Drugs PEGylation

Keywords Drug delivery Nanomedicine Nanoparticle PEGylated drug PEGylation... 

The covalent attachment of polyethylene glycol (PEG) polymers to therapeutic drugs (pegylation) is one of the most widely used and well-established engineer-... 

Pasut, G., Guiotto, A., Veronese, F.M., Protein, peptide, and non-peptide drug PEGylation for therapeutic application. Expert Opin. Then Patents 14(5), 1-36, 2004. 

DOX, as EPI seems to form fewer amounts of ROS and secondary alcohol metabolite, (ii) encapsulation of anthracyclines in uncoated or pegylated liposomes that ensure a good drug delivery to the tumor but not to the heart, (iii) conjugation of anthracyclines with chemical moieties that are selectively recognized by the tumor cells, (iv) coadministration of dexrazoxane, an iron chelator that diminishes the disturbances of iron metabolism and free radical formation in the heart, and (v) administration of anthracyclines by slow infusion rather than 5-10 min bolus (Table 1). Pharmacological interventions with antioxidants have also been considered, but the available clinical studies do not attest to an efficacy of this strategy. 

Two forms of pegylated IFN-a have been approved by the Food and Drug Administration (FDA) and by the European Medicines Agency (EMEA) for the... 

The results of IFN-a-based therapy can theoretically be improved by using better-tolerated drugs that mimic the action of ribavirin and/or by using HCV inhibitors that, when combined, substantially reduce HCV replication. Since the mechanism of action of ribavirin is still unknown, no credible alternative approach is currently available. In contrast, many specific inhibitors of the HCV replication cycle are in preclinical development and several have reached chnical development (Pawlotsky et al. 2007). A number of them are being tested in combination with pegylated IFN-a, with or without ribavirin. 

Persons with confirmed chronic hepatitis B should be evaluated for treatment, which may include interferon, pegylated interferon, lamivudine, adefovir dipivoxil, or entecavir. The drug of choice for chronic hepatitis B depends on the patient s past medical history, aminotransferase level, HBV DNA level, and most importantly, HBeAg status. 

Pegylated interferon is interferon that is attached to a polyethylene glycol molecule that increases the half-life of the drug, thus allowing once-weekly dosing versus thrice-weekly administration required for the unmodified formulation. Pegylated interferon is well tolerated and is superior in efficacy to unmodified interferon for the treatment of chronic hepatitis B.26... 

Most patients treated with either interferon or pegylated interferon experience flulike symptoms (fevers, chills, rigors, and myalgias). These symptoms may be mild to moderate in severity and usually occur with the first injection and diminish as the treatment continues. The flulike symptoms may be minimized by premedication with acetaminophen or a nonsteroidal anti-inflammatory drug. 

RH is admitted to the pediatric oncology service. She is started on allopurinol and intravenous fluids with sodium bicarbonate to prevent tumor lysis syndrome. According to her risk status, she will receive a three-drug induction with vincristine, dexamethasone, and pegylated asparaginase. She also will receive intrathecal (IT) chemotherapy for CNS prophylaxis with methotrexate, cytarabine, and hydrocortisone. 

At present, the most frequently used methods for PEGylation are chemical conjugation between reactive groups in the drug, such as the primary amine of lysine in protein, and end-reactive PEG derivatives, such as the A-hydroxysuccinimide-... 

Fig. 1 PEGylation technologies. Nonspecific and irreversible PEGylation is associated with several limitations, such as altered drug properties. To overcome this problem, a new generation of PEGylation technologies that enable highly specific and reversible PEGylation have been developed...

ProLynx LLC has developed another type of releasable PEGylation technology based on the p-elimination reaction shown in Scheme 4. In this system, the release rate of the native drug is determined by the acidity of the proton adjacent to the... 

The concept of de-PEGylation can be applied to the development of nanoparticle-based drug delivery systems. PEG is used for the modification of liposomes to increase their blood circulation time [38], However, it also prevents cellular uptake, resulting in a decrease in therapeutic efficiency thus, modifications of the liposome surface with PEG interfere with membrane fusion to the cell membrane and liposome decomposition [39]. One of the possible strategies to solve this problem is to cleave the PEG chains after the nanoparticle reaches the target site (Fig. 9). This system of de-PEGylation of liposomes is also useful in avoiding the immune... 

Fig. 9 Utility of de-PEGylation technology in liposomes, (a) PEG derivative possessing a lipid moiety. The covalent bond between PEG and the lipid moiety can be cleaved by stimuli such as those within the acid environment of cancer and inflammation, (b) After binding the target cell via specific recognition of the receptor by the ligand, PEG molecules on the surface of the liposome are cleaved. The release of PEG facilitates membrane fusion of the liposome and liposome decomposition, resulting in efficient drug delivery...

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