Dual Receptor Uptake of Low-Density Lipoprotein Docosahexaenoic Acid (LDL-DHA) Elicits Differential Sensitivity Across Breast Cancer Subtypes

We proposed to treat breast cancer with a novel nanomedicine previously shown to be effective in the treatment of primary liver tumors in rats. This nanoparticle is comprised of the low-density lipoprotein which acts as a carrier for the omega-3 fatty acid docosahexaenoic acid (DHA). The LDL-DHA nanoparticle has demonstrated cancer selective cytotoxicity with little ill effects on healthy cells. Our research began by selecting a panel of breast cancer cell lines representative of the various subtypes of clinical breast cancer. This panel was screened for expression of LDL and SR-B1 receptors, in addition LDL nanoparticle uptake kinetics was evaluated in each cell line. Thereafter, the cytotoxicity of LDL-DHA nanoparticles was assessed across the panel of breast cancer cells. Animal experiments showing efficacy of LDL-DHA nanoparticle are currently in progress, with the expectation that LDL-DHA treatment of tumors will induce significant tumor necrosis. Our current data suggests that our LDL-DHA nanoparticles are avidly taken up by breast cancer cells, with triple negative breast cancer cells showing some of the highest uptake, mediated by LDLR and SR-B1. LDL-DHA has a higher affinity for LDLR compared to SR-B1 with both receptors being able to mediate uptake. Concurrently, we showed that there is a reciprocal relationship between LDLR and SR-B1, where one receptor compensates for loss of the other to maintain cholesterol homeostasis. Thus, ensuring uptake of LDL-DHA nanoparticles in breast cancer cells. Moreover, LDL-DHA nanoparticles elicit significant cytotoxicity with triple negative breast cancer subtypes being most sensitive to LDL-DHA. As such, in vivo and clinical use of this nanomedicine is anticipated to be effective for metastatic breast cancer tumors with potentially more utility in triple negative breast cancer.

Author dc:creator

• Bower, Joseph Louis

Contributors dc:contributor

• Malladi, Srinivas
• Brekken, Rolf A.
• Raj, Ganesh V.
• Corbin, Ian R.

• Breast Neoplasms
• Cell Death
• Docosahexaenoic Acids
• Lipoproteins, LDL
• Nanoparticles
• Antineoplastic Agents

Language dc:language

en

Identifier

1535537207

OAI identifier oai:identifier

oai:utswmed-ir.tdl.org:2152.5/10696