Novel nanoparticle drug delivery systems: application in the in vitro study of Bisnaphthalimidopropyl derivatives against human colorectal cancer cell lines.
Colorectal cancer is one of the most severe causes of mortality worldwide accounting for 10% of total cancer cases. Although recent advances in early diagnosis have reduced the mortality rate associated with CRC, patients suffering from the later metastatic stage of the disease have a 5-year survival rate of only 14%. To enhance the current treatment options, bisnaphthalimides (BNIPs) were developed as a new group of chemotherapeutic agents. Presenting promising results in vitro against colon cancer cell lines, these anti-cancer drugs are limited by a poor aqueous solubility and a dose-limiting toxicity. In recent years, nanoparticle drug delivery systems have been developed to enhance the solubility and the clinical response of encapsulated anti-cancer agents. In this study, the latest generation of BNIP derivatives including bisnaphthalimidopropyl-piperidylpropane (BNIPPiProp), bisnaphthalimidopropyl- ethylenedipiperidine (BNIPPiEth) and bisnaphthalimidopropyl diaminodicyclohexylmethane (BNIPDaCHM) have been studied against SW480 and SW620 colorectal cancer cell lines. First, BNIPPiProp has been successfully encapsulated within solid lipid nanoparticles and a comparative cytotoxicity study was performed using MTT assay. After a 24-hour treatment, the 3 compounds alone demonstrated a strong cytotoxicity with IC50 values ranging from 1.3 to 2.6 μM in both SW620 and SW480. However, the drug-free nanoparticle formulation was found to cause a high toxicity level. BNIP-treatments also led to a significant increase of ROS levels after a 24-hour treatment associated with an increase of DNA damage with the significant creation of DNA strand breaks against both cell lines (both at IC50). According to proteome profiler array, BNIPPiProp, BNIPPiEth and BNIPDaCHM were found to up-regulate and downregulate apoptosis-related proteins in a cell line and drug dependant manner. However, no increase in caspase-3 levels was detected after 24 hours against both cell lines using the 3 compounds studied. Together, these findings demonstrate the relevance of BNIP derivatives in the treatment of colorectal cancer and offer a first-stepping stone in the design of a BNIP-drug delivery system.
Bisnaphthalimidopropyl, Solid lipid nanoparticles, Colorectal cancer
Networked Digital Library of Theses and Dissertations