Novel pH-sensitive triptolide-loaded micelles: a potential approach to increase anti-tumor activity of the diterpenoid epoxide

Abstract Tripterygium wilfordii Hook F, a traditional medicine in China has bioactive but toxic triptolide (TP, a diterpenoid triepoxide) as its main active constituents. The applications of TP are hampered by its prominent toxicity and low solubility in water. In this study, a safe pH-sensitive material [methoxy polyethylene glycol (mPEG)- adipic dihydrazide (ADH)] was synthesized and loaded with TP to form pH-sensitive polymeric micelles, thereby improving the safety and solubility of TP, as well as providing a theoretical basis for the wide application of TP. The mPEG-ADH/TP micelles were characterized by a series of indicators [namely entrapment efficiency (EE), critical micellar concentration (CMC), electrokinetic potential, stability, polydispersed index (PDI), and particle size]. Also, we ascertained the in vitro release of TP from mPEG-ADH/TP micelles along with pharmacokinetic investigations in vivo. Besides, we evaluated the cytotoxicity of mPEG-ADH/TP micelles against A549 cells, HCT116 cells, and HaCat cells and further conducted in vivo toxicity studies in rats. The TP-loaded mPEG-ADH micelles had smaller sized particles (48.3 nm), excellent PDI (0.142), stable property and higher EE (89.87%). Importantly, the TP in the mPEG-ADH/TP micelles was almost completely released at acidic pH (pH 5.0), while the drug was released slowly and sparingly at physiological pH (pH 7.4). The results suggest the release of TP from mPEG-ADH/TP micelles was sensitive to pH, which could facilitate targeting of the drug into intra-cellularly low pH endosomes and lysosomes as well as enhance cytotoxicity in cancer tissues. Moreover, mPEG-ADH/TP micelles exhibited excellent proliferation inhibition on tumor cells. In addition, the liver injury of rats in the 1 mg/kg dose of mPEG-ADH/TP micelles group was significantly reduced by Hematoxylin–eosin (HE) staining. Taken together, mPEG-ADH/TP micelles could act as a promising alternative to enhance the efficacy of oncologic treatments.