Size-Dependent Effects of Silver Nanoparticles in Colorectal Cancer Treatment: Apoptosis Activation, Anti-Metastatic Properties, and Tissue Accumulation

Abstract

Abstract Nanoparticles possess unique characteristics due to their small size and high surface area-to-volume ratios, enabling facile interactions with biomolecules, cells, and tissues upon entry into the body. This study investigates the size-related effects of silver nanoparticles (AgNPs) in the context of colorectal cancer treatment. The proposed mechanism, resembling “Trojan horses”, elucidates the toxicity of AgNPs; AgNPs transport metallic silver across cell membranes and then dissolve intracellularly to release Ag2+ ions. To explore the impact of AgNP size, a range of AgNPs with varying sizes was synthesized. The cytotoxic effects of synthesized AgNPs (5 nm, 10 nm, 40 nm, and 100 nm) in colorectal cancer cell lines; CaCo-2, SW-620, DLD-1, HT-29, and healthy colon epithelial cell line CCD-18Co were determined in vitro. The distribution and amount of different-sized AgNPs in rat tissues at 24-hour and 48-hour post-administration were determined by ICP-MS method. Experimental findings revealed that the apoptotic pathway in DLD-1 and HT-29 cells was activated by AgNPs, and this activation exhibited a positive correlation with increasing AgNP size. Furthermore, an increase in size was associated with decreased metastatic properties, resulting in a reduced ability to form colonies. AgNP therapy induced the activation of proteins and genes involved in various pathways, including TGFβ, WNT, MAPK, PI3K-Akt, and p53. In vivo studies demonstrated the effective penetration of AgNPs into the circulatory system following intraperitoneal (IP) administration. These nanoparticles were found to accumulate extensively in the lungs, liver, heart, kidneys, and colon. 5 nm AgNPs were rapidly cleared from the kidney at 48 h, while 40 nm AgNPs exhibited the highest concentration in the lung at 24 h. Notably, different-sized AgNP nanoparticles exhibited distinct accumulation sites, suggesting a potential passive targeting approach for specific tissues. In conclusion, this study highlights the size-dependent effects of AgNPs in colorectal cancer treatment. The findings underscore the ability of AgNPs to activate apoptosis and modulate metastatic properties in colorectal cancer cells, with larger AgNPs exhibiting more pronounced effects. Moreover, the differential accumulation of AgNPs in various tissues offers a promising alternative strategy for passive targeting based on nanoparticle size. These insights contribute to the development of targeted therapies utilizing AgNPs in the field of cancer treatment.