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Research and application of DSPE-PEG derivative properties

Drug delivery system is one of the important research contents in pharmacy. Common drug carriers include liposomes, viruses, lipid microspheres, multimeric complexes and protein polypeptides. Controlled-release and targeted liposome formulations are the current research hotspots for drug delivery systems. Liposomes have the advantages of low toxicity, easy preparation, can be used as a carrier for both water-soluble drugs and lipid-soluble drugs, suitable for various administration routes, improve the stability of drugs, and achieve targeted drug delivery. However, after the liposome enters the body, due to the specific opsonization of the liposome by the opsonins in the plasma and the non-specific hydrophobic interaction between the reticuloendothelial system (RES) cells and the liposome, the liposome is easily absorbed by the RES cells. Uptake, clearance, short half-life in blood circulation (usually 30min), poor active targeting and poor stability, its application is limited. Long circulation liposome (LCL) can be obtained by modifying the surface of liposomes with polyethylene glycol (PEG), which can prolong the half-life of liposomes, improve its stability in blood circulation, and change lipids. Biological distribution of plastids with targeting

PEG is a linear polymer material polymerized by ethylene glycol monomer, and its molecular composition is HO-CH2-CH2(OCH2CH2O)n-CH2-CH2-OH. The mechanism by which PEG prolongs the blood circulation half-life of liposomes is as follows. A large number of ethoxy groups in PEG molecules can form hydrogen bonds with water, making PEG water-soluble and highly flexible, forming a layer of hydration film on the surface of liposomes; PEG overlaps and overlaps on the surface of liposomes, forming dense The mushroom-shaped, brush-shaped or pancake-shaped conformation cloud constitutes steric hindrance, hinders the adsorption of certain proteins and cell adhesion, and masks the hydrophobic binding sites on the surface of liposomes, reducing the interaction between plasma proteins and liposomes. The intervening van der Waals force prevents plasma components from approaching liposomes, thereby effectively avoiding the recognition and phagocytosis of RES, and prolonging the half-life of liposomes in the blood circulation significantly [3]. Compared with liposomes without PEG, DSPE-PEG-liposomes have high stability in plasma in vitro, slow adsorption to plasma components, and prolonged blood circulation clearance time by 30% in vivo[4,5], so PEG-modified liposomes have high stability in plasma. This liposome is characterized by long circulation, stealth and steric stability.

In the PEG-liposome complex, the uptake of RES to liposomes cannot be effectively reduced due to the weak connection between simple PEG or PEG-stearic acid and liposomes. The ability of PEG-dipalmitoyl phosphatidylglyceride and PEG-* to prolong liposome T1/2 was stronger than that of simple PEG or PEG-stearic acid, but lower than that of DSPE-PEG. PEG and DSPE are connected by carbamate bonds, there are two saturated fatty acyl chains, the lipophilic end is DSPE, the hydrophilic end is PEG, the connection with the liposome is firm, and the ability to protect the liposome from being destroyed is the strongest . Therefore, the basic method of making LCL is to add DSPE-PEG to the phospholipid bilayer of liposome.

There are two ways to connect PEG to liposomes: one is to couple on the surface of the prepared liposome by covalent bond; the other is to adsorb or bind to the liposome by the hydrophobic interaction of hydrophobic substituents. s surface. The hydrophobic chain moieties of the bound or adsorbed polymers in both methods are exposed in solution to protect the liposomes from interacting with plasma proteins in the blood.

The steric protective effect of PEG on liposomes depends on the molecular weight, chain length, flexibility, hydrophilicity, phospholipid composition, different additives and particle size of the LCLs formed. The best formula for preparing LCL is: low concentration of short-chain or medium-long chain PEG, no unsaturated bond, phosphatidyl* with 16 or less carbon atoms, and the concentration of * is greater than 30%. In general, the longer the PEG chain (molecular mass up to 5000), the longer the circulation time of liposomes; but for colloidal liposomes, PEG with molecular mass between 1000 and 2000 has a long circulation effect [6]. When the concentration of DSPE-PEG was 5～7mol/L, the blood circulation time was the longest. After intravenous injection of LCL prepared with PEG-750-DSPE, PEG-2000-DSPE or PEG-5000-DSPE as film-forming materials, the plasma T1/2 were 0.7, 1.7 and 6.2 h, respectively, while the plasma half-life of liposomes (T1 /2) is 0.5h. Therefore, with the increase of PEG molecular weight, LCL plasma T1/2 prolonged. The long-circulation effect of PEG-LCL with a particle size of 160-220 nm is the most obvious.