Trisulfide bond–mediated doxorubicin dimeric prodrug nanoassemblies with high drug loading, high self-assembly stability, and high tumor selectivity

Abstract

Rational design of nanoparticulate drug delivery systems (nano-DDS) for efficient cancer therapy is still a challenge, restricted by poor drug loading, poor stability, and poor tumor selectivity. Here, we report that simple insertion of a trisulfide bond can turn doxorubicin homodimeric prodrugs into self-assembled nanoparticles with three benefits: high drug loading (67.24%, w/w), high self-assembly stability, and high tumor selectivity. Compared with disulfide and thioether bonds, the trisulfide bond effectively promotes the self-assembly ability of doxorubicin homodimeric prodrugs, thereby improving the colloidal stability and in vivo fate of prodrug nanoassemblies. The trisulfide bond also shows higher glutathione sensitivity compared to the conventional disulfide bond, and this sensitivity enables efficient tumor-specific drug release. Therefore, trisulfide bond–bridged prodrug nanoassemblies exhibit high selective cytotoxicity on tumor cells compared with normal cells, notably reducing the systemic toxicity of doxorubicin. Our findings provide new insights into the design of advanced redox-sensitive nano-DDS for cancer therapy.

Nanoparticulation of Prodrug into Medicines for Cancer Therapy

“…For instance, compared with disulfide and thioether linkers, the trisulfide bond effectively promotes the self-assembly ability of DOX homodimeric prodrugs (Figure 5D), thereby improving the colloidal stability and the fate of prodrug nanoassemblies; further MD simulation disclosed that the trisulfide bond had more sulfur-containing bond angles, and were close to 90°, [80] which were believed the optimal angle to constructed the most stable conformation, and kept agreement with the lowest calculated free energy. [80] Amino acid valine linked PTX and MTX to offered prodrug conjugate then assembled into NPs. [81] It is also found that the drug-drug conjugate may change the mechanism of action, exemplified by temozolomide (TMZ)-Dox prodrug double intercalating with DNA although TMZ itself is a weak DNA binder and functioned as an induced intercalator.…”

ROS-responsive dimeric prodrug-based nanomedicine targeted therapy for gastric cancer

“…These results confirmed the good colloidal stability of four NPs. The stability of iRGD-TK-NP and TK-NPs was higher than that of iRGD-CC-NPs as well as CC-NPs, which may be due to the fact that the TK linkage improves the structural flexibility of dimeric prodrugs, thereby increasing the stability of DPNS (Yang et al, 2020). NPs 91.8 ± 2.1 0.21 ± 0.03 -(17.7 ± 0.7) 50.1 ± 2.1 75.3 ± 2…”

ROS-Responsive Dimeric Prodrug-Based Nanomedicine Targeted Therapy for Gastric Cancer

“…The stability of iRGD-TK-NP and TK-NPs was higher than that of iRGD-CC-NPs, which may be due to the fact that the TK linkage improves the structural exibility of dimeric prodrugs, thereby increasing the stability of DPNS. [34] When the addition of H 2 O 2 , UA release behavior was enhanced and sustained. In the presence of 1 mM H 2 O 2 , around 25% of UA was released from NPs after 48 h incubation.…”