Cancer Drug “Envelope” Protects Against Heart-Damaging Side Effects

Researchers have developed a chemotherapy drug packaged in a protein shell that decreases the drug’s toxic side effects on lab-grown, stem cell-derived heart cells. The research is published in Stem Cell Reports.

Chemotherapy drugs can have implications for heart health

Cancer drugs target tumor cells but are also often taken up by healthy cells, which causes side effects.

The chemotherapy drug doxorubicin is widely used to treat breast and blood cancers, for example, but can also cause harmful side effects such as heart damage (cardiotoxicity). Doxorubicin is designed to enter cancer cells and kill them by damaging their DNA, but it coincidentally enters and damages healthy heart cells.

Patients treated with doxorubicin can experience abnormal heart rhythms or low blood pressure that resolves after their treatment is completed. However, in the long run, some doxorubicin-treated patients experience heart damage that can potentially lead to heart failure.

Researchers are now devising ways to target these kinds of chemotherapy drugs specifically toward cancer cells and away from healthy cells, reducing side effects while preserving their anti-cancer activity. In the current study, researchers from Cedars-Sinai Medical Center and Sunstate Biosciences developed a protein “envelope” that surrounds doxorubicin, both increasing its chances of being taken up by cancer cells and decreasing its toxic effects on heart cells.

Protein “envelope” reduces toxicity in lab models

The researchers coated doxorubicin with human serum albumin (HSA), a protein that is rapidly consumed by cancer cells as a source of nutrients, making it ideal as a kind of “packaging” to direct the delivery of doxorubicin to cancer cells.

This packaged drug – named SPEDOX-6 – has previously been tested in mice, revealing its improved anti-cancer properties and pharmacokinetic profiles (how the body processes the drug) compared to the unenveloped doxorubicin (UF DOX).

However, as animal models can have significant differences in heart physiology compared to humans, the researchers tested SPEDOX-6 on lab-grown human cells to investigate if it could indeed reduce cardiotoxicity.

They first used heart muscle cells (cardiomyocytes) derived from human induced pluripotent stem cells (hiPSCs) – cells that have been reprogrammed to an embryonic-like state to produce other cell types. This showed that SPEDOX-6 was markedly less toxic to these cells than UF DOX and also suggested that they maintained the cells’ contractile functionality. Other tests using heart cells made from patients with an increased genetic risk for doxorubicin-induced heart damage also showed reduced toxicity with SPEDOX-6.

However, tests on other cardiovascular cell types – namely endothelial cells and cardiac fibroblasts – also derived from hiPSCs showed that SPEDOX-6 had a similar toxicity to UF DOX for these cells.

Clinical trial planned

“We demonstrate that SPEDOX-6 retains the anticancer efficacy of UF DOX, while minimizing its cardiotoxicity,” the authors write in the study. They also suggest that further studies of this protein-encapsulation technology could help to tackle cardiotoxicity caused by other chemotherapy drugs.

However, they note some limitations to the study, stating that the hiPSC-derived cardiomyocytes are “structurally, functionally and genetically immature in comparison with adult human cardiomyocytes,” while remarking that they are also costly and time-intensive to produce.

For SPEDOX-6 and the research team, the next steps include a Phase 1B/2A clinical trial, recently given the go-ahead by the US Food and Drug Administration (FDA).

Reference: Arzt M, Gao B, Mozneb M, et al. Protein-encapsulated doxorubicin reduces cardiotoxicity in hiPSC-Cardiomyocytes and cardiac spheroids while maintaining anticancer efficacy. Stem Cell Rep. 2023. doi: 10.1016/j.stemcr.2023.08.005