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

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