Recent advances in drug delivery and targeting to the brain

Abstract

Our body keeps separating the toxic chemicals in the blood from the brain. A significant number of drugs do not enter the central nervous system (CNS) due to the blood-brain barrier (BBB). Certain diseases, such as tumor growth and stroke, are known to increase the permeability of the BBB. However, the heterogeneity of this permeation makes it difficult and unpredictable to transport drugs to the brain. In recent years, research has been directed toward increasing drug penetration inside the brain, and nanomedicine has emerged as a promising approach. Active targeting requires one or more specific ligands on the surface of nanoparticles (NPs), which brain endothelial cells (ECs) recognize, allowing controlled drug delivery compared to conventional targeting strategies. This review highlights the mechanistic insights about different cell types contributing to the development and maintenance of the BBB and summarizes the recent advancement in brain-specific NPs for different pathological conditions. Furthermore, fundamental properties of brain-targeted NPs will be discussed, and the standard lesion features classified by neurological pathology are summarized.

Keywords: Blood-brain barrier; Brain cancer; Glioblastoma; Medulloblastoma; Nanomedicine.

Fig. 1.

Structural components of blood brain barrier.

Fig. 2.

Strategies to improve therapeutics across the blood brain barrier.

Fig. 3.

Drug molecules designed to penetrate the blood brain barrier.

Fig. 4.

NPs uptake mechanisms of different molecules and carrier particles across the blood brain barrier.

Fig. 5.

ApoE mimetic peptide (COG-133) enhances the therapeutic efficacy of drug loaded nanoparticles (NPs) in orthotopic medulloblastoma bearing NSG mice. A) COG-133-NPs loaded with BRD4 inhibitor JQ1 decreased MB tumor burden. B) COG-133 decoration increased drug uptake and tumor biodistribution in orthotopic MB mice. The uptake of i) MDB5 and SF2523 loaded COG-133-NPs were increased in DAOY cells measured at 2 and 4 h time points. COG-133 decoration on NPs enhanced iii) MDB5 and iv) SF2523 in intracranial MB tumors compared to free drug and non-targeted NPs.

Fig. 6.

Types of brain-targeted nanomedicine and BBB-targeting peptides derived from venom. A) Commonly reported nanomedicines for brain delivery. B and C) Peptides designed for BBB penetration.