the biggest challenge in colorectal cancer therapy is to avoid intestinal drug absorption before reaching the colon, while focusing on tumor specific delivery with high local concentration and minimal toxicity. in our work, thymoquinone (tQ)-loaded polymeric nanocapsules were prepared using the nanoprecipitation technique using Eudragit S100 as polymeric shell. Conjugation of anisamide as a targeting ligand for sigma receptors overexpressed by colon cancer cells to Eudragit S100 was carried out via carbodiimide coupling reaction, and was confirmed by thin layer chromatography and 1 H-nMR. tQ nanocapsules were characterized for particle size, surface morphology, zeta potential, entrapment efficiency % (EE%), in vitro drug release and physical stability. A cytotoxicity study on three colon cancer cell lines (HT-29, HCT-116, Caco-2) was performed. Results revealed that the polymeric nanocapsules were successfully prepared, and the in vitro characterization showed a suitable size, zeta potential, EE% and physical stability. TQ exhibited a delayed release pattern from the nanocapsules in vitro. Anisamide-targeted tQ nanocapsules showed higher cytotoxicity against HT-29 cells overexpressing sigma receptors compared to their non-targeted counterparts and free TQ after incubation for 48 h, hence delineating anisamide as a promising ligand for active colon cancer targeting. Sigma receptors are expressed in normal cells of various organs including brain, kidney, liver, immune, endocrine and reproductive organ 1,2. Two distinguished subtypes were recognized and known as sigma-1 and sigma-2 3. Neurosteroids are the likely endogenous ligands for sigma-1 receptors 4 , and N,N-dimethyltryptamine; a natural alkaloid, was also found to be an endogenous ligand for sigma-1 receptors 5,6. A correlation between sigma receptors and diseases such as Parkinson's, Alzheimer's disease and cancer has been proposed 7 , and ligands for sigma-1 receptor were proven to improve various neurodegenerative disorders 8. Sigma-2 receptor is thought to be crucial for cell morphology, survival and differentiation 9. Sigma receptors are overexpressed in cancer cells of various organs 10 including cancers of the brain 11 , lung 12,13 , breast 14 , prostate gland 15 , kidney and colon 16. The tumor environment characterized by oxidative stress, hypoxia, low pH and insufficient supply of glucose and amino acids mediates disruption of endoplasmic reticulum protein folding. This in turn contributes to sigma-1 receptors activation to promote cell survival 7,17. In addition, sigma-2 receptors upregulation in cancerous tissues compared to healthy ones has been widely demonstrated 18,19. Benzamide derivatives demonstrate a high affinity towards sigma receptors 20-22. Anisamide (AA); a small molecular weight benzamide derivative was proven to exhibit high affinity for sigma receptors 23-25. In a review article previously published by our team the use of AA as a targeting ligand in several drug delivery systems was detailed 26. AA-functionalized doxorubicin-loade...
