A Targeted and Responsive Nanoprodrug Delivery System for Synergistic Glioma Chemotherapy

Abstract

Doxorubicin (DOX) is widely used as a chemotherapeutic agent for both hematologic and solid tumors and is a reasonable candidate for glioma treatment. However, its effectiveness is hindered by significant toxicity and drug resistance. Moreover, the presence of the blood–brain barrier (BBB) brings a crucial challenge to glioma therapy. In response, a GSH‐responsive and actively targeted nanoprodrug delivery system (cRGD/PSDOX‐Cur@NPs) are developed. In this system, a disulfide bond‐bridged DOX prodrug (PEG‐SS‐DOX) is designed to release specifically in the high glutathione (GSH) tumor environment, markedly reducing the cardiotoxicity associated with DOX. To further address DOX resistance, curcumin, serving as a P‐glycoprotein (P‐gp) inhibitor, effectively increased cellular DOX concentration. Consequently, cRGD/PSDOX‐Cur@NPs exhibited synergistic anti‐tumor effects in vitro. Furthermore, in vivo experiments validated the superior BBB penetration and brain‐targeting abilities of cRGD/PSDOX‐Cur@NPs, showcasing the remarkable potential for treating both subcutaneous and orthotopic gliomas. This research underscores that this nanoprodrug delivery system presents a novel approach to inhibiting glioma while addressing resistance and systemic toxicity.

A Big Prospect for Hydrogel Nano-System in Glioma

“…This system is designed to respond to high levels of GSH in the TME, which triggers the decomposition of a disulfide bond-bridged PEG-SS-DOX prodrug and releases DOX for killing the glioma cells. 65 These findings highlight the potential of hydrogel nano-systems that take advantage of the high expression of GSH in the TME, providing a novel approach for the treatment of gliomas. By designing hydrogels capable of responding to ROS, controlled drug release and targeted therapy can be achieved in glioma treatment.…”

“…This system is designed to respond to high levels of GSH in the TME, which triggers the decomposition of a disulfide bond-bridged PEG-SS-DOX prodrug and releases DOX for killing the glioma cells. 65 …”