Engineering Thermo/pH-Responsive Lactoferrin Nanostructured Microbeads for Oral Targeting of Colorectal Cancer
Ahmed S. Abd Elhamid, Lamia Heikal, Doaa A. Ghareeb, Shaymaa A. Abdulmalek, Omar Y. Mady, Mohamed Teleb, Sherine N. Khattab, Sanaa A. El‐Gizawy
Abstract
AIM: Colorectal cancer is an extremely aggressive form of cancer that often leads to death. Lactoferrin shows potential for targeting and treating colorectal cancer; however, oral delivery faces hurdles hampering clinical applications. We engineered dual-responsive lactoferrin nanostructured microbeads to overcome delivery hurdles and enhance drug targeting. METHODS: The hydrophobic drug mesalazine (MSZ) was coupled to lactoferrin to form amphiphilic conjugate nanoparticles, dispersed in water. The lipid-soluble polyphenolic drug resveratrol (RSV) was then encapsulated into the hydrophobic core of LF-MSZ nanoparticles. To impart thermoresponsive properties, the dual-payload NPs were coupled with a PNIPAAm shell; finally, to further endow the nanoparticles with gastrointestinal resistance and pH responsiveness, the nanoparticles were microencapsulated into ionically cross-linked pectin-alginate beads. RESULTS: The nanoparticles showed enhanced internalization and cytotoxicity against HCT colon cancer cells via LF-receptor-mediated endocytosis. Thermal triggering and tuned release were conferred by the temperature-sensitive polymer. The coatings protected the drugs from degradation. Orally delivered microbeads significantly reduced tumor burden in a mouse colon cancer model, lowering carcinoembryonic antigen and elevating antioxidant enzymes. Apoptotic pathways were stimulated, indicated by heightened Bax/Bcl2 ratio and caspase-3/9 expression. CONCLUSION: Overall, we propose the innovative lactoferrin nanostructured microbeads as a paradigm shift in oral colorectal cancer therapeutics.