Liposomal Encapsulation of Radiotherapeutics Holds Promise in Treating Glioblastoma

Andrew Brenner, MD, PhD

Neuro-Oncologist, Medical Oncologist

Cancer Therapy & Research Center

Assistant Professor

School of Medicine,

UT Health Science Center San Antonio, TX

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.

Rhenium-186 (¹⁸⁶Re) 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 (^99mTc), which is a commonly used isotope for diagnostic imaging. The average ¹⁸⁶Re 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- ¹⁸⁶Rhenium 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

To better characterize the potential delivery, toxicity, and efficacy of these high specific activity RNL, intracranial application by convection enhanced delivery (CED) in a U87 glioma rat model was investigated. RNL remained confined to the site of injection over 96 hours, and doses of up to 1850 Gy were administered without evidence of toxicity. Animals treated with RNL had a median survival of 126 days (95% CI, 78.4-173 days) compared to 49 days (95% CI, 44-53 days) in controls. Log rank analysis between these two groups was highly significant (P = .0013), and was even higher when 100 Gy was used as a cutoff (P <.0001). MRI and luciferase imaging showed significant difference in tumor size (Figure), with many tumors completely ablated. Duplication of tumor volume differences and survival benefit was possible in a more invasive U251 orthotopic model with median survival in treated animals not reached at 120 days due to lack of mortality, and log rank analysis of survival highly significant (P = .0057). Analysis of tumors by histology revealed minimal areas of necrosis and gliosis.

Good Laboratory Practice (GLP) toxicology studies in beagles have shown that intracranial administration of RNL up to 360 Gy produced no significant test article related pathologic changes in the brains of dogs at 24 hours or 14 Days, supporting the study of RNL in humans. I am currently leading a phase I clinical trial of RNL in patients with glioblastoma supported by NanoTx Therapeutics at the CTRC in San Antonio, Texas.

References

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2. Stupp R, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10): 987-996.
3. Chang JE, et al. Radiotherapy and radiosensitizers in the treatment of glioblastoma multiforme. Clin Adv Hematol Oncol. 2007;5(11):894-902, 907-915.
4. Werner-Wasik M, et al. Final report of a phase I/II trial of hyperfractionated and accelerated hyperfractionated radiation therapy with carmustine for adults with supratentorial malignant gliomas. Radiation Therapy Oncology Group Study 83-02. Cancer. 1996;77(8):1535-1543.
5. Bao A, et al. A novel liposome radiolabeling method using 99mTc- ”SNS/S” complexes: in vitro and in vivo evaluation. J Pharm Sci. 2003;92(9):1893-1894.
6. French JT, et al. Interventional therapy of head and neck cancer with lipid nanoparticle-carried rhenium 186 radionuclide. J Vasc Interv Radiol. 2010;21(8):1271-1279.
7. Wang SX, et al. Intraoperative 186Re-liposome radionuclide therapy in a head and neck squamous cell carcinoma xenograft positive surgical margin model. Clin Cancer Res. 2008;14(12):3975-3983.
8. Wang SX, et al. Intraoperative therapy with liposomal drug delivery: retention and distribution in human head and neck squamous cell carcinoma xenograft model. Int J Pharm. 2009;373(1-2):156-164.