Enhanced Bioavailability of a Thionated IMiD Derivative Nanosuspension for Parkinson’s Disease Targeting α-Synuclein

Luca Casula,1 Maria Francesca Palmas,2 Maria Cristina Cardia,1 Donatella Valenti,1 Elena Pini,3 Michela Etzi,2 Salvatore Marceddu,4 Chiara Sinico,1 David Tweedie,5 Nigel H Greig,5 Dong Seok Kim,6,7 Anna Rosa Carta,2 Francesco Lai1 1Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy; 2Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy; 3Departmentof Pharmaceutical Sciences, University of Milan, Milan, Italy; 4Institute of Sciences of Food Production (ISPA-CNR), Baldinca (Sassari), Italy; 5Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA; 6AevisBio, Inc., Gaithersburg, MD, USA; 7Aevis Bio, Inc., Daejeon, KoreaCorrespondence: Francesco Lai, Department of Life and Environmental Sciences, University of Cagliari, S.P. Monserrato-Sestu km 0.700, Cagliari, 09042, Italy, Email [email protected]: Chronic neuroinflammation and the accumulation of misfolded α-synuclein are hallmarks of Parkinson’s disease (PD), a progressive neurodegenerative disorder that leads to neuronal loss and dysfunction. Immunomodulatory imide drugs (IMiDs) are thalidomide analogs that exhibit potent anti-inflammatory and neuroprotective effects by regulating NF-κB and TNF-α levels. However, their therapeutic use is limited by their teratogenic actions mediated via Cereblon (CRBN) binding. Previous studies have demonstrated the efficacy of pomalidomide (POM) in mitigating neuroinflammation and providing neuroprotection in a rodent model of PD. Building on these findings, a novel derivative, 3-monothiopomalidomide (MTPOM), was synthesized, with reduced teratogenic potential compared to POM. Nevertheless, like other IMiDs, MTPOM shows poor aqueous solubility and low gastrointestinal bioavailability following oral administration.Methods: MT-POM was formulated as a nanosuspension (NS) via wet ball media milling using Tween 80 as a stabilizer. The morphology of nanocrystals was characterized by SEM, while the average diameter, size distribution and zeta potential were assessed via DLS and M3-PALS. The crystalline/amorphous nature was investigated by means of ATR-FT-IR and XRPD. Moreover, the aqueous solubility and dissolution rate were tested in vitro, and plasma and brain concentrations were evaluated in rats.Results: The produced NS (~226 nm, PDI 0.22, zeta potential − 26 mV) demonstrated enhanced aqueous solubility and dissolution rate compared to the raw drug. MTPOM retained crystallinity and showed optimal stability over 60 days of storage. Pharmacokinetic studies in rats established that MTPOM-NS provided significantly higher plasma and brain concentrations, prolonged systemic exposure, and greater drug accumulation in brain tissue.Conclusion: This enhancement in bioavailability supports the formulation of NS as a promising strategy for CNS-targeted therapies, providing a strong rationale for further investigation into the efficacy of MTPOM-NS in the chronic treatment of PD, which will be the focus of future studies. Keywords: 3-Monothiopomalidomide, nanocrystals, Parkinson’s disease, brain delivery, immunomodulatory imide drugs, IMiDs, pomalidomide