Lisa Sequeira

PC35 – Lisa Sequeira

RISE-Health, Faculty of Medicine, University of Porto, Portugal

lsequeira@med.up.pt

Polymerization-induced self-assembly of ROS-sensitive nanovesicles for dual-drug delivery in ALS therapy
Sequeira Lisa¹, SaraivaRita¹, Alfenim Ana Rita¹, Moreira Joana¹, Eberhardt J.², Pinto Miguel¹, Brendel Johannes², Fernandes Carlos¹ ¹ RISE-Health, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal ² Macromolecular Chemistry, University of Bayreuth, Universitätsstr. 30, 95447 Bayreuth, Germany
Abstract Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder with a multifactorial pathophysiology characterized by an oxidative environment. Current therapies primarily focus on extending survival and slowing the progression of physical decline¹, underscoring the urgent need for neuroprotective strategies that target multiple mechanisms simultaneously. Nanotechnology-based delivery systems offer a promising approach to enhance therapeutic efficacy compared to conventional drug administration that when combined with reactive oxygen species (ROS)-sensitive moieties enable the controlled and targeted release of therapeutic agents. The combination of Riluzole (RIL), an FDA-approved drug for ALS, with Rasagiline Mesylate (RAS), which provides neuroprotective effects, represents a strategy to achieve synergistic benefits and improve treatment outcomes. To realize this potential, ROS-sensitive RIL/RAS-loaded vesicles were synthesized via polymerization-induced self-assembly (PISA). Poly(N-acryloylmorpholine) (PNAM) served as the macro chain transfer agent, while N-acryloylthiomorpholine (NAT) was used as the monomer². Different PNAM/NAT ratios were tested as well as the concentration of NAT in the reactional mixture. The drug content in the vesicles was quantified using a high-performance liquid chromatography (HPLC) system, while the size and morphology of the vesicles were characterized through dynamic and electrophoretic light scattering (DLS and ELS). The study of the degradation kinetics was performed under physiological and oxidative environment conditions at 37 ºC. A preliminary evaluation of the pharmacological effect of the novel ROS-sensitive nanoformulations was performed using neuronal and nasal epithelial cell lines.
References [1] Mead, R. J.; Shan, N.; Reiser, H. J.; Marshall, F.; Shaw, P. J. Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation. Nature Reviews Drug Discovery 2022, 22 (3), 185–212. DOI: 10.1038/s41573-022-00612-2 [2] Sobotta, F. H.; Kuchenbrod, M. T.; Grune, C.; Fischer, D.; Hoeppener, S.; Brendel, J. C. Elucidating preparation-structure relationships for the morphology evolution during the RAFT dispersion polymerization of N-acryloyl thiomorpholine. Polymer Chemistry 2021, 12 (11), 1668–1680. DOI:10.1039/d0py01697g. This work was funded by FEDER funds through national funds by FCT – Foundation for Science and Technology under research grants 2023.13291.PEX, 2024.16701.PEX and under the project RISE-Health – UID/06397/2025. This work was also supported by the project IMPULSE (Funding programme: Horizon Europe; Grant agreement number: 101132028). This work was also supported by FCT project reference 2021. 04016.CEECIND/CP1655/CT000(DOI: 10.54499/2021.04016.CEECIND/CP1655/CT0004). M.P. (101132028), J.M. (2023.13291.PEX/201569) and A.R.A. (2023.01250.BD) grants are also supported by FCT. C.F. thanks the FCT for the financial support of his work contract through the Scientific Employment Stimulus—Individual Call (2021. 04016.CEECIND/CP1655/CT0004).