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

Abstract

Tanshinone IIA (TS-IIA) and salvianic acid A (SAA) are the main pharmacological active constituents of Danshen, which exhibit potent effects on atherosclerosis. A combination of TS-IIA and SAA might exert a synergistic antiatherosclerotic effect. However, the opposite solubility profiles of TS-IIA and SAA might lead to difficulty in achieving a synergistic combined effect of the two active components. Therefore, in this work, we fabricated a ROS-responsive prodrug micelle for the codelivery of TS-IIA and SAA (TS-IIA-PM) by self-assembling amphiphilic block copolymer PEG 5000 -SAA/PLA 10000 -APBA. The amphiphilic polymer was characterized by 1 H NMR, FTIR, and alizarin red S competition tests. The ROS responsiveness of TS-IIA-PM was evidenced by time-course monitoring of particle size and morphology changes and drug release behavior in the presence of 1 mM H 2 O 2 . We found TS-IIA-PM was stable according to its critical micelle concentration and the unchanged particle sizes in 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 could produce synergistic antiatherosclerotic effect based on the results of the antioxidant study, which was further confirmed by a series of pharmocodynamics studies, such as in vitro DiI-oxLDL uptake study, oil red O staining, cholesterol efflux study, inflammatory cytokine analysis, in vivo CD68 immunostaining, and lipid disposition staining studies. Collectively, TS-IIA-PM holds great potential for the safe and efficient codelivery of TS-IIA and SAA for synergistic antiatherosclerosis.

Precise Modulation of Pericyte Dysfunction by a Multifunctional Nanoprodrug to Ameliorate Alzheimer’s Disease

“…Synchronized modulation promises optimal therapeutic effects of combination drugs. − We thus tested the ROS-responsiveness of VLC@Cur-NPs in vitro . Upon dispersal in 100 μM hydrogen peroxide (H 2 O 2 ), the NPs underwent a dramatic increase in diameter from 137.5 ± 0.49 nm to 1405 ± 3.28 nm within 2 h and dissociated (Figure J–K).…”

Multifunctional nanoparticle-mediated combining therapy for human diseases

“…Therefore, establishing an analysis method that can precisely study the drug release is critical for the development of NP-codelivery. 480 , 481 Moreover, the translation always involves enormous efforts, such as the initial selection of combination drugs and dosage forms, screening and characterization, the final large-scale batch production, and quality control. In addition, even though various NPs have been proven to target the diseased lesions and improve treatment efficacy, less than 1% of nanomedicines accumulate in the target site due to sequestration or clearance of RES and renal system, etc.…”

Fabrication of GSH‐Responsive Poly(Tertiary Amine‐Oxide)‐Based Nanomedicines for Enhanced Anticancer Drug Release

“…The introduction of stimulus-responsive chemical groups to nanomedicines is thus a more versatile approach. [25] Tremendous stimuli-responsive polymers capable of responding to the tumor microenvironment signals including pH, [26][27][28] temperature, [29,30] reactive oxy-gen species, [31][32][33] and glutathione (GSH) [34,35] have been developed so far. Of the reported stimuli approaches, the application of GSH-sensitive polymers containing disulfide bridges is of particular importance owing to the distinct difference in the GSH levels between normal cells (≈2 mm) and specific tumor cells (≈10 mm).…”