Research Progress Of Self-Assembled Drug Delivery Systems I

The current research on self-assembled drug delivery system (SADDS) mainly uses nucleoside analogue antiviral drugs, antituberculosis drugs, and antitumor drugs as model drugs, which covalently combine with various long-chain lipid molecules to form amphiphilic prodrugs. Then it is dispersed into water by a certain method (mainly injection method) to form a highly dispersed aggregate. Aggregates are generally nanostructures, and their shapes can be vesicles, nanoparticles, nanotubes, etc. One of the advantages of nanoassemblies or nanostructures is that they can circulate in the blood relatively freely and can produce targeting effects. Sometimes certain polymers can be added to increase system stability. These self-assemblies have strong targeting of liver, lung, and spleen (which belong to the mononuclear macrophage system, MPS). After SADDS reaches the target site, it achieves a certain controlled release by controlling the rate of dissociation and degradation of the amphiphilic prodrug from the self-assembly to the original drug. Oral or subcutaneous injection also shows targeted distribution of tissues (such as the lymphatic system) and organs. After adding some hydrophilic polymers to the self-assembly system, the cycle time can be appropriately extended.

Acyclovir
The anti-herpes simplex virus nucleoside drug Acyclovir (ACV) and monostearoylglycerol are linked via succinyl to obtain the amphiphilic stearoylglycerol succinyl acyclovir (SGSA). The prodrug has special solubility and can be arbitrarily dissolved in chloroform. When dissolved in a large enough concentration, it will form a gel state. It is slightly soluble in methanol or ethanol, almost insoluble in cyclohexane, and insoluble in water. This property is different from traditional fat-soluble substances.
SGSA can form a stable monolayer on the air-water interface, but at the same time maintains a certain chain flexibility, which is conducive to self-assembly in water. The research was carried out on Langmuir trough. After SGSA is dissolved in tetrahydrofuran, it is slowly injected into water through a micro syringe to form a nano-assembly, which is in the shape of a short rod, which should be the result of the hydrophobic interaction of the fatty chain of SGSA. The average particle size of the nano-assembly is 83.2nm, and the Zeta potential is -31.3mV. Differential scanning calorimetry (DSC) found that the SGSA self-assembly has a gel-liquid crystal phase transition temperature of 50.38°C, which is also a proof of the layered structure, similar to the phospholipid bilayer of liposomes. After solvent evaporation and concentration, the self-assembled body can obtain a concentration of more than 10mg/mL SGSA, which is stable and convenient for animal administration.

The physical stability of SGSA self-assembly is good, it can be stable for more than 1 year at room temperature, and the stability will not be destroyed by high-speed centrifugation. This is related to its higher surface potential. However, the self-assembly is sensitive to cations, and the latter passes through the neutralization of surface charge of SGSA makes its structure unstable. The chemical stability of the SGSA self-assembly is a very important indicator, because SGSA is a prodrug first, and it needs to be dissociated into the original drug in the body to be effective. SGSA is effective on enzymes and plasma It is more sensitive, especially in mouse and rat plasma. It has been reported that the carboxylesterase activity of murine plasma is much higher than that of human plasma. After intravenous injection of SGSA self-assembly in rabbits, it showed typical characteristics of nanoparticles, that is, they are quickly cleared from the blood, with a distribution half-life of only 1.5 minutes and an elimination half-life of 47 minutes. Tissue distribution found that the prodrug SGSA is mainly distributed in the liver, lung and spleen, and the latter belongs to the mononuclear macrophage system (MPS). The in vitro antiviral experiment of the prodrug SGSA proved that it has a certain pharmacological effect, and its cytotoxicity is stronger than that of the original drug acv. The reason may be that the amphiphilic SGSA molecule easily fuses with the cell membrane.

Didanosine
Didanosine (ddI) is a typical anti-HIV nucleoside drug. The main adverse reactions are pancreatitis and peripheral neuropathy. The researchers synthesized cholesteryl succinyl desoxyinosine (CSD) and cholesteryl adipyl desoxyinosine (CAD), which have the same solubility and amphiphilic properties, and are highly soluble in chloroform and tetrahydrofuran. Slightly soluble in alcohol solvents, but insoluble in water, solubility is directly related to molecular structure. The intermolecular hydrogen bonds of CSD and CAD and the possible solvent-solute intermolecular hydrogen bonds determine their solubility. The vesicle-like nanostructures formed by self-assembly of water molecules are obtained by the injection method. It is very interesting that the nanostructures obtained after CSD injection are related to the concentration of the prodrug, the ratio of organic solvents in the water, and the post-processing method. At the beginning of the injection, the concentration of CSD and solvent (tetrahydrofuran) in the water are very low, and the CSD forms a vesicle. As the injection progresses, the concentration of tetrahydrofuran increases and is inserted into the CSD bilayer to form soft and long nanobelts. After the solvent is volatilized, the nanoribbons harden and break into short nanotubes.

There are several key problems in the research and development of SADDS: 1, The selection of appropriate original drug and the design of amphiphilic prodrugs with good self-assembly ability; 2, The synthesis of amphipathic prodrugs; 3, The amphipathic prodrugs in aqueous solution Self-assembly; 4, The self-assembly has good physical stability; 5, The prodrug can be degraded properly at the target site. The most important thing here is the prodrug molecular design, because the molecular structure determines all the properties and behaviors in vivo and in vitro.