The Potential of the Fibronectin Inhibitor Arg-Gly-Asp-Ser in the Development of Therapies for Glioblastoma

Glioblastoma (GBM) is the most lethal and common malignant primary brain tumor in
adults. An important feature that supports GBM aggressiveness is the unique composition of its
extracellular matrix (ECM). Particularly, fibronectin plays an important role in cancer cell adhesion,
differentiation, proliferation, and chemoresistance. Thus, herein, a hydrogel with mechanical properties
compatible with the brain and the ability to disrupt the dynamic and reciprocal interaction
between fibronectin and tumor cells was produced. High-molecular-weight hyaluronic acid (HMWHA)
functionalized with the inhibitory fibronectin peptide Arg-Gly-Asp-Ser (RGDS) was used to
produce the polymeric matrix. Liposomes encapsulating doxorubicin (DOX) were also included
in the hydrogel to kill GBM cells. The resulting hydrogel containing liposomes with therapeutic
DOX concentrations presented rheological properties like a healthy brain. In vitro assays demonstrated
that unmodified HMW-HA hydrogels only caused GBM cell killing after DOX incorporation.
Conversely, RGDS-functionalized hydrogels displayed per se cytotoxicity. As GBM cells produce
several proteolytic enzymes capable of disrupting the peptide–HA bond, we selected MMP-2 to
illustrate this phenomenon. Therefore, RGDS internalization can induce GBM cell apoptosis. Importantly,
RGDS-functionalized hydrogel incorporating DOX efficiently damaged GBM cells without
affecting astrocyte viability, proving its safety. Overall, the results demonstrate the potential of the
RGDS-functionalized hydrogel to develop safe and effective GBM treatments.