How The Nano-Drug Delivery System Performs Brain Targeting
Brain diseases such as brain tumors, Alzheimer’s disease, Parkinson’s disease, central nervous system infections, chronic pain, drug addiction, periodic migraine, neurodegenerative diseases, epilepsy, and schizophrenia are the threat of human body and mind of improtant diseases of health. However, during the treatment process, the blood-brain barrier (BBB) prevents most drugs from entering the brain, resulting in poor drug effects. Brain targeted delivery of drugs to the brain is to use various techniques to promote the drug to break through the BBB into the brain. The current brain targeted delivery methods mainly include changing the physicochemical properties of the drug, preparing prodrugs, and carriers. Among them, nanocarriers have attracted much attention because they can penetrate the biofilm barrier, surface modification can reduce the phagocytosis of mononuclear macrophage systems, enhance BBB penetration, and increase the concentration of drugs in the brain.
Nanocarrier Brain Targeting Mechanism
The mechanism of nanocarriers penetrating BBB may include: 1). Nanoparticles can directly pass through the cerebral vascular endothelium by virtue of their small volume; 2). Nanoparticles can be adsorbed on the brain microvascular wall, prolong the microvascular retention of drugs, increase the maintenance time of drug concentration gradients inside and outside the vascular wall, Helps to drug the human brain; 3). brain microvascular endothelial cells swallow part of the nanoparticles, and then exocytosis on the contralateral side to make the drug enter the brain; 4). nanoparticles open tight junctions in BBB, and promote the entry of nanoparticles into the brain; 5). Improving the fluidity of lipid membrane of vascular endothelial cells and increasing the permeability of BBB to drugs; 6). Some modified nanoparticles such as polysorbate 80 can inhibit the drug efflux effect of P-gp and prolong the local maintenance concentration of drugs. These mechanisms may work alone or in combination. BBB has a special receptor-mediated transport system that can bind to specific ligands to achieve endogenous polar and macromolecular transport. These ligands are used to modify the nanocarrier, and through the recognition of the ligand, they are localized in the brain to achieve targeted delivery. Specific receptors on brain capillary endothelial cells include transferrin receptor, insulin receptor, insulin-like growth factor receptor, and angiotensin I receptor. Common modification ligands are: transferrin and its receptor antibodies, insulin receptor monoclonal antibodies, thiamine, TAT peptide, folic acid, low density lipoprotein receptor ligands, and the like.
- Transferrin Receptor Antibody Modification
Transferrin (Tf) is a single-chain glycoprotein synthesized by the liver. It contains 4 negatively-charged sialic acid genes with a biological half-life of 8d. Tf is the main iron-containing protein in plasma. It is directly involved in iron metabolism in the body, and undertakes the transfer between the absorption, storage and utilization of iron. According to previous research find that Tf can combine with trivalent iron to form a stable Fe-Tf complex, and then transport the iron to the tissue cells that require iron for normal growth and development with blood circulation. The transferrin receptor is widely expressed in humans, among which the expression of primitive red blood cells is the highest; it is also abundantly expressed in brain cells and brain capillary endothelial cells. Therefore, it can be used as a channel for nanocarrier drugs to enter the brain. However, due to the high content of endogenous Tf in the blood, the binding to TfR is nearly saturated; in addition, the transmembrane Tf will recirculate back to the surface of the brain microvascular wall, so transferrin itself is not suitable for drug transport Carrier. Antibodies against TfR, on the one hand, can bind to TfR to trigger cell endocytosis, on the other hand, they do not compete with Tf for TfR binding sites and thus do not affect normal iron metabolism and absorption. Therefore, it is more suitable for mediating targeted drug delivery. Using this antibody-modified nanocarrier can carry drug to the brain across the BBB.
- Insulin Receptor Antibody Modification
There are more insulin receptors on human brain microvascular endothelial cells. So insulin can bind to brain microvessels and transport them through the BBB. The problems of insulin as a brain-targeted transporter are: 1). the blood half-life of insulin is very short, only 10 minutes, which is difficult to meet its requirements as a mediated targeting; 2). insulin can affect the normal sugar, fat and protein metabolism in the body. Similar to TfR, insulin receptor antibodies can be prepared to mediate brain targeted drug delivery, such as 83-14 insulin receptor murine monoclonal antibodies.
- RGD Modification
The arginine-glycine-aspartate (RGD) tripeptide specifically binds to integrin receptors that are highly expressed on the surface of monocytes and neutrophils. Brain inflammation will promote leukocytes to reach the site of inflammation. Therefore, lymphocyte targeting carriers can also achieve brain targeting to a certain degree. RGD peptides are linked to the surface of liposomes to make RGD-modified liposomes, which can bind to integrin receptors on the surface of leukocytes, which in turn allows the liposomes to cross the BBB.