Envisioning the future of polymer therapeutics for brain disorders

Abstract

The growing incidence of brain‐related pathologies and the problems that undermine the development of efficient and effective treatments have prompted both researchers and the pharmaceutical industry to search for novel therapeutic alternatives. Polymer therapeutics (PT) display properties well suited to the treatment of neuro‐related disorders, which help to overcome the many hidden obstacles on the journey to the central nervous system (CNS). The inherent features of PT, derived from drug(s) conjugation, in parallel with the progress in synthesis and analytical methods, the increasing knowledge in molecular basis of diseases, and collected clinical data through the last four decades, have driven the translation from “bench to bedside” for various biomedical applications. However, since the approval of Gliadel® wafers, little progress has been made in the CNS field, even though brain targeting represents an ever‐growing challenge. A thorough assessment of the steps required for successful brain delivery via different administration routes and the consideration of the disease‐specific hallmarks are essential to progress in the field. Within this review, we hope to summarize the latest developments, successes, and failures and discuss considerations on designs and strategies for PT in the treatment of CNS disorders. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

Breaking Barriers: Bioinspired Strategies for Targeted Neuronal Delivery to the Central Nervous System

“…Therefore, besides having successful applications, the use of certain targeting moieties must be carefully equated due to the high competition with endogenous ligands, which may hamper the process of the desired target ligand-receptor interaction. A solution could be the development of alternative targeting ligands with an affinity to slightly different epitopes of the receptors, such as the ones developed in the case of TfR (OX26 and 8D3, for example) [238].…”

Polyornithine-based polyplexes to boost effective gene silencing in CNS disorders

“…delivery, the final design will include a blood-brain barrier-targeting moiety (e.g., the Angiopep2 peptide) to favor uptake [17]. Another possibility will be the formulation of our polyplexes for intranasal administration, providing a direct delivery via nose-to-brain pathway [17]. Please do not adjust margins Please do not adjust margins of the observed nucleus, g the gradient strength, δ the length of the gradient, and Δ the diffusion time.…”

“…To date, CALAA-01 represents the most successful example, comprising an siRNA targeting the M2 subunit of ribonucleotide reductase complexed with a transferrin-coated self-assembling cationic cyclodextrin polymer conjugated with polyethylene glycol (PEG) that targets tumor cells overexpressing the transferrin receptor [8]. Polymers commonly investigated for CNS-related applications include polyethyleneimine, PEGylated-poly(amidoamine) (PAMAM) systems or PEGylated-polyaminoacids [17]. Although polyplexes have successfully delivered siRNA to the brain via intravenous or intranasal routes in preclinical studies, neurotoxicity-related issues and off-target effects related to poor biodistribution can hamper clinical translation, thus requiring the development of optimized siRNA delivery systems.…”

Targeting Alzheimer’s disease with multimodal polypeptide-based nanoconjugates

“…To enhance the ability of multimodal polypeptide-based nanoconjugates to cross the BBB, we modified our nanocarrier to also carry Angiopep-2 (ANG), a specific peptide ligand for the low-density lipoprotein receptor-related protein 1 (LRP1) that promotes transcytosis from blood to brain and thereby represents a target for delivery of substances into the central nervous system (CNS) (7,35,36). In AD, LRP1 expression in the brain endothelium mediates the rapid removal of A from the brain via transport across the BBB, making LRP1 a therapeutic target (35).…”