No abstract

Glioblastomas (GBM) are characterized by resistance to chemotherapy and radiotherapy, and therefore, alternative therapeutic approaches are needed. TRAIL induces apoptosis in cancer but not in normal cells and is considered to be a promising anti-tumor agent. However, its short in vivo half-life and lack of efficient administration modes are serious impediments to its therapeutic efficacy. Nanoparticles (NP) have been used as effective delivery tools for various anticancer drugs. TRAIL was conjugated to magnetic ferric oxide NP by binding the TRAIL primary amino groups to activated double bonds on the surface of the NP. The effect of NP-TRAIL was examined on the apoptosis of glioma cells and self-renewal of glioma stem cells (GSCs). In addition, the ability of the NP-TRAIL to track U251 cell-derived glioma xenografts and to affect cell apoptosis, tumor volume, and survival among xenografted rats was also examined. Conjugation of TRAIL to NP increased its apoptotic activity against different human glioma cells and GSCs, as compared with free recombinant TRAIL. Combined treatment with NP-TRAIL and γ-radiation or bortezomib sensitized TRAIL-resistant GSCs to NP-TRAIL. Using rhodamine-labeled NP and U251 glioma cell-derived xenografts, we demonstrated that the NP-TRAIL were found in the tumor site and induced a significant increase in glioma cell apoptosis, a decrease in tumor volume, and increased animal survival. In summary, conjugation of TRAIL to NP increased its apoptotic activity both in vitro and in vivo. Therefore, NP-TRAIL represents a targeted anticancer agent with more efficient action for the treatment of GBM and the eradication of GSCs.

Convection-enhanced drug delivery (CED) is a novel approach to delivering drugs into brain tissue. Drugs are delivered continuously via a catheter, enabling large volume distributions of high drug concentrations with minimum systemic toxicity. Previously we demonstrated that CED formation/extent of small molecules may be significantly improved by increasing infusate viscosities. In this study we show that the same methodology can be applied to monodispersed maghemite nanoparticles (MNPs). For this purpose we used a normal rat brain model and performed CED of MNPs over short infusion times. By adding 3% sucrose or 3%-6% polyethylene glycol (PEG; molecular weight 400) to saline containing pristine MNPs, we increased infusate viscosity and obtained increased CED efficacy. Further, we show that CED of dextran-coated MNPs (dextran-MNPs) resulted in increased efficacy over pristine MNPs (p < 0.007). To establish the use of MRI for reliable depiction of MNP distribution, CED of fluorescent dextran-MNPs was performed, demonstrating a significant correlation between the distributions as depicted by MRI and spectroscopic images (r(2) = 0.74, p < 0.0002). MRI follow-up showed that approximately 80%-90% of the dextran-MNPs were cleared from the rat brain within 40 days of CED; the rest remained in the brain for more than 4 months. MNPs have been tested for applications such as targeted drug delivery and controlled drug release and are clinically used as a contrast agent for MRI. Thus, combining the CED method with the advantages of MNPs may provide a powerful tool to treat and monitor brain tumors.