Multifunctional Nano-Realgar Hydrogel for Enhanced Glioblastoma Synergistic Chemotherapy and Radiotherapy: A New Paradigm of an Old Drug

Abstract

Purpose Realgar, as a kind of traditional mineral Chinese medicine, can inhibit multiple solid tumor growth and serve as an adjuvant drug in cancer therapy. However, the extremely low solubility and poor body absorptive capacity limit its application in clinical medicine. To overcome this therapeutic hurdle, realgar can here be fabricated into a nano-realgar hydrogel with enhanced chemotherapy and radiotherapy (RT) ability. Our objective is to evaluate the superior biocompatibility and anti-tumor activity of nano-realgar hydrogel. Methods We have successfully synthesized nano-realgar quantum dots (QDs) coupling with 6-AN molecules (NRA QDs) and further encapsulated with a pH-sensitive dextran hydrogel carrier with hyaluronic acid coating (DEX-HA gel) to promote bioavailability, eventually forming a multifunctional nano-realgar hydrogel (NRA@DH Gel). To better investigate the tumor therapy efficiency of the NRA@DH Gel, we have established the mice in situ bearing GL261 brain glioblastoma as animal models assigned to receive intratumor injection of NRA@DH Gel. Results The designed NRA@DH Gel as an antitumor drug can not only exert the prominent chemotherapy effect but also as a “sustainable reactive oxygen species (ROS) generator” can inhibit in the pentose phosphate pathway (PPP) metabolism and reduce the production of nicotinamide adenine dinucleotide phosphate (NADPH), thereby inhibiting the conversion of glutathione disulfide (GSSG) to glutathione (GSH), reducing GSH concentrations in tumor cells, triggering the accumulation of ROS, and finally enhancing the effectiveness of RT. Conclusion Through the synergistic effect of chemotherapy and RT, NRA@DH Gel effectively inhibited the proliferation and migration of tumor cells, suppressed tumor growth, improved motor coordination, and prolonged survival in tumor-bearing mice. Our work aims to improve the NRA@DH Gel-mediated synergistic chemotherapy and RT will endow a “promising future” for the old drug in clinically comprehensive applications.

Enhancing Hydrogels with Quantum Dots

“…The design of the nano-realgar hydrogel aims to optimize cancer treatment by harnessing the unique properties of realgar quantum dots within a pHsensitive dextran hydrogel. This inventive approach has shown significant enhancements in chemotherapy and radiotherapy outcomes, leading to substantial inhibition of tumor growth (Figure 3) [35].…”

“…The trend towards creating hybrid and composite hydrogels underlines the movement towards multifunctional materials, which show improved performance across a range of applications, including medical engineering, environmental remediation, and energy harvesting [26][27][28][29][30]. The research community's increasing interest in self-healing and environmentally responsive hydrogels indicates a shift towards dynamic and adaptive materials, with advancements in biodegradable and bioresponsive hydrogels aligning with sustainable solutions in tumor therapy and tissue regeneration [31][32][33][34][35][36].…”

“…Enhanced functionalization is achieved through materials like carbon quantum dots and black phosphorus quantum dots, aiming to improve aspects such as fluorescence, mechanical strength, and therapeutic effects, which are crucial in medical and biomedical applications like drug delivery, tissue engineering, biosensing, and cancer therapy [31,32,[34][35][36][37][38][39][40][41][42][43]. Optoelectronic applications are prevalent too, with the development of photoluminescent and fluorescent hydrogels for uses in imaging, sensing, and diagnostics [39,[42][43][44][45][46].…”

“…energy harvesting [26][27][28][29][30]. The research community's increasing interest in self-healing and environmentally responsive hydrogels indicates a shift towards dynamic and adaptive materials, with advancements in biodegradable and bioresponsive hydrogels aligning with sustainable solutions in tumor therapy and tissue regeneration [31][32][33][34][35][36].…”

Empagliflozin: a potential anticancer drug

“…Nanoparticles have shown considerable promise in tumor radiation therapy, and their combination has the potential to improve the tumor’s lack of oxygen [ 26 ] and enhance the therapeutic effect. Wang et al developed pH-responsive functionalized nano-andrographic hydrogels coupled with 6-aminonicotinamide to inhibit the pentose phosphate pathway’s metabolism, thereby reducing NADPH production, inhibiting the conversion of oxidized glutathione to reduced glutathione, and enhancing sustained ROS production to increase radiotherapy sensitivity [ 27 ]. Furthermore, the incorporation of highly effective and specific anticancer drugs as radiosensitizers in combination with chemotherapy is expected to produce more effective therapeutic outcomes.…”