May 4 2009
In 2007, an estimated 20,500 new cases of primary malignant brain and central nervous system tumors were diagnosed and approximately 12,740 deaths were attributed to these tumors. High grade glioma or glioblastoma multiforme (GBM) is the most common malignancy, as well as the most devastating, accounting for 19 percent of all primary brain tumors. This is the type of brain tumor that was recently diagnosed in several prominent people, most notably - Senator Ted Kennedy, in May 2008. The median age of GBM diagnosis is 64, with the highest rate of incidence in people ages 75 to 84. High grade gliomas remain a vexing problem for neurosurgeons. Resection and radiation therapy are not curative, and the 5-year survival rate is only about 3 percent.
Researchers at the University of Virginia Health Science Center evaluated a novel glioma therapy through the targeted delivery of controlled-release nanoparticles to an immunocompromised mouse model. The results of this study, In Vitro and In Vivo Targeted Delivery of Controlled-Release Nanoparticles to High Grade Gliomas Using Contrast Agent Microbubbles and High-Intensity Focused Ultrasound, will be presented by Jason P. Sheehan, MD, PhD, 4:01 to 4:15 pm, Monday, May 4, 2009, during the 77th Annual Meeting of the American Association of Neurological Surgeons in San Diego. Co-authors are Caitlin Burke, BS, and Richard Price, PhD.
“Chemotherapeutic and novel gene delivery agents are problematic to deliver to the tumor in a specific fashion and of sufficient quantity to have meaningful impact on patient outcome. In fact, many agents that are effective against gliomas in vitro cannot reach the tumor cells in vivo because the drugs are not able to penetrate the blood brain barrier,” stated Dr. Sheehan.
This study evaluates the targeted delivery of controlled-release nanoparticles to gliomas using high intensity focused ultrasound (HIFU). Nanoparticles can carry tumor destroying agents to a site and targeted high intensity ultrasound can be used to release the agents in the microvessels feeding the tumor. A microbubble-nanoparticle composite agent was constructed using Poly(lactide-co-glycolide) (PLGA) nanoparticles and the chemotherapeutic drug Fluorouracil (5-FU). Nanoparticles were constructed with fluorescence markers, 5-FU, or as a negative control. Cell viability assays were performed using the C6 glioma line to study the biologic activity.
Glioma cells were injected into a dorsal skinfold window chamber of an immunocompromised mouse model. The microbubble-nanoparticle construct was injected intravenously, spread to the grafted tumor in the blood vessels, and selectively released with targeted HIFU. Tumor response was characterized by studying the microvasculature and the release of a fluorescent marker. The following results were noted:
- The 5-FU nanoparticles were shown to reduce glioma cell viability to a level that was comparable to that achieved with the soluble drug; the soluble drug cannot penetrate the blood brain barrier of the central nervous system to a sufficient degree.
- At day 1, 4, and 5, PLGA nanoparticles containing 5-FU reduced tumor cell viability in a significant fashion (P<0.05).
- The application of ultrasound induced a 10-fold increase in monolayer fluorescence within the glioma.
- Using confocal microscopy to recreate a 3-dimensional image, nanoparticles were localized within the glioma cells’ cytoplasm. 5-FU release was accomplished and resulted in cell death of the in vivo glioma cells.
Targeted delivery of controlled-release nanoparticles to malignant gliomas can be accomplished with HIFU. “The delivery of novel chemotherapeutic agents or gene therapy to humans could be achieved through this unique approach. Use of nanoparticles to deliver tumor destroying agents and high intensity ultrasound like an intracranial knife hold significant promise in the treatment of patients with high grade gliomas and other malignant brain tumors,” concluded Dr. Sheehan.
Founded in 1931 as the Harvey Cushing Society, the American Association of Neurological Surgeons (AANS) is a scientific and educational association with more than 7,400 members worldwide. The AANS is dedicated to advancing the specialty of neurological surgery in order to provide the highest quality of neurosurgical care to the public. All active members of the AANS are certified by the American Board of Neurological Surgery, the Royal College of Physicians and Surgeons (Neurosurgery) of Canada or the Mexican Council of Neurological Surgery, AC. Neurological surgery is the medical specialty concerned with the prevention, diagnosis, treatment and rehabilitation of disorders that affect the entire nervous system, including the spinal column, spinal cord, brain and peripheral nerves.
Funding provided by the Focused Ultrasound Foundation, Charlottesville, Va. The author reports no conflicts of interest.