Tumor Targeting and Lipid Rafts Disrupting Hyaluronic Acid-Cyclodextrin-Based Nanoassembled Structure for Cancer Therapy.

CD44 receptor targeting and lipid rafts destroying nanoassembly (NA) was developed for breast cancer therapy. Methyl-β-cyclodextrin (MbCD), as a cholesterol depletion moiety, was conjugated to hyaluronic acid-ceramide (HACE) structure via an ester linkage. HACE-MbCD NA with 198 nm hydrodynamic size, unimodal size distribution, and spherical shape was fabricated by self-assembly strategy. By filipin III staining, it was identified that HACE-MbCD NA extracted cholesterol from the cellular membrane of MDA-MB-231 (human breast adenocarcinoma) cells more efficiently rather than MbCD and HACE NA. Efficient lipid rafts disruption of HACE-MbCD NA compared to MbCD and HACE NA groups seems to lead to the increment in apoptosis and antiproliferation efficiencies in MDA-MB-231 cells. Improvement in tumor targeting efficiency of HACE-MbCD NA compared to HACE NA in MDA-MB-231 tumor-bearing mice can be explained by the extraction process of cellular cholesterol by MbCD. Following intravenous injection in MDA-MB-231 tumor-bearing mice, the most efficient suppression of tumor growth and highest apoptotic region were observed in HACE-MbCD NA group rather than MbCD group. All of these findings suggest that CD44 receptor-targetable HACE-MbCD NA retaining cholesterol depletion activity from cancer cells may be one of the remarkable nanosystems for breast cancer therapy.