Minor Changes in Response Modules Leading to a “U-Shaped” Conversion Rate of Docetaxel Prodrug Nanoassemblies

Abstract

The prodrug-based nanoassemblies offer an alternative to settle the deficiencies of traditional chemotherapy drugs. In this nanosystem, prodrugs typically comprise drug modules, modification modules, and response modules. The response modules are crucial for facilitating the accurate conversion of prodrugs at specific sites. In this work, we opted for differentiated disulfide bonds as response modules to construct docetaxel (DTX) prodrug nanoassemblies. Interestingly, a subtle change in response modules leads to a "U-shaped" conversion rate of DTX-prodrug nanoassemblies. Prodrug nanoassemblies with the least carbon numbers between the disulfide bond and ester bond (PDONα) offered the fastest conversion rate, resulting in powerful treatment outcomes with some unavoidable toxic effects. PDONβ, with more carbon numbers, possessed a slow conversion rate and poor antitumor efficacy but good tolerance. With most carbon numbers in PDONγ, it demonstrated a moderate conversion rate and antitumor effect but induced a risk of lethality. Our study explored the function of response modules and highlighted their importance in prodrug development.

Carbon-Spaced Tandem-Disulfide Bond Bridge Design Addresses Limitations of Homodimer Prodrug Nanoassemblies: Enhancing Both Stability and Activatability

“…Disulfide bonds are widely used in the design of intelligent drug delivery systems because of their high redox reactivity. − Moreover, disulfide bonds with nearly 90° dihedral angles can introduce “structural defects”, thus preventing excessive aggregation of prodrug molecules and facilitating the formation of RHPNs. ,, Previous studies have shown that the position of disulfide bonds relative to ester bonds in the chemical linkage significantly affected the assembly ability and drug release efficiency of RHPNs. − Regarding assembly ability, a farther distance between disulfide and ester bonds provided stronger hydrophobicity, effectively maintaining assembly stability. − Regarding drug release efficiency, it was observed that a closer distance between disulfide and ester bonds tends to facilitate the hydrolysis of ester bonds, expediting drug release. ,− The opposing effects on assembly ability and drug release efficiency made it a great challenge to construct RHPNs that could achieve stable assembly and rapid release simultaneously.…”