REACT produced a robust portfolio of scientific innovations with direct translational potential. At its core was the design of hybrid organic-inorganic nanoparticles capable of encapsulating a broad range of therapeutic and diagnostic agents, including standard chemotherapeutics (e.g. doxorubicin, temozolomide, paclitaxel) and a novel organoruthenium compound with selective cytotoxicity against GBM cells. The latter exhibited an eightfold increase in intracellular concentration when delivered via the nanocarrier system, compared to the free drug. In addition to small molecules, the porous nanostructure was adapted for the delivery of nucleic acids, most notably siRNA targeting VEGF in retinal cells, demonstrating the flexibility and modularity of the platform.
A pivotal innovation was the development of molecular gates -peptide, pH-, and redox-sensitive moieties- that allowed for stimulus-triggered drug release in response to tumor-specific conditions. These gates were engineered to degrade in the presence of matrix metalloproteinases, acidic environments, or elevated levels of glutathione, all commonly found in tumor tissue. This enabled highly selective release of payloads at the tumor site, minimizing off-target effects and improving therapeutic index. The integration of diagnostic imaging agents further allowed real-time tracking of drug release, moving the platform into the realm of theranostics.
To achieve localized administration, these nanoparticles were incorporated into injectable hydrogels based on hyaluronic acid and chitosan/beta-glycerophosphate. These hydrogels could form a solid depot upon injection, releasing their cargo over time as the matrix degraded. Chemical crosslinking strategies improved their flexibility and drug-loading capacity, and cytotoxicity assays in both 2D and 3D GBM models confirmed their efficacy.
The system was tested in preclinical animal models, including an orthotopic GBM model involving surgical resection followed by hydrogel implantation into the tumor cavity. This clinically relevant setup showed reduced tumor recurrence and improved therapeutic outcomes. Additionally, an intranasal administration route was explored as a non-invasive alternative for delivering the hydrogel-nanoparticle system directly to the central nervous system, bypassing the BBB.
REACT also played a key role in advancing in vitro tumor modeling by developing scaffold-free 3D GBM spheroids. These models more closely mimic the architecture and microenvironment of real tumors compared to conventional 2D cultures, and were instrumental in correlating in vitro drug response with in vivo outcomes.
Results were disseminated through nine high-impact publications, including:
- Sci Rep 2023, 13, 5094: Demonstrated the efficacy of nanocomposite hydrogels for GBM treatment.
- Pharmaceutics 2023, 15(4), 1071: Detailed hydrogel formulation and injectable system design.
- Heliyon 2025, 11(1), e41151: Showcased pH-responsive chlorotoxin-functionalized nanoparticles.
- Int J Mol Sci 2023, 24(3), 2753: Presented siRNA-loaded nanoparticle delivery in retinal models.
- J Sol-Gel Sci Technol 2024, 111, 95–105: Described MRI-visible, pH-triggered drug release.
In addition, a patent application (ES2816632A1) has been filed to protect the hydrogel-based delivery technology, and further development toward clinical translation is ongoing.
