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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.
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.
