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

Abstract

Background: Malignant gliomas (MGs) are highly chemotherapy-resistant. Temozolomide (TMZ) and carmustine (BiCNU) are alkylating agents clinically used for treating MGs. However, their effectiveness is restrained by overexpression of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) in tumors. O6-benzylguanine (O6-BG) is a nonreversible inhibitor of MGMT, it promotes the cytotoxicity of alkylating chemotherapy. The authors have developed a hybrid-structured nanofibrous membrane (HSNM) that sequentially delivers high concentrations of O6-BG, BiCNU, and TMZ in an attempt to provide an alternative to the current therapeutic options for MGs. Methods: The HSNMs were implanted onto the cerebral surface of pathogen-free rats following surgical craniectomy, while the in vivo release behaviors of O6-BG, TMZ, and BiCNU from the HSNMs were explored. Subsequently, the HSNMs were surgically implanted onto the brain surface of two types of tumor-bearing rats. The survival rate, tumor volume, malignancy of tumor, and apoptotic cell death were evaluated and compared with other treatment regimens. Results: The biodegradable HSNMs sequentially and sustainably delivered high concentrations of O6-BG, BiCNU, and TMZ for more than 14 weeks. The tumor-bearing rats treated with HSNMs demonstrated therapeutic advantages in terms of retarded and restricted tumor growth, prolonged survival time, and attenuated malignancy. Conclusion: The results demonstrated that O6-BG potentiates the effects of interstitially transported BiCNU and TMZ. Therefore, O6-BG may be required for alkylating agents to offer maximum therapeutic benefits for the treatment of MGMT-expressing tumors. In addition, the HSNM-supported chemoprotective gene therapy enhanced chemotherapy tolerance and efficacy. It can, therefore, potentially provide an improved therapeutic alternative for MGs.

Role of Polymeric Local Drug Delivery in Multimodal Treatment of Malignant Glioma: A Review

“…This versatility in degradation has made PLGA a good candidate for use in implants as part of treatment with a tailored period and order (Figure 2C). Liu et al 35,36 40,41 The PCV regimen demands an intricate course of therapy, whereas biodegradable multiagent polymeric vehicles can contemporaneously transport different chemotherapy agents [42][43][44][45] or biopharmaceutic agents 35,[46][47][48] into the CNS in one step.…”

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

“…Glioblastoma multiforme (GBM) is the most common type of malignant glioma (MG) in adults [ 1 , 2 ]. The median survival time for patients with GBM is only 12–15 months, with a low 5-year survival rate of less than 5% [ 2 , 3 , 4 ]. Surgery followed by radiotherapy with concomitantly administered chemotherapy is a mainstay in treatments for GBM.…”

“…Surgery followed by radiotherapy with concomitantly administered chemotherapy is a mainstay in treatments for GBM. Temozolomide (TMZ) is generally used as a chemotherapeutic agent in clinical situations to treat patients with GBM [ 1 , 2 ]. However, TMZ resistance in GBM is one of the greatest challenges physicians encounter in treating GBM [ 1 , 2 , 5 , 6 , 7 ].…”

“…In addition, TMZ is also found to generate O 6 - methylguanine (O6MeG), N 7 -methylguanine (N 7 -meG), and N 3 -methyladenine (N 3 -meA) in DNA. This eventually leads to DNA lesion-induced cytotoxicity, which results in cell death [ 2 , 8 , 10 , 11 , 12 ]. Evidence shows that DNA lesions caused by TMZ, such as O6MeG, activate the O 6 -methylguanine-DNA methyltransferase (MGMT)-mediated DNA repair process [ 8 , 9 , 11 , 12 ].…”

“…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.…”