Advanced interstitial chemotherapy combined with targeted treatment of malignant glioma in rats by using drug-loaded nanofibrous membranes

Abstract

Glioblastoma multiforme (GBM), the most prevalent and malignant form of a primary brain tumour, is resistant to chemotherapy. In this study, we concurrently loaded three chemotherapeutic agents [bis-chloroethylnitrosourea, irinotecan, and cisplatin; BIC] into 50:50 poly[(d,l)-lactide-co-glycolide] (PLGA) nanofibres and an antiangiogenic agent (combretastatin) into 75:25 PLGA nanofibres [BIC and combretastatin (BICC)/PLGA]. The BICC/PLGA nanofibrous membranes were surgically implanted onto the brain surfaces of healthy rats for conducting pharmacodynamic studies and onto C6 glioma-bearing rats for estimating the therapeutic efficacy.The chemotherapeutic agents were rapidly released from the 50:50 PLGA nanofibres after implantation, followed by the release of combretastatin (approximately 2 weeks later) from the 75:25 PLGA nanofibres. All drug concentrations remained higher in brain tissues than in the blood for more than 8 weeks. The experimental results, including attenuated malignancy, retarded tumour growth, and prolonged survival in tumour-bearing rats, demonstrated the efficacy of the BICC/PLGA nanofibrous membranes. Furthermore, the efficacy of BIC/PLGA and BICC/PLGA nanofibrous membranes was compared. The BICC/PLGA nanofibrous membranes more efficiently retarded the tumour growth and attenuated the malignancy of C6 glioma-bearing rats. Moreover, the addition of combretastatin did not significantly change the drug release behaviour of the BIC/PLGA nanofibrous membranes. The present advanced and novel interstitial chemotherapy and targeted treatment provide a potential strategy and regimen for treating GBM.

Metabolic response patterns in brain microdialysis fluids and serum during interstitial cisplatin treatment of high-grade glioma

“…Although in vitro experiments have found cisplatin to be effective on glioma cells, cisplatin's limited ability to penetrate the blood-brain and blood-tumour barriers have restricted its practical use for the treatment of glioblastoma. Therefore, recent focus has been to deliver the drug interstitially 24,25 or by using targeted methods. 26,27 In the present study, we used microdialysis which has the advantage of delivering the drug locally and simultaneously allow for the monitoring of treatment effects in the target tissue.…”

Novel multi-drugs incorporating hybrid-structured nanofibers enhance alkylating agent activity in malignant gliomas

“…26 The BBB restricts the delivery of a chemotherapeutic agent inside a brain tumor, even at toxic systemic levels. 7,27 Nanomaterials have long been proposed as carriers to promote the entry and delivery of therapeutic agents into the brain. 7,28,29 PLGA-based nanoparticles are currently being investigated for applications in cancer imaging and therapy.…”

“…The number of cells expressing GFAP is inversely proportional to the extent of anaplasia. 27,39 The loss of GFAP repression could be a step in MG and anaplastic astrocytoma development and progression. 39,40 The Ki-67 labeling index has been widely used as an indicator of cell proliferation in glioma.…”

Biodegradable hybrid-structured nanofibrous membrane supported chemoprotective gene therapy enhances chemotherapy tolerance and efficacy in malignant glioma rats

“…Even with systemic levels in the toxic range, the drug concentration in the brain remains below the therapeutic level. To achieve effective local drug delivery with minimal side effects, different novel methods have been introduced [27,28], including the administration of biopharmaceuticals via intracranially implanted catheters and convection-enhanced drug delivery, as well as administration through controlled-release polymers. The only one of these new agents that has been approved by the FDA to treat MG is the 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU or carmustine) implant marketed as the Gliadel V R wafer.…”