To PEGylate or not to PEGylate: Immunological properties of nanomedicine’s most popular component, polyethylene glycol and its alternatives

Shi, Da; Beasock, Damian; Fessler, Adam B.; Szebeni, János; Ljubimova, Julia Y.; Afonin, Kirill A.; Dobrovolskaia, Marina A.

doi:10.1016/j.addr.2021.114079

Cited by 283 publications

(193 citation statements)

References 290 publications

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“…PEG modification is believed to provide a steric hindrance on the surface, reduce adsorption, and prolong the blood circulation time by reducing MPS uptake. In addition, there have been reports on the development of anti-PEG antibodies and repeated administration of PEGylated liposomes leading to an acceleration in blood clearance [20,35].…”

Section: Discussionmentioning

confidence: 99%

“…However, much of the research carried out regarding the role of PEGylation has been focused on relatively high PEG concentrations and mostly on PEG 2000, the most used PEG chain [3,15,20]. Our study aimed to explore how the PEG chain length affects liposomes' pH responsiveness as well as the overall impact that the PEGylation and pH-responsiveness have on cellular uptake of a model marker in GL261 glioblastoma cells.…”

Section: Discussionmentioning

confidence: 99%

“…Utilizing the acidity of the extracellular environment surrounding glioblastoma as a possible drug release trigger [18,19], we developed pH-responsive liposomes able to release the model marker calcein in a pH-responsive manner. Addressing the debate of Pegylation versus non-Pegylation [20], we compared the PEGylated pH-responsive liposomes of two chain lengths (750 and 2000, respectively) with non-PEGylated pH-responsive vesicles for their calcein release pattern and cellular fate. The GL261 glioblastoma cells served as a tumor model, and cellular uptake on liposomal calcein was followed in vitro by both flow cytometry and confocal microscopy [21].…”

Section: Introductionmentioning

confidence: 99%

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The pH-Responsive Liposomes—The Effect of PEGylation on Release Kinetics and Cellular Uptake in Glioblastoma Cells

et al. 2022

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Nanomedicine has been, to a certain degree, a success story in the development of superior anticancer therapies. However, there are tumors that remain a huge challenge for nanoformulations, for instance, brain tumors such as glioblastoma, the most common and aggressive brain tumor. To utilize the fact that such tumors are characterized by an acidic extracellular environment, we selected pH-responsive liposomes as a potential drug delivery system for superior delivery to GBM. Liposomes comprising PEGylated lipid of two chain lengths with encapsulated fluorescent marker calcein were characterized and challenged against non-PEGylated vesicles. The in vitro calcein release from three liposomal formulations (<200 nm), namely non-PEGylated (pH-Lip) and PEGylated, pH-Lip–PEG750, and pH-Lip–PEG2000, was followed at three pH conditions to prove the pH-responsiveness. The intracellular delivery of a liposomally encapsulated marker was determined in GL261 glioblastoma cell lines in vitro using both flow cytometry and confocal microscopy. The inclusion of PEG2000 within liposomal formulation resulted in reduced in vitro pH-responsiveness compared to pH-Lip and pH-Lip750. All three pH-responsive liposomal formulations improved intracellular uptake in GL261 cells compared to non-pH-responsive liposomes, with negligible differences regarding PEG length. The proposed formulations should be further evaluated in glioblastoma models.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The pH-Responsive Liposomes—The Effect of PEGylation on Release Kinetics and Cellular Uptake in Glioblastoma Cells

et al. 2022

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“…Furthermore, Luo et al ( Luo et al, 2017 ) found that PEGylated graphene oxide (GO) nanosheets provoked cytokine secretion in macrophages by enhancing integrin β 8 -related signalling. Indeed, computational modelling suggested that PEGylation, which is thought to “passivate” nanomaterials ( Shi et al, 2022 ), may transform GO into a biologically relevant signalling entity ( Zhang et al, 2021 ).…”

Section: The Other Side Of the Coin: Adverse Effects Of Pegmentioning

confidence: 99%

Understanding the Role and Impact of Poly (Ethylene Glycol) (PEG) on Nanoparticle Formulation: Implications for COVID-19 Vaccines

Padín-González

Lancaster

Bottini

et al. 2022

Front. Bioeng. Biotechnol.

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Poly (ethylene glycol) (PEG) is a widely used polymer in a variety of consumer products and in medicine. PEGylation refers to the conjugation of PEG to drugs or nanoparticles to increase circulation time and reduce unwanted host responses. PEG is viewed as being well-tolerated, but previous studies have identified anti-PEG antibodies and so-called pseudoallergic reactions in certain individuals. The increased use of nanoparticles as contrast agents or in drug delivery, along with the introduction of mRNA vaccines encapsulated in PEGylated lipid nanoparticles has brought this issue to the fore. Thus, while these vaccines have proven to be remarkably effective, rare cases of anaphylaxis have been reported, and this has been tentatively ascribed to the PEGylated carriers, which may trigger complement activation in susceptible individuals. Here, we provide a general overview of the use of PEGylated nanoparticles for pharmaceutical applications, and we discuss the activation of the complement cascade that might be caused by PEGylated nanomedicines for a better understanding of these immunological adverse reactions.

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“…Nanostructured molecules coated with hydrophilic, noncharged molecules such as PEG and administered systematically have been shown to have reduced cellular uptake through phagocytotic pathways, thus increasing circulation time, although potential immunological responses to PEG remain a subject of active investigation. [ 64 ] Benefits of PEGylation of nanocarriers generally outnumber weaknesses and this approach has been demonstrated with many drug delivery systems including liposomes and have led to PEGylated nanomedicine products in widespread use. [ 19 ] Modification of NP surface properties is also critical for targeted delivery.…”

Section: Delivery Barriers That Nanostructures Must Overcome For Ther...mentioning

confidence: 99%

Toward Gene Transfer Nanoparticles as Therapeutics

Kavanagh

Green

2022

Adv Healthcare Materials

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Genetic medicine has great potential to treat the underlying causes of many human diseases with exquisite precision, but the field has historically been stymied by delivery as the central challenge. Nanoparticles, engineered constructs the size of natural viruses, are being designed to more closely mimic the delivery efficiency of viruses, while enabling the advantages of increased safety, cargo-carrying flexibility, specific targeting, and ease in manufacturing. The speed in which nonviral gene transfer nanoparticles are making progress in the clinic is accelerating, with clinical validation of multiple nonviral nucleic acid delivery nanoparticle formulations recently FDA approved for both expression and for silencing of genes. While much of this progress has been with lipid nanoparticle formulations, significant development is being made with other nanomaterials for gene transfer as well, with favorable attributes such as biodegradability, scalability, and cell targeting. This review highlights the state of the field, current challenges in delivery, and opportunities for engineered nanomaterials to meet these challenges, including enabling long-term therapeutic gene editing. Delivery technology utilizing different kinds of nanomaterials and varying cargos for gene transfer (DNA, mRNA, and ribonucleoproteins) are discussed. Clinical applications are presented, including for the treatment of genetic diseases such as cystic fibrosis.

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To PEGylate or not to PEGylate: Immunological properties of nanomedicine’s most popular component, polyethylene glycol and its alternatives

Cited by 283 publications

References 290 publications

The pH-Responsive Liposomes—The Effect of PEGylation on Release Kinetics and Cellular Uptake in Glioblastoma Cells

The pH-Responsive Liposomes—The Effect of PEGylation on Release Kinetics and Cellular Uptake in Glioblastoma Cells

Understanding the Role and Impact of Poly (Ethylene Glycol) (PEG) on Nanoparticle Formulation: Implications for COVID-19 Vaccines

Toward Gene Transfer Nanoparticles as Therapeutics

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