In a recent publication in the Journal Science Translational Medicine, scientists from Northwestern University in Chicago used gold nanoparticles to deliver small interfering RNA (siRNA) against the Bcl2L12 oncogene. The study demonstrated in non-human primates, and in a small proof-of-concept clinical trial that the treatment can be safely administered, it travels to the brain and into the tumors. Importantly, the nanoparticles reduced the levels of Bcl2L12 and caused an increase in proteins associated with cell death.
Glioblastoma (GBM) is a type of brain cancer that originates from cells called astrocytes. It has a 5-year survival rate of only 6.8% and it accounts for almost 50% of all malignant brain tumors. In 2020, more than 13,000 were expected to be diagnosed with glioblastoma, and more than 10,000 people will die from this disease.
Currently, there are very few therapeutic options for the treatment of glioblastoma, these include surgery, radiation therapy, chemotherapy. Additionally, a few FDA-approved medications are approved to treat GBM. New and innovative approaches to treat this deadly disease are necessary.
Gold-Nanoparticles to Transport siRNA
In the study, researchers created and tested NU-0129, an RNA interference-based- spherical nucleic acids therapy, which consisted of the following:
- A gold-based metal core for the nanoparticle.
- Densely packed siRNA against the Bcl2L12 gene sticking out radially from the core.
By choosing gold as the core for the nanoparticle, researchers were able to precisely quantify the spatial distribution of the nanoparticles in cells and tumors. Additionally, the researchers targeted Bcl2L12 for two reasons 1) it is an oncogene that prevents normal cell death and allows cancer cells to survive, and 2) it is elevated in GBM tumors, while still relatively low expressed in the adult brain.
NU-0129 in Non-Human Primates
To determine the toxicity of NU-0129, researchers first dose cynomolgus monkeys at three different concentrations, 1, 4, 8mg/kg via a single large dose (bolus) intravascular injection. The toxicology and toxicokinetic analyses revealed:
- NU-0129 was well tolerated as all animals survived the injection and there was no effect on body weight, hematology, serum chemistry, body temperature, or almost any other parameter measured.
- All animals treated had blue discoloration associated with gold treatment and perivascular hemorrhage at the site of injection.
- The 8mg/kg group had lower diastolic and mean arterial pressure and it was determined to be the no-observed-adverse-effect level (NOAEL) based on systemic and local assessments.
Phase 0 Clinical Trials
Based on the results from the non-human primate models, the researchers initiated a first-in-human, single-arm, open-label clinical trial to determine the safety and biodistribution of NU-0129. A total of 8 patients with recurrent GBM were recruited for the trial. Patients received a single intravenous injection with 1/50th NOAEL dose of 0.04mg/kg. The study revealed:
- NU-0129 is well-tolerated, no grade 4 or 5 adverse events were observed, and perivascular hemorrhage at the site of injection was not observed.
- The most common adverse effects were hypophosphatemia and decreased lymphocyte count.
- NU-0129 crossed the blood-brain barrier and enter the tumors
- 50% of patients treated with NU-0129 showed a decrease in Bcl2L12 in recurrent tumors, while control patients showed no change in Bcl2L12 in their recurrent tumors.
- NU-0129 treatment lead to an increase in cell death-associated proteins.
Although more studies are necessary to determine efficacy, NU-0129 could be a great new tool in fighting GBM.
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