Overexpression of Epidermal Growth Factor Receptor (EGFR) on Glioblastoma, the most lethal brain tumor, often contributes to high tumorigenicity. Taking into account the clinical failures of single therapy small molecule EGFR inhibitors (Erlotinib, Gefitinib, etc), synchronized administration of dual therapies from an appropriate delivery platform could be effective. Herein, we show that co-administration of Erlotinib and Doxorubicin under a time staggered Erlotinib→Doxorubicin regimen can sensitize human glioblastoma cells towards apoptosis. We employ an orthogonally self-assembled, injectable peptide hydrogel designed to sequentially deliver these two drugs after being implanted by syringe directly to the tumor or to the brain parenchyma as an adjuvant to resection therapy. We exploit a de novo designed amphiphilic β-hairpin peptide that can self-assemble in presence of free Erlotinib and Doxorubicin-loaded liposomes to form a rigid Sequogel under physiological conditions. Sequogels can achieve co-encapsulation of the dual chemotherapeutics while affording their segregation in two different compartments in the resulting gel network. Prompt release of Erlotinib and concomitant sustained delivery of Doxorubicin, achieved through this multicomponent encapsulation strategy, leads to significantly enhanced apoptotic activity in human glioblastoma cells via caspase-mediated signaling. Thus, Sequogels represent an effective delivery platform for localized release of multiple drug candidates necessitating a time-staggered action. In addition, sustained and preferential delivery of the loaded drugs directly to the tumor or resected tissue margins holds promise for minimizing toxic side-effects to the surrounding neural tissues.

Divided we stand: Exploiting sequogels for time-staggered delivery of dual chemotherapeutics

253rd National Meeting (2017)

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