PEGylation of Small Molecule Drugs

Small molecule drugs, especially anti-tumor drugs, generally have defects such as poor water solubility, short half-life, poor targeting of biological tissue distribution and high toxicity, which greatly limit their clinical applications. PEGylated small molecule drugs can significantly improve the water solubility of drug molecules and in vivo pharmacokinetic parameters, as well as reduce their toxic and side effects, which makes many small molecule drugs with significant curative effects but limited in clinical applications have new development prospects.

What Kind of PEG?

The most commonly used conjugating agent is linear monomethoxy polyethylene glycol (mPEG), which couples with one end of the activated small molecule drugs. This method has few side effects, and the reaction conditions are easy to accomplish. Through this kind of simple coupling reaction, the physical and chemical properties of the drugs can be changed, the solubility can be improved.

However, linear PEG has shortcomings that cannot be ignored, that are, limited conjugation sites and low drug loading. These drawbacks can be overcome by using various chemical modifications to obtain branched PEG, forked PEG and multi-armed PEG.

  • Branched PEG has an "umbrella-like" structure, which allows it to have more conjugation sites and larger molecular volume, giving better protection that linear PEG against proteolytic enzymes, antibodies, etc. .
  • Forked PEG provides multi-proximal reactive groups at the end of one or both ends of a linear PEG chain, which enhance the drug loading of the PEG by increasing active sites.
  • With the advancement of technology, a multi-armed PEG with a star-like structure carrying multi-hydroxyl groups has been developed, which largely ,increase the active sites for drug conjugation.

PEGylation Type

Based on the bonding type between PEG and small molecule drugs, PEGylation can be classified as "permanent" or "releasable" PEGylation. 

Fig. 1 PEGylated drug systems. A) PEG–drug conjugate system; B) Double prodrug conjugate system. (Journal of controlled release 2014, 192, 67-81)

  • "Permanent bonding" means that the PEG and the drugs are permanently bonded through a chemical bond to form a new stable compound, which the drugs can exert its efficacy without breaking the bonding. Permanent PEG links can improve the oral availability of the drugs and reduce the penetration of the blood-brain barriers. Permanent PEGylation requires low molecular weight (Mw) PEGs (Mw < 1000 Da) because macro-molecular PEGs may block activity of small active agents at the target cells via steric hindrance.
  • On the other hand, the "releasable bonding" is a form of composition of prodrugs, which means that PEGs bind to drug molecules unstably. In order to exert the drug effect, it needs to be hydrolyzed and released in the presence of a certain pH value or certain specific enzymes. Only after the original free drug can it exert its effect. Releasable PEGylation requires large Mw PEGs (1000 Da < Mw < 60,000 Da) to increase the solubility of the drugs, prolong the circulating half-life and improve the biodistribution of the drugs. At present, releasable PEGylation is the most used method of PEGylation of small molecule drugs in the research.

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  1. 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.
  2. Pasut, G.; Veronese, F. M., State of the art in PEGylation: the great versatility achieved after forty years of research. Journal of Controlled Release 2012, 161 (2), 461-472.

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