Recently, researchers at Yale University and the University of Connecticut collaborated to develop a nanoparticle-based treatment to fight glioblastoma (GBM), one of the most harmful malignancies with a high recurrence rate and poor clinical outcome. This newly developed technique targets multiple factors associated with GBM progression and invasiveness. The findings were published in Science Advances.
GBM: Cause and Conventional Treatment
Around 14.5% of nervous system tumors have been linked to GBM, with a survival rate of approximately 15 months. The incidence rate of GBM in the US is 4.32 per 100,000 persons a year, with a poor survival rate.
Conventional treatment of GBM includes surgery, followed by radio-and-chemo-therapy. Notably, temozolomide (TMZ), a chemotherapy treatment in combination with radiotherapy has improved survival rate by two years.
MicroRNAs (miRNAs) are approximately 25 nucleotides long non-coding RNAs involved with genetic expressions at the post-transcriptional level. Several studies have indicated that miRNA dysregulation, at an up-regulation (oncomiRNAs) or down-regulation, is a potential driver of malignancies.
Unusual miRNA expression levels were observed in patients with GBM, which resulted in poor prognosis and survival rates. For instance, miR-10b and miR-21 were identified to be the significantly up-regulated oncomiRs, manifesting GBM.
Mechanistically, miR-10b increases GBM growth by negatively regulating transcription factor AP-2γ (TFAP2C), cyclin-dependent kinase inhibitor I (p21) expression, BCL2 interacting mediator of death (Bim), and tumor suppressor cyclin-dependent kinase 2A inhibitor (CDKN2A/16). Similarly, GBM invasiveness is increased by up-regulated miR-21 levels.
Mechanistically, an up-regulated miR-21 inhibits matrix metalloproteinase (MMP) and stimulates cell proliferation via negative regulation of phosphatase and tensin homolog (PTEN) and insulin-like growth factor–binding protein-3 (IGFBP3). It also induces tumor stemness through SRY-box transcription factor-2 (SOX-2).
In vivo experiments revealed that miR-10b inhibition reduces intracranial GBM tumor growth, which ultimately prompted the development of antisense oligonucleotide (RGLS5799, Regulus Therapeutics) targeting miR-10b.
Alternatively, knocking down miR-21 decreases GBM advancement and invasion. This treatment also reduces GBM cell’s chemoresistance to TMZ and taxol. The available GBM therapeutics mainly target a single oncomiR, which has shown reduced efficacy.
A New Nano-based GBM Treatment
As stated above, scientists from Yale and the University of Connecticut have designed a nanoparticle-based treatment for GBM. This therapy targets both miRNAs, i.e., miR-10b and miR-21 simultaneously, to increase the chemosensitization of GBM toward TMZ.
In this study, bioadhesive nanoparticles were used, which contained newly synthesized peptide nucleic acids (PNAs). PNAs were able to actively regulate gene expression, particularly oncomiRs. They are synthetic nucleic acid analogs, in which the phosphodiester backbone is replaced with neutral N-(2-aminoethyl) glycine units. The newly developed bioadhesive nanoparticles adhere to the tumor site, slowly release the PNAs that target oncomiRNAs, and inhibit tumor-promoting activity.
Typically, PNAs bind to targeted miRNAs via a complementary DNA base pairing system, and this structure is enzymatically stable. However, compared to classical PNAs, serine-gamma PNAs (γPNAs), with specific modification at the γ position, exhibit superior binding affinity, physicochemical features, and specificity. Previous studies have also indicated that anti-seed sγPNAs are clinically more translatable with minimal toxicity.
The newly designed γPNAs are complementary to the seed region of oncomiR-21 and oncomiR-10b, to improve anti-miRNA activity. Besides its simplistic synthesis methodology, γPNAs are also ideal for conjugation with fluorophores or other probes, which are useful for imaging.
The convection-enhanced delivery (CED) system has been developed to directly introduce polymeric nanoparticles (NPs) loaded with active agents to brain tumors. In this study, the bioadhesive NPs (BNPs) comprised hyperbranched polyglycerol (PLA-HPG) and a copolymer of poly(lactic acid), ultimately forming PLA-HPG-CHO, which is highly beneficial to deliver PNA anti-miRs.
In this study, PLA-HPG-CHO BNPs were loaded with two sγPNAs, one bound to miR-10b and the other to miR-21. The Gel shift assays showed the binding of the synthesized sγPNAs (sγPNA-21 and sγPNA-10b) with the respective miR. This finding indicated that the newly designed sγPNAs were highly specific and had a strong affinity for target oncomiRs.
Compared to classical PNAs loaded in the PLA-HPG-CHO BNPs, sγPNAs loaded in PLA-HPG-CHO BNPs exhibited a greater miR inhibition. When sγPNAs loaded PLA-HPG-CHO BNPs were evaluated in a GBM challenged mice model, the treated mice lived longer compared to the control mice.
Notably, sγPNAs loaded PLA-HPG-CHO BNPs remained at the target site for about 40 days, which is extremely advantageous compared to conventional site-specific treatments that wane off fairly quickly.
In addition, as the current treatment knocks down both GBM targets simultaneously, it is more powerful than existing treatments. Mark Saltzman, a professor at the Yale Cancer Center, who was involved with this research, stated, “These results are the best I’ve ever seen in this sort of aggressive brain tumor.”

News
Studies detail high rates of long COVID among healthcare, dental workers
Researchers have estimated approximately 8% of Americas have ever experienced long COVID, or lasting symptoms, following an acute COVID-19 infection. Now two recent international studies suggest that the percentage is much higher among healthcare workers [...]
Melting Arctic Ice May Unleash Ancient Deadly Diseases, Scientists Warn
Melting Arctic ice increases human and animal interactions, raising the risk of infectious disease spread. Researchers urge early intervention and surveillance. Climate change is opening new pathways for the spread of infectious diseases such [...]
Scientists May Have Found a Secret Weapon To Stop Pancreatic Cancer Before It Starts
Researchers at Cold Spring Harbor Laboratory have found that blocking the FGFR2 and EGFR genes can stop early-stage pancreatic cancer from progressing, offering a promising path toward prevention. Pancreatic cancer is expected to become [...]
Breakthrough Drug Restores Vision: Researchers Successfully Reverse Retinal Damage
Blocking the PROX1 protein allowed KAIST researchers to regenerate damaged retinas and restore vision in mice. Vision is one of the most important human senses, yet more than 300 million people around the world are at [...]
Differentiating cancerous and healthy cells through motion analysis
Researchers from Tokyo Metropolitan University have found that the motion of unlabeled cells can be used to tell whether they are cancerous or healthy. They observed malignant fibrosarcoma cells and [...]
This Tiny Cellular Gate Could Be the Key to Curing Cancer – And Regrowing Hair
After more than five decades of mystery, scientists have finally unveiled the detailed structure and function of a long-theorized molecular machine in our mitochondria — the mitochondrial pyruvate carrier. This microscopic gatekeeper controls how [...]
Unlocking Vision’s Secrets: Researchers Reveal 3D Structure of Key Eye Protein
Researchers have uncovered the 3D structure of RBP3, a key protein in vision, revealing how it transports retinoids and fatty acids and how its dysfunction may lead to retinal diseases. Proteins play a critical [...]
5 Key Facts About Nanoplastics and How They Affect the Human Body
Nanoplastics are typically defined as plastic particles smaller than 1000 nanometers. These particles are increasingly being detected in human tissues: they can bypass biological barriers, accumulate in organs, and may influence health in ways [...]
Measles Is Back: Doctors Warn of Dangerous Surge Across the U.S.
Parents are encouraged to contact their pediatrician if their child has been exposed to measles or is showing symptoms. Pediatric infectious disease experts are emphasizing the critical importance of measles vaccination, as the highly [...]
AI at the Speed of Light: How Silicon Photonics Are Reinventing Hardware
A cutting-edge AI acceleration platform powered by light rather than electricity could revolutionize how AI is trained and deployed. Using photonic integrated circuits made from advanced III-V semiconductors, researchers have developed a system that vastly [...]
A Grain of Brain, 523 Million Synapses, Most Complicated Neuroscience Experiment Ever Attempted
A team of over 150 scientists has achieved what once seemed impossible: a complete wiring and activity map of a tiny section of a mammalian brain. This feat, part of the MICrONS Project, rivals [...]
The Secret “Radar” Bacteria Use To Outsmart Their Enemies
A chemical radar allows bacteria to sense and eliminate predators. Investigating how microorganisms communicate deepens our understanding of the complex ecological interactions that shape our environment is an area of key focus for the [...]
Psychologists explore ethical issues associated with human-AI relationships
It's becoming increasingly commonplace for people to develop intimate, long-term relationships with artificial intelligence (AI) technologies. At their extreme, people have "married" their AI companions in non-legally binding ceremonies, and at least two people [...]
When You Lose Weight, Where Does It Actually Go?
Most health professionals lack a clear understanding of how body fat is lost, often subscribing to misconceptions like fat converting to energy or muscle. The truth is, fat is actually broken down into carbon [...]
How Everyday Plastics Quietly Turn Into DNA-Damaging Nanoparticles
The same unique structure that makes plastic so versatile also makes it susceptible to breaking down into harmful micro- and nanoscale particles. The world is saturated with trillions of microscopic and nanoscopic plastic particles, some smaller [...]
AI Outperforms Physicians in Real-World Urgent Care Decisions, Study Finds
The study, conducted at the virtual urgent care clinic Cedars-Sinai Connect in LA, compared recommendations given in about 500 visits of adult patients with relatively common symptoms – respiratory, urinary, eye, vaginal and dental. [...]