Novel strategies for enhanced fluorescence visualization of glioblastoma tumors based on HPMA copolymers conjugated with tumor targeting and/or cell-penetrating peptides

Abstract

Nano-sized polymer systems are often used as carriers for drugs and contrast agents to increase circulation time and solubility and to reduce possible side effects. These nanomedicines usually accumulate in tumor tissue due to the enhanced permeability and retention (EPR) effect. However, a targeting group may be attached to the polymer carrier in addition to the active substance to further increase tumor accumulation and specificity. In this study, the oligopeptide sequence RGD was chosen to target α_vβ₃ integrins overexpressed in the tumor vasculature and on some tumor cells. A set of polymer conjugates bearing a fluorescent dye and RGD peptide of different structures (linear, cyclic, branched) was prepared for use in tumor diagnosis, with a potential future application in navigated surgery. The accumulation of the most promising candidate, a targeted fluorescent nanoprobe, increased by 35%in glioblastoma tumors compared to the non-targeted control, which accumulated only due to the EPR effect. However, the administration of a polymer-boundmodified cilengitide as an antiangiogenic treatment did not show a beneficial effect in the suppression of angiogenesis.

Keywords

cell-penetrating peptides / diagnostics / HPMA copolymers / RGD sequence / tumor angiogenesis

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