Multicomponent Nanoscintillators for Enhanced Radiotherapy Ad Alzheimer’s Disease Treatment

Multicomponent nanomaterials consisting of dense scintillating particles functionalized by or embedding optically active conjugated photosensitizers (PSs) for cytotoxic reactive oxygen species (ROS) have been proposed in the last decade as coadjuvant agents for radiotherapy of cancer. [1] They have been designed to make scintillation-activated sensitizers for ROS production in an aqueous environment under exposure to ionizing radiations. However, a detailed understanding of the global energy partitioning process occurring during the scintillation is still missing, in particular regarding the role of the non-radiative energy transfer between the nanoscintillator and the conjugated moieties which is usually considered crucial for the activation of PSs and therefore pivotal to enhance the therapeutic effect. We investigate this mechanism in a series of PS-functionalized scintillating hydrated magnesium silicate nanotubes (NT) where the non-radiative energy transfer yield has been tuned by control of the intermolecular distance between the nanotube and the conjugated system. The obtained results indicate that non-radiative energy transfer has a negligible effect on the ROS sensitization efficiency, [2] thus opening the way to the development of different architectures for breakthrough radiotherapy coadjutants to be tested in clinics.<br/>The obtained results allow to design effective therapeutic agents for the radiothterapy of the Alzheimer disease. [3] Soluble A�� oligomers are identified as neurotoxic species in AD and targeted in antibody-based drug development to mitigate cognitive decline. However, controversy exists concerning their efficacy and safety. In this study, an alternative strategy is proposed to inhibit the formation of A�� oligomers by selectively oxidizing specific amino acids in the A�� sequence, thereby preventing its aggregation. Targeted oxidation is achieved using biocompatible and blood-brain barrier-permeable multicomponent nanoscintillators that generate singlet oxygen upon X-ray interaction. Surface-modified scintillators interact selectively with Aβ and, upon X-ray irradiation, inhibit the formation of neurotoxic aggregates both in vitro and in vivo. Feeding transgenic Caenorhabditis elegans expressing human Aβ with the nanoscintillators and subsequent irradiation with soft X-ray reduces Aβ.<br/>Surface-modified scintillators interact selectively with Aβ and, upon X-ray irradiation, inhibit the formation of neurotoxic aggregates both in vitro and in vivo. Feeding transgenic Caenorhabditis elegans expressing human Aβ with the nanoscintillators and subsequent irradiation with soft X-ray reduces Aβ oligomer levels, extends lifespan, and restores memory and behavioral deficits<br/><br/>[1] I. Villa, C. Villa, et al. <i>ACS Applied Materials & Interfaces</i> <b>2021</b> 13, 12997-13008<br/>[2] V. Secchi, F. Cova, I. Villa, et al. <i>ACS Appl. Mater. Interfaces</i> <b>2023</b>, 15, 24693−24700.<br/>[3] S. Senapati, V. Secchi, et al. <i>Adv. Healthcare Mater.</i> <b>2023</b>, 2301527