Drug delivery to the central nervous system

Abstract

Despite the rising global incidence of central nervous system (CNS) disorders, CNS drug development remains challenging, with high costs, long pathways to clinical use and high failure rates. The CNS is highly protected by physiological barriers, in particular, the blood-brain barrier and the blood-cerebrospinal fluid barrier, which limit access of most drugs. Biomaterials can be designed to bypass or traverse these barriers, enabling the controlled delivery of drugs into the CNS. In this Review, we first examine the effects of normal and diseased CNS physiology on drug delivery to the brain and spinal cord. We then discuss CNS drug delivery designs and materials that are administered systemically, directly to the CNS, intranasally or peripherally through intramuscular injections. Finally, we highlight important challenges and opportunities for materials design for drug delivery to the CNS and the anticipated clinical impact of CNS drug delivery.

Fig. 1 |. Physiological and pathological changes of the central nervous system in cancer and traumatic brain injury.

The impact of vascular, enzymatic, extracellular, cellular and interstitial barriers on drug delivery is shown in normal brain tissue (panel a), cancer (panel b) and traumatic brain injury (panel c). BBB, blood–brain barrier; ECM, extracellular matrix; MMP, matrix metalloproteinase; TAM, tumour-associated macrophage.

Fig. 2 |. Physiological and pathological changes of the central nervous system in chronic neurodegeneration and stroke.

The impact of vascular, enzymatic, extracellular, cellular and interstitial barriers on drug delivery is shown in normal brain tissue (panel a), chronic neurodegeneration (panel b) and stroke (panel c). BBB, blood–brain barrier; ECM, extracellular matrix; MMP, matrix metalloproteinase; TAM, tumour-associated macrophage.

Fig. 3 |. Different human diseases present different central nervous system drug delivery challenges.

a | Computed tomography scan of a malignant middle cerebral artery (MCA) stroke, area outlined in yellow. The highlighted area (magenta) shows injured brain parenchyma occupying much of the left hemisphere, in which drug delivery solutions may be able to salvage tissue in the stroke penumbra that is transiently ischaemic but not yet infarcted or lost owing to cell death. b | Magnetic resonance image of a spinal cord injury (blue outline) shows a compressed spinal cord from cervical stenosis. The yellow outline shows a C7–T1 traumatic herniated disc displacing the spinal cord. Thus, two distinct areas (red arrows) of injury would need to receive a drug at therapeutic dose to preserve or recover white matter tracts, which could be accessible during surgery. c | Magnetic resonance imaging scan of glioblastoma multiforme (GBM) brain tumour, showing a large mass effect (enhancement within the left temporal lobe, yellow outline) causing mass effect and displacing the brain by over 1 cm from left to right. Resection surgeries for tumour removal (cyan) allow placement of local antineoplastic drug delivery devices. The technical challenge of targeting microscopic tumour cells in the brain beyond the large macroscopic tumour could benefit from materials that facilitate the delivery of therapeutic doses across a large tissue volume. Images obtained by R. Saigal.

Fig. 4 |. Drug delivery across the blood–brain barrier.

a | Drug delivery systems can take advantage of several transport mechanisms across the blood–brain barrier (BBB). (1) Paracellular transport can occur for low- molecular-weight hydrophilic molecules; (2) transporters can facilitate movement of specific endogenous small molecules or mimics/derivatives of small molecules; (3) absorptive transcytosis can be driven by charge-based binding and transport of macromolecules and nanoparticles, followed by internalization and transcytosis; (4) transcellular diffusion can occur for low-molecular-weight hydrophobic molecules; and (5) receptor-mediated transcytosis involves receptor-mediated shuttling of ligands and ligand–drug conjugates from the apical to the basolateral side. b | Material properties of drug delivery systems can influence adsorption, distribution and clearance of drug delivery systems following systemic administration. PEG, poly(ethylene glycol).

Fig. 5 |. Local central nervous system drug delivery routes.

Direct drug delivery to the central nervous system can be achieved by intraparenchymal injection, intraventricular or intrathecal infusion, or by implants, such as wafers or hydrogels loaded with drug or drug delivery systems. ECM, extracellular matrix.