Chitosan-Decorated Doxorubicin-Encapsulated Nanoparticle Targets and Eliminates Tumor Reinitiating Cancer Stem-like Cells

TLDR

Tumor reinitiating cancer stem‑like cells drive cancer recurrence after conventional chemotherapy. The study develops a chitosan‑decorated, doxorubicin‑loaded nanoparticle that targets CD44 receptors on these cells. The nanoparticle releases doxorubicin in acidic tumor microenvironments and intracellular endosomes/lysosomes, enabling targeted cytotoxicity. The design increases doxorubicin cytotoxicity sixfold against CD44⁺ cancer stem‑like cells in 3D mammary tumor spheroids, reduces tumor size in an orthotopic xenograft model, and shows no systemic toxicity, offering a new low‑toxicity treatment to improve patient survival.

Abstract

Tumor reinitiating cancer stem-like cells are responsible for cancer recurrence associated with conventional chemotherapy. We developed a doxorubicin-encapsulated polymeric nanoparticle surface-decorated with chitosan that can specifically target the CD44 receptors of these cells. This nanoparticle system was engineered to release the doxorubicin in acidic environments, which occurs when the nanoparticles are localized in the acidic tumor microenvironment and when they are internalized and localized in the cellular endosomes/lysosomes. This nanoparticle design strategy increases the cytotoxicity of the doxorubicin by six times in comparison to the use of free doxorubicin for eliminating CD44+ cancer stem-like cells residing in 3D mammary tumor spheroids (i.e., mammospheres). We further show these nanoparticles reduced the size of tumors in an orthotopic xenograft tumor model with no evident systemic toxicity. The development of nanoparticle system to target cancer stem-like cells with low systemic toxicity provides a new treatment arsenal for improving the survival of cancer patients.