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Principles of Nanoparticle Design for Overcoming Biological Barriers to Drug Delivery *
Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Elvin Blanco, Haifa Shen, Mauro Ferrari
The strategy of functionalizing nanoparticles with poly(ethylene glycol) (PEG), or PEGylation, stemmed largely from the observation that nanoparticles had low circulation lifetimes following intravascular administration. PEGylation involves the grafting of PEG to the surface of nanoparticles, wherein ethylene glycol units form tight associations with water molecules, resulting in the formation of a hydrating layer [25]. This hydrating layer in turn hinders protein adsorption and subsequent clearance by the MPS (Fig. 9.2). The transformative potential of PEGylation to prolong the circulating lifetimes of nanoparticles was best exemplified by the PEGylation of liposomal doxorubicin, which increased the lifetime of the drug from minutes to hours [26]. Although functionalization of nanoparticles with materials that possess similar shielding effects has been attempted, such as with polaxamer, polyvinyl alcohol, poly(amino acid)s and polysaccharides [27], PEG remains the most widely used material. Huang and coworkers [28] demonstrated effective evasion of the MPS through the use of PEGylated liposome-polycation-DNA nanoparticles. The strategy consists of coating a negatively charged, nucleic acid-containing compact core with two cationic lipid bilayers, with the hypothesis that a supported and stabilized bilayer would tolerate a higher amount of distearoylphosphatidylethanolamine (DSPE)-PEG2000 and result in proper evasion of the MPS. Findings indeed demonstrated low liver sinusoidal uptake and a high amount of injected dose (∼33%) in NCI-H460 tumors.
The science of biotechnology
Published in Ronald P. Evens, Biotechnology, 2020
Pegylation is a process in which polyethylene glycol (PEG) molecules are added to the protein structure. It has been done for eight different types of molecules: interferons (e.g., interferon-2a), a growth factor (e.g., filgrastim), all liposomes (e.g., doxorubicin), three enzymes (e.g., pegasparaginase, pegademase, and pegloticase), three coagulation proteins (e.g., Jivi), a hormone (e.g., pegvisomant), an aptamer (e.g., pegaptanib), and an antibody (e.g., certolizumab pegol). Figure 5.6 presents a diagram of a pegylated molecule, peg-filgrastim compared to its original molecule, filgrastim.
Enzymatic Amino Acid Deprivation Therapies Targeting Cancer
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Carla S. S. Teixeira, Henrique S. Fernandes, Sérgio F. Sousa, Nuno M. F. S. A. Cerqueira
Similarly to what happens with other enzymes used in therapy, pegylation is one of the most appropriate manners to improve de plasma half-life and reduce the immunogenicity of the ASNase. Pegylation is a process in which the enzyme is modified with 5 kDa units of monomethoxypolyethylene glycol (PEG) to reduce de exposition of immunogenic patterns in the enzyme’s surface (Rytting, 2010). The pegylated ASNase keeps its enzymatic activity, but the half-life time in the bloodstream increases about five times, and the immunogenicity is also lower (Zeidan et al., 2008).
Early stage clinical trials for the treatment of hemophilia A
Published in Expert Opinion on Investigational Drugs, 2022
Gianna M Guzzardo, Robert Sidonio, Jr, Michael U Callaghan, Katherine Regling
PEGylation is a technique which covalently attaches polyethylene glycol (PEG) to a protein, peptide or small molecule. In HA, PEG covalently attaches to FVIII which creates a hydrophilic ‘protective’ barrier around the molecule by way of increased molecular weight and size of the protein. This is thought to be protective of activity and subsequent degradation of FVIII, leading to decreased clearance and a prolonged plasma half-life [36,37]. Currently, there are approved PEGylated FVIII products and ongoing investigation of new products. One such product is FRSW117 (Jiangsu Gensciences Inc), a PEGylated rhFVIII-Fc fusion protein for severe hemophilia A. A phase 2, multicenter, open-label study to evaluate the PK, safety and efficacy has been opened but remains in the pre-recruitment phase (NCT05265286) [38].
PEGylated drug delivery systems in the pharmaceutical field: past, present and future perspective
Published in Drug Development and Industrial Pharmacy, 2022
Eva Sanchez Armengol, Alexander Unterweger, Flavia Laffleur
Furthermore, next-generation techniques for PEGylation introduce unique PEG shapes capable of reducing steric hindrance of the active site. As it is known, the size and shape of the PEG, as well as the PEGylation site can foster active compounds in the therapeutic effects. Future advances in affinity purification of PEGylated proteins will be highlighted in two main pathways. The first one is the search or synthesis of novel ligands for PEG-modified proteins and the second one will be centered on developing non chromatographic affinity strategies. Moreover, PEGylation will be applied to a more diverse set of therapeutic agents just like aptamers and peptides. It is the most established process for extending half-life. New PEGylated agents will increase demands for stable and long-lasting drugs.
Factors affecting the dynamics and heterogeneity of the EPR effect: pathophysiological and pathoanatomic features, drug formulations and physicochemical factors
Published in Expert Opinion on Drug Delivery, 2022
Rayhanul Islam, Hiroshi Maeda, Jun Fang
PEGylation is the most widely used and accepted drug carrier strategy. One drawback of using PEG as a drug carrier is that it can conjugate only one active component at the end of the PEG chain. That is, the payload for the PEG chain is limited, although the payload can be increased by adding branched, dendron, or comb-like structures. Other important issues regarding PEG include the so-called PEG dilemma [76] and formation of antibodies against the chemical structure between the PEG and the linker [77]. If the antibody (IgG type) is formed, accelerated blood clearance occurs, this event being called the accelerated blood clearance (ABC) phenomenon [77]. In contrast, as far as we know, the N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer seems to have no such problems, is more biocompatible, and has greater drug-loading capacity [78].