Small molecule prodrugs self-assembled nano-delivery systems with tumor responsive linkages are emerging as an effective platform. However, the heterogeneity of tumor microenvironment may limit the anti-tumor effect of prodrug nanomedicines with a single response module. Here, we chose disulfide bond as the response module and branched chain alcohol as the self-assembly modification module to construct a single-responsive prodrug. We also constructed a double-responsive paclitaxel prodrug combining triglyceride and disulfide bond, taking into account of the highly expressed lipase and glutathione levels in tumor cells. The results showed that the anti-tumor effect of single-responsive branched chain alcohol modified prodrug nanoparticles was inferior to triglyceride prodrug nanoparticles with dual response modules. The triglyceride structure can not only serve as a self-assembly modification module, but also serve as a response module for intelligent drug release in tumor. Such dual roles will facilitate the efficient delivery of small molecule self-assembled prodrugs to tumor sites.
Jiaxin Wu,Shuai Yang,Yuyue Xiong,Jiacheng Liu,Zhongkui Wu,Ruogu Qi,Lesan Yan
Polyurethane (PU) is considered an ideal nanocarrier for drug delivery due to its excellent biocompatibility and efficient drug-loading capacity. Sulfur bonds (such as monosulfide, disulfide, and trisulfide bonds), have attracted considerable attention in drug delivery systems due to their redox-responsive properties. However, current research primarily focuses on the application of sulfur bonds in prodrug nanoassemblies, where designs rely on specific chemical conjugation groups, limiting their applicability to a narrow range of drug molecules and thus restricting broader utility. Integrating sulfur bonds into polyurethane structures offers a promising approach to enhance carrier biocompatibility while significantly expanding their versatility for delivering various hydrophobic small-molecule drugs. Nevertheless, whether sulfur bonds retain their inherent redox-responsive behavior within a polyurethane requires systematic validation. To address this, we designed and synthesized three amphiphilic polyurethane materials incorporating monosulfide, disulfide, and trisulfide bonds as core components. These polymers self-assembled into nanomicelles, enabling a systematic comparison of their redox-responsive properties. Furthermore, the hydrophobic anticancer drug doxorubicin (DOX) was encapsulated as a model payload to evaluate the in vivo antitumor efficacy of the resulting drug-loaded nanomicelles. Our findings demonstrate that the incorporation of sulfur bonds markedly enhances the redox responsiveness of polyurethane nanocarriers, with the trisulfide bonds exhibiting the most pronounced reduction-sensitive behavior. This study provides deep insights into the influence of sulfur bonds type on the redox-responsive behavior of polyurethane nanomicelles and underscores the exceptional potential of trisulfide bonds in developing redox-responsive polyurethane-based nanocarriers for drug delivery. These results offer critical theoretical and experimental foundations for the design and optimization of smart polyurethane-based drug delivery systems.
危险品化学品经营许可证（带存储）