Pathways for Small Molecule Delivery to the Central Nervous System across the Blood-Brain Barrier

Abstract

The treatment of central nervous system (CNS) disease has long been difficult due to the ineffectiveness of drug delivery across the blood-brain barrier (BBB). This review summarizes important concepts of the BBB in normal versus pathophysiology and how this physical, enzymatic, and efflux barrier provides necessary protection to the CNS during drug delivery, and consequently treatment challenging. Small molecules account for the vast majority of available CNS drugs primarily due to their ability to penetrate the phospholipid membrane of the BBB by passive or carrier-mediated mechanisms. Physiochemical and biological factors relevant for designing small molecules with optimal capabilities for BBB permeability are discussed, as well as the most promising classes of transporters suitable for small-molecule drug delivery. Clinically translatable imaging methodologies for detecting and quantifying drug uptake and targeting in the brain are discussed as a means of further understanding and refining delivery parameters for both drugs and imaging probes in preclinical and clinical domains. This information can be used as a guide to design drugs with preserved drug action and better delivery profiles for improved treatment outcomes over existing therapeutic approaches.

Identification of a small-molecule ligand that activates the neuropeptide receptor GPR171 and increases food intake

“…This is surprising given that MS0015203 has two carboxyl (COOH) groups and such compounds typically poorly penetrate the CNS. However, MS0015203 fulfills other criteria proposed for good CNS penetration (36, 37). In addition, the observation that intraperitoneal administration of MS0015203 also increases food intake and this is not seen in animals in which GPR171 is knocked down in the hypothalamus further supports the notion that MS0015203 can reach the brain from the periphery.…”

Targeted Brain Delivery of Bioactive Molecules Using Nanocarriers

“…Vinblastin and Zidovudine (AZT)] do not stay in the brain cells for appropriate time due to the fact that these molecules are substrate for the efflux transporters present on the brain cells [11]. These transporters are responsible for the expulsion of the substrate molecules [12]. Several transporter protein families have been identified, which act as an efflux transporter of the molecules [13].…”

Imaging and therapeutic applications of zinc(ii)-dipicolylamine molecular probes for anionic biomembranes

“…95, 141 Nonspecific disruption of the BBB has been employed to facilitate entrance of BBB-impermeable probes into brain parenchyma, but these approaches induce uncontrolled neuronal injuries and expose the brain to circulating neuroactive and neurotoxic agents. 140,144 ZnDPA probes have been reported to possess high affinity for neurofibrillary tangles of hyperphosphorylated tau proteins, a component of amyloid plaques which are an established biomarker of Alzheimer’s disease. 142,143 Radiolabeled ZnDPA probes that can safely cross the BBB are likely to be excellent tools for quantifying and diagnosing tau protein-related neurodegenerative disorders.…”

“…Recent community success at formulating small molecules and nanoparticles with BBB-permeation properties is reason for pursuit and optimism. 144-147 …”