Targeted intracellular delivery of molecular cargo to hypoxic human breast cancer stem cells

Abstract

Cancer stem cells (CSCs) comprise the root of cancers and remain a therapeutic challenge since they are quiescent, resist traditional therapies and are fundamentally tumorigenic. Therefore, effective cancer treatments require CSC-targeted approaches that function in representative CSC microenvironments. CSCs exhibit few distinguishable and targetable characteristics, however phosphatidylserine (PS) exposure on the cell surface and localization to hypoxic regions of the tumor are speculated traits. We have reported that a truncated protein S (GlaS) binds PS and is internalized, enabling intracellular delivery of molecular payloads. GlaS delivery was evaluated in patient-derived CD44+ mammary CSCs under different oxygen concentrations. A higher percentage of CD44+GlaS+ cells were observed in hypoxia compared to cells in physoxia or hyperoxia that tracked to small CD44+ cells, which are likely aggressive tumorigenic CSC. Delivery of therapeutics to the cytoplasm of CSCs will enable new therapies directed at intracellular targets, ultimately eliminating CSC.