Nanoparticulate strategies for the treatment of polyglutamine diseases by halting the protein aggregation process^†

Abstract

Polyglutamine (polyQ) diseases are a class of neurodegenerative disorders that cause cellular dysfunction and, eventually, neuronal death in specific regions of the brain. Neurodegeneration is linked to the misfolding and aggregation of expanded polyQ-containing proteins, and their inhibition is one of major therapeutic strategies used commonly. However, successful treatment has been limited to date because of the intrinsic properties of therapeutic agents (poor water solubility, low bioavailability, poor pharmacokinetic properties), and difficulty in crossing physiological barriers, including the blood–brain barrier (BBB). In order to solve these problems, nanoparticulate systems with dimensions of 1–1000 nm able to incorporate small and macromolecules with therapeutic value, to protect and deliver them directly to the brain, have recently been developed, but their use for targeting polyQ disease-mediated protein misfolding and aggregation remains scarce. This review provides an update of the polyQ protein aggregation process and the development of therapeutic strategies for halting it. The main features that a nanoparticulate system should possess in order to enhance brain delivery are discussed, as well as the different types of materials utilized to produce them. The final part of this review focuses on the potential application of nanoparticulate system strategies to improve the specific and efficient delivery of therapeutic agents to the brain for the treatment of polyQ diseases.

Keywords:

• PolyQ diseases
• protein aggregation
• therapeutic agents
• brain
• blood–brain barrier
• nanotechnology
• nanoparticulate systems

Acknowledgements

Oscar Escalona-Rayo and Paulina Fuentes-Vázquez acknowledge the support provided by CONACyT, Mexico (576545 and 576766) and the Postgraduate Program in Chemical Sciences at the UNAM, Mexico. This work was supported by PAPIIT/UNAM under Grant 201914; CONACYT CB under Grant 221629; CONACYT INFRA under Grant 251940; and PIAPIC under Grant 01.

Disclosure statement

This research work is original, and the authors declare no conflict of interest. This work is consistent with the Journal´s guidelines for ethical publication.

Additional information

Funding

Oscar Escalona-Rayo and Paulina Fuentes-Vázquez acknowledge the support provided by CONACyT, Mexico (576545 and 576766) and the Postgraduate Program in Chemical Sciences at the UNAM, Mexico. This work was supported by PAPIIT/UNAM IT201914-3, CONACYT CB221629, CONACYT INFRA251940, and PIAPI001.