Biodegradable and biocompatible subcutaneous implants consisted of pH-sensitive mebendazole-loaded/folic acid-targeted chitosan nanoparticles for murine triple-negative breast cancer treatment

Abstract

Background: Mebendazole (MBZ) is a well-known anti-parasite drug with significant anti-cancer properties. However, MBZ exhibits low solubility, limited absorption efficacy, extensive first-pass effect, and low bioavailability. Therefore, multiple oral administration of high dose MBZ is required daily for achieving the therapeutic serum level which can cause severe side effects and patients' non-compliance. Method: In the present study, MBZ-loaded/folic acid-targeted chitosan nanoparticles (CS-FA-MBZ) were synthesized, characterized, and used to form cylindrical subcutaneous implants for 4T1 triple-negative breast tumor (TNBC) treatment in BALB/c mice. The therapeutic efficacy of the CS-FA-MBZ implants was investigated after subcutaneous implantation in comparison with Control, MBZ (40 mg/kg, oral administration, twice a week for 2 weeks), and CS-FA implants, according to 4T1 tumors' growth progression, metastasis, and tumor-bearing mice survival time. Also, their biocompatibility was evaluated by blood biochemical analyzes and histopathological investigation of vital organs. Results: The CS-FA-MBZ implants were completely degraded 15 days after implantation and caused about 73.3, 49.2, 57.4 decrease in the mean tumors' volume in comparison with the Control (1050.5 +/- 120.7 mm(3)), MBZ (552.4 +/- 76.1 mm(3)), and CS-FA (658.3 +/- 88.1 mm(3)) groups, respectively. Average liver metastatic colonies' number per microscope field at the CS-FA-MBZ group (2.3 +/- 0.7) was significantly (P < 0.05) lower than the Control (9.6 +/- 1.7), MBZ (5.0 +/- 1.5), and CS-FA (5.2 +/- 1) groups. In addition, the CS-FA-MBZ treated mice exhibited about 52.1, 27.3, and 17 more survival days after the cancer cells injection in comparison with the Control, MBZ, and CS-FA groups, respectively. Moreover, the CS-FA-MBZ implants were completely biocompatible based on histopathology and blood biochemical analyzes. Conclusion: Taking together, CS-FA-MBZ implants were completely biodegradable and biocompatible with high therapeutic efficacy in a murine TNBC model.