Synthesis of polyprodrug based on cytarabine for cancer therapy

Abstract

Chemotherapeutic agents always produce severe side effects in clinic settings. Although drug delivery systems have addressed the side effects of small-molecule drugs to some degree, the overdose of carrier, complicated preparation and low drug loading rate limit the development of novel nanomedicines. Herein, we prepared a polyprodrug nanomedicine with a fixed drug loading rate based on cytarabine (Ara-C) by a one-step radical polymerization method. This poly-cytarabine (Poly-Ara-C) nanomedicine was characterized using NMR and FT-IR. The fixed drug loading rate of Ara-C in Poly-Ara-C is 81.5%, and the average nanoparticle size of Poly-Ara-C is 116.8 nm, as measured using DLS. Cell viability results showed that viable A20 cells treated with Poly-Ara-C (30 μg mL⁻¹) were 49% and 62.4% at 24 h, as evaluated using CCK-8 assays and flow cytometry experiments, respectively. Cellular uptake experiments proved that DID@Poly-Ara-C could be distributed into nuclei at 8 h. An in vivo tracking experiment demonstrated that DID@Poly-Ara-C could accumulate in tumor tissue and remain there for a longer time (4 days) compared to free DID. Moreover, the fluorescence imaging of sliced tissues demonstrated that the red fluorescence increased from 2 h to 76 h in tumor tissues. Meanwhile, tumor inhibition results indicated that the tumor volume of the Poly-Ara-C group (295 mm³) is significantly smaller than that of the free Ara-C group (472 mm³) and 0.9% saline group (1535 mm³). Furthermore, cell apoptosis of tumor tissues was observed in both the Poly-Ara-C and free Ara-C groups, as evaluated using TUNEL slices. Additionally, the side effects evaluated using H&E slices revealed that the side effects of the Poly-Ara-C group decreased compared to that of free Ara-C. In summary, this polyprodrug with a fixed drug loading rate based on Ara-C will probably be developed as a novel nanomedicine for cancer therapy and for clinical application in the future.