Multi-layered core-sheath fiber membranes for controlled drug release in the local treatment of brain tumor

Interstitial chemotherapy plays a pivotal role in the treatment of glioblastoma multiforme (GBM), an aggressive form of primary brain cancer, by enhancing drug biodistribution to the tumor and avoiding systemic toxicities. The use of new polymer structures that extend the release of cytotoxic agents may therefore increase survival and prevent recurrence. A novel core-sheath fiber loaded with the drug carmustine (BCNU) was evaluated in an in vivo brain tumor model. Three-dimensional discs were formed from coaxially electrospun fiber membranes and in vitro BCNU release kinetics were measured. In vivo survival was assessed following implantation of discs made of compressed core-sheath fibers (NanoMesh) either concurrently with or five days after intracranial implantation of 9L gliosarcoma. Co-implantation of NanoMesh and 9L gliosarcoma resulted in statistically significant long-term survival (>150 days). Empty control NanoMesh confirmed the safety of these novel implants. Similarly, Day 5 studies showed significant median, overall, and long-term survival rates, suggesting optimal control of tumor growth, confirmed with histological and immunohistochemical analyses. Local chemotherapy by means of biodegradable NanoMesh implants is a new treatment paradigm for the treatment for brain tumors. Drug delivery with coaxial core-sheath structures benefits from high drug loading, controlled long-term release kinetics, and slow polymer degradation. This represents a promising evolution for the current treatment of GBM.

Radiosensitization of malignant gliomas following intracranial delivery of paclitaxel biodegradable polymer microspheres

Object The aim of this study was to demonstrate that paclitaxel could function as a radiosensitizer for malignant glioma in vitro and in vivo. Methods The radiosensitizing effect of paclitaxel was tested in vitro using the human U373MG and rat 9L glioma cell lines. Cell cycle arrest in response to paclitaxel exposure was quantified by flow cytometry. Cells were subsequently irradiated, and toxicity was measured using the clonogenic assay. In vivo studies were performed in Fischer 344 rats implanted with intracranial 9L gliosarcoma. Rats were treated with control polymer implants, paclitaxel controlled-release polymers, radiotherapy, or a combination of the 2 treatments. The study end point was survival. Results Flow cytometry demonstrated G2-M arrest in both U373MG and 9L cells following 6–12 hours of paclitaxel exposure. The order in which the combination treatment was administered was significant. Exposure to radiation treatment (XRT) during the 6–12 hours after paclitaxel treatment resulted in a synergistic reduction in colony formation. This effect was greater than the effect from either treatment alone and was also greater than the effect of radiation exposure followed by paclitaxel. Rats bearing 9L gliosarcoma tumors treated with paclitaxel polymer administration followed by single-fraction radiotherapy demonstrated a synergistic improvement in survival compared with any other treatment, including radiotherapy followed by paclitaxel treatment. Median survival for control animals was 13 days; for those treated with paclitaxel alone, 21 days; for those treated with XRT alone, 21 days; for those treated with XRT followed by paclitaxel, 45 days; and for those treated with paclitaxel followed by XRT, more than 150 days (p < 0.0001). Conclusions These results indicate that paclitaxel is an effective radiosensitizer for malignant gliomas because it renders glioma cells more sensitive to ionizing radiation by causing G2-M arrest, and induces a synergistic response to chemoradiotherapy.

Efficacy of local polymer-based and systemic delivery of the anti-glutamatergic agents riluzole and memantine in rat glioma models

Object The poor outcome of malignant gliomas is largely due to local invasiveness. Previous studies suggest that gliomas secrete excess glutamate and destroy surrounding normal peritumoral brain by means of excitotoxic mechanisms. In this study the authors assessed the effect on survival of 2 glutamate modulators (riluzole and memantine) in rodent glioma models. Methods In an in vitro growth inhibition assay, F98 and 9L cells were exposed to riluzole and memantine. Mouse cerebellar organotypic cultures were implanted with F98 glioma cells and treated with radiation, radiation + riluzole, or vehicle and assessed for tumor growth. Safety and tolerability of intracranially implanted riluzole and memantine CPP:SA polymers were tested in F344 rats. The efficacy of these drugs was tested against the 9L model and riluzole was further tested with and without radiation therapy (RT). Results In vitro assays showed effective growth inhibition of both drugs on F98 and 9L cell lines. F98 organotypic cultures showed reduced growth of tumors treated with radiation and riluzole in comparison with untreated cultures or cultures treated with radiation or riluzole alone. Three separate efficacy experiments all showed that localized delivery of riluzole or memantine is efficacious against the 9L gliosarcoma tumor in vivo. Systemic riluzole monotherapy was ineffective; however, riluzole given with RT resulted in improved survival. Conclusions Riluzole and memantine can be safely and effectively delivered intracranially via polymer in rat glioma models. Both drugs demonstrate efficacy against the 9L gliosarcoma and F98 glioma in vitro and in vivo. Although systemic riluzole proved ineffective in increasing survival, riluzole acted synergistically with radiation and increased survival compared with RT or riluzole alone.

Increased expression of glutamate transporter GLT-1 in peritumoral tissue associated with prolonged survival and decreases in tumor growth in a rat model of experimental malignant glioma

Object Gliomas are known to release excessive amounts of glutamate, inducing glutamate excitotoxic cell death in the peritumoral region and allowing the tumor to grow and to expand. Glutamate transporter upregulation has been shown to be neuroprotective by removing extracellular glutamate in a number of preclinical animal models of neurodegenerative diseases, including amyotrophic lateral sclerosis and Parkinson disease as well as psychiatric disorders such as depression. The authors therefore hypothesized that the protective mechanism of glutamate transporter upregulation would be useful for the treatment of gliomas as well. Methods In this study 9L gliosarcoma cells were treated with a glutamate transporter upregulating agent, thiamphenicol, an antibiotic approved in Europe, which has been shown previously to increase glutamate transporter expression and has recently been validated in a human Phase I biomarker trial for glutamate transporter upregulation. Cells were monitored in vitro for glutamate transporter levels and cell proliferation. In vivo, rats were injected intracranially with 9L cells and were treated with increasing doses of thiamphenicol. Animals were monitored for survival. In addition, postmortem brain tissue was analyzed for tumor size, glutamate transporter levels, and neuron count. Results Thiamphenicol showed little effects on proliferation of 9L gliosarcoma cells in vitro and did not change glutamate transporter levels in these cells. However, when delivered locally in an experimental glioma model in rats, thiamphenicol dose dependently (10–5000 μM) significantly increased survival up to 7 days and concomitantly decreased tumor size from 46.2 mm2 to 10.2 mm2 when compared with lesions in nontreated controls. Furthermore, immunohistochemical and biochemical analysis of peritumoral tissue confirmed an 84% increase in levels of glutamate transporter protein and a 72% increase in the number of neuronal cells in the tissue adjacent to the tumor. Conclusions These results show that increasing glutamate transporter expression in peritumoral tissue is neuroprotective. It suggests that glutamate transporter upregulation for the treatment of gliomas should be further investigated and potentially be part of a combination therapy with standard chemotherapeutic agents.