Folate functionalized pH-sensitive nanoparticulate system to decrease the toxicity and enhance the anti-cancer activity of pirarubicin for lymphoma therapy via downregulation of H3K18la and H3K9la

Although pirarubicin (THP) was widely used for treatment of lymphoma, systemic toxicity especially cardiotoxicity, still limits its application in cancer therapy. This project designed a new folate functionalized drug delivery system (5%FA-THP-NP) containing poly (2-ethyl-2-oxazoline)-distearoyl phosphatidyl ethanolamine (PEOz 2000 -DSPE) and DOTAP for targeted delivery and controlled release of pirarubicin (THP), thus offering a strategy for overcoming the dose-limiting toxicity by facilitating the efficient accumulation of THP in cancer cells and achieving superior anti-lymphoma efficacy. The obtained 5%FA-THP-NP showed an anticipated THP drug loading (DL) reaching 27.39 %, had outstanding storage stability, excellent hemocompatibility and presented a pH-responsive drug release performance, achieving a cumulative release of 80.54 % due to their disassembly under acidic stimulation (pH 5.5). Studies on Raji lymphoma cells in vitro showed that 5%FA-THP-NP had significant advantages compared to controls, with the highest cell uptake and strongest apoptosis . More importantly, targeted delivery and controlled release of THP with 5%FA-THP-NP exhibited higher anti-lymphoma effect and lower toxicity to normal cells than Free THP. In addition, systemic injection of 5%FA-THP-NP into tumor bearing mice not only showed excellent anti-tumor activities with the tumor inhibition ratio up to 85 % via more efficient downregulation of H3K18la and H3K9la than Free THP, but also efficiently reduced the systemic toxicity of THP by encapsulation of THP in the nanoparticles. In conclusion, the targeting nanoparticulate system developed in the current study shows potency as an alternative platform for effectively delivering chemotherapeutic agents to enhance therapeutic efficacy against lymphoma and decrease the systemic toxicity of THP.