(725g) Targeting P-Selectin Using Fucoidan-Doxorubicin Nanoparticles for Effective Metastatic Breast Cancer Therapy

Metastatic breast cancer (MBC) is the second leading cause of cancer deaths in women in the U.S. Targeting biomarkers associated with MBC in combination with chemotherapeutic agents will greatly help improve therapeutic potential for patients diagnosed with MBC. Among these biomarkers, P-selectin, which is found in tumor vasculature, plays an important role in metastasis as it enhances the adhesion of cancer cells to activated platelets in distant organs. Fucoidan (Fuc), a type of sulfated polysaccharide known for its anticoagulant, anti-tumor and anti-inflammatory effects, has been reported to have strong affinity towards P-selectin. Doxorubicin (Dox), one of the widely used chemo drugs for the treatment of MBC, exhibits cardiotoxicity as the major side effect. Conjugating doxorubicin to fucoidan could diminish its adverse effects by slowing down the release and enhancing the preferential accumulation in cancer sites. In this study, we first show positive P-selectin expressions on MDA-MB-231, MDA-MB-468, and BT474 cell lines using polymerase chain reaction (PCR), suggesting the feasibility of targeting P-selectin for breast cancer. Then, we synthesized fucoidan-Doxorubicin direct conjugate nanoparticles (Fuc-Dox NPs), in which Fuc was conjugated through the alcohol groups to the primary amine group of Dox via carbamate bond, to target P-selectin. Fuc-Dox NPs form a Fuc corona surrounding Dox molecules with a size of ~100 nm and Dox loading of ~10% (wt) measured by dynamic light scattering (DLS) and fluorescence reader, respectively. These NPs have shown slow Dox release and superior cellular uptake and localization of Dox visualized by confocal imaging and flow cytometry. This therapeutic strategy has a great potential for targeting and treating MBC with maximum anti-tumor therapeutic efficacy and minimum side effects.