistant cancer therapy.