PhD Student: Roger Gómez Herrera

In person Event - Register HERE to attend

Directors: CSIC Research Prof. Daniel Ruiz Molina, Nanostructured Functional Materials Group Leader and Dr Fernando Novio, Associate Professor UAB.

Short Abstract:

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumour in adults. The current clinical standard treatment, established back in 2005, includes surgical resection followed by radiotherapy and temozolomide chemotherapy. Still, GBM presents a median survival rate of less than two years and less than 6% five-year survival. This situation underscores the need to develop better therapeutic agents. Pt compounds, like cisplatin, remain among the most potent anticancer agents. However, these drugs encounter obstacles in GBM due to blood–brain barrier permeability, systemic toxicities, and resistance.

This Thesis develops on Pt-based drugs that address these barriers by exploring multi-target nanotherapies that improve tumour selectivity and targeting, minimize systemic exposure, while exploiting local therapeutic windows. In these lines we investigate combination therapies, and bioinspired biomaterials as strategies to overcome these limitations. More specifically, this Thesis focuses on four research lines whose novelty varies as described next:

First, Pt(IV) catechol-based coordination nanoparticles (CNP) formed by oxidative polymerization of a Pt(IV) prodrug monomer (PtBC). This platform yields melanin-like nanoparticles (NPs), a Trojan-horse approach for brain diseases, with pH and redox-sensitive Pt(IV) release.

Second, squaraine (SQ)-based Pt(II) supramolecular NPs combining photoactivated chemotherapy (PACT) and photodynamic (PDT) prospects of SQs. According with the experimental results, PACT was discarded while interesting PDT effects were found on SQ supramolecular NPs without Pt.

Third, a bi-functional core-shell NP was designed with a superparamagnetic iron-oxide (SPION) core and a zirconium-based CNP shell bearing 9,10-diphenylanthracene moieties. The shell is capable to store singlet oxygen under ultraviolet irradiation and release it on demand via magnetic hyperthermia (MHT) generated by the SPION core. In vitro studies on GL261 murine GBM model display a cooperative heat and reactive oxygen species (ROS) cytotoxicity effect. In vivo experiments demonstrated the core-shell NP to be highly specific and sensitive to traverse relaxation weighted (T2w) magnetic resonance imaging. Unexpectedly, the platform demonstrated as selective contrast agent for bladder at very low concentrations, far from the GBM target. On this research a second NP platform based the CNP shell itself was developed and displayed excellent cytotoxic effect on GL261 murine GBM model under MHT stimulus.

Fourth, based on the PtBC monomer developed in the first approach, we developed bioinspired catechol-based Pt(IV) free-standing membranes (FSMs) as conformable, wet‑adhesive patches for insertion into resection cavities. This FSMs are formed by oxidative co‑polymerization between a PtBC monomer and an amine co-monomer to yield malleable membranes that release Pt locally. Physicochemical characterisation, controlled-release assays and in vitro cytotoxicity against GBM lines demonstrated the FSM’s potential as a post-surgical local therapy with plausible ROS synergistic effects.

All in all, this Thesis provides proof-of-concepts for multimodal treatments, exploiting complementary mechanisms (DNA damage, oxidative stress, hyperthermia and sustained local delivery) to increase tumour selectivity and reduce systemic toxicity