Development of poly(lactic acid)-poly(ethylene glycol) nanoparticles for the delivery of non- toxic drug in combination therapy for the treatment of glioblastoma and neuroblastoma

Glioblastoma and neuroblastoma are both solid-form tumors. Glioblastomas primarily reside in the brain, while neuroblastomas are found in the sympathetic nervous system. Both glioblastoma and neuroblastoma re classified as orphan diseases, which affect less than 200,000 individuals a year. Over the course of 5 years, 40% of patients diagnosed with neuroblastomas and only 6% of patients diagnosed will glioblastomas will be living.73,74. Glioblastoma and neuroblastoma tumors possess a gene known as MGMT. MGMT is used by tumors as a DNA repair mechanism, which increases the likelihood these tumors will become resistant to traditional drug therapies.28,37 Other pathways, such as the BER pathway, also contribute to drug resistance in tumors and cause them to be especially difficult to treat.65 The traditional treatment options for patients with glioblastomas or neuroblastomas are chemotherapy, radiation or surgery resecting the tumor. 5,18 These treatment options are ineffective due to the tumors’ ability to resist drug treatments28 and due to the complicated nature of the resection surgery.2,,15 Combinations of traditional treatments are also becoming more popular and now patients are being treated with surgery and then with alkylating agents like TMZ for the remaining cells left behind. The focus of this research is to treat tumor cells with TMZ and increase it’s effectiveness through combination drug therapy. The goal of this research was to formulate a polymeric nanoparticle delivery system that could deliver a non-toxic drug that will aid in the increased effectiveness of Temozolomide. Two drugs were encapsulated in poly(lactic acid)-poly(ethylene glycol) nanoparticles. The first drug, O6 -Benzylguanine methylates the O6 loci on MGMT, which inhibits the gene. The second drug, methyl methanesulfonate, which inhibits the ALKb protein that also aids in DNA repair. 75 The polymer was tested with NMR to ensure that the functional groups were all present and particle sizing ensured that drug could be loaded within the particles. Nanoparticle uptake studies were also performed to demonstrate the particle’s ability to enter the tumor cells. Nanoparticle toxicity studies, free drug studies, and drug loaded combination studies were also performed to determine the efficacy of the treatment