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Physiologic Patient Derived 3D Spheroids for Anti-neoplastic Drug Screening to Target Cancer Stem Cells

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Hypoxia-Responsive Polymersomes for Stemness Reduction in Patient-Derived Solid Tumor Spheroids.

Connor Edvall¹, Narendra Kale¹, Sakurako Tani²

¹Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota 58105, United States.

ACS Applied Bio Materials

|March 8, 2025

Summary

Hypoxia-responsive polymersomes loaded with doxorubicin (Dox) and all-trans retinoic acid (ATRA) synergistically combat aggressive solid tumors. This novel drug delivery system effectively reduces tumor volume and cancer stemness in triple-negative breast cancer models.

Keywords:

cancer stemness drug delivery hypoxia nanomaterials polymersomes

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Area of Science:

Biomedical Engineering
Nanotechnology
Cancer Research

Background:

Aggressive solid tumors exhibit rapid growth, early hypoxia, and resistance to therapies, leading to poor patient outcomes.
Hypoxic tumor regions promote stem-cell-like phenotypes, increasing metastasis and drug resistance.
Targeted therapies are lacking for these challenging tumor microenvironments.

Purpose of the Study:

To develop hypoxia-responsive polymersomes for co-delivery of doxorubicin (Dox) and all-trans retinoic acid (ATRA).
To overcome drug resistance in hypoxic solid tumors, specifically triple-negative breast cancer (TNBC).
To investigate the synergistic effects of Dox and ATRA on cancer cell killing and stemness.

Main Methods:

Designed hypoxia-responsive polymersomes with an azobenzene linker, encapsulating Dox and ATRA.
Utilized reductase enzyme-mediated drug release triggered by tumor hypoxia.
Evaluated drug efficacy on patient-derived TNBC spheroids and analyzed underlying mechanisms.

Main Results:

Co-delivery polymersomes synergistically enhanced Dox efficacy, reducing TNBC spheroid volumes by 90%.
Dox alone reduced spheroid volumes by 70%, while ATRA alone showed 19% reduction.
ATRA inhibited efflux pumps, increasing intracellular Dox concentration and decreasing cancer stemness markers.

Conclusions:

Hypoxia-responsive polymersomes offer a promising strategy for synergistic co-delivery of anticancer drugs and stemness modulators.
The combination therapy effectively targets aggressive, hypoxic solid tumors like TNBC.
This approach enhances drug efficacy and reduces cancer stemness, potentially improving treatment outcomes.