Abstract
Notable obstacles to successful treatment of pediatric brain tumor patients include the presence of the blood brain barrier (BBB), tumor heterogeneity and the development of drug resistance. Nanotechnology-based drug delivery systems (DDS) have the potential to overcome these obstacles and improve outcomes by delivering chemotherapies through the BBB directly to brain tumor cells. To develop a brain tumor targeted dual DDS, we utilized non-toxic carbon dots (C-dots) as the nanocarriers. C-dots were functionalized transferrin as the targeting ligand and the chemotherapies epirubicin and temozolomide via the classical EDC/NHS coupling reaction. The cytotoxicity of the C-dot conjugates (targeted and non-targeted, single and dual drug) was evaluated in the pediatric brain tumor cell lines SJGBM2, CHLA200 (both GBM) and CHLA266 (ATRT). The non-targeted dual drug conjugated C-dots induced more cell death in all cell lines compared to either single drug conjugate. A concentration of 10uM reduced cell viability by 79–93% to depending on the cell line with SJGBM2 cells being the most sensitive. Furthermore, the increased cell death was more than additive suggestive of synergy. The addition of transferrin increased cytotoxicity of the dual drug conjugated C-dots by 100 to 1000 fold. The dual drug transferrin conjugate reduced viability by over 80% at concentrations ranging between 0.01uM to 0.1uM with again SJGBM2 cells being the most sensitive. To date most nanoparticle DDS deliver a single chemotherapy, this potentially can lead to treatment resistance and patient relapse. To address this issue, we have successfully developed brain tumor targeted dual drug delivery system. Our data indicates that non-toxic C-dots are an excellent platform in which multiple drugs and a targeting ligand(s) can be covalently conjugated and both the drugs and the ligand remain functional. Such C-dot DDS represents a promising therapeutic strategy for the treatment of pediatric brain tumors.
PEDIATRIC BRAIN TUMOR MODELS