A novel nanoparticle-based treatment that combines two innovative tumor-targeting techniques has the potential to improve therapeutic outcomes for people with glioblastoma, suggests research published in Science Advances.
The treatment, developed by researchers from Yale and the University of Connecticut, uses bioadhesive nanoparticles that adhere to the tumor and then slowly release the synthesized peptide nucleic acids (PNAs) that they’re carrying. The PNAs target microRNAs (miRs)—that is, short strands of noncoding RNA that regulate gene expression at the posttranscriptional level.
The dysregulation of miRs, either up-regulation (where they are known as oncomiRs) or down-regulation, plays an important role in several malignancies, including the proliferation of cancer cells and tumor growth. Targeting them with PNAs can stop the tumor-promoting activity.
“While other groups have shown that different oncomiRs can influence gliomas, all of the previous studies have looked at one oncomiR at a time,” said Mark Saltzman, the Goizueta Foundation Professor of Biomedical Engineering, Chemical & Environmental Engineering & Physiology and member of Yale Cancer Center. “We first did experiments asking the question: can the simultaneous delivery of two anti-oncomiRs influence cell survival and gene expression? The answer was yes. We then solved the practical problem of simultaneous delivery of two anti-oncomiRs to animals with brain tumors.”
Saltzman told Inside Precision Medicine that the bioadhesive nanoparticles are formed from a copolymer with two segments: a biodegradable segment and a water-soluble segment. The biodegradable segment forms a core—which traps the drug within it—and the water-soluble segment forms the surface corona. That surface corona is made of a special chemical, which can be converted quickly into a bioadhesive state.
He explained that the nanoparticles are delivered to the brain tumor by a clinically-proven process known as convection-enhanced delivery (CED). In CED, a catheter is introduced into the brain at the tumor site, and a solution containing the drug substance is slowly infused. “In our case, the solution was a suspension of our nanoparticles containing the two anti-oncomiRs,” he said.
Using CED overcomes the problem of crossing the blood–brain barrier, which makes glioblastoma difficult to treat. Another factor that contributes to the aggressiveness of these tumors is that there is a subpopulation of cells within the glioma that are resistant to most therapies. “We overcome that problem by delivering anti-oncomiRs that sensitize the most resistance tumor cells to the therapy,” Saltzman remarked.
The two oncomiRs the team targeted were miR-10b and miR-21, which are considered the most highly up-regulated oncomiRs contritubing to glioblastoma and are associated with poor prognosis and low overall survival.
The researchers carried out a series of in vitro experiments to confirm the specificity of the PNAs and cellular uptake of the nanoparticles, and to show that they inhibit the expression of miR-10b and miR-21 and enhance tumor cell death when combined with the chemotherapeutic agent temozolomide, which is a standard treatment for glioblastoma.
They then tested the treatment in mouse models of glioblastoma and found that animals given the nanoparticles in combination with temozolomide survived until the end of the 120-day study, compared with median survival times of 81 days with temozolomide monotherapy, 53 days with nanoparticle monotherapy, and 45 days with no treatment.
“The most important finding is that all of this can be done safely in animals with intracranial tumors, and that the results show dramatic improvements in survival,” said Saltzman.
He noted that although the study focused on two common oncomiRs, in future it “might be possible to profile an individual patient’s tumor, to ask which oncomiRs are the most important in that tumor. Then a doctor could administer nanoparticles that are loaded with anti-oncomiRs that are specific for that individual’s tumor.”
The team is now hoping to find partners who will help develop the treatment and push it toward clinical trials.