A new approach to treating malignant glioma by bypassing the blood-brain barrier with nanotechnology
Every year, thousands of people face a diagnosis of glioblastoma multiforme (GBM), the most aggressive and common form of malignant brain cancer. For decades, the standard treatment—surgery, radiation, and chemotherapy—has barely moved the needle in survival rates, with most patients surviving just 12 to 15 months after diagnosis. The reason behind these grim statistics lies in the very organ this cancer attacks: the human brain is protected by a remarkable biological shield that has learned to keep enemies out, including the very drugs designed to save it.
This article explores a revolutionary approach that's turning this problem inside out: advanced interstitial chemotherapy. Instead of fighting to get through the brain's defenses, this innovative treatment method delivers powerful cancer-fighting agents directly to the battlefield, offering new hope in one of medicine's most challenging frontiers.
Months median survival for GBM patients with standard treatment
Of pharmaceutical compounds blocked by the blood-brain barrier
Complete tumor regression in rat studies with advanced interstitial chemotherapy
To understand why brain cancer is so difficult to treat, we must first appreciate the brain's extraordinary security system—the blood-brain barrier (BBB). This isn't just a metaphorical wall but a sophisticated cellular structure that lines the blood vessels throughout our brain. Composed of tightly packed endothelial cells, it acts as a highly selective gatekeeper, carefully controlling what substances can pass from the bloodstream into brain tissue.
The BBB protects the brain from harmful toxins and pathogens in the bloodstream, maintaining the delicate environment required for proper neural function.
While protective, the BBB blocks approximately 95% of pharmaceutical compounds, including most chemotherapy drugs, making brain cancer extremely difficult to treat 1 .
The challenge doesn't end there. Brain tumors create what scientists call a "tumor blood-brain barrier"—a compromised but uneven version of the normal BBB. At the core of the tumor, where blood vessels are leaky and disorganized, some drugs can penetrate. However, at the growing edges where cancer cells infiltrate healthy brain tissue, the BBB remains largely intact, creating safe havens for cancer cells to escape treatment and cause eventual recurrence 1 .
This biological reality has fueled the search for alternative approaches, leading researchers to a clever solution: if chemotherapy can't reliably reach the brain through the bloodstream, why not deliver it directly to the source?
The concept of interstitial chemotherapy is both simple and brilliant: instead of administering drugs intravenously and hoping they cross the blood-brain barrier, bypass this obstacle entirely by placing the medicine directly into the tumor cavity after surgical removal of the cancer.
The earliest approved form of interstitial chemotherapy was the Gliadel® wafer, a small, biodegradable polymer disc impregnated with the chemotherapy drug carmustine (BCNU) 2 .
Neurosurgeons can place up to eight of these wafers in the space where the tumor was removed, where they slowly dissolve over 2-3 weeks, releasing high concentrations of chemotherapy directly to the area most likely to see recurrence 2 .
More importantly, Gliadel wafers proved the fundamental principle that local drug delivery could be safe and effective, paving the way for more advanced second-generation technologies.
While Gliadel wafers represented an important first step, researchers continued to push the boundaries of what interstitial chemotherapy could achieve. A groundbreaking 2016 study published in the journal Oncotarget showcased a remarkable advance: the use of drug-loaded nanofibrous membranes that could deliver not just one, but multiple therapeutic agents in a carefully timed sequence 4 8 .
A research team led by Dr. Yuan-Yun Tseng and Dr. Shih-Jung Liu developed an innovative approach using electrospun nanofibers made from biodegradable polymers called poly(lactide-co-glycolide) (PLGA). These nanofibers—thinner than a human hair—could be loaded with different drug combinations and engineered to release them at specific times 4 .
The team created two types of nanofibrous membranes using different PLGA ratios loaded with chemotherapy drugs and antiangiogenic agents 4 .
The membranes were surgically implanted onto the brain surfaces of rats that had been specially bred to develop malignant gliomas 4 .
The team monitored tumor growth through MRI imaging, measured survival times, and examined brain tissue to evaluate effectiveness 4 .
The findings were striking. The nanofibers created a sustained, localized drug delivery system that maintained high drug concentrations in the brain while minimizing systemic exposure. The chemotherapy drugs were released rapidly initially, while the antiangiogenic combretastatin was released approximately two weeks later, creating a sequential treatment approach 4 .
| Drug | Brain-to-Blood Ratio |
|---|---|
| Cisplatin | 985.78 |
| BCNU | 115.76 |
| Irinotecan | 272.59 |
Source: Adapted from Tseng et al. Oncotarget, 2016 4
| Treatment Group | Median Survival (Days) |
|---|---|
| Control (No treatment) | 22.87 ± 8.21 |
| BIC Nanofibers (Chemotherapy only) | 60.00 ± 44.43 |
| BICC Nanofibers (Chemotherapy + Anti-angiogenic) | 86.50 ± 48.41 |
Source: Adapted from Tseng et al. Oncotarget, 2016 4
The group that received the full combination therapy (BICC) showed the most impressive results, with some rats experiencing complete tumor regression. MRI scans revealed that 43.75% of rats in the BICC group showed complete responses, with another 31.25% showing partial responses 4 . The addition of combretastatin to the chemotherapy cocktail provided a dual attack—first directly killing cancer cells, then disrupting the blood vessels that feed the tumor.
Creating these sophisticated delivery systems requires specialized materials and technologies. Here are the key components making these advances possible:
| Tool/Material | Function | Example Use in Research |
|---|---|---|
| Biodegradable Polymers (PLGA, PCPP:SA) | Serve as the structural matrix that gradually releases embedded drugs as they break down | PLGA nanofibers for multi-drug delivery; PCPP:SA in Gliadel wafers 2 4 |
| Chemotherapeutic Agents (BCNU/carmustine, Irinotecan, Cisplatin) | Directly target and kill rapidly dividing cancer cells through various mechanisms | BCNU causes DNA crosslinking; irinotecan inhibits topoisomerase I; cisplatin triggers programmed cell death 4 |
| Anti-angiogenic Agents (Combretastatin) | Disrupt the tumor's blood supply by targeting existing vasculature | Causes vascular shutdown in tumor blood vessels, starving the tumor of oxygen and nutrients 4 |
| Convection-Enhanced Delivery (CED) | Uses pressure to enhance distribution of therapeutic agents through brain tissue | Improves penetration of drugs into areas where cancer cells have infiltrated healthy brain tissue |
| Nanocarriers (Liposomes, Nanoparticles) | Package drugs to improve their stability, solubility, and delivery efficiency | Surface-modified nanocarriers can target specific receptors on glioma cells 9 |
The field of interstitial chemotherapy is rapidly evolving, with researchers exploring even more sophisticated approaches. Clinical trials are currently investigating combinations of local chemotherapy with immunotherapies, targeted therapies based on individual tumor genetics, and oncolytic viruses that selectively infect and kill cancer cells 5 6 .
The vision for the future is a personalized local therapy approach. After surgical removal of a brain tumor, the specific genetic and molecular profile of the cancer would be analyzed. Based on these findings, doctors would select the optimal combination of drugs to load into a biodegradable matrix tailored to release each agent at the most effective time and concentration 7 9 .
While challenges remain—including optimizing drug distribution throughout the tumor bed and preventing the development of treatment resistance—the progress in advanced interstitial chemotherapy represents a paradigm shift in neuro-oncology.
By respecting the unique biology of the brain while leveraging cutting-edge materials science and pharmaceutical technology, researchers are developing increasingly sophisticated ways to deliver powerful treatments exactly where they're needed.
The wall that has long protected brain tumors from treatment is finally being breached—from the inside.
To learn more about ongoing clinical trials for malignant glioma, visit the National Brain Tumor Society's Clinical Trial Finder at clinicaltrials.braintumor.org.