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Knockin' on wood : starring Peg Leg Bates
Presents a picture book biography of Clayton \"Peg Leg\" Bates, an African American who lost his leg in a factory accident at the age of twelve and went on to become a world-famous tap dancer.
Book
Nanoparticle PEGylation for imaging and therapy
Nanoparticles are an essential component in the emerging field of nanomedical imaging and therapy. When deployed
, these materials are typically protected from the immune system by polyethylene glycol (PEG). A wide variety of strategies to coat and characterize nanoparticles with PEG has established important trends on PEG size, shape, density, loading level, molecular weight, charge and purification. Strategies to incorporate targeting ligands are also prevalent. This article presents a background to investigators new to stealth nanoparticles, and suggests some key considerations needed prior to designing a nanoparticle PEGylation protocol and characterizing the performance features of the product.
Journal Article
The Importance of Poly(ethylene glycol) Alternatives for Overcoming PEG Immunogenicity in Drug Delivery and Bioconjugation
Poly(ethylene glycol) (PEG) is widely used as a gold standard in bioconjugation and nanomedicine to prolong blood circulation time and improve drug efficacy. The conjugation of PEG to proteins, peptides, oligonucleotides (DNA, small interfering RNA (siRNA), microRNA (miRNA)) and nanoparticles is a well-established technique known as PEGylation, with PEGylated products have been using in clinics for the last few decades. However, it is increasingly recognized that treating patients with PEGylated drugs can lead to the formation of antibodies that specifically recognize and bind to PEG (i.e., anti-PEG antibodies). Anti-PEG antibodies are also found in patients who have never been treated with PEGylated drugs but have consumed products containing PEG. Consequently, treating patients who have acquired anti-PEG antibodies with PEGylated drugs results in accelerated blood clearance, low drug efficacy, hypersensitivity, and, in some cases, life-threatening side effects. In this succinct review, we collate recent literature to draw the attention of polymer chemists to the issue of PEG immunogenicity in drug delivery and bioconjugation, thereby highlighting the importance of developing alternative polymers to replace PEG. Several promising yet imperfect alternatives to PEG are also discussed. To achieve asatisfactory alternative, further joint efforts of polymer chemists and scientists in related fields are urgently needed to design, synthesize and evaluate new alternatives to PEG.
Journal Article
The Mystery of Antibodies Against Polyethylene Glycol (PEG) - What do we Know?
Purpose
Recent findings demonstrated anti-PEG antibody formation in some healthy individuals and patients who have not received PEGylated biotherapeutics. Some of these findings evoked criticism because of shortcomings in the antibody assays used. To better understand this topic, we established robust antibody analytics and screened two cohorts of healthy individuals and one cohort of hemophilia patients for the expression of anti-PEG antibodies.
Methods
A flow cytometry approach and a fully validated ELISA platform were established to detect specific anti-PEG antibodies. Immunohistochemistry was used to test for potential binding of anti-PEG antibodies to human tissues.
Results
IgM and/or IgG anti-PEG antibodies are expressed by some healthy individuals and by some patients with hemophilia who have not received PEGylated biotherapeutics. These antibodies can be either transient or persistent and recognize PEGs of different sizes with or without terminal methoxy groups. Age and location of healthy individuals influence the prevalence of IgG but not of IgM antibodies. Anti-PEG antibodies do not cross-react with human tissues supporting the safety of the antibodies.
Conclusion
We confirm that some healthy individuals and some patients with hemophilia express specific antibodies against PEG which are not associated with any pathology and do not bind to human tissues.
Journal Article
PEGylated liposomes: immunological responses
A commonly held view is that nanocarriers conjugated to polyethylene glycol (PEG) are non-immunogenic. However, many studies have reported that unexpected immune responses have occurred against PEG-conjugated nanocarriers. One unanticipated response is the rapid clearance of PEGylated nanocarriers upon repeat administration, called the accelerated blood clearance (ABC) phenomenon. ABC involves the production of antibodies toward nanocarrier components, including PEG, which reduces the safety and effectiveness of encapsulated therapeutic agents. Another immune response is the hypersensitivity or infusion reaction referred to as complement (C) activation-related pseudoallergy (CARPA). Such immunogenicity and adverse reactivities of PEGylated nanocarriers may be of potential concern for the clinical use of PEGylated therapeutics. Accordingly, screening of the immunogenicity and CARPA reactogenicity of nanocarrier-based therapeutics should be a prerequisite before they can proceed into clinical studies. This review presents PEGylated liposomes, immunogenicity of PEG, the ABC phenomenon, C activation and lipid-induced CARPA from a toxicological point of view, and also addresses the factors that influence these adverse interactions with the immune system.
Journal Article
Dual pH-sensitive liposomes with low pH-triggered sheddable PEG for enhanced tumor-targeted drug delivery
pH-sensitive liposomes (pSL) have emerged as promising nanocarriers due to their endo/lysosome-escape abilities, however, their pH sensitivity is compromised by poly(ethylene glycol) (PEG) coating. This study investigates whether an intracellular PEG-detachment strategy can overcome this PEG dilemma.
First, PEG2000 was conjugated with a phospholipid via an acid-labile hydrazide–hydrazone bond (–CO–NH–N = CH–), which was postinserted into pSL, forming PEG-cleavable pSL (CL-PEG-pSL). Their endo/lysosomal-escape abilities in MIA PaCa-2 cells, pharmacokinetics and tumor accumulation abilities were studied using PEG-pSL as reference.
CL-PEG-pSL showed rapid endo/lysosome-escape abilities in the cancer cells and higher tumor accumulation in MIA PaCa-2 xenograft model in contrast to PEG-pSL.
Cleavable PEGylation is an efficient strategy to ameliorate the PEG dilemma of pSL for cancer drug delivery.
Journal Article
Toxicity and immunogenicity concerns related to PEGylated-micelle carrier systems: a review
Polymeric-micelle carrier systems have emerged as a novel drug-carrier system and have been actively studied for anticancer drug targeting. In contrast, toxicological and immunological concerns related to not only polymeric-micelle carrier systems, but also other nanocarrier systems, have received little attention owing to researchers' focus on therapeutic effects. However, in recent clinical contexts, biopharmaceuticals' effects on immune responses have come to light, requiring that researchers substantively explore the potential negative side effects of nanocarrier systems and of therapeutic proteins in order to develop nanocarrier systems suitable for clinical use. The present review describes current insights into both toxicological and immunological issues regarding polymeric-micelle carrier systems. The review focuses on immunogenicity issues of polymeric-micelle carrier systems possessing poly(ethylene glycol) (PEG). We conclude that PEG-related immunogenicity is deeply related to characteristics of a counterpart block of PEG-conjugates, and we propose future directions for addressing this unresolved issue.
Journal Article
PEGylated lipids in lipid nanoparticle delivery dynamics and therapeutic innovation
Lipid nanoparticles (LNPs) have become significant vehicles in the delivery of therapeutic substances, particularly for nucleic acid vaccines and gene therapies. A key component in the nanoparticle formulation is polyethylene glycol-modified (i.e., PEGylated) lipids (PEG lipids), which can significantly influence the stability, cell interactions, and overall effectiveness of LNP delivery vehicles. This review collates insights into the role of PEG lipids in LNPs by illustrating how the PEG chains arrange on the nanoparticle surface and the potential impacts on LNPs’ physicochemical properties by varying surface PEG density or PEG chemistry. Subsequently, PEG conformations are discussed in terms of their modulation of protein corona formation, cellular uptake, and immunogenic responses, particularly the pathways of anti-PEG antibody production and complement activation. Building on these understandings, functionalized PEG lipids are reviewed for ligand conjugation and targeted LNP delivery function. Promising alternatives to replace the benchmark PEG lipids are also systematically reviewed to address PEGylation associated immunogenicity. By conducting a critical analysis of the recent literature and identifying potent candidates for PEGylation strategies or PEG-free platforms, this review aims to provide insights and support the advancement of LNP mediated delivery.
Journal Article
Anti-PEG IgM Response against PEGylated Liposomes in Mice and Rats
We have reported that PEGylated liposomes lose their long-circulating properties when they are administered repeatedly at certain intervals to the same animal. This unexpected phenomenon is referred to as the accelerated blood clearance (ABC) phenomenon. We recently showed that the ABC phenomenon is triggered via the abundant secretion of anti-PEG IgM in response to the first dose of PEGylated liposomes. However, the details of the underlying mechanism for the induction of anti-PEG IgM production are yet to be elucidated. The present study demonstrated that the spleen is a major organ involved in the secretion of anti-PEG IgM in mice and rats. Anti-PEG IgM production was detected in nude, T-cell deficient mice, but not in SCID mice with B- and T-cell deficiencies. These observations indicate that splenic B-cells secret anti-PEG IgM without help from T-cells. Sequential injections of PEGylated liposomes into the same mice did not promote isotype switching from IgM to IgG. Accordingly, PEGylated liposomes may function as a type-2, T-cell-independent antigen (TI-2 antigen) during anti-PEG IgM production. Although the underlying mechanism that causes an anti-PEG IgM response against PEGylated liposomes is not yet clear, our findings give implications in revealing the anti-PEG IgM response against PEGylated liposome.
Journal Article
Gastrostomy tract metastasis presenting as a large abdominal wall mass following percutaneous endoscopic gastrostomy for esophageal squamous cell carcinoma: a case report
Abstract
Percutaneous endoscopic gastrostomy (PEG) is a standard method for providing enteral access in patients with obstructive aerodigestive cancer. However, gastrostomy tract metastasis is a rare but devastating complication in patient with aerodigestive cancers who have undergone PEG tube placement. Due to its rarity, the standard therapeutic approach remains undefined. We report the case of an 83-year-old male who developed gastrostomy tract metastasis following pull-type PEG tube placement, presenting as a large abdominal wall mass detected during surveillance following definite chemoradiation for locally advanced thoracic esophageal squamous cell carcinoma. The patient underwent en bloc resection of the abdominal wall mass along with the PEG tube. The abdominal wall defect was closed using an inter-layer polyglactin mesh repair, followed by delayed split-thickness skin grafting.
Journal Article