How to Achieve Brain Targeting in Nano Drug Delivery System
The blood-brain barrier (BBB) is a barrier system that exists between the blood system and the brain tissue, and is mainly composed of polarized intercellular tight junctions of polarized brain capillary endothelial cells (BCECs). It maintains a relatively stable internal environment for brain tissue, guarantees the normal physiological function of the central nervous system (CNS), and transports nutrients to the brain; but at the same time, its existence also hinders the drug of diagnosis and treatment into the brain. About 98% of small molecule drugs and almost 100% of macromolecular drugs, including proteins, peptides and gene drugs, cannot be directly delivered into the brain by peripheral administration, which is a hindrance to the diagnosis and treatment of brain diseases.
Blood-brain Barrier Breakthrough Technology
There have been many explorations in recent years on how to solve the problem of the blood-brain barrier. Among them, the most popular one is the use of nanoparticles to achieve brain targeting. Nanotechnology is primarily the study of functional materials or devices ranging in size from a few nanometers to hundreds of nanometers. Due to the special properties of nano-sized materials or devices in terms of specific surface area, surface energy, and surface atoms, they have nano-effects. Using nano-effects, nanotechnology can be applied to the study of drug delivery to the brain. The basic components of brain-targeted nano drug delivery systems include nanoscale drug delivery vehicles and appropriate brain targeting strategies. The research and development of a wide-ranging and in-depth nano drug delivery system includes nano-sized polymer materials and drug-constituting nanoparticles, liposomes composed of amphiphilic materials, and polymer-loaded micelles. The targeting strategy mainly includes cell penetrating peptide mediated, active targeting molecular mediated, adsorption mediated and magnetic targeting mediated brain targeting strategies.
Nanocarrier for Brain Targeted Drug Delivery System Application
The ideal drug carrier should have the following characteristics: 1 The carrier material is safe, non-toxic, can be degraded or eliminated by a certain mechanism, has no immunogenicity, and has high biocompatibility; 2 the carrier system should contain the drug in an appropriate manner and have a higher drug loading to achieve an effective concentration for diagnosis or treatment; 3 the surface of the carrier should have suitable reactive groups for further functional modification. At present, more researches on nanocarriers include nanoparticles, liposomes and polymer micelles.
Targeting Strategy for Brain-Targeted Drug Delivery Systems
Cell-Penetrating Peptide-Mediated Brain-Targeted Drug Delivery
Cell penetrating peptides (CPPs) are polypeptides that have the ability to cross cell membranes. They are polypeptide fragments of varying lengths, have positive charges, are rich in basic amino acid residues such as arginine and lysine, and their secondary structure generally has the conformation of the α-spiral. Different types of cell penetrating peptides have different cell-incorporation mechanisms. It is thought that the conformation of α-helix is used to “perforate” on the cell membrane. CPPs can enter cells from the pores on the surface of cell membrane. The mechanism does not rely on classical endocytosis, for example, the human immunodeficiency virus (HIV) reverse transcriptional activator Tat peptide, which efficiently mediates the entry of foreign substances into cells. Simon et al. used Tat peptide modification for drug delivery across the blood-brain barrier of ischemic injury. The results show that the Tat peptide-modified fusion protein GFP-Tat peptide can effectively cross the in vitro model of ischemic injury. In addition to the Tat peptide, studies have found that polypeptides with transmembrane action such as polyarginine and low molecular weight protamine can also be used in brain-targeted drug delivery systems.
Active Targeting Molecule-Mediated Brain-Targeted Drug Delivery
Active targeting molecules are primarily a class of molecules that specifically bind to receptors or transporters on the blood-brain barrier. Administration systems that employ active targeting molecular modifications can mimic the process by which receptors or transporters on the blood-brain barrier mediate the transport of the corresponding endogenous ligand or substrate across the blood-brain barrier. The sources of active targeting molecules are mainly divided into three categories: 1 Endogenous ligands or substrates of receptors or transporters, generally proteins or small molecules. The use of such targeting molecules requires attention to be endogenous ligand or substrate competitively binds to a specific site on the receptor or transporter, resulting in reduced efficiency of the release. 2 Receptors or transporter endogenous ligands or derivatives of substrates, generally polypeptides and small molecules, mainly to find receptor binding sequences of endogenous ligands, directly using the polypeptide formed by the binding sequence to the drug The recursive system is modified. 3 Find novel brain-targeted transporters through sequence alignment, phage screening, aptamer screening, and computer simulations. These molecules often differ from the structures of endogenous ligands and substrates. They mainly include: protein active targeting molecules such as transferrin (Tf), lactoferrin (Lf); peptide active targeting molecules such as RVG29 polypeptide, angiopep-2 polypeptide, phage display peptide; nucleic acid active target molecules and small molecule compounds to actively target molecules.
Adsorption-Mediated Delivery of Brain-Targeted Drugs
The basic principle of adsorption-mediated brain-targeted drug delivery strategy is that under physiological conditions, the positively charged carrier can be combined with the negative electricity on the surface of the brain capillary endothelial cell membrane by electrostatic interaction, and then the endocytosis and polar transport of the cell can be used to achieve cross-translocation of the blood-brain barrier.
Magnetic Targeting for Brain Targeted Drug Delivery
The brain-targeted drug delivery mediated by magnetic targeting is mainly to attract the magnetic material in the drug delivery system by using an external magnetic field, so that it crosses the BBB and enters the brain.
The study of brain-targeted drug delivery systems has important implications for the diagnosis and treatment of a variety of brain diseases including Parkinson’s disease, Alzheimer’s disease, glioma and HIV infection. Problems still existing in the study of brain-targeted drug delivery systems: Brain-targeted delivery is less efficient than other tissues; after intravenous administration, the nano drug delivery system is easily non-specifically taken up by the reticuloendothelial system including the liver and the spleen, and the tissue selectivity is poor; In addition, current brain-targeted drug delivery systems generally perform drug trans-blood-brain barrier transport, but the specific distribution in the brain is not clear. These issues require a more in-depth and thorough study of brain-targeted drug delivery systems.