Targeted Intracellular Delivery of Molecular Cargo to Hypoxic Human Breast Cancer Stem Cells

Overview

Journal bioRxiv

Date 2024 Nov 28

PMID 39605477

Authors

Ashley V Makela

Anthony Tundo

Huiping Liu

Doug Schneider

Terry Hermiston

Pavlo Khodakivskyi

Elena Goun

Christopher H Contag

Affiliations

Soon will be listed here.

Abstract

Cancer stem cells (CSCs) drive tumorigenesis, are responsible for metastasis, and resist conventional therapies thus posing significant treatment challenges. CSCs reside in hypoxic tumor regions and therefore, effective therapies must target CSCs within this specific microenvironment. CSCs are characterized by limited distinguishable features, however, surface displayed phosphatidylserine (PS) appears to be characteristic of stem cells and offers a potential target. GlaS, a truncated coagulation protein that is internalized after binding PS, was investigated for intracellular delivery of molecular payloads to CSCs. Intracellular delivery via GlaS was enhanced in patient-derived CD44+ mammary CSCs under hypoxic conditions relative to physoxia or hyperoxia. , GlaS successfully targeted hypoxic tumor regions, and functional delivery of molecular cargo was confirmed using luciferin conjugated to GlaS via a disulfide linkage (GlaS-SS-luc), which releases luciferin upon intracellular glutathione reduction. Bioluminescence imaging demonstrated effective GlaS-mediated delivery of luciferin, a model drug, to CSCs in culture and . These findings offer the promise of directed delivery of therapeutic agents to intracellular targets in CSCs.

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