Too much of a good thing: Livers of young mice filter out nanodrugs, making them less effective

There’s little question that young livers work better than old ones. But for pediatric, adolescent and young adult patients who need to take nanodrugs—formulations of medicines packaged into nanoparticles about 100,000 times smaller than a red blood cell—having optimal liver function might actually backfire.  

That's the conclusion of a study published Sept. 18 in Nature Nanotechnology, in which researchers from the University of Texas MD Anderson Cancer Center showed that the livers of young mice filtered out a common chemotherapy drug before it could take effect. They also identified a potential solution: blocking a key receptor in liver immune cells.

“In oncology, this is a big problem for pediatrics and adolescents,” Wen Jiang, Ph.D., a scientist at the cancer center, told Fierce Biotech Research in an interview. Nano delivery systems offer a way to treat young cancer patients with medications that, in their standard form, could cause serious, lifelong side effects, he explained. They’re also considered invaluable to the future of gene therapy, which increasingly relies on highly targeted nanoparticles to get viral vectors into the right cells without straying elsewhere.

But first, they have to work. The 50-plus nano-based therapies that have been approved by the FDA since 1995, including 19 for use in cancer, are far outnumbered by clinical failures, as researchers have pointed out. And of the cancer nanodrugs that have been greenlighted, only a few can be used in children, as Harvard and Northeastern scientists noted in a 2021 review.

Following earlier clues suggesting age impacts tumor treatment efficacy and research showing that immune cells called macrophages are key to clearing nanoparticles from the body, Jiang’s team set out to see whether they could figure out what was holding nanodrugs back from reaching their potential in younger patients. They started by assessing how age affected the performance of a nanoformulation of the common chemo drugs paclitaxel—marketed by Bristol Myers Squibb as Abraxane—and the nanodrug liposomal doxorubicin, a Baxter drug with the trade name Doxil. The scientists also looked at how well these drugs were cleared from circulation by the liver.

Their experiment compared six- to eight-week-old male and female mice, comparable to late childhood to adolescence in humans, with 50- to 60-week-old mice, which would be on par with late middle age. Mice in both age groups were injected with breast cancer cells; when the tumors grew to sufficient size, the animals were randomly assigned to one of three treatment groups. One received nano-paclitaxel, a second received liposomal doxorubicin and the third, a control group, received a saline solution.

Age had a marked impact on how well the treatments worked. While there was no difference in tumor size among the control mice, the tumors in the older mice that received either of the nanodrugs were smaller than in their younger counterparts. When the researchers analyzed the animals' liver cells, they found a possible explanation: Liver macrophages were clearing the nanodrugs more efficiently in the younger mice than in the older ones, so less of the therapies were making it to the young animals’ tumors.

When they took a closer look at gene expression patterns in the macrophages, the researchers saw distinct differences between young and old mice. The young had greater expression of genes linked to phagocytosis, or the breakdown of foreign substances, and those genes were more responsive to stimulation by nanoparticles in the young than in the old. One type of macrophage in particular, called a Kupffer cell, was especially reactive.

This prompted the researchers to hunt for a drug target on the Kupffer cells. Previous research had suggested that a scavenger receptor called a macrophage receptor with collagenous structure, or MARCO, could be activated by exposure to foreign objects. Scavenger receptors remove debris from the stream of blood that flows through the liver; if the liver is the body’s janitor, scavenger receptors on macrophages like Kupffer cells are the brooms that pick up the debris, Jiang explained.

If the number of MARCO receptors on Kupffer cells declined with age, it could explain why the cells were less active in the old mice. Indeed, exposing young Kupffer cells to nanoparticles induced “robust increases” of MARCO expression, as the researchers put it in the paper. In contrast, MARCO expression was much more subdued in the old mice, suggesting that the receptor was responsible for the differences in drug uptake they had observed.

Next, Jiang’s team looked at gene expression in primate Kupffer cells to see whether the mechanism was conserved across species. They saw the same thing they had seen in the mice: MARCO expression declined as the subjects from which the cells were taken got older. Data from the Human Protein Atlas and human liver tissue samples further validated their findings: MARCO expression in adults over 50 was lower than in younger subjects. 

Now, it was time to see whether blocking their target could make the therapies more effective. The researchers tried two different strategies: an antibody to MARCO to be given along with the drug and a nanoparticle that was modified with a peptide that competed with debris for the MARCO receptor.

Using the nanoformulation of paclitaxel as their test therapy, the researchers saw that both strategies decreased the number of nanoparticles in the livers of young mice with breast cancer and increased the time the treatments spent circulating in the bloodstream. They also inhibited the tumors from growing. Meanwhile, there were no changes in the older mice that received MARCO-blocking drugs.

Another round of experiments showed even more encouraging results in male mice with lung tumors, also treated with nano-paclitaxel. Blocking MARCO not only enhanced the drug’s effects but also lowered the amount of weight the mice lost as a side effect of the chemotherapy—a finding that suggests reducing the amount of drug that’s taken up by cells outside of the tumor can lower toxicity. Once again, the findings weren’t replicated in the older mice.

“These results support that blocking MARCO in young hosts reduces the liver uptake and clearance, enhances (delivery to the tumor), improves effectiveness and reduces the toxicity of nanotherapeutics,” the researchers wrote.

The next step will be to develop anti-MARCO antibodies designed for use in humans and test whether adding them to a conventional nanotherapeutic can improve its anti-tumor effect or reduce toxicity, Jiang told Fierce in a follow-up email.