Improving delivery of elacridar to enhance efficacy of molecularly-targeted agents in treatment of glioblastoma.

摘要

Treatment of glioblastoma with new molecularly-targeted agents has been largely ineffective in clinical trials. Many of these molecularly-targeted agents are substrates for the efflux transporters P-gp and BCRP, and therefore, one of the reasons for the lack of efficacy could be the limitations to drug delivery to the target site. P-gp and BCRP are efflux transporters that are expressed at the blood-brain barrier, which acts as a protective mechanism and prevents chemotherapeutics from reaching the brain parenchyma. P-gp and BCRP are also expressed at the tumor cell surface. These two sequential barriers could restrict the access of chemotherapeutics to the target site and therefore could reduce their efficacy. The main objective of this work was to overcome these sequential barriers by use of a pharmacological inhibitor of P-gp and BCRP, elacridar. The ultimate aim was to develop a chronic dosage regimen of a molecularly-targeted agent with elacridar as an adjuvant to enhance drug delivery to the brain in preclinical models of glioma. We demonstrated that the bioavailability of elacridar is limited due to its poor physicochemical properties. We also showed that the distribution of elacridar into the brain is limited by the presence of P-gp and BCRP and is governed by a saturable efflux process that can be overcome by increasing the dose of elacridar. We developed a microemulsion formulation of elacridar that improved its bioavailability several-fold and allowed us to decrease the dose of elacridar required to show an inhibitory effect. We examined the effect of elacridar as an adjuvant to erlotinib in treatment of tumor-bearing mice. It was found that while the co-administration of elacridar definitely improved the brain distribution of erlotinib, it did not offer any advantage in improving overall survival of the tumor bearing animals.;These observations show that improving the distribution of a single molecularly targeted agent may not be sufficient in order to effectively target a heterogenous tumor such as glioma. To effectively treat an aggressive disease such as glioblastoma, a combination of drugs that target a number of growth pathways; combined with a pharmacological inhibitor of transporters could help formulate an effective strategy to target tumor cells.