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  • Elacridar Various domains of the HSA molecule have also been

    2020-01-29

    Various domains of the HSA molecule have also been used to make bioconjugates with increased stability, better targeting properties, and/or extended half-lives in blood. For example, domain I of HSA has been used in the preparation of antibody conjugates. This was achieved through the use of a cyclohexene sulfonamide compound that site-selectively labels Lys64 in this HSA domain. [63] Similarly, the half-life the of granulocyte colony stimulating factor (G-CSF) was prolonged by genetic fusion to domain III of I to its N-terminus [64].
    Diseases that have been treated with PEGylated proteins Several PEGylated molecules have been approved for clinical use. For example, PEGylated interferon for such infections, PEG-interferon alfa-2b, was approved by the FDA in August 2001. [55] Table 2 lists some PEGylated products that have received FDA approval [8].
    PEGylation to improve drug delivery and targeting of cancer cells The number of therapeutics involving drug delivery has increased markedly, especially for cancer treatment (Table 2) [65]. While most of the PEGylated products to date are non-protein-based, the use of peptide- and protein-based PEGylated products is now being investigated. In principle, PEGylation of proteins, due to its enhanced permeability and retention (EPR) effect, is an excellent way to achieve a longer circulation time and for drug delivery to a tumor site [66]. For example, a succinimide-activated PEG derivative has been used to PEGylate the ε-amino groups of lysine residues of xanthine oxidase, which mediates anticancer activity because of its ability to generate cytotoxic reactive oxygen species. In animal studies, this derivative exhibited 2.8-fold higher tumor accumulation at solid tumors when compared to the native enzyme in a 24 h injection period [65]. Bispecific Elacridar have been studied as a method in cancer immunotherapy, and the use of PEGylation is an effective method to improve their antitumor efficiency. Site-specific PEGylation has been used to modify a bispecific single-domain antibody-linked Fab (S-Fab), which was designed to link an anti-carcinoembryonic antigen (anti-CEA) nanobody with an anti-CD3 Fab. The resulting construct, polyethylene glycol-S-Fab (PEGylated S-Fab), had slightly decreased tumor cell cytotoxicity in vitro when compared to the free S-Fab, but an increased half-life (t1/2) - 12-fold – resulting in effective inhibition of tumor growth in vivo [68]. PEGylation can be combined with other strategies to improve drug delivery. For example, it has been used in conjunction with niosomes, i.e. non-ionic surfactant-based vesicles that can carry various drugs within them, to improve cell targeting. Niosomes are first rendered magnetic with Fe3O4@SiO2 nanoparticles prior to modifying their surface by PEGylation. In this case, the role of PEGylation increases the bioavailability of niosomes, and magnetization makes them capable of targeting specific tissues. In one application, carboplatin, an antitumor drug, was loaded into PEGylated magnetic niosomes, leading to an increased drug release rate (Fig. 3). Moreover, using an external magnetic field significantly increases their toxicity towards cancerous cells [69]. In addition to the use of drug encapsulation using a vesicular carrier, drugs can be delivered to a tumor site by attaching them to a drug delivery module via acid-cleavable linkers, which can be hydrolyzed in the acidic environment of the tumor. Alternatively, some other type Elacridar of specialized linkage can be used that permits the drug to be released in situ within the tumor microenvironment. Thus, both pro-drug and active targeting strategies can be used. [12] To minimize the loss of activity reversible PEGylation has been developed and a large number of cleavable linkages, mediated in vivo by specific enzymes, hydrolytic cleavage or reduction, have been identified [8,70,71]. The use of pH sensitive cleavable PEG has proved to be an effective approach in which cleavage of a PEG-lipid moiety is triggered in the vicinity of the tumor. In order to achieve a tumor-specific cleavable PEG system, the enzymes specifically expressed in the tumor have also been exploited for cleavage, e.g. matrix metalloproteinases (MMP). [66] Another comparable example in facilitating drug delivery to tumor cells is the peptide-loaded pH-sensitive PEGylation to liposomes (PEG-PpHL) which are characterized and delivered to cis-platinum resistant ovarian cancer C13 cells. The carrier entraps the drug and exhibits a pH-dependent release in the tumor site. Moreover, the PEGylated PpHL behaved differently against macrophage cells due to its ability to protect liposomes from the cells of the reticuloendothelial system [72].