Dual Receptor Targeting Ensures Uptake and Anticancer Efficacy of Low-Density Lipoprotein-Docosahexaenoic Acid...

Aberrant acquisition of lipoprotein cholesterol remains a hallmark feature of breast cancer biology. Low- and high-density lipoprotein receptors (LDLR and scavenger receptor class B type 1 (SR-B1)) are often upregulated to facilitate the tumor cells' high demand for cholesterol. To date, few attempts have been made to therapeutically exploit the high activity of lipoprotein receptors in breast cancer cells.

In the present study, we examined the utility of engineered low-density lipoprotein nanoparticles to deliver the natural anticancer omega-3 fatty acid docosahexaenoic acid (LDL-DHA) across a panel of breast cancer cells.

Our data showed that LDL-DHA nanoparticles were avidly taken up (K_D 28 µg/mL to 1.9 µg/mL) and cytotoxic to all breast cancer subtypes (LD₅₀ 52.2 µM to 4.7µM), with triple negative breast cancer cells showing some of the highest uptake and sensitivity to LDL-DHA. Follow-up receptor knockout studies in MDA-MB-231 cells revealed that LDL nanoparticle uptake is mediated by both LDLR and SR-B1. These receptors were shown to operate concurrently as well as in a compensatory manner to ensure ample uptake of LDL is maintained. Double knockout of LDLR and SR-B1 significantly impeded LDL nanoparticle uptake (<50%) and protected against LDL-DHA cytotoxicity (viability >70%).

In summary, our studies have shown that malignant cell dependence upon cholesterol acquisition can be exploited for lipoprotein-based drug delivery to breast cancer cells. Furthermore, the capacity of LDL nanoparticles to target both LDLR and SR-B1 ensures this as an efficient drug delivery platform against breast cancer cells.