RESUMO
The prognosis of pancreatic cancer (PCa) is extremely poor because of its resistance to conventional therapies. Many previous studies have demonstrated that triptolide (TPL) has a potent tumoricidal activity on PCa. However, the clinical application of TPL in tumor therapy has been greatly limited by its poor aqueous solubility, short half-time, high toxicity and inefficient delivery. Here, through the engineering of prodrug technology combined with the nanodrug-delivery system (NDDS) strategy, we modified the main active site of TPL C14-OH by esterification reaction to obtain a highly lipophilic prodrug, and then encapsulated the drug in a phospholipid bilayer in liposomal vehicles through the thin-film hydration method for efficient delivery. A delivery system based on TPL lignocerate liposomes (TPL-LA-lip) for drug loading for targeted therapy against PCa was established. Our results showed that TPL-LA demonstrates exceptional compatibility with the phospholipid layer of liposomes, thereby enhancing drug retention in liposomal vehicle and improving tumor targeting and cellular uptake. Moreover, The system of TPL-LA-lip exhibited a sustained drug release profile in vitro, and intravenous administration significantly impedes tumor progression while reducing the toxicity of TPL in the PCa mouse model. These results demonstrated that the prodrug-loaded liposomes could significantly reduce the toxicity of TPL and enhance the biosafety. Overall, this prodrug approach is a simple and effective method to transform the highly toxic TPL into a safe and efficacious nanomedicine with excellent in vivo tolerability for PCa treatment.