Tetrasulfide bond boosts the anti-tumor efficacy of dimeric prodrug nanoassemblies.

Dimeric prodrug nanoassemblies (DPNAs) stand out as promising strategies for improving the efficiency and safety of chemotherapeutic drugs. The success of trisulfide bonds (-SSS-) in DPNAs makes polysulfide bonds a worthwhile focus. Here, we explore the comprehensive role of tetrasulfide bonds (-SSSS-) in constructing superior DPNAs. Compared to trisulfide and disulfide bonds, tetrasulfide bonds endow DPNAs with superlative self-assembly stability, prolonged blood circulation, and high tumor accumulation. Notably, the ultra-high reduction responsivity of tetrasulfide bonds make DPNAs a highly selective "tumor bomb" that can be ignited by endogenous reducing agents in tumor cells. Furthermore, we present an "add fuel to the flames" strategy to intensify the reductive stress at tumor sites by replenishing exogenous reducing agents, making considerable progress in selective tumor inhibition. This work elucidates the crucial role of tetrasulfide bonds in establishing intelligent DPNAs, alongside the combination methodology, propelling DPNAs to new heights in potent cancer therapy.

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

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. PDONß, 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.

Cabazitaxel prodrug nanoassemblies with branched chain modifications: Narrowing the gap between efficacy and safety.

The clinical application of cabazitaxel (CTX) is restricted by severe dose-related toxicity, failing to considering therapeutic efficacy and safety together. Self-assembled prodrugs promote new drug delivery paradigms as they can self-deliver and self-formulate. However, the current studies mainly focused on the use of straight chains to construct self-assembled prodrugs, and the role of branched chains in prodrug nanoassemblies remains to be clarified. In this study, we systematically explored the structure-function relationship of prodrug nanoassemblies using four CTX prodrugs that contained branched chain aliphatic alcohols (BAs) with different alkyl lengths. Overall, CTX-SS-BA20 NPs with the proper alkyl length exhibited significant improvements in both antitumor efficacy and biosafety. Furthermore, compared with straight chain (SC) modified prodrug nanoassemblies (CTX-SS-SC20 NPs), CTX-SS-BA20 NPs still hold great therapeutic promise due to its good biosafety. These findings illustrated the significance of BAs as modified chains in designing prodrug nanoassemblies for narrowing the efficacy-to-safety gap of cancer therapy.

Rational Engineering Docetaxel Prodrug Nanoassemblies: Response Modules Guiding Efficacy Enhancement and Toxicity Reduction.

Prodrug-based nanoassemblies have been developed to solve the bottlenecks of chemotherapeutic drugs. The fabricated prodrugs usually consist of active drug modules, response modules, and modification modules. Among three modules, the response modules play a vital role in controlling the intelligent drug release at tumor sites. Herein, various locations of disulfide bond linkages were selected as response modules to construct three Docetaxel (DTX) prodrugs. Interestingly, the small structural difference caused by the length of response modules endowed corresponding prodrug nanoassemblies with unique characteristic. α-DTX-OD nanoparticles (NPs) possessed the advantages of high redox-responsiveness due to their shortest linkages. However, they were too sensitive to retain the intact structure in the blood circulation, leading to severe systematic toxicity. ß-DTX-OD NPs significantly improved the pharmacokinetics of DTX but may induce damage to the liver. In comparison, γ-DTX-OD NPs with the longest linkages greatly ameliorated the delivery efficiency of DTX as well as improved DTX's tolerance dose.