Applications of PEG-DSPE: Drug Carriers and Drug Delivery

PEG end modifications and the use of PEG lipids (such as DSPE-PEG) have had a significant impact on drug delivery systems using nanocarriers. PEG terminal modification has significant effects on extending blood circulation time, improving stability, improving bioavailability and drug efficacy, and is being explored for the development of drug delivery systems with improved pharmacokinetic properties and biodistribution. Different DSPE-PEG modified nanocarriers show different Zeta potentials and encapsulation efficiencies, but almost all Zeta potentials are negative and nearly neutral, and the encapsulation rates can be very high. According to the available literature, DSPE-PEG 2000 is the best component in the delivery system. Because as mentioned above, 2000mW polyethylene glycol ester has suitable hydrophilicity and suitable spatial structure. DSPE-PEG is also used in the field of regenerative medicine to create implants and biomedical devices with the ability to control drug release or change the surface properties of polymer materials.

PEG-DSPE for Drug Carriers

Amphiphilic PEG-DSPE block copolymers contain a hydrophilic PEG segment and a hydrophobic DSPE segment, which can self-assemble into various micelle structures. In addition, PEG-DSPE block copolymer has been used to prepare PEG end-modified liposomes, which are biocompatible and inert and have a long half-life in vivo.

Liposomes

Traditional liposomes have low bioavailability, short blood circulation time, and are easily absorbed by RES. To overcome these difficulties, strategies have been developed by coating the surface of liposomes with hydrophilic polymers or glycolipids, such as PEG or monosialoganglioside (GMI). PEG has high flexibility, good hydrophilicity, anti-phagocytosis to macrophages, resistance to immune recognition, non-binding to proteins, and good biocompatibility, which makes PEG-modified liposomes widely used in drug delivery.

Fig. 1. Bionanointeraction between PEG-modified liposomes and human plasma (Nanoscale. 2014, 6(5): 2782-2792).

PEG-terminated liposomes have attracted widespread attention as passive targeted drug delivery carriers for the treatment of cancer and infectious diseases. They are superior to other carriers in increasing the systemic circulation time of drugs, delivering active molecules to the site of action, and protecting healthy tissue from damage by toxic effects. During the preparation process, a key step in developing long-circulating liposomes is the addition of synthetic polymer PEG, such as PEG-DSPE, to the liposome composition. Adding PEG-DSPE to lipid carriers can significantly extend the circulation life of liposomes. Dos Santos et al. demonstrated that only 0.5 mol% PEG2000-DSPE can significantly increase the plasma circulation life of 1,2-distearoyl-sn-glycero-3-phosphatidylcholine (DSPC) liposomes. 2 mol% PEG2000-DSPE can completely prevent liposome aggregation. This suggests that PEG2000-DSPE reduces the in vivo clearance of cholesterol-free liposome formulations and the adsorption of plasma proteins mainly by inhibiting surface interactions, especially through liposome-liposome aggregation.

Polymer Nanoparticles

Polymer nanoparticles (NPs) can be obtained through the self-assembly of biodegradable amphiphilic copolymers, with a structure of hydrophobic core and hydrophilic shell. The core-shell structure of polymeric nanoparticles has advantages in entraining poorly soluble drugs, extending circulation half-life, sustained drug release, and functional surfaces with targeting ligands for differential drug delivery. The most common and widely used amphiphilic copolymers include PEG-polylactic-glycolic acid (PEG-PLGA), PEG-polylactic acid (PEG-PLA), polycaprolactone (PEG-PCL) and PEG-DSPE. The amphiphilic polymer of PEG-DSPE can self-assemble into micelles and can be easily modified.

Gill et al. prepared PEG5000-DSPE micelles containing paclitaxel through a solvent evaporation method and examined their drug release behavior in vitro and in vivo. In addition, the toxicological properties of PEG5000-DSPE were also studied, and it was found that PEG lipid micelles have a sustained-release effect in simulated lung fluid. By intravenous injection AUC0-12, the amount of paclitaxel accumulated in the lungs is 45 times that of intravenous administration and 3 times that of intratracheal administration. At the same time, paclitaxel concentrations in other non-target tissues and plasma were significantly reduced compared with other groups. Additionally, toxicity studies showed no significant increase in lung injury marker levels in the PEG5000-DSPE treatment group compared with the saline group.

Microemulsion

Microemulsions containing lipophilic agents without an aqueous phase may be a more suitable vehicle for lipophilic drug delivery. Microemulsions prepared with PEG-DSPE have many advantages in delivering drugs to tumors, such as enhanced drug loading of hydrophobic drugs, prolonged blood circulation time, and improved bioavailability.

Shiokawa et al. constructed FA-linked microemulsions using FA-PEG-DSPE for the delivery of lipophilic antitumor antibiotics and aclarithromycin A. The results showed that the binding force of FA-PEG5000-linked microemulsion to KB cells was 200 times that of non-FA microemulsion, and its cytotoxicity was 90 times that of non-FA microemulsion. In addition, the accumulation amount of FA-PEG-linked microemulsions in solid tumors 24 hours after intravenous injection was 2.6 times that of the control group.

Lipid-polymer Hybrid Nanoparticles

Polymer hybrid nanoparticles consist of a hydrophobic polymer core such as PLGA that carries hydrophobic drugs released at a sustained rate, a lipid monolayer, and an outer corona layer typically composed of lecithin and PEG-DSPE. Lipid-polymer hybrid nanoparticles have emerged as a promising drug delivery platform due to their biocompatibility, biodegradability, sustained release, functional surface, good blood stability, and high drug loading capacity. In addition, nanohybrid materials are used as cancer therapeutics in chemotherapy and radiotherapy, mainly due to the controllable process parameters of nanohybrid materials in forming particles with specific sizes, shapes and other basic properties.

Fig. 2. Formulation of lipid-polymer hybrid nanoparticles (Acs Nano. 2008, 2(8): 1696-702).

Hu et al. prepared paclitaxel-loaded anti-carcinoembryonic antigen (antiCEA) lipid-polymer hybrid nanoparticles for targeted drug delivery to pancreatic cancer cells. The hydrophobic drug paclitaxel was encapsulated in a lipid polymer nanomaterial composed of PLGA as a hydrophobic polymer core. This polymer-drug composition is encapsulated in the lipid layer of lecithin and then covalently coupled with DSPE-PEG as a hydrophilic polymer. The results show that the prepared nanoparticles have a small particle size (95nm), a small negative Zeta potential (-55 mV), and a good spherical structure. They also verified the targeting nature of the synthesized anti-CEA nanoparticles and their enhanced cytotoxicity to target cells compared with non-targeted nanoparticles.

Solid Lipid Nanoparticles

In the 1990s, solid lipid nanoparticles (SLNs), including emulsions, liposomes, and polymers, were developed as an alternative carrier system. Solid lipid nanoparticles have attracted increasing attention due to their improved micelle stability and adaptability to industrial production. As a particle system, solid lipid nanoparticles refer to natural or synthetic solid lipids, such as lecithin, PEG-DSPE and its derivatives, triglycerides and other carrier materials with an average particle size between 50-1000 nm. The solid core contains a hydrophobic drug dissolved or dispersed in a high-melting solid lipid matrix.

PEG-DSPE in Drug Delivery

Delivery of Nucleic Acids

With the development of biotechnology, many biotech drugs have been discovered, some of which have been successfully used clinically. Many chronic diseases, such as cancer and cardiovascular dysfunction, can be effectively prevented and treated using biotech drugs. Nucleic acids, RNA, and DNA show great potential in treating cancer, but their delivery to target sites can be inefficient. Therefore, a drug delivery system is needed to improve the therapeutic effect of unstable macromolecule drugs. Currently used nanocarriers, such as liposomes, polymeric nanoparticles, nanoemulsions, and solid lipid nanoparticles, have been shown to be useful in delivering nucleic acids. Therefore, PEG-DSPE has been widely used to prepare nanocarriers as drug carrier materials to deliver nucleic acids. For example. Stuart et al. developed a small, stable, long-circulating liposome carrier for antisense oligonucleotides (AsODN). Anti-CD19 ligand is conjugated to butyric acid-PEG-DSPE in a liposome carrier. The results showed that most antisense oligonucleotides were cleared from the blood with a half-life of more than 10 hours, while the half-life of free antisense oligonucleotides was less than 1 hour.

Fig. 3. PEG-lipid for drug delivery (Advanced Materials Interfaces. 2019, 1801807).

Delivery of Proteins and Peptides

Recently, protein and peptide drugs are being developed to cover many therapeutic areas, including oncology, metabolic diseases, and cardiovascular diseases. Their status stems mainly from the well-known advantages of peptides as drugs, such as specificity, efficacy, and low toxicity. However, the development of bioactive proteins and peptides as therapeutic agents is severely limited in most cases because of their lack of oral bioavailability, poor stability, no specific targets, and rapid clearance from the blood. Therefore, choosing PEG-DSPE to prepare long-circulating liposomes can extend the duration of proteins and peptides. Lim et al. constructed sterically stable phospholipid nanomicelles carrying vasoactive intestinal peptide (VIP), glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP) during the freeze-drying process. Peptide drugs are successfully lyophilized, potentially increasing the shelf life of these products as degradation of the drug and lipids in the dry state may be reduced.

Delivery of Hydrophobic Drugs

Many important active substances, such as docetaxel and camptothecin, have very low solubility. In pharmacology, hydrophobicity has a conductive effect on the relationship between drugs and tissues, so the formulation, solubilization and stabilization of these drugs are issues that need to be addressed. In aqueous media, amphiphilic PEG-DSPE block copolymers can self-assemble into polymer micelles with a core-shell structure. The poorly soluble drugs are then combined with the core of the DSPE, which will increase the concentration of the hydrophobic drug, improve bioavailability, and protect the drug from inactivation in biological media.

Although DSPE-PEG has been extensively studied for its applications in drug delivery and imaging, some uncertainties remain regarding its interaction with target cells in vivo. A more detailed evaluation of its effect on cellular uptake and interaction with protein molecules is required to optimize the use of this material in nanocarrier modification. Nonetheless, the overall application potential of DSPE-PEG in nanotherapeutics and imaging cannot be overstated. Unless better materials are developed in the near future, DSPE-PEG will continue to be an important component of many formulations that will be approved for clinical studies. Therefore, BOC Sciences not only provides lipid nanoparticles development services, but also provides PEG solutions for lipid nanoparticles.

References

1. Pozzi, D. et al. Effect of polyethyleneglycol (PEG) chain length on the bio-nano-interactions between PEGylated lipid nanoparticles and biological fluids: from nanostructure to uptake in cancer cells. Nanoscale. 2014, 6(5): 2782-2792.
2. Zhang, L.F. et al. Self-assembled lipid--polymer hybrid nanoparticles: a robust drug delivery platform. Acs Nano. 2008, 2(8): 1696-702.
3. Eliasen, R. et al. PEG-lipid post insertion into drug delivery liposomes quantified at the single liposome level. Advanced Materials Interfaces. 2019, 1801807.