Comparative Investigation of Cellular Effects of Polyethylene Glycol (PEG) Derivatives

Abstract

Nowadays, polyethylene glycols referred to as PEGs are widely used in cosmetics, consumer care products, and the pharmaceutical industry. Their advantageous properties such as chemical stability, low immunogenicity, and high tolerability explain why PEGs are applied in many fields of pharmaceutical formulations including parenteral, topical, ophthalmic, oral, and rectal preparations and also in modern drug delivery systems. Given their extensive use, they are considered a well-known group of chemicals. However, the number of large-scale comparative studies involving multiple PEGs of wide molecular weight range is low, as in most cases biological effects are estimated upon molecular weight. The aim of this publication was to study the action of PEGs on Caco-2 cells and G. mellonella larvae and to calculate the correlation of these effects with molecular weight and osmolality. Eleven PEGs of different molecular weight were used in our experiments: PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG 1500, PEG 4000, PEG 8000, PEG 10,000, 12,000, and PEG 20,000. The investigated cellular effects included cytotoxicity (MTT and Neutral Red assays, flow cytometry with propidium iodide and annexin V) and autophagy. The osmolality of different molecular weight PEGs with various concentrations was measured by a vapor pressure osmometer OSMOMAT 070 and G. mellonella larvae were injected with the solutions of PEGs. Sorbitol was used as controls of the same osmolality. Statistical correlation was calculated to describe the average molecular weight dependence of the different measured effects. Osmolality, the cytotoxicity assays, flow cytometry data, and larvae mortality had significant correlation with the structure of the PEGs, while autophagosome formation and the proportion of early apoptotic cells showed no statistical correlation. Overall, it must be noted that PEGs must be tested individually for biological effects as not all effects can be estimated by the average molecular weight.

Fluctuations of Dry and Total Mass of Cells Exposed to Different Molecular Weights of Polyethylene Glycol

“…These findings agree with previous literature, [9][10][11][12] which has shown that colorectal adenocarcinoma (Caco-2) cells exposed to 4000, 6000, and 10 000 Da PEG lead to a viability above 90% if the PEG concentration was between 0.01% and 4% w/v, while 400 and 15 000 Da PEG was toxic (viability <50%) at a concentration of 4% w/v. [11] In HeLa cells, 400, 1000, 2000, and 4000 Da PEG at low concentrations (≤0.5% w/v) lead to a cell viability close to 100% and viability of >90% at higher concentrations (≥1% w/v).…”

“…[6] During this intracellular redistribution process, PEG has a very high residence time in cells, which can even exceed 96 h. [5] When the concentration of extracellular solutes increases by PEG addition, water is forced out of the cell by osmotic pressure which leads to a decreased cell volume with strong effects on the cells' physiological processes, cytotoxicity, and mechanics. [7,8] PEG is considered to be almost nontoxic in medical applications; [9] however, cytotoxicity of different MWs and concentrations of PEG has been reported in various crowding studies, [9][10][11][12] mainly due to hyperosmotic stress. [9] Metabolically activated low MW PEG (200-400 Da) has also been reported to have genotoxic effects on numerous cell lines.…”

Ultra‐high‐performance liquid chromatography with tandem mass spectrometry method for cellular toxicity and pharmacokinetic study of PEG1K polymers

“…For example, Ha Pham Le Khanh and his collaborators investigated the cellular effects of PEG derivatives. Their results indicated that PEGs with small molecular weight could decrease cell viability significantly [14]. DAVID A. HEROLD's study suggested that acid metabolites of PEGs with small molecular weight are calcium chelators and are associated with hypercalcemia [15].…”

Evaluation of Physical Properties of Coated Polydioxanone Threads

“…It is excreted through the kidneys without accumulating in the body and is widely used commercially in different pharmaceutical formulations. 10,11 Furthermore, PEG hydrogels can accelerate wound healing. 12…”

“…It is excreted through the kidneys without accumulating in the body and is widely used commercially in different pharmaceutical formulations. 10,11 Furthermore, PEG hydrogels can accelerate wound healing. 12 Hyaluronic acid is widely used in esthetic medicine to stimulate soft tissue enlargement and skin rejuvenation owing to its high water content, excellent biocompatibility, and similarity to human tissues.…”