Daniel Ehrsam
University of Basel, Switzerland
Title: Early findings in the development of an enzymatically triggered nanoformulation
Biography
Biography: Daniel Ehrsam
Abstract
In order to spare healthy cells and decrease adverse effects, innovative concepts of tumor targeting aim at bringing the cytotoxic payload most selectively to tumor cells. One concept is to use enzymes overexpressed in the surrounding of proliferating cells, like the gelatinase matrix-metalloproteinase 9 (MMP-9), as a trigger for drug release.
Our aim is to synthesize and characterize self-assembling nanoformulations consisting of an MMP9-labile peptide coupled to an anti-cancer drug.
By use of bioconjugate chemistry an amphiphilic molecule containing paclitaxel and an MMP9-labile peptide was synthesized to form nanoparticles. To identify a tumor entity as a target for our novel nanoformulation we quantified expression of MMP-9 in a commercially available tissue collection by multiplex real-time PCR. Several tumor entities showed significantly increased expression comparing normal to malignant tissue. Immunohistochemistry and database analysis suggested brain tumors, particularly glioblastoma multiforme, as a tumor entity where MMP-9 could be used to trigger drug release. Established brain cancer cell lines were characterized for MMP-9 expression and activity. LN-18 and U87-MG cells were selected for in vitro characterization of the synthesized nanoformulation. In preparation of in vivo xenograft studies LN-18 and U87-MG cells were stably transfected with mKate2 and characterized for expression.
Taken together, we verified overexpression of MMP9 in glioblastoma multiforme. Commonly used brain cancer cell lines were characterized prior to in vitro studies on MMP9 triggered drug release, and preparations for in vivo xenograft studies have been finished. Further studies are warranted to fully characterize the nanoformulation and understand its effects in vivo.