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  • In contrast to PEGylated proteins which tend

    2020-10-19

    In contrast to PEGylated proteins which tend to have reduced AZD8055 in the body relative to their native counterparts, proteins conjugated to albumin tend to accumulate in certain locales in vivo. This means that albumin-based drug carrier systems have particular applications in the field of chemotherapy as they can improve the passive tumor targeting properties of anti-cancer drugs. Proliferating tumor cells utilize albumin and other plasma proteins for their nutrition and take up albumin by fluid phase endocytosis at a greater rate than normal tissues. After lysosomal digestion, the derived amino acids serve as a source for nitrogen and energy in the tumor cells. These favorable properties make albumin an attractive choice as a drug carrier where the conjugates enjoy the same favorable tumor targeting properties as albumin itself, e.g. high tumor uptake rates, low liver uptake rates and a very long biologic half-life. Both approaches have the ability to conjugate to proteins without comprising the critical property of the target protein. In mice, the serum half-life using the HSA and the PEG was typically around 9- and 7-fold greater, respectively, than that of the sfGFP-WT. Although the binding affinity of HSA to a mouse is much greater than that of a human, it is still much greater than that of a PEG-conjugated protein in human. A disadvantage in both techniques is that the handling and chemical modification of HSA during modification can lead to slight denaturation which may generate a significant immune response [21]. The hydrophobic moieties present on the polymers can bind to proteins through hydrophobic interactions (e.g., PEG with aromatic groups). Additionally, these polymers can also destabilize the native protein conformation by stabilizing unfolded protein conformations. Protein excipients, for example human serum albumin (HSA), stabilize biopharmaceuticals by competitively adsorbing to surfaces and interfaces and preventing interface induced aggregation of the drug product [55]. The production of long-acting protein therapeutics using techniques such as PEGylation, and others to overcome the patient’s immunogenicity has been established and covered extensively in the literature. We successfully produced two forms of long-acting glucarpidase using PEGYlation and HSA fusion with glucarpidase. The two forms produced are more resistant to proteases than the free enzyme (Fig. 5). They also less immunogenic than the free glucarpidase (Fig. 6) [11] In our recent work, we established a different and new strategy to overcome the immunogenicity problem. We showed that isolation of a novel form of the protein used AZD8055 with different epitops could also minimize the patient immune response. We showed that the antibody of one form of the enzyme does not neutralize the other form (Fig. 7) [10]. We therefore proposed that the two forms of the proteins or the enzymes could be used consecutively instead of using one form of the enzyme.
    Conclusions
    Conflict of interest statement
    Acknowledgements QNRF grant number NPRP6-065-3-012, Qatar National Research Fund, Doha Qatar for funding this work with grant number NPRP No.: NPRP6-065-3-012.
    Introduction Fetal growth restriction (FGR) occurs as a consequence of fetal environmental deterioration. It results in small for gestational age (SGA) newborns who are smaller in size than expected, with birth weight (BW) more than two standard deviations (SDs) below the mean BW of newborns of the same gestational age.2, 3 The number of low BW infants has recently risen in Japan because of increases in FGR, and children born SGA have an increased risk of developing adult non-communicable diseases such as developmental origins of health and disease (DOHaD).1, 5 Therefore, an understanding of the pathophysiology of FGR and the introduction of preventative strategies are urgently needed. In animal studies, intrauterine undernutrition was shown to result in low BW and the development of postnatal obesity, which were associated with altered gene expression in adipose tissue. Epigenetic regulation was recently proposed to be a major link between postconceptional fetal stress and gene expression changes. Moreover, in humans, the epigenetic changes caused by FGR were also suggested to affect postnatal growth; however, the evidence for this is limited.