Surface Charge-Switchable Doxorubicin-Containing Polyurethane Prodrug Nanoparticles for Targeted Cancer Therapy

Cancer remains one of the foremost causes of mortality worldwide. Among the different cancer therapies, chemotherapy is one of the widely used treatments, but its clinical efficacy is often compromised by serious side effects arising from the off-target release of cytotoxic drugs. Here, we reported an amphiphilic polyurethane integrated with tertiary amine groups on the backbone and a pendant doxorubicin drug linked via a disulfide-based self-immolative linker. In water, the polymer self-assembles into a spherical nanostructure via an entropy-driven process as probed by isothermal titration calorimetry analysis. The nanoparticle/nanoaggregate formation was probed by dynamic light scattering and transmission electron microscopy image analysis. The prodrug nanoparticle showed doxorubicin release by the cleavage of self-immolative bonds in the presence of a simulated redox environment (10 mM concentration of glutathione, i.e., GSH) of cancer cells. Interestingly, in the absence of GSH, no drug release was observed, confirming the leakage-free nature of the nanoparticle. It exhibited a tumor extracellular matrix-relevant pH-induced surface charge transition from neutral to positive. The biological evaluation revealed insignificant toxicity toward normal cells, while showing pronounced cytotoxicity against aggressive triple-negative breast cancer cells with a lower IC 50 (half-maximal inhibitory concentration) value (3.92 μM) compared to that of the free drug (6.22 μM). The fluorescence microscopy image further confirmed the selective uptake of the polymer prodrug by cancer cells with minimal internalization in normal cells. The clonogenic and cellular migration assays separately indicated a marked reduction in cell colony formation and a significant delay in cellular migration, respectively, compared with the free doxorubicin. Overall, the simplicity of the design, aggregation stability, and leakage-free and cancer cell-specific drug delivery, along with boosted cellular uptake, collectively position this system as a highly promising candidate for chemotherapeutic applications with minimal off-target-mediated side effects.