Functional Poly(ε-caprolactone)/Poly(ethylene glycol) Copolymers with Complex Topologies for Doxorubicin Delivery to a Proteinase-Rich Tumor Environment

Doxorubicin (DOX)-loaded polymer nanoparticles based on poly(ethylene glycol)-poly(ε-caprolactone) copolymers with a complex macromolecular topology are proposed to tackle the matrix metalloproteinase (MMP)-rich tumor environment. Linear, 4-arm comb-like and brush block were synthesized through combination of ring opening polymerization atom transfer radical polymerization, in order control molar mass distribution, arm/brush architecture, as well final size DOX loading self-assembled obtained by nanoprecipitation. The optimized nanocarriers conjugated penetrating low molecular weight protamine peptides coupled polyanionic inhibitory domain cleavable metalloproteinase-2 (MMP2). DOX-loaded, MMP2-activable evaluated context glioblastoma (GBM), brain characterized remarkable relevant MMP2 expression. Uptake cytotoxicity patient-derived GBM cells correlated level enzymatic activity dose- time-dependent manner. No effects observed nontumoral endothelial that do not express MMP2. Results demonstrated that, tuning peptide sequence, nanoparticle self-assembly, encapsulation, delivery can be for development an advanced treatment MMP2-overexpressing tumors.