Folate-mediated targeting of carrageenan-cholesterol micelles for enhanced breast cancer treatment

Abstract

A major cause of cancer-related mortality worldwide is metastatic breast cancer. Effective treatment relies on the targeted penetration of tumors and the controlled drug delivery. Here, the amphiphilic conjugates were constructed with a combination of carrageenan polysaccharides (CRG), folic acid (FA)-mediated active targeting, and lipid raft cholesterol (CHS) modification for the intracellular delivery of DOX. A series of biocompatible carrageenan-cholesterol (CRG-CHS) and folic acid-modified carrageenan-cholesterol (FA-CRG-CHS) was synthesized by varying cholesterol and folate contents. The findings suggested that elevating the lipophilicity of the carrageenan chains led to a reduction in the size of the micelles. It was demonstrated that these amphiphilic copolymers formed spherical nanomicelles with excellent drug-loading capacity and encapsulation capability. Micelles were stable under physiological conditions but possessed fast-sustained DOX release in an acidic environment. Micelles were non-cytotoxic, and according to the uptake study, CRG-CHS are primarily internalized via lipid-raft endocytosis when cholesterol content is high. Because of FR-mediated endocytosis, FA-modified micelles showed significantly greater cytotoxicity against MDA-MB-231 cells (folate-receptor overexpression) than MCF-7 cells. According to flow cytometry and live/dead assays, micelles trigger apoptosis in both MCF-7 and MDA-MB-231 cells. These findings indicate that synthesized CRG-CHS and FA-CRG-CHS micelles exhibit significant promise as efficient carriers for delivering hydrophobic anti-cancer drugs within intracellular delivery systems.