Standard laboratory tests (seeSidebar 1) that can quantitatively and accurately measure -PEG Ab levels and determine a patients -PEG Ab status are crucial to this effort, as suggested by others.11,66,87Importantly, clinical trial designs must screen for pre-existing anti-PEG immunity, as well as monitor treatment history, since previous exposure to PEGylated therapeutics could prime future responses to subsequent therapy with PEGylated drugs. in humans, must be answered in order to fully address the potential complications of anti-PEG immunity. == Introduction == Extended circulation of proteins and nanoparticle therapeutics is often necessary to achieve adequate drug concentrations in target tissues.13Unfortunately, many peptide and protein drugs are rapidly degraded and/or cleared from the systemic circulation due to their small size,4and nanoparticulate drug carriers are readily eliminated by the cells of the mononuclear phagocyte system (MPS).3,5To overcome these challenges, proteins and nanoparticles are frequently conjugated to various hydrophilic polymers, which can significantly reduce degradation and opsonization, consequently extending the circulation half-lives of the modified therapeutics.1,6These polymers are frequently referred to as stealth polymers, reflective of their ability to render proteins and particles inert to the biological environment. Polyethylene glycol (PEG) has been, and continues to be, the most widely used stealth polymer in drug delivery, with over a dozen PEGylated pharmaceuticals currently on the market and many more in clinical testing.2,3PEG has a long history of safe use in humans, and the polymer is classified under the Generally Recognized As Safe (GRAS) category by the FDA. Despite the frequent use of PEG to extend circulation kinetics, a number of investigators have observed the rapid clearance of some PEGylated systems upon IRL-2500 repeated administration.7,8This accelerated blood clearance phenomenon was ultimately attributed to the formation of PEG-specific antibodies.9Indeed, animals that receive repeated doses of PEGylated systems often generate a potent IgM antibody response to PEG, which causes the complete elimination of subsequent doses of PEGylated agents from the circulation within minutes to a few hours.8The induction of anti-PEG antibodies (-PEG Abs) in humans was also observed in recent clinical trials of PEGylated proteins and has been correlated with poor drug efficacy. Interestingly, there is emerging evidence that -PEG Abs can be found in the general population in individuals who likely have never received PEGylated therapeutics injected systemically.10,11As many more PEGylated protein and nanoparticle therapeutics are expected to enter the market over the next several years, an improved understanding of the prevalence, induction, and effects of anti-PEG immunity is undoubtedly critical for the continued clinical use of PEGylated systems. == ADVANTAGES AND PHYSICOCHEMICAL PROPERTIES OF EFFECTIVE STEALTH PEGYLATION == The stealth properties of PEG are rooted in several distinctive molecular and physical characteristics. Mouse monoclonal to CRTC2 First, PEG is exceedingly hydrophilic, with each ethylene glycol subunit (-CH3-CH3-O-) surrounded by a minimum of 23 water molecules.12,13Thus, PEG coatings generate a hydration shell with a large excluded volume IRL-2500 that sterically prevents biomacromolecules from penetrating into the polymer layer and binding to the underlying core via hydrophobic or electrostatic interactions.1416Second, PEG is highly flexible and exhibits high chain mobility, which results in an exceedingly large number of polymer chain conformations. As a result, any substantial reduction in the conformational freedom of PEG, including the displacement of PEG chains by intruding biomacromolecules, is thermodynamically unfavorable.1719Together, these features greatly suppress interactions between PEGylated systems and the biological environment. For proteins, PEG conjugation decreases enzymatic degradation, opsonization, and immunogenicity of the IRL-2500 IRL-2500 protein core;4PEGylation can also improve stability and solubility.2Additionally, the resulting increase in the hydrodynamic diameter can reduce renal elimination and improve the biodistribution and pharmacokinetics of PEGylated proteins.4For nanocarriers, PEGylation reduces opsonization and MPS cell clearance, resulting in significantly prolonged circulation kinetics.5,6For oncological applications, this effect often leads to greater tumor distribution via the enhanced permeability and retention (EPR) effect, while decreasing accumulation in non-targeted organs.3PEGylation can also improve nanocarrier stability and minimize the premature release of cargo therapeutics. Finally, PEG coatings have been shown to decrease nanocarrier association with structural components of mucus and extracellular matrix, thereby improving distribution and delivery.
Standard laboratory tests (seeSidebar 1) that can quantitatively and accurately measure -PEG Ab levels and determine a patients -PEG Ab status are crucial to this effort, as suggested by others