%0 Journal Article
%T Engineering Thermo/pH-Responsive Lactoferrin Nanostructured Microbeads for Oral Targeting of Colorectal Cancer.
%A Abd Elhamid AS
%A Heikal L
%A Ghareeb DA
%A Abdulmalek SA
%A Mady O
%A Teleb M
%A Khattab SN
%A El-Gizawy SA
%J ACS Biomater Sci Eng
%V 10
%N 8
%D 2024 Aug 12
%M 39079030
%F 5.395
%R 10.1021/acsbiomaterials.4c00666
%X OBJECTIVE: 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.
CONCLUSIONS: Overall, we propose the innovative lactoferrin nanostructured microbeads as a paradigm shift in oral colorectal cancer therapeutics.