Polyethylene glycol (PEG) is a polymer composed of repeating ethylene glycol units. It is known for its excellent biocompatibility, allowing it to dissolve in body fluids and be rapidly eliminated without causing side effects. When PEG is conjugated to other molecules—a process known as PEGylation—it imparts these beneficial properties to the resulting compound. This technique has become a cornerstone in drug modification and delivery, enhancing the solubility, stability, and pharmacokinetic profiles of therapeutic agents. Notably, PEGylation has received approval from regulatory agencies like the FDA, underscoring its recognized safety and efficacy in medical applications.

Figure 1. Structure of PEG

PEGylation enables the creation of active substances or drug delivery systems with prolonged circulation times in the body. This concept was first introduced by Davis and Abuchowski in 1970, when they used melamine as a coupling agent to covalently attach methoxy PEG to bovine serum albumin (BSA). The PEGylated BSA demonstrated enhanced water solubility and avoided immune clearance by not reacting with antibodies targeting natural BSA. Furthermore, the PEGylated protein exhibited notable changes in properties such as solubility, electrophoretic mobility, ion-exchange chromatography behavior, and sedimentation compared to its unmodified counterpart.

Over the years, PEGylation technology has evolved significantly and is now widely applied in pharmaceuticals. PEGylated active compounds or drug delivery systems offer several key benefits:

A. Enhanced Pharmacokinetic and Pharmacodynamic Properties: Research indicates that PEGylation leads to significant improvements in a drug's pharmacokinetics, including prolonged plasma half-life, enhanced bioavailability, and reduced renal clearance.

B. Increased Stability: PEGylation of proteins and peptides creates a protective hydration layer on their surface, preventing aggregation and precipitation. The attachment of PEG to lipid derivatives (via acyl, ether, or disulfide bonds) also enhances liposome stability. Moreover, the flexible PEG chains generate steric hindrance, shielding the modified molecules from proteolytic enzymes, thereby improving their overall stability.

C. Optimized Drug Distribution: By increasing the molecular weight of drugs, PEGylation reduces renal filtration and urinary excretion during systemic administration. PEGylated drugs exhibit greater stability and prolonged circulation in the bloodstream, promoting improved distribution. This is particularly advantageous for large-molecule drugs, which can accumulate more effectively at tumor or inflammation sites, enhancing therapeutic efficacy through the enhanced permeability and retention (EPR) effect.

Despite the significant potential of PEG in various drug delivery systems, it faces several challenges. PEG, being a mixture of molecules with varying molecular weights, can lead to inconsistencies in the molecular weight distribution of modified drugs. This variability affects drug uniformity and stability, complicating chemical characterization, purity control, bioactivity, safety, and pharmacokinetics. These factors introduce complexities in the drug development and purification processes, ultimately impacting the drug's efficacy and safety.

As the pharmaceutical industry advances, there is an increasing demand for higher quality standards. Polydisperse PEG, with its heterogeneous molecular makeup, is no longer sufficient to meet modern requirements for high-quality drugs. Monodisperse PEG, which consists of uniform molecules with precise, discrete molecular weights and well-defined configurations, offers a solution to these issues. Monodisperse PEG allows for accurate molecular weight determination, easier purification and characterization, and excellent batch-to-batch reproducibility—key features in pharmaceutical manufacturing. The use of monodisperse PEG is particularly critical in areas such as gene therapy and antibody-drug conjugate (ADC) linkers, where precision and reproducibility are essential.

Example of Drugs with Monodispersed PEGs

In 2014, AstraZeneca's Movantik received FDA approval, becoming the world's first PEGylated small molecule drug. Movantik employs a uniform monodisperse PEG7 conjugated to a μ-opioid antagonist, effectively preventing it from crossing the blood-brain barrier. This mechanism allows it to treat opioid-induced constipation (OIC) without impacting the central nervous system.

Figure 2. Structure of Movantik

IMMU-132 (Trodelvy) is a Trop-2 targeted antibody-drug conjugate (ADC) that combines sacituzumab and SN-38 via a cleavable CL2A linker. Approved by the FDA in 2020, it is indicated for the treatment of triple-negative breast cancer (TNBC) and metastatic urothelial cancer. The CL2A linker includes a short polyethylene glycol (PEG) residue that enhances solubility and is attached to SN-38 at the 20th position of the lactone ring. This configuration stabilizes the compound and prevents its conversion to the less active carboxylate form.

Figure 3. Structure of Trodelvy

Loncastuximab tesirine (Zynlonta), an ADC developed by ADC Therapeutics, was approved in 2021 for the treatment of large B-cell lymphoma. It uses a maleimide-PEG8 linker to conjugate the antibody with the dimeric cytotoxin pyrrolobenzodiazepine (PBD).

Figure 4. Structure of Zynlonta

ZILBRYSQ® (zilucoplan), approved bty FDA in 2023 for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) antibody-positive, is composed of a 15-amino acid macrocyclic peptide, including four unnatural amino acids, designed to inhibit TCC activation.The incorporation of a C16 lipid through a short monodisperse polyethylene glycol (PEG24) linker provides a pharmacokinetic profile suitable for daily dosing in humans.

Figure 5. Structure of Zilucoplan

Huateng Pharma's monodisperse PEG products are synthesized from high-purity building blocks through stepwise reactions to achieve specific molecular weights and functional groups suited for a wide variety of applications. The PEG products feature methoxy, alcohol, and carboxylic acid end-capping, with protective groups like Fmoc and Boc, and functional groups for conjugating to various molecules such as amines, thiols, and carboxylic acids, etc.

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