Problems of targeted preparations

All preparations that can specifically direct therapeutic drugs to the site (target area) where they need to act, but have no or almost no interaction with non-target tissues are collectively called targeted preparations. The targeting of targeted preparations can be divided into three levels from the point of arrival. The first stage refers to reaching a specific target tissue or organ, the second stage refers to reaching a specific cell, and the third stage refers to reaching a specific part in the cell. According to the classification of methods, targeted preparations can be roughly divided into the following three categories: passive targeted preparations, that is, natural targeted preparations. Drug-loaded particles are ingested by macrophages in the monocyte-macrophage system (especially Kupffer cells in the liver) and transported to organs such as liver and spleen through normal physiological processes, but it is difficult to reach other targets. After intravenous injection, the distribution of passive targeting particles in the body first depends on the particle size. Usually, when the particle size is 2.5~ 10 micron, most of them accumulate in macrophages. When it is less than 7 microns, it is usually absorbed by macrophages in the liver and spleen. Nanoparticles of 200~400 nm are concentrated in the liver and quickly removed by the liver, while nanoparticles smaller than 10 nm are slowly accumulated in the bone marrow. Particles larger than 7 microns are usually intercepted by the smallest capillary bed of the lung by mechanical filtration and absorbed into lung tissue or alveoli by mononuclear leukocytes. In addition to particle size, particle surface properties also play an important role in distribution. The uptake of microparticles by monocyte-macrophage system is mainly accomplished by the adsorption of opsonin (including igg, c3b or fibronectin) and related receptors in blood on macrophages: the microparticles adsorbed with opsonin adhere to the surface of macrophages, and then are absorbed by macrophages through internal biochemical actions (endocytosis, fusion, etc.). ). The particle size and surface properties of particles determine which opsonin components are adsorbed and the degree of adsorption, and also determine the way and mechanism of phagocytosis. The drug-loaded particles of passive targeted preparations include liposomes, emulsions, microcapsules and microspheres, nanocapsules and nanospheres. ① Liposomes refer to tiny vesicles formed by wrapping drugs in lipid-like bilayers, that is, lipid microspheres or liquid crystal microcapsules. ② The targeting property of targeted emulsion lies in its affinity to lymph. O/W or O/W/O intravenous emulsion made of oily drugs or lipophilic drugs makes the original drug concentrate on tissues and organs rich in macrophages such as liver, spleen and kidney. ③ Microcapsules and microspheres refer to tiny spherical entities or vesicles formed when drugs are dissolved or dispersed in excipients. ④ Nanocapsules and nanospheres belong to the membrane shell type of drug storehouse, and nanospheres belong to the matrix skeleton type. The solution with the particle size of 10~ 1000nm forms capsules in water. It can penetrate the cell wall and hit the target, without blocking blood vessels, and can target liver, spleen and bone marrow. Active targeting preparation Active targeting preparation is to use modified drug carrier as a "missile" to deliver drugs to the target area to exert their efficacy. For example, after surface modification, drug-loaded particles are not recognized by macrophages, or because specific ligands are connected to the receptors of target cells, or because monoclonal antibodies are connected to become immune particles, which can avoid the uptake of macrophages, prevent them from being concentrated in the liver, change the natural distribution of particles in the body and reach specific targets; Drugs can also be modified into prodrugs, that is, pharmacologically inert substances that can be activated at active sites and at specific target areas. If particles want to reach the target site through active targeting without being intercepted by capillaries (4~7 microns in diameter), the particle size should generally not be greater than 4 microns. Physical and chemical targeted preparations (physical and chemical targeted preparations) The application of some physical and chemical methods can make targeted preparations exert their efficacy in specific parts. For example, a magnetic targeting preparation made of magnetic materials and drugs can reach and locate in a specific target area through blood vessels under the guidance of a sufficiently strong external magnetic field; Or a thermosensitive preparation is prepared by using a thermosensitive carrier, and the thermosensitive preparation is released in the target area under the local action of hyperthermia; Ph sensitive preparations can also be prepared by using ph sensitive carriers, so that drugs can be released in specific ph target areas. Blocking the blood supply and nutrition of the target area with embolic agents plays a dual role in embolization and targeted chemotherapy, and can also belong to physical and chemical targeting.