Many of us are old enough to know that tiny bubbles in the wine made Don Ho feel happy and fine. Well now, a team of investigators at Michigan State (MSU) and Stanford Universities are feeling pretty fine themselves, but it is less to do with wine and more to do with the findings they recently released showing that engineered microvesicles could become mini treatment transporters, carrying a combination of therapeutic drugs and genes that target cancer cells and kill them. The researchers published their results, which focused on breast cancer cells in mice, in Molecular Cancer Therapeutics through an article titled “Microvesicle-mediated delivery of minicircle DNA results in effective gene-directed enzyme prodrug cancer therapy.”

“What we’ve done is improve a therapeutic approach to delivering enzyme-producing genes that can convert certain drugs into toxic agents and target tumors,” explained lead study investigator Masamitsu Kanada, PhD, assistant professor of pharmacology and toxicology in MSU’s Institute for Quantitative Health Science and Engineering.

The drugs, or prodrugs, start out as inactive compounds. But once they metabolize in the body, they’re immediately activated and can get to work on fighting everything from cancer to headaches. Aspirin is an example of a common prodrug.

In this case, the researchers used extracellular vesicles, or EVs, to deliver the enzyme-producing genes that could activate a prodrug combination therapy of ganciclovir and CB1954 in breast cancer cells. Minicircle DNA and regular plasmid—two different gene vectors that act as additional delivery mechanisms for DNA—were loaded into the vesicles to see which was better at helping transport treatment. This is known as a gene-directed enzyme, prodrug therapy.

“In this study, delivery vehicles comprised of microvesicles loaded with engineered minicircle (MC) DNA that encodes prodrug converting enzymes were developed as a cancer therapy in mammary carcinoma models,” the authors wrote. “We demonstrated that MCs can be loaded into shed microvesicles with greater efficiency than their parental plasmid counterparts and that microvesicle-mediated MC delivery led to significantly higher and more prolonged transgene expression in recipient cells than microvesicles loaded with the parental plasmid. Microvesicles loaded with MCs encoding a thymidine kinase (TK)/nitroreductase (NTR) fusion protein produced prolonged TK-NTR expression in mammary carcinoma cells. In vivo delivery of TK-NTR and administration of prodrugs led to the effective killing of both targeted cells and surrounding tumor cells via TK-NTR-mediated conversion of co-delivered prodrugs into active cytotoxic agents.”

Amazingly, the research team found that the minicircle DNA was 14 times more effective at delivery and even more successful at killing cancerous tumors.

“Interestingly, the plasmid delivery method didn’t show any tumor cell killing,” Kanada said. “Yet the minicircle DNA-based therapy killed more than half of the breast cancer cells in the mice.”

According to Kanada, this new approach could effectively become a better cancer treatment option than chemotherapy down the road.

“Conventional chemotherapy isn’t able to differentiate between tumors and normal tissue, so it attacks it all,” Kanada noted. “This non-specificity can cause severe side effects and insufficient drug concentration in tumors.”

With EVs, treatment can be targeted and because of their compatibility with the human body, this type of delivery could minimize the risk of unwanted immune responses that can come with other gene therapies.

“If EVs prove to be effective in humans, it would be an ideal platform for gene delivery and it could be used in humans sooner than we expect,” Kanada said.

A Phase I clinical trial, separate from Kanada’s work, is set to start soon in the United States and will use EVs and a type of therapeutic RNA molecule for the treatment of metastatic pancreatic cancer.

While that trial moves forward, Kanada and his team will continue to further engineer and test EVs, improving their effectiveness and safety so using them as a cancer-fighting gene therapy in humans becomes reality.


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