SN-38-indoximod conjugate: carrier free nano-prodrug for cancer therapy

The integration of immunotherapy alongside chemotherapy represents a crucial approach in the treatment of cancer. Herein we report the SN-38-indoximod conjugate nano-prodrug to address the difficulties encountered by individuals. In this prodrug, SN-38 is connected to indoximod through a specific disulfide linker, which enables the release of the components in response to the tumor microenvironment characterized by elevated levels of glutathione, thereby facilitating programmed chemoimmunotherapy. SN-38-indoximod conjugate was synthesized and fabricated to nano-prodrug by reprecipitation method. It showed comparable anti-cancer activity against A549 cells than SN-38 (IC₅₀ = 0.24 ± 0.01 µM) with IC₅₀ value 0.32 ± 0.04 µM. It inhibited 90% A549 cell at very lower concentration (IC₉₀ = 6.07 ± 0.41 µM) as compared with SN-38 (IC₉₀ = 24.60 ± 1.24 µM) and mixture of SN-38: indoximod (1:1, IC₉₀ >30 µM). The nano-prodrug showed better size distribution profile and dispersion stability contains nanoparticles in effective size range (80–160 nm) required for the EPR effect. This research offers valuable insights into the advancement of conjugate nano-prodrugs exhibiting synergistic pharmacological effects, while also presenting novel opportunities for the design of prodrug molecules capable of releasing drugs in response to diverse triggers.