Novel therapeutic approach in treatment of glioblastoma using sustained delivery of Connxin43 carboxy-terminal peptide encapsulated in biodegradable nanoparticles in combination with temozolomide

DESCRIPTION provided by applicant Glioblastoma GBM is an incurable cancer even with aggressive therapies such as surgical resection followed by radiotherapy and chemotherapy using temozolomide TMZ Efforts to improve surgical resection or the efficacy of irradiation are limited by the potential damage these interventions cause to the brain In contrast sensitizing GBM to TMZ is an appealing strategy because TMZ has excellent brain penetration and a low toxicity profile Recent research has suggested that targeting the gap junction protein connexin Cx holds promise for enhancing TMZ sensitivity in GBM Dr Gourdieandapos s co Investigator laboratory has developed a synthetic peptide ACT which comprises the carboxy terminus of Cx and has demonstrated therapeutic effects in promoting healing of chronic wounds FirstString Research has licensed ACT for further development and clinical application and has advanced Granexin tm Gel the topical formulation of ACT peptide through three successfully completed Phase human clinical trials for scar reduction and the treatment of chronic wounds In collaboration with the Shengandapos s co Investigator laboratory we observed that Cx expression inversely correlates to TMZ sensitivity and GBM patient survival and demonstrated that ACT significantly increases TMZ sensitivity in vitro and in vivo thus encouraging us to further investigate its therapeutic potential in sensitizing GBM tumors to TMZ However intracranial delivery of this peptide is limited by its relatively short half life Therefre the overall objective of this application is to develop a novel delivery approach for ACT to treat GBM in vivo The use of biodegradable nanoparticles for peptide delivery is a powerful approach due to its high biocompatibility and sustained peptide release The rationale of this study is that ACT loaded nanoparticles ACT NP will efficiently deliver ACT into the brain by constantly and continuously supply GBM tumor cells with this peptide Our hypothesis is that ACT NP will sensitize GBM to TMZ which will then be tested in two specific aims to engineer ACT NP and optimize controlled delivery of ACT in vitro to assess in vivo the therapeutic potential of ACT NP in tandem with TMZ treatment of brain tumors We will first generate ACT NP in collaboration with Dr Foster co Investigator and his laboratory using poly lactic co glycolic acid PLGA copolymer After in vitro characterization of ACT NP and effect on human GBM cells we will intracranially inject ACT NP into the brains of GBM mice followed by TMZ treatment We will monitor the tumor growth using magnetic resonance imaging and analyze mice survival These results will validate the therapeutic effect of ACT in vivo We expect that this approach will efficiently deliver ACT in a sustained way and sensitize GBM tumors to TMZ The proposed research is significant because this innovative approach will not only allow us to develop novel combinational therapies for lethal GBM but also will lay foundation on potential clinical trials in newly diagnosed GBM patients in the near future Finally our new ACT NP may be scalable to other CNS diseases that could benefit from Cx targeting PUBLIC HEALTH RELEVANCE Glioblastoma is a very aggressive type of brain tumor and one of the most deadly diseases with no efficient therapy to cure it The proposed research aims at developing a new combinational therapy to enhance the effectiveness of temozolomide the front line chemotherapy for glioblastoma Therefore this work will have important impact on therapeutic intervention for glioblastoma and is relevant to public health and NIHandapos s mission