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

Abstract

Chemotherapy is ineffective for treating malignant glioma (MG) because of the low therapeutic levels of pharmaceuticals in tumour tissues and the well-known tumour resistance. The resistance to alkylators is modulated by the DNA repair protein O-alkylguanine-DNA alkyltransferase (AGT). O-benzylguanine (O-BG) can irreversibly inactivate AGT by competing with O-methylguanine and has been confirmed to increase the therapeutic activity of alkylators. We developed hybrid-structured poly[(d,l)-lactide-co-glycolide] nanofibrous membranes (HSNMs) that enable the sequential and sustained release of O-BG and two alkylators (carmustine and temozolomide [TMZ]). HSNMs were surgically instilled into the cerebral cavity of pathogen-free rats and F98 glioma-bearing rats. The release behaviours of loaded drugs were quantified by using high-performance liquid chromatography. The treatment results were compared with the rats treated with intraperitoneal injection of O-BG combined with surgical implantation of carmustine wafer and oral TMZ. The HSNMs revealed a sequential drug release behaviour with the elution of high drug concentrations of O-BG in the early phase, followed by high levels of two alkylators. All drug concentrations remained high for over 14 weeks. Tumour growth was slower and the mean survival time was significantly prolonged in the HSNM-treated group. Biodegradable HSNMs can enhance therapeutic efficacy and prevent toxic systemic effects.

Causes of drug resistance and glioblastoma relapses

“…Инвазивные методы для увеличения доставки лекарств в мозг включают микродиализ мозга, внутримозговую имплантацию (carmustine wafer) и внутрижелудочковое введение препаратов [51][52][53]. Однако эти подходы могут вызвать повреждение окружающей здоровой ткани и серьезные побочные эффекты у пациентов.…”

Glioblastoma Chemoresistance: The Double Play by Microenvironment and Blood-Brain Barrier

“…As shown in Figure 2 , different invasive methods have been tested to increase drug delivery into the brain; these methods include brain microdialysis [ 73 ], intracerebral implantation [ 74 ], and intraventricular delivery [ 75 ]. However, these approaches could cause damage to the surrounding healthy tissue and severe side effects in patients.…”

Enhanced Anti-Tumor Activity in Mice with Temozolomide-Resistant Human Glioblastoma Cell Line-Derived Xenograft Using SN-38-Incorporated Polymeric Microparticle

“…This, in turn, reduces the efficiency of TMZ in killing cancer cells. Indeed, a lack of MGMT gene promoter methylation, which leads to an elevated expression of functional MGMT proteins, has been observed in approximately half of GBM tumors and is linked to TMZ resistance in GBM [ 1 , 2 , 5 , 6 , 7 , 13 ]. Approved chemotherapeutic agents for treating GBM are very limited.…”

“…Approved chemotherapeutic agents for treating GBM are very limited. Aside from TMZ, bis-chloroethylnitrosourea (BCNU, carmustine), is the only chemotherapeutic alkylating agent approved by the US Food and Drug Administration for treatment of GBM [ 10 , 13 , 14 ]. TMZ is administered orally, while BCNU is loaded into wafers of polifeprosan 20 (Gliadel, Guilford Pharmaceuticals-MGI Pharma, Bloomington, MN) and administered by being placed onto the brain cavity after removal of a brain tumor.…”

“…BCNU has been considered an important treatment option for GBM since 1995, as its systemic toxicity was limited when Gliadel wafers were introduced to deliver BCNU [ 10 , 14 ]. While both of them are alkylating agents, BCNU is similar to TMZ in that it also induces DNA damage through alkylating DNA at the O 6 position of guanine [ 8 , 10 , 11 , 12 , 13 ]. Therefore, it is not surprising that the therapeutic effectiveness of BCNU is greatly attenuated in patients with high MGMT expression [ 10 ].…”