Primary brain tumors are a cause of marked debility and are characterized by poor survival. In 2015, an estimated 23,180 new cases of primary malignant brain tumors will be diagnosed and 16,570 patients will die from these tumors.1
Glioblastoma (GBM, grade IV astrocytoma) is the most common and most aggressive of the primary malignant brain tumors in adults, with historical 1-year and 5-year survival rates of 29.3% and 3.3%, respectively.1
Currently, frontline treatment consists of a multimodality approach that includes maximal surgical resection and adjuvant radiation therapy with concurrent temozolomide. This multimodal approach has been the standard of care since the EORTC phase III trial demonstrated a median survival of 14.6 months in the temozolomide group versus 12.1 months in the radiation alone group.2
While this was a significant improvement, it is clear that radiation remains the most effective component of the combined approach on median survival with multiple randomized studies showing a 5-month improvement in survival with XRT alone3
compared to an additional 2.5 months with the addition of temozolomide.
Theoretically, any tumor can be controlled if a sufficient dose of radiation is delivered to the tumor. The main limiting factor in delivering a tumoricidal dose is the toxicity to surrounding normal tissue. As the traditional x-ray radiation beam passes through the skull and brain to reach the tumor it is absorbed by the body and shows exponential decrease in the dose delivered with tissue depth. Even using highly conformal applications such as TomoTherapy or Intensity Modulated Radiation Therapy, doses are limited to less than 80 Gy4
due to progressive toxicity with increasing dose. With brachytherapy, the most successful example has been in the use of radioactive iodine to treat thyroid cancer, which can be completely ablated with doses of nearly 1000 Gy with almost no toxicity to surrounding normal tissue. The reason that other therapeutic radionuclides have not been successfully developed for other types of cancer is due to an inability to specifically deliver these isotopes.
Re) is a reactor-produced isotope with great potential for medical therapy if it can be successfully delivered. It is in the same chemical family as technetium-99m (99m
Tc), which is a commonly used isotope for diagnostic imaging. The average 186
Re beta particle path length in tissue of 2 mm is ideal for treatment of solid tumors and the half-life of 90 hours is clinically meaningful. However, a carrier is needed to deliver the isotope to the brain and maintain its localization at the desired site, as it would otherwise quickly disperse and be carried away from the site of injection by the circulatory system.
Liposomes, spontaneously forming lipid nanoparticles, have rapidly evolved as carriers of cancer therapeutics. They consist of naturally occurring lipid bilayers that are nearly identical to the lipid membranes of normal cells. The list of FDA-approved liposomal drugs includes Doxil (liposomal doxorubicin) and Depocyt (liposomal cytarabine) to just name two.
For treatment of locally invasive tumors, liposomal encapsulation of radiotherapeutics holds significant promise. To achieve this, we have developed a proprietary encapsulation method using a custom lipophilic molecule that carries radionuclides into the aqueous compartment of the liposomes. The final investigational product is BMEDA-chelated- 186
Rhenium encapsulated within liposomes. These rhenium-labeled nanoliposomes (RNL) have shown great promise in preclinical studies for the treatment of cancer by regional and local administration.5-8