Introduction: Together, medulloblastoma (MB) and atypical teratoid/rhabdoid tumors (AT/RT) represent two of the most prevalent pediatric brain malignancies in the youngest patients. Current treatment of these tumors typically involves radiation therapy, which carries significant risk of developmental sequelae, especially for patients under the age of three. In prior studies involving murine glioblastoma models, nanoparticles capable of carrying plasmids have shown promise as an alternative mode for delivering treatment. Our previous work with polymer based delivery (PEI) of genes demonstrated intolerable cytotoxicity in normal gray matter due to nonspecific polymer effects. We thus set out to use less cytotoxic poly(beta-amino ester) (PBAE) nanoparticles for delivery of treatment in malignant pediatric brain tumors.
Methods: Our interdisciplinary team investigated the efficacy of PBAE nanoparticles for delivering genes of interest such as HSV-TK to treat medulloblastoma and AT/RT. Experiments were first run in vitro using nanoparticles carrying eGFP or HSV-TK plasmids for both MB and AT/RT cell lines to test transfection efficacy/cytotoxicity and cell killing ability, respectively. Subsequent experiments in murine models implanted with MB and AT/RT were used to test efficacy and safety in vivo.
Results: In vitro studies using nanoparticle delivery of HSV-TK + ganciclovir resulted in over 90% cell killing of cancer cells with eGFP particles demonstrating greater than 40% transfection and less than 6% cytotoxicity in controls. In vivo, medulloblastoma and AT/RT groups treated with intracranial convection enhanced delivery of PBAE HSV-TK nanoparticles with intraperitoneal ganciclovir had a greater mean overall survival (25 days and >45 days) compared to untreated controls (19 days and 35 days), respectively (P<0.0001).
Conclusions: Our data suggest a novel alternative to higher risk treatments like radiation therapy and provides proof of principle for using nanoparticles as a safe and effective method of delivery for treating pediatric malignant brain tumors.
Patient Care: Currently, treatment options for pediatric brain malignancies for patients under the age of three are severely limited, as their development is adversely impacted by radiation therapy. As such, there is a need for different and effective modes of treatment for these patients. The PBAE nanoparticle approach described in my research is the first demonstration of using nanoparticles to deliver treatment for pediatric brain malignancies like medulloblastoma and AT/RT. Moreover, this research is foundational in that it demonstrates a safe and effective mode of delivering treatment to cancer cells. While this paper focused on using the already established HSV-TK + ganciclovir schema to show proof of principle in the nanoparticle's ability to deliver genes of interest, the possibility of using other treatment schemas that require reliable delivery to cancer cells can now be explored.
Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the importance of alternative cancer therapies for the youngest pediatric populations, 2) Compare and contrast current standards for nanoparticle based delivery with the poly(beta-amino ester) (PBAE) approach, 3) Appreciate the in vitro and in vivo data of using PBAE polymeric nanoparticles to treat cancer, and 4) Have a discussion as to how this template for gene delivery can be expanded to include more current treatments beyond HSV-TK delivery (e.g. using immunotherapy strategies involving IL-12 or GM-CSF delivery).