Cosmetics, Medicines, Shower Gels: Why the Omnipresence of Polyethylene Glycol Raises Questions and What Are the POx That Could Replace It?

Polyethylene glycols (PEGs) are ubiquitous in modern life, found in an astonishing array of everyday products. From the soothing feel of shower gels and shampoos to the efficacy of lubricants, sanitizers, vaccines, and medications, and even in moisturizing creams and paints, PEGs have become indispensable. Their widespread adoption is largely attributed to their remarkable ability to enhance the solubility of various active substances. Coupled with their cost-effectiveness and straightforward production processes, PEGs have cemented their place across numerous industrial sectors, including pharmaceuticals, chemistry, detergents, paints, and inks.

For a considerable period, PEGs were considered inert substances, posing no significant risks. However, a growing body of research and evolving scientific understanding have brought these versatile polymers under scrutiny. Concerns are mounting regarding their petrochemical origins, their limited biodegradability, and lingering questions about their long-term effects on human health and the environment. This evolving perspective has spurred an intensified search for alternative solutions. Among the promising polymer families being explored, poly(2-oxazolines) (POx) are increasingly capturing scientific attention. Their unique properties position them as strong contenders to eventually replace PEGs in many applications.

Understanding Polyethylene Glycol (PEG)

Derived from petrochemical feedstocks, PEGs constitute a broad category of compounds extensively utilized in cosmetics and pharmaceuticals. At its core, polyethylene glycol (PEG) is a polymer formed by the repetitive linking of a fundamental unit: ethylene oxide. The distinct characteristics of different PEGs are primarily determined by their molecular weight, which is a direct consequence of the number of repeating ethylene oxide units in their molecular chain. This molecular weight, typically expressed in grams per mole (g/mol), often features in their nomenclature, such as PEG-40 or PEG-400. High molecular weight PEGs, like macrogol, are employed as laxatives, with specific variants such as PEG-3350 or PEG-4000 being common.

The molecular weight of a PEG profoundly influences its physical properties. PEGs with molecular weights below approximately 500 g/mol are generally liquid and are frequently incorporated into cosmetic formulations. As their molecular weight increases, PEGs become more viscous, transitioning to oily or waxy substances. This characteristic is desirable in certain pharmaceutical formulations and for specific industrial additives.

The Versatility of PEG: A "Swiss Army Knife" of Modern Formulations

PEGs are frequently lauded as the "Swiss Army knives" of modern cosmetic science, largely due to their low cost and remarkable versatility, enabling them to perform multiple functions within product formulations. As hydrophilic compounds, they possess an affinity for water, aiding in skin hydration by forming a film that limits evaporative water loss. They also function as effective emulsifiers, stabilizing the delicate balance between oil and water phases in creams and lotions. Furthermore, PEGs play a crucial role in cleansing products by facilitating the removal of greasy impurities.

These inherent properties explain their widespread use not only in cosmetics but also as excipients in pharmaceuticals. In this capacity, they enhance the solubility and stability of active pharmaceutical ingredients. Beyond personal care and medicine, certain PEG derivatives are approved as technological agents in the food and cleaning product industries, albeit under more stringent regulatory frameworks.

PEGs in mRNA Vaccines: A Critical Component

PEGs have also played a pivotal role in the development of messenger RNA (mRNA) vaccines, including those designed to combat SARS-CoV-2, the virus responsible for the COVID-19 pandemic. The inherent fragility of mRNA necessitates protection to ensure its effective delivery to cells without degradation. This protective function is carried out by minuscule vesicles known as "lipid nanoparticles." These nanoparticles encapsulate the mRNA and facilitate its entry into cells.

These sophisticated lipid nanoparticles are composed of various lipids and surfactants – substances possessing both hydrophobic (water-repelling) and hydrophilic (water-attracting) components. Among these crucial constituents is a "PEGylated" lipid, meaning it is functionalized with a PEG chain. This PEGylated lipid plays a vital role in stabilizing the lipid nanoparticles carrying the mRNA. It achieves this by limiting their aggregation and controlling their interactions with the biological environment.

Moreover, the PEG chain forms a hydrophilic layer on the nanoparticle’s surface, rendering it less visible to the immune system. This "stealth" effect prolongs the nanoparticle’s circulation time within the body, thereby enhancing the efficiency of mRNA delivery. The successful deployment of mRNA vaccines during the COVID-19 pandemic, which reached billions of individuals globally, underscores the critical importance of PEGylation in this advanced vaccine technology. For instance, by late 2023, over 600 million doses of mRNA COVID-19 vaccines had been administered in the United States alone, highlighting the massive scale of PEG utilization in this specific application.

The Limitations and Emerging Concerns Surrounding PEGs

Despite their widespread success and indispensable role in numerous industries, PEGs are not without their limitations. Their manufacturing processes can sometimes result in residual by-products, notably ethylene oxide and 1,4-dioxane. Both of these compounds are classified as toxic and potentially carcinogenic, leading to strict regulatory oversight. While generally absent in finished products due to purification processes, their presence as potential impurities remains a point of concern for some regulatory bodies and consumer advocacy groups.

On a biological level, some individuals have exhibited immune responses to PEG exposure, characterized by the production of anti-PEG antibodies. In rare instances, these reactions have been associated with allergic responses and, in very infrequent cases, anaphylaxis, particularly following the administration of certain medications or vaccines. It is crucial to emphasize that such severe events remain exceedingly rare, especially when considered against the backdrop of billions of doses administered globally. For example, reports of anaphylaxis following mRNA vaccination, while concerning, have been estimated to occur at rates of approximately 2 to 5 per million doses, with PEGs identified as a potential, though not sole, contributing factor in some cases.

Furthermore, the environmental fate of PEGs raises significant questions. While low molecular weight PEGs are largely eliminated renally, some variants can persist in aquatic environments. The long-term ecotoxicological effects of these persistent PEGs are not yet fully understood, prompting ongoing research into their environmental impact.

The Search for Alternatives: Introducing Poly(2-oxazolines) (POx)

In light of these limitations, the scientific community is increasingly focusing on alternative polymers, with poly(2-oxazolines) (POx) emerging as a particularly promising area of research.

The Rediscovery of an Old Polymer: POx

Known since the 1960s, POx polymers were historically underutilized, partly due to less standardized and industrialized synthesis processes compared to those for PEGs. However, recent advancements in polymer chemistry have significantly improved control over their fabrication, reigniting interest in these versatile materials.

A key advantage of POx over PEGs lies in their enhanced "functionalizability." This refers to the ability to chemically modify their ends or their backbone by attaching other molecular units, such as fluorescent probes or biological ligands. This fine-tuned control over their architecture and inherent modularity offers greater flexibility in designing advanced therapeutic systems. Consequently, POx possess several properties that are of considerable interest to researchers in nanomedicine.

Promising Properties for Nanomedicine

Available studies indicate that POx exhibit low immunogenicity, meaning they are less likely to trigger an adverse reaction from the immune system. This superior biocompatibility makes them highly attractive, particularly in fields like vaccination and cancer therapy. Their reduced immunogenic potential positions POx as candidates for repeated use, even in patients already sensitized to other polymers, including PEGs.

Moreover, the biodegradability of POx can be chemically modulated. This allows for the design of structures that remain stable for their therapeutic lifespan and then degrade in a controlled manner within the body. This degradation can be triggered by biological stimuli such as changes in pH, the presence of specific enzymes, or unique chemical environments. This capability paves the way for personalized medicine, especially for long-term treatments or high-dose therapies.

Additionally, the behavior of POx can be influenced by temperature, a property known as thermosensitivity. This characteristic is particularly valuable in pharmaceutical formulation (the art of transforming an active ingredient into an administrable drug). For instance, it enables the creation of injectable gels that remain liquid at room temperature but solidify within the body, or vice versa. This adaptable nature opens exciting avenues for controlled drug release and targeted delivery applications.

Applications and Limitations of POx

These compelling properties make POx strong candidates for drug delivery, especially in oncology. Research is currently exploring systems designed to improve the delivery of chemotherapies, such as taxanes (derived from yew trees, including paclitaxel). While promising, these experimental applications are primarily in the preclinical or early clinical trial stages. Studies are also underway for potential applications in vaccines and cosmetics, though these remain largely experimental.

A Developing Alternative, Not an Immediate Replacement

It is crucial to understand that POx do not yet represent an established alternative. While industrialization is progressing, their production can be more complex and less standardized than that of PEGs. Furthermore, long-term toxicological data and their environmental impact are still being thoroughly investigated, necessitating a cautious approach.

Currently, POx are not replacing PEGs wholesale. Instead, they offer a complementary avenue, being explored for specific applications where chemical modularity and immunological tolerance are paramount. Their large-scale development will hinge on scientific advancements and their ability to be produced reproducibly, safely, and economically. The journey from laboratory discovery to widespread commercial adoption is often lengthy, involving rigorous testing, regulatory approvals, and scaling of manufacturing processes.

The ongoing research into POx signifies a critical step in the evolution of materials science and its application in medicine and consumer products. As our understanding of both the benefits and drawbacks of existing technologies like PEGs deepens, the pursuit of innovative, safer, and more sustainable alternatives like POx becomes increasingly vital. The scientific community and industry stakeholders are working collaboratively to navigate the complexities of bringing these novel materials from the lab bench to the global market, ensuring they meet the stringent demands of safety, efficacy, and environmental responsibility.

Author: Oksana Krupka, Professor, University of Angers.

This article was originally published on The Conversation under a Creative Commons license.