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.