Tratamento multi-modal loco-radiossensível para quimioterapia auto-reforçada e terapia direcionada de ARN para glioblastoma

Our AIM is to pioneer the development of a stimuli-triggered co-delivery hydrogel of TMZ μPs, O6-BG, and P-Cadh siRNA H-NPs as a multi-modal transformative treatment to eradicate GBM recurrence (Annex1). The disintegration and therapeutic release of this first-in-class hydrogel, implantable into the post-resection GBM cavity, will be controlled by the SOC RT daily dose. Thus, LOCALISE significantly advances beyond the current state-of-the-art by utilizing a new GBM therapeutic cocktail and introducing a novel category of radiolysed hydrogel platforms. 4 challenges (C) underpinning LOCALISE’s rationale have been identified, each tackled by an objective (O) and task (T): C1. Conventional TMZ chemotherapy presents limited BBB transport and MGMT-mediated tumor resistance [1,2]. O1. Fabricate μPs as TMZ releasing depots with maximized efficacy through O6-BG co-administration [T1]: TMZ will be loaded into locally delivered μPs of poly(lactic-co-glycolic acid) (PLGA, FDA-approved [3]), enhancing BBB crossing and brain bioavailability. Our i3S team is expert in leveraging PLGA technology [4-8], and PLGA μP formulations (e.g., Lupron Depot®) are well-established in clinics. Capitalizing on our preliminary data demonstrating the potent chemosensitization ability of the O6-BG MGMT inhibitor (Annex2), the therapeutic advantage of TMZ μPs/O6-BG co-administration will be validated. C2. Despite the potent anti-cancer effect of siRNAs silencing P-Cadh, they are unable to sufficiently target tumor cells [9,10]. O2. Develop H-NPs as tumor-targeted nano-vehicles for P-Cadh siRNA [T2]: A functional P-cadh silencing siRNA [11] will be loaded into H-NPs, previously reported by our i3S team for improving tumor targeting and enhancing anti-tumor effects in GBM mice (Annex3) [4,7]. As our UM team first reported P-Cadh's key role in GBM aggressiveness (Annex4) [10], we will assess the capacity of P-cadh siRNA H-NPs to downregulate P-Cadh levels in the TME, impairing tumor growth. C3. Conventional passive diffusion hydrogels exhibit incomplete drug release, thus resulting in poor efficacy [12]. O3. Synthesize a library of radiolysed hydrogels, with stratification of the top-candidate for incorporation of TMZ μPs, O6-BG and P-Cadh siRNA H-NPs [T3]: RT is an attractive stimulus for on-demand hydrogel degradation, independent from tumor heterogeneity and with unlimited tissue penetration depth. Thus, an array of RT-sensitive polymer hydrogels will be developed with guidance from our UoN team member, a global expert in hydrogel design [13]. The top-candidate is expected to respond to the SOC RT daily dose (2-Gy), causing gradual hydrogel disintegration and therapeutic release over the 6-week chemoradiation treatment window of GBM SOC. C4. While co-delivering TMZ μPs, O6-BG and P-cadh siRNA H-NPs within a RT-sensitive hydrogel is appealing, therapeutic advantage needs to be demonstrated under disease conditions. O4. Provide a preclinical proof of efficacy and safety [T4]: In vivo trials will be conducted in relevant preclinical orthotopic mice models of GBM, part of the core expertise of UM, to parallel the results with future responses in GBM patients. SJ-Hospital will be an elite clinical force in our team, providing access to a GBM clinical biobank and guidance on treatment design. Overall, LOCALIZE introduces an innovative, groundbreaking treatment strategy that has the potential to revolutionize patient outcomes and reshape the GBM therapeutic landscape.