One of the prospects of nanotechnology is to minimize toxicity through the precise delivery of therapeutics to where they are needed, which enables the delivery of highly toxic agents only to those cells where they are needed.

Researchers recently turned that concept on its ear, mitigating toxicity through nanotubes in basically the opposite way.

The team used functionalized carbon nanotubes to deliver siRNAs that could protect kidneys from cisplatin toxicity.

Acute kidney injury is a risk of many different drug treatments. The kidney's job is to filter out toxins, and it does so to an impressive extent while protecting itself.

But "the kidney does reabsorb some of those drugs, and can concentrate them," corresponding author Michael McDevitt, a radiochemist at Memorial Sloan-Kettering Cancer Center, told BioWorld Today.

According to data in the Thomson Reuters Incidence & Prevalence Database, acute kidney injury "occurred in 1 in 5 adults and 1 in 3 children hospitalized with acute illness." In severe cases, such injury can progress to renal failure.

If kidney injury is frequent, serious and not limited to any one indication, though, it is also predictable. Antibiotics, antivirals and chemotherapies can all lead to kidney injury, as can low oxygen during surgical procedures.

In their work, the authors tested whether preventive treatment with three different siRNAs could prevent kidney toxicity.

They used carbon nanotubes to deliver such siRNAs specifically to the kidneys. Because nanotubes have a high aspect ratio – or more simply put, are long and thin – they align with blood flow in the circulation, and tend to be filtered out by the kidneys.

That filtering can be a feature or a bug, depending on the circumstances. On the one hand, it means that carbon nanotubes have fewer toxicity issues than some other nanomaterials. On the other hand, too-rapid clearance is itself a problem.

McDevitt and his co-authors have previously used a combination of nanotubes, antibodies and oligonucleotides to deliver self-assembling therapies to specific tissues. (See BioWorld Today, Oct. 2, 2013.)

In their new work, which they published in the March 23, 2016, issue of Science Translational Medicine, the team instead used the nanotubes' natural inclinations to deliver siRNAs to the kidneys themselves.

The team first treated mice with several different siRNAs for five days, and then followed up with a dose of the chemotherapy cisplatin that was toxic to the kidneys.

The team tested several different siRNAs, including one to knock down a transporter, one that targeted the apoptosis protein p53, and one aimed at the metalloprotease meprin-1beta.

The team found that to make the siRNA work, they needed to deliver a combination of p53 and meprin-1beta-targeting siRNAs.

Animals given the protective combination two days before a toxic dose of cisplatin had higher survival rates. While the cisplatin killed more than half of the animals that were treated with control siRNA, almost 90 percent of animals with the knockdown of p53 and meprin-1beta survived.

The authors followed the survivors out for six months and then checked their kidneys for signs of scarring. Treated animals had significantly less scarring, as well as fewer inflammatory cells in the kidney both 11 days and six months after receiving cisplatin.

The nanotubes themselves did not cause toxicity in either mice or primates, leading the authors to conclude that if the drugs are found safe in clinical trials, "a clinical strategy using the fibrillar nanocarbon platform could enable targeted siRNA protection of the kidney safely and effectively and prevent [acute kidney injury] in those on chronic pharmacological regimens, especially the elderly and cancer patients."

McDevitt said the team is "testing some other animal models" to see whether the approach is broadly effective against kidney injury due to different underlying reasons. "We are actively pursuing it as something to move forward with clinically," he said.

He and his colleagues are also testing whether nanotubes with a different aspect ratio could be used for specific targeting of other organs, particularly the liver.