الفهرس 
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Abstract
Cosmetics are extensively used worldwide, and they have become an indispensable feature of the modern lifestyle of individuals. Globally, the cosmetic market was valued at 380.2 billion dollars in 2019 and is predicted to reach 463.5 billion dollars by 2027. Vitamin C and flavonoids are the most abundant and widely used antioxidants in cosmetics formulations due to their potent antioxidant, anti-aging, photoprotective, and anti-pigmentary activity. Polyethylene glycol (PEG) is considered the gold standard in bioconjugation technology and nanoformulations to improve the circulation half-life of the modified materials and enhance their stability. The PEG derivatives are also widely used in cosmetics as emulsifiers and surfactants. PEGs are generally recognized as biologically inert and non-immunogenic polymers. However, surprisingly, the “pre-existing” anti-PEG antibodies (Abs) are detected in 45 % of healthy individuals who have never received treatment with PEGylated formulations. To the best of our knowledge, we are the first who try to explain the cause of these pre-existing anti-PEG antibodies in healthy individuals. Unfortunately, several reports have been issued about the effect of pre-existing anti-PEG Abs on the therapeutic efficacy of PEGylated products, where anti-PEG Abs can enhance the clearance of PEGylated products that compromise their efficacy, which is the so-called accelerated blood clearance (ABC) phenomenon. In the same manner, it was reported that the ABC phenomenon is accompanied by complement system activation, which is predicted to be the potential source of hypersensitivity reactions reported post-PEGylated products administration. In our recent study, we tried to focus on the anti-PEG Abs induction following topical application of vitamin C and flavonoids cosmetic formulations containing PEG and studying the effect of these Abs on the efficacy of PEGylated vaccination models, including protein-based vaccines and messenger ribonucleic acid (mRNA)-based vaccines such as COVID-19 vaccines. Also, we studied the role of pre-existing anti-PEG Abs in the allergic reactions reported following mRNA-based COVID-19 vaccination.
First, we demonstrated that following topical application, PEG derivatives in cosmetic products could efficiently penetrate the stratum corneum and subsequently reach the systemic circulation. Also, we noticed that PEG derivative penetration was enhanced in the injured or compromised skin. The penetrated PEG derivatives primed the immune system, resulting in the induction of anti-PEG immunoglobulins M (IgM) production. The anti-PEG IgM was detected at a higher level on Day 14 in mice with normal skin. The anti-PEG IgM was earlier detected on Day 7 in mice with injured skin. In addition, interestingly, we observed in the mice with pre-existing anti-PEG IgM that topically applied PEG derives containing cosmetic products consumed the pre-existing anti-PEG IgM.
Secondly, we reported that pre-existing anti-PEG Abs could enhance the immune response of protein-based vaccines. Ovalbumin PEGylated liposomes (OVA-PEG Lips) were used as a model of protein-based vaccines and the immune response was measured as a function of anti-OVA IgM and immunoglobulins G (IgG) production. We detected a significant increase in anti-OVA IgG in the anti-PEG bearing mice model compared to the control group. These observations may be attributed to the presence of anti-PEG Abs induced by topical application of PEG-containing cosmetics, which can enhance the splenic accumulation of OVA-PEG Lip and induce the transfer of PEGylated liposomes from the marginal zone to the follicular region of the spleen. Follicular accumulation of antigenic protein enhances its immune response where splenic follicles represent the main site of Abs proliferation and maturation. On the other hand, we reported that pre-existing anti-PEG Abs affect the efficacy of mRNA-based vaccines where we observed a significant decrease in Firefly luciferase (FLuc) mRNA expression following FLuc mRNA lipid nanoparticles (LNPs) administration in anti-PEG bearing mice compared to the control group. Also, we reported that pre-existing anti-PEG Abs induce complement system activation following FLuc mRNA LNPs administration. We reported that the complement system compromises the surface integrity of LNPs, which induces pre-mature release of the encapsulated mRNA before it reaches their target of expression (the cytosol), which leads to exposure of mRNA to RNases and other hydrolytic enzymes that negatively affects their expression and the production of encoded antigenic molecules. Decreasing mRNA expression in anti-PEG bearing mice reflects on the immune response of mRNA-encoded antigenic molecules.
In addition, the effect of anti-PEG Abs on the efficacy of COVID-19 mRNA-based vaccines was also studied. Surprisingly, anti-PEG Abs induced by topical application of cosmetic products compromise the therapeutic efficacy of spike (S)-mRNA LNPs. We reported a significant decrease in anti-S1 IgG production following spike-mRNA administration in anti-PEG-bearing mice compared to the control group. Also, we detected a significant complement system activation that occurred following immunization with spike-mRNA LNPs in the anti-PEG bearing mice model. Complement system activation is accompanied by the release of proinflammatory cytokines like interleukin-6 (IL-6), which may be responsible for the development of allergic reactions following mRNA-based vaccine administration. Finally, we proposed that pre-infusion of a large dose of high molecular weight PEG may enhance the consumption of pre-existing anti-PEG Abs, which may represent a successful strategy to rescue the therapeutic efficacy of subsequent administered PEGylated therapeutics.
In conclusion, current results indicate that PEG derives in some cosmetic products may be one of the major causes of inducing “pre-existing” anti-PEG IgMs that have been detected in healthy individuals. Pre-existing anti-PEG Abs can significantly affect the therapeutic efficacy of PEGylated therapeutics and vaccines, and they may represent a potential source of post-vaccination induced hypersensitivity. Also, the consumption of pre-existing anti-PEG Abs may represent a tentative hypothesis to rescue the therapeutic efficacy of PEGylated products and abolish the complement system activation and consequently post-vaccination reported allergic reactions.