ABOVE: Researchers slowed the spread of skin cancer in mice using nutrient nanobubbles that restarted metabolic pathways. ©istock, Nasekom
When cancer takes control of a cell’s metabolism, it reshapes it in the pursuit of growth.1 Cancer cells shut down cellular processes that don’t serve this goal. In a new research study published in the journal Nature Nanotechnology, researchers found that rekindling those dormant pathways suppressed cancer’s spread.2 The findings could herald new treatments that target cancer cells more efficiently.
Dayong Jin, a materials scientist at the University of Technology Sydney and coauthor on the study, approaches big problems in science using the tiniest tools available: nanoparticles. Jin previously used nanoparticles to look inside bone marrow and detect miniscule molecules released by cancer cells.3,4 His latest study was even more ambitious; he wanted to know whether tiny nanostructures could treat cancer.
His team was inspired by previous research on liver and kidney cancers where researchers manipulated cancer cells’ metabolisms to restore healthy cellular processes and restrict growth. 5 Jin wondered whether a nanoparticle-based delivery system could make it easier to alter the inner workings of cancer cells. For their experiments, Jin’s team focused on skin cancer. To redirect their energy towards cell proliferation, melanoma cells slow down production of the pigment molecule melanin. The first challenge Jin’s team faced was to find a way to accelerate melanin production.
Interventions that change how a cell’s internal processes work often target metabolic enzymes. Developing enzyme activators is a tricky process and the resulting drugs are usually cleared from the body before they have an effect.6 Another option is to identify and make available the nutrients that the cell uses during melanin production. In skin cells, the amino acid tyrosine is a vital component of melanin synthesis, but it’s hard to deliver amino acids to specific cells.7 This is where nanotechnology exceled.
“We engineered the natural form of tyrosine to create a minicell structure,” said Jin. These minicells, also called nanomicelles, are small spheres roughly 60 nanometers in diameter, which can easily cross the cellular membranes of cultured mouse- or human-derived cancer cells. Following three days of incubation, Jin and his team found that melanin levels increased sixfold in targeted cells compared to control cells not exposed to minicells.
The cancer cells, now pumping out melanin, soon ran out of energy; additional assays showed that increased minicell concentration made cancer cells less likely to spread.
To test their minicells in a living system, the researchers used a mouse model of melanoma. When they intravenously injected the minicells for the first time, they thought something had gone wrong. The tumors darkened in color, which caused the team to think that the cancer became more aggressive. After all, as Jin pointed out, melanoma means “black tumor”.
Instead, the researchers found that the tumors’ darker shade signaled higher melanin production and cancer cell death. After 50 days of treatment, the minicells brought breakneck tumor growth to a crawl and significantly prolonged survival.
These are all signs of a successful treatment, but cancer treatments are rarely given alone in modern medicine, noted Navdeep Chandel, a cell biologist at Northwestern University who was not involved in the study.
Jin and colleagues decided to test a combination therapy of minicells and an experimental treatment called photothermal therapy that exploited the tumors’ newly increased melanin levels. They fired an 808-nanometer infrared laser at the mice’s tumors for six days, five minutes per day. The melanin absorbed the light, heating the tumor cells. This technique, which Jin said leaves surrounding normal tissue undamaged, eradicated the tumors and increased survival rates relative to treatment with minicells alone.
Chandel said that the results are promising, but more work is needed. “I would like to see it, first of all, in multiple mouse models, and second, I'd like to see it with standard-of-care therapy,” he said.
Standard-of-care treatments, like radiotherapy or chemotherapy, can interact negatively with new approaches. For example, chemotherapy induces oxidative stress to kill tumor cells, but clinical trials have shown that antioxidant treatment lessened chemotherapy’s efficacy.8
Looking ahead, Jin hopes that minicells could be incorporated into early-stage interventions, before chemo- or radiotherapies are required. “If we can prevent cancer…we won't have to worry about limited treatment options,” he concluded.
- Martínez-Reyes I, Chandel NS. Cancer metabolism: Looking forward. Nat Rev Cancer. 2021;21(10):669-680
- Chen Y, et al. Nutrient-delivery and metabolism reactivation therapy for melanoma. Nat Nanotechnol. 2024:1-10
- Mi C, et al. Bone disease imaging through the near-infrared-II window. Nat Commun. 2023;14(1):6287.
- Zhand S, et al. Improving capture efficiency of human cancer cell derived exosomes with nanostructured metal organic framework functionalized beads. Appl Mater Today. 2021;23:100994.
- Ma R, et al. Switch of glycolysis to gluconeogenesis by dexamethasone for treatment of hepatocarcinoma. Nat Commun. 2013;4(1):2508
- Werle M, Bernkop-Schnürch A. Strategies to improve plasma half life time of peptide and protein drugs. Amino Acids. 2006;30(4):351-367
- Zhuang C, et al. Small molecule-drug conjugates: A novel strategy for cancer-targeted treatment. Eur J Med Chem. 2019;163:883-895
- Bairati I, et al. Randomized trial of antioxidant vitamins to prevent acute adverse effects of radiation therapy in head and neck cancer patients. JCO. 2005;23(24):5805-5813.