The abundant extracellular matrix (ECM) in the
glioma microenvironment play a critical role in the maintenance of
glioma morphology,
glioma cells differentiation and proliferation, but little has been done to understand the feasibility of ECM as the therapeutic target for
glioma therapy. In this study, a drug delivery system targeting
fibronectins (FNs), a prevailing component in the ECM of many solid
tumors, was constructed for
glioma therapy based on the interaction between the abundant FNs in
glioma tissues and the FNs-targeting moiety
CLT1 peptide.
CLT1 peptide was successfully conjugated to
PEG-PLA nanoparticles (CNP). FNs were demonstrated to be highly expressed in the ECM of
glioma spheroids in vitro and
glioma tissues in vivo. CLT1 modification favored targeting nanoparticles penetration into the core of
glioma spheroids and consequently induced more severe inhibitive effects on
glioma spheroids growth than traditional NP. In vivo imaging, ex vivo imaging and
glioma tissue slides showed that CNP enhanced nanoparticles retention in
glioma site, distributed more extensively and more deeply into
glioma tissues than that of conventional NP, and mainly located in
glioma cells rather than in extracellular matrix as conventional NP. Pharmacodynamics outcomes revealed that the median survival time of
glioma-bearing mice models treated with
paclitaxel-loaded CNP (CNP-PTX) was significantly prolonged when compared with that of any other group. TUNEL assay demonstrated that more extensive cell apoptosis was induced by CNP-PTX treatment compared with other treatments. Altogether, these promising results indicated that this ECM-targeting drug delivery system enhanced retention and
glioma cell uptake of nanoparticles and might have a great potential for
glioma therapy in clinical applications.