PEG for Drug Delivery

The ability of Polyethylene glycol (PEG) to influence the pharmacokinetic properties of drugs and drug carriers is currently utilized in a wide variety of established and emerging applications. The change in the pharmacokinetics of administered drugs by being shielded by or bound to PEG results in prolonged blood circulation times. This consequently increases the probability that the drug reaches its site of action before being recognized as foreign and cleared from the body. Therefore, the majority of small molecule drugs, proteins and peptides, as well as liposomal and micellar nanocarriers on the market or in advanced clinical trials are PEGylated products, i.e. PEGylation.

Fig. 1 Overview of PEGylated-carrier systems for drug delivery.

Advantages of PEG

Limitations

The increasing use of PEG and PEGylated products in pharmaceutical research as well as clinical applications not only provides new insight into the underlying mechanism of the beneficial properties of PEG, it also increases the likelihood of encountering potential side reactions.

• Hypersensitivity

Research has shown that adverse reactions of PEG often occur through complement (C) activation, which leads to hypersensitivity reactions (HSR) that can provoke an anaphylactic shock. Although the exact trigger for this phenomenon has not yet been clarified, an immediate HSR in 5–10% of treated patients was shown for different PEG-containing liposomal carriers.

• Changes in Pharmacokinetic Behavior

Researchers have reported that the presence of PEG can also cause another potential immune reaction---Accelerated blood clearance (ABC) phenomenon, a preceding injection of PEGylated liposomes can alter the circulation time of repeatedly injected PEG liposomes. The ABC phenomenon not only affects the bioavailability of the drugs, but passive targeting is also decreased.

• Toxicity of Side-products

The most prominent side product formed during the synthesis of PEG is the cyclic dimer of ethylene oxide, 1,4-dioxane. Currently, 1,4-dioxane is stripped off from the product under reduced pressure. Furthermore, PEG can also contain residual ethylene oxide and/or formaldehyde from polymerization, which are carcinogenic to humans. Thus, it is necessary to use pharmaceutical grade PEG for biomedical applications.

• Degradation Under Stress

Up to now, PEG has been observed to undergo heat-triggered degradation in the solid state and solution from 100 kDa to 10 kDa, or UV degradation in the range of 55 ~ 390 kDa. Moreover, the heating of PEG probes of various molar masses (1–4000 kDa) under a non-oxidative atmosphere at 50℃ also showed slight chain scissions. Although none of these studies involved pharmaceutical grade PEGs and the conditions were harsher than those occurring in vivo, degradability has to be taken into consideration, in particular during storage of the PEG polymer as well as the drug formulation.

• Non-biodegradability

Although PEG with a molecular weight below 20 kDa is easily secreted into urine, the PEG itself cannot be biodegradable. In addition, higher molecular weight PEG will be eliminated rather slowly, and clearance through the liver becomes predominant. Therefore, using PEGs with low molecular weight would be preferable. Multi-arm and branched biodegradable PEGs were also investigated that form low-molecular-weight PEGs which can be excreted more easily after cleavage in the body.

Potential Alternatives to PEG

References

1. Knop, K.; Hoogenboom, R.; et al. Poly (ethylene glycol) in drug delivery: pros and cons as well as potential alternatives. Angewandte chemie international edition 2010, 49 (36), 6288-6308.
2. Kolate, A.; Baradia, D.; et al. PEG - a versatile conjugating ligand for drugs and drug delivery systems. Journal of controlled release : official journal of the Controlled Release Society 2014, 192, 67-81.