Physiological and Pathological Factors Affecting Drug Delivery to the Brain by Nanoparticles

Abstract

The prevalence of neurological/neurodegenerative diseases, such as Alzheimer's disease is known to be increasing due to an aging population and is anticipated to further grow in the decades ahead. The treatment of brain diseases is challenging partly due to the inaccessibility of therapeutic agents to the brain. An increasingly important observation is that the physiology of the brain alters during many brain diseases, and aging adds even more to the complexity of the disease. There is a notion that the permeability of the blood-brain barrier (BBB) increases with aging or disease, however, the body has a defense mechanism that still retains the separation of the brain from harmful chemicals in the blood. This makes drug delivery to the diseased brain, even more challenging and complex task. Here, the physiological changes to the diseased brain and aged brain are covered in the context of drug delivery to the brain using nanoparticles. Also, recent and novel approaches are discussed for the delivery of therapeutic agents to the diseased brain using nanoparticle based or magnetic resonance imaging guided systems. Furthermore, the complement activation, toxicity, and immunogenicity of brain targeting nanoparticles as well as novel in vitro BBB models are discussed.

Keywords: aging brain; blood-brain barrier model; complement activation; drug delivery to the brain; immunogenicity; nanoparticles; neurodegenerative diseases.

Figure 1

TEM image of healthy human neurovascular unit in the brain. Reproduced with permission.^{[ 30 ]} Copyright 2011, IntechOpen. (P: pericyte, BL: basal lamina, EC: endothelial cell, A: astrocyte, TJ: tight junction.

Figure 2

Schematic presentation of basal lamina (BL) in the neural vascular unit (NVU). This diagram presents a protein network within the BL, which affects the diffusion of NCs that cross the BBB toward brain parenchyma, with smaller NCs being more efficient in crossing the network compared to larger NCs, which may be trapped in the protein network.

Figure 3

A schematic diagram of arachnoid barrier at the meninges. This diagram shows that NPs may exit the fenestrated blood vessels in the dura mater. It also shows that CSF in the subarachnoid space (SAS) enters the brain parenchyma via the paravascular space and interstitial fluid ISF exits the brain parenchyma along the BL and mixes with CSF in the SAS. The arachnoid barrier separates the dura mater from the SAS, and the pia mater separates brain parenchyma from the SAS. Glia limitans and astrocytes form a barrier between the pia mater and the brain parenchyma. The subpia mater is mainly composed of collagen fibers.

Figure 4

A schematic diagram of choroid plexus in the brain. Choroid plexus is a highly vascularized tissue with fenestrated blood vessels which provides the opportunity for small NCs to exit the blood vessels and enter the tissue of the choroid plexus (stroma). The choroid plexus is located within each ventricle of the brain, and it is separated from the CSF in the ventricles by epithelial cells, which have numerous villi on the surface. As a consequence of aging, calcified bodies are formed within the stroma called psammoma bodies. Brain parenchyma is separated from the CSF by ependymal cells. Also, white blood cells (myeloid cells) exit the blood vessels in the choroid plexus and occupy the stroma.

Figure 5

Schematic diagram of the median eminence (ME), one of the circumventricular organs (CVOs). This diagram shows three types of ependymal cells: the ventral part (also called HPZ cells), the arcuate nucleus of the hypothalamus (ARH), and the border (the bottom part). This figure shows occludin and ZO‐1 at the ARH ependymal cells, all three TJ proteins (ZO‐1, occluding, and claudin1) at the ventral side, and claudin 1 at the border side. The ME contains rich fenestrated capillaries, which could allow dislocation of NCs from the blood vessels into the CVOs. The tanycytes with their TJ proteins prevent diffusion of NCs to the brain parenchyma. However, the drug molecules released from NCs may enter the CSF in the ventricle by the transporter/receptors at the HPZ cells.

Figure 6

Schematic presentation of the glia limitans interface between the CSF and the brain parenchyma and the circulation of the CSF in the brain. This diagram presents injection of NCs/NPs with two sizes into the CSF large and small. Large NCs/NPs will circulate within the brain as well as the small NCs/NPs but will not cross the glia limitans, while small NCs/NPs will cross the glia limitans and penetrate into the brain parenchyma. This figure also shows that NCs/NPs will start their journeys from the ventricle (site of injection) and via the CSF will flow into the SAS, and then into the brain through the perivascular space along the arteries. After transporting along the BL and along the walls of veins, the NCs/NPs will return into the SAS. Due to the size of NCs/NPs (both large and small sizes), they will not be able to leave the CSF via the arachnoid villus into the dural venous sinus, which joins the systemic circulation.

Figure 7

A schematic depiction of the glymphatic pathway. This diagram shows that CSF arrives in the brain through paravascular paths, by passing the glia limitans, washes the brain parenchyma, mixes with ISF, leaves the brain parenchyma through the opposite‐side glia limitans, and is cleared from the brain via paravenous paths. In this diagram, two different sizes of NPs are shown (small and large). Large NPs will stay within the arteriole paravascular path, while small NPs will cross the glia limitans and reach the brain parenchyma. The small NPs may leave the brain by following the convective flow of ISF. In addition, large NCs may release their cargo in the basement membrane due to degradation by enzymes such as MMP‐9. The cargo would be distributed within the brain by the convective flow of the ISF in the brain.

Figure 8

PET imaging of [¹⁸F]‐labeled PEG‐liposomes in the ischemic region of p‐MCAO rats. p‐MCAO rats were injected intravenously with [¹⁸F]‐labeled PEG‐liposomes at 1 h after the onset of occlusion. The distribution of [¹⁸F] Step 2 was determined for 2 h with the Clairvivo PET system. Each single image for every 10 min period was obtained by integration of the total photon numbers during this period. The arrow indicates the ischemic region, and the right hemisphere of these images shows the ischemic side. Reproduced with permission.^{[ 228 ]} Copyright 2014, International Center for Artificial Organs and Transplantation and Wiley Periodicals, LLC.

Figure 9

In vivo fluorescence imaging of brains collected from Balb/c mice after intravenous injection at a dose of 5 mg DOX‐equiv. kg⁻¹ body weight. a) DOX‐O‐MWNTs‐PEG‐ANG group is shown on the upper row, b) DOX‐O‐MWNTs‐PEG group is on the middle row, and c) DOX group is on the lower row. It can be seen that NCs without targeting ligands achieved a considerable accumulation in the brain. Reproduced with permission.^{[ 277 ]} Copyright 2012, Elsevier.

Figure 10

Outlines of three types of in vitro BBB models currently available.

Figure 11

Complement activation. Complement system is composed of three different pathways. The classical pathway (CP) is activated by immune complex formation on pathogen surface and by calreticulin expressed on apoptotic cells, leading to C1 complex association. The LP recognizes mannose‐terminating glycan on pathogens leading to MBL MASP complex activation. Both induce formation of the classical C3 convertases C4b2b. The AP is permanently activated at low level by spontaneous hydrolysis of C3 into C3 (H₂O). Lack of complement inhibitor on pathogens induces alternative C3 convertase activation C3bBb. Complement activation leads to opsonization and phagocytosis by C3b deposition, bacterial lysis by C5b–9 complex formation and inflammation by recruitment of immune cells, endothelial and epithelial cell activation, and platelet activation. Membrane cofactor protein (MCP), decay accelerating factor (DAF), complement receptor 1 (CR1), and C4 binding protein (C4BP) inhibit the complement activation by the classical pathway. DAF, MCP, CR1, and Factor H inhibit the complement activation by the AP.