Mechanistic Insights Into Dose-Dependent Alleviation of Colorectal Cancer Through Artemisinin-Loaded Mesoporous Silica Nanoparticles in 1,2-Dimethylhydrazine-Induced Albino Wistar Rats.

The current study investigates the suitability of encapsulating the Artemisinin-plant-originated lipophilic drug molecule into polyethylene glycol-coated mesoporous silica nanoparticles in a suitable dose regimen for the specific targeting of the drug in colorectal cancer. Mesoporous silica nanoparticles (MSNPs) were synthesized through the sol-gel method, and Artemisinin was loaded. Then characterization of Artemisinin-loaded mesoporous silica nanoparticles coated with polyethylene glycol (MSN-PEG@Artemisinin) was performed by Fourier transform infrared spectroscopy (FTIR), Zeta analysis, Polydispersity index (PDI) and X-Ray diffraction (XRD) techniques and compared with the standard drug Gemcitabine. The in vivo analysis of 1,2-dimethylhydrazine (DMH) was used to induce colorectal tumors in the colon of inbred male Wistar rats. The treatment group of rats was administered MSN-PEG@Artemisinin through intraperitoneal injection. Hematoxylin and eosin staining were performed to the histopathological examination of tumors. The average size of MSN-PEG@Artemisinin was 203.6 ± 64.78 nm with a zeta potential of -10.9mV. PDI was measured at 0.106. FTIR analysis also supported the successful loading of Artemisinin in mesoporous silica nanoparticles with PEG coating without showing interactions. The encapsulation efficiency (EE) and Drug loading (DL) percentages were 82.75% and 33.10%, respectively. XRD indicated a uniform mesoporous structure with a proper hexagonal symmetry. The in-vitro release was carried out in phosphate buffer with 7.4 pH following biphasic system with 26% drug release during the first 2.5 hours and 57% in 24 hours, indicating a good controlled release rate. In-vivo study revealed DMH-induced colorectal rats showed the increased tumor weight (34.8±0.75mg) tumor length (8.2±0.6) and tumor width (6.0±0.5) at a dose level of 0.5 ml/kg. Artemisinin loaded MSNPs significantly (p < .005) suppressed tumor weight (15.6±1.56), tumor length (5.7±0.23) and tumor width (2.3±0.8) at a dose level of 100 mg/kg body weight. Overexpression of 8-OHdG, MMP-7, CA-19-9, KRAS, IL-8, Caspase-8, PD-1 and PDL-1 in CRC, which were successfully treated with MSN-PEG@Artemisinin and standard Gemicitabine ((p≥0.056). MSNPs-PEG@Artemisinin suppressed DMH-induced colorectal carcinogenesis by targeting oxidative stress, KRAS/MMP-7/IL-8 inflammatory signaling, PD-1/PD-L1-mediated immune evasion, and Caspase-8-associated apoptotic dysregulation. These results highlight the potential of modified MSNPs as a versatile drug delivery system for colorectal cancer, providing a viable approach to enhance the therapeutic window of Artemisinin by controlling the dose while reducing the adverse effects of cancer therapies. This research contributes to advancements in pre-clinical studies and to improvements in targeted colorectal cancer therapies by providing insights into the development and use of mesoporous silica nanoparticles as a promising drug delivery system.