Novel thymoquinone lipidic core nanocapsules with anisamide-polymethacrylate shell for colon cancer cells overexpressing sigma receptors

Abstract

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...

Development of a Thymoquinone Polymeric Anticancer Nanomedicine through Optimization of Polymer Molecular Weight and Nanoparticle Architecture

“…On the other hand, Fakhoury et al reported that TQ NPs exhibited equal or more potent anticancer activity compared to free TQ depending on the cancer model [ 18 ]. Moreover, a recent study by Ramzy et al described TQ-encapsulated polymeric NPs targeted to colon cancer cells where the NPs were significantly less potent than free TQ due to sustained drug release [ 40 ].…”

Thymoquinone loaded calcium alginate and polyvinyl alcohol carrier inhibits the 7,12‐dimethylbenz[a]anthracene‐induced hamster oral cancer via the down‐regulation of PI3K/AKT/mTOR signaling pathways

“…The weaker band noted at a higher wave number about 3040 cm −1 was allocated to the stretching noted at the vinylic CH in the CCH groups. The strong intense peak was observed for Ca‐alg/PVA blends which may due to the presence of strong hydrogen bond interaction with in the alginate chains in the matrix 43 . The XRD patterns of TQ, Ca‐alg/PVA blend and TQ loaded Ca‐alg/PVA blend was shown, the strong intense peak was observed for Ca‐alg/PVA blends which may due to the presence of strong hydrogen bond interaction with in the alginate chains in the matrix.…”

Nanoparticle Surface Functionalization: How to Improve Biocompatibility and Cellular Internalization

“…Other simple molecules used to perform NPs active uptake are anisamide (AA) and phenylboronic acid (PBA) able to bind sigma receptors and sialic acid (SA), respectively. These molecules were successfully investigated by and Ramzy et al (2020). Ramzy et al, functionalized the surface polymeric NPs loaded with thymoquinone (TQ) by using AA, in order to enhance uptake and drug accumulation in colon cancer cells.…”