5-Fluorouracil enteric-coated nanoparticles for improved apoptotic activity and therapeutic index in treating colorectal cancer

Abstract

5-Fluorouracil (5-FU) is one among the anti-cancer agents in FOLFORINOX treatment along with oxaliplatin and irinotecan for the treatment of colorectal cancer. Despite its potential activity on the tumor cells, it lacks site specificity partly attributed by its biodistribution to healthy cells resulting in toxic effects to healthy cells. Therefore, we have formulated 5-fluorouracil entericcoated nanoparticles (5-FUEC) to localize the drug in the colon area that enables its prolonged presence in target area in a sustained manner. The current work emphasizes on enhanced anticancer activity of 5-FUEC sequencing its apoptotic activity on HCT 116 colorectal cancer cell lines in vitro. MTT assay exhibited 5.5-fold decrease in IC50 value of nanoparticles comparable to 5-FU. Nuclear fragmentation with irregular edges in nucleus of cells justified its improved activity. Furthermore, flow cytometric analysis confirms the majority of cells gated in early apoptotic (39.75%) and late apoptotic phase (36.25%). Acridine orange/ethidium bromide staining (AO/EB) exhibited cells with red fluorescence (indicating apoptosis) comparable to the control and 5-FU. g-Scintigraphic studies determined the applicability and feasibility of the enteric coating with mean gastric emptying time, mean intestinal transit time and mean colon arrival time of 1.89 ± 0.03, 2.15 ± 0.05 and 4.03 ± 0.27 h, respectively. Moreover, nanoparticulate approach was found significant in reducing tumor size and volume in xenograft tumor models in vivo along with sustained release. These superior anti-cancer activities exhibited by 5-FUEC indicated that it could be a potential alternative to chemotherapy for colorectal cancer.

Bcl-2-associated athanogene 3(BAG3) is associated with tumor cell proliferation, migration, invasion and chemoresistance in colorectal cancer

“…To evaluate the differences in chemoresistance properties according to the expression levels of BAG3 in HCT-116 cells, cells were seeded in 96-well plates with 80–90% confluence and treated with 0,5,25,50 μg/ml 5-FU, the concentrations used were determined by referring to previous report [ 27 ]. 5-FU was dissolved in DMSO (stock concentration 50 mg/ml) and a starting working concentration used in experiments was 5 mg/ml which was further diluted 1000-fold, 200-fold and 100-fold to 5 μg /ml, 25 μg /ml and 50 μg /ml.…”

<p>Enteric-Coated Strategies in Colorectal Cancer Nanoparticle Drug Delivery System</p>

“…Enteric-coated nanoparticles are one of the drug delivery technologies that can improve the bioavailability of drugs by oral administration, 50,[133][134][135] increase intracellular penetration and retention time, control the release of encapsulated drugs and targeted delivery in specific parts of the gastrointestinal tract such as in the treatment of colorectal cancer. 136 Cellular uptake and efficacy of nanoparticle drug delivery systems for colorectal cancer therapy are influenced by several factors, namely, size, shape, and surface chemistry.…”

“…of enteric-coated nanoparticles was determined compared with free nanoparticles and pure 5-FU 133 In conclusion, an enteric-coated nanoparticle system with a significant sustained and localized release and enhanced anticancer activity for colorectal cancer treatment was successfully developed.…”

Polymeric nanoparticles for colon cancer therapy: overview and perspectives

“…This particle behavior allowed for a significant reduction in the tumor size compared to the free 5-FU control. 76 Polymeric micelles are other major nanostructures used in drug delivery systems. They can be formulated by amphiphilic block copolymers to self-assemble into a core-shell structure.…”