ROS-Responsive Prodrug Micelle Co-Delivery System for Synergistic Antiatherosclerotic Therapy

Authors：Tang, Qingfa; Chen, Yao; Zhang, Yusheng; Wang, Kewei; Liu, Li; Pan, Dongmei^*; Liu, Qiang^*; Jiang, Cuiping^*

Source：MOLECULAR PHARMACEUTICS, 2023, 20(9): 4478-4490.

DOI：10.1021/acs.molpharmaceut.3c00127

• prodrug micelle
• ROS responsive
• self-assemble
• codelivery drug delivery system
• anti-atherosclerosis

Tanshinone IIA (TS-IIA) and salvianic acid A (SAA) arethe mainpharmacological active constituents of Danshen, which exhibit potenteffects on atherosclerosis. A combination of TS-IIA and SAA mightexert a synergistic antiatherosclerotic effect. However, the oppositesolubility profiles of TS-IIA and SAA might lead to difficulty inachieving a synergistic combined effect of the two active components.Therefore, in this work, we fabricated a ROS-responsive prodrug micellefor the codelivery of TS-IIA and SAA (TS-IIA-PM) by self-assemblingamphiphilic block copolymer PEG(5000)-SAA/PLA(10000)-APBA. The amphiphilic polymer was characterized by (HNMR)-H-1, FTIR, and alizarin red S competition tests. The ROS responsivenessof TS-IIA-PM was evidenced by time-course monitoring of particle sizeand morphology changes and drug release behavior in the presence of1 mM H2O2. We found TS-IIA-PM was stable accordingto its critical micelle concentration and the unchanged particle sizesin 10% FBS for 7 days. The results of in vitro and in vivo tests revealed that TS-IIA-PM was safe and biocompatible.Furthermore, it was observed that TS-IIA and prodrug micelle couldproduce synergistic antiatherosclerotic effect based on the resultsof the antioxidant study, which was further confirmed by a seriesof pharmocodynamics studies, such as in vitro DiI-oxLDLuptake study, oil red O staining, cholesterol efflux study, inflammatorycytokine analysis, in vivo CD68 immunostaining, andlipid disposition staining studies. Collectively, TS-IIA-PM holdsgreat potential for the safe and efficient codelivery of TS-IIA andSAA for synergistic antiatherosclerosis.

• Institution
  南方医科大学