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 O 6 -methylguanine-DNA methyltransferase (MGMT) in tumors. O 6 -benzylguanine (O 6 -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 O 6 -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 O 6 -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 O 6 -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 O 6 -BG potentiates the effects of interstitially transported BiCNU and TMZ. Therefore, O 6 -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.