Glioblastoma, a grade-IV brain malignancy, is often associated with the overexpression of Epidermal Growth Factor Receptor (EGFR) on the cell surface. Despite this, clinical efficacy of small molecule EGFR inhibitors has been limited in Glioblastoma. However, the combination of appropriate EGFR inhibitors with proper cytotoxic drugs could potentiate the effects at appreciably low dosage by modulating multiple cell signaling cascades. Herein, we show the pre-treatment with Erlotinib (EGFR inhibitor) can sensitize Glioblastoma cells for synergized apoptotic response with Doxorubicin. In order to afford a sustained and preferential delivery of these dual drugs directly into the tumor resection cavity, we design a multi-compartment, syringe-injectable hydrogel material. We employ an amphiphilic β-hairpin peptide that can self-assemble under physiological condition in presence of free Erlotinib and Doxorubicin-loaded nanoparticles allowing for quantitative and homogeneous encapsulation of the two therapeutic agents within different compartments of the resulting hydrogel. The multi-component gel effectively exerts temporal control of drug release kinetics resulting in rapid delivery of Erlotinib followed by sustained release of Doxorubicin. The sequential release significantly improves apoptotic activity in Glioblastoma cells through up-regulation of caspase-mediated signaling. This work demonstrates the effectiveness of such multi-component hydrogel as a simple local delivery platform extendable to multiple drugs requiring temporal control for optimized efficacy. Further, this approach could be beneficial for minimizing collateral toxicity to the healthy neural tissue.<br/>

Multi-compartment hydrogel synergizes combination chemotherapeutics with temporal control

254th National Meeting (2017)

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