The term PEGylation describes the modification of biological molecules by covalent conjugation with polyethylene glycol (PEG), a non-toxic, non-immunogenic polymer, and is used as a strategy to overcome disadvantages associated with some biopharmaceuticals. PEGylation changes the physical and chemical properties of the biomedical molecule, such as its conformation, electrostatic binding, and hydrophobicity, and results in an improvement in the pharmacokinetic behavior of the drug. In general, PEGylation improves drug solubility and decreases immunogenicity. PEGylation also increases drug stability and the retention time of the conjugates in blood, and reduces proteolysis and renal excretion, thereby allowing a reduced dosing frequency. In order to benefit from these favorable pharmacokinetic consequences, a variety of therapeutic proteins, peptides, and antibody fragments, as well as small molecule drugs, have been PEGylated. This paper reviews the chemical procedures and the conditions that have been used thus far to achieve PEGylation of biomedical molecules. It also discusses the importance of structure and size of PEGs, as well as the behavior of linear and branched PEGs. A number of properties of the PEG polymer--e.g. mass, number of linking chains, the molecular site of PEG attachment--have been shown to affect the biological activity and bioavailability of the PEGylated product. Releasable PEGs have been designed to slowly release the native protein from the conjugates into the blood, aiming at avoiding any loss of efficacy that may occur with stable covalent PEGylation. Since the first PEGylated drug was developed in the 1970s, PEGylation of therapeutic proteins has significantly improved the treatment of several chronic diseases, including hepatitis C, leukemia, severe combined immunodeficiency disease, rheumatoid arthritis, and Crohn disease. The most important PEGylated drugs, including pegademase bovine, pegaspargase, pegfilgrastim, interferons, pegvisomant, pegaptanib, certolizumab pegol, and some of the PEGylated products presently in an advanced stage of development, such as PEG-uricase and PEGylated hemoglobin, are reviewed. The adaptations and applications of PEGylation will undoubtedly prove useful for the treatment of many previously difficult-to-treat conditions.
Polyoxazoline polymers with methyl (PMOZ), ethyl (PEOZ), and propyl (PPOZ) side chains were prepared by the living cationic polymerization method and purified by ion-exchange chromatography. The following properties of polyoxazoline (POZ) were measured: apparent hydrodynamic radius by aqueous size-exclusion chromatography, relative lipophilicity by reverse-phase chromatography, and viscosity by cone-plate viscometry. The PEOZ polymers of different molecular weights were first functionalized and then conjugated to model biomolecules such as bovine serum albumin, catalase, ribonuclease, uricase, and insulin. The conjugates of catalase, uricase, and ribonuclease were tested for in vitro activity using substrate-specific reaction methods. The conjugates of insulin were tested for glucose lowering activity by injection to naïve Sprague-Dawley rats. The conjugates of BSA were injected into New Zealand white rabbits and serum samples were collected periodically and tested for antibodies to BSA. The safety of POZ was also determined by acute and chronic dosing to rats. The results showed that linear polymers of POZ with molecular weights of 1 to 40 kDa can easily be made with polydispersity values below 1.10. Chromatography results showed that PMOZ and PEOZ have a hydrodynamic volume slightly lower than PEG; PEOZ is more lipophilic than PMOZ and PEG; and PEOZ is significantly less viscous than PEG especially at the higher molecular weights. When PEOZ was attached to the enzymes catalase, ribonuclease, and uricase, the in vitro activity of the resultant bioconjugates depended on the extent of protein modification. POZ conjugates of insulin lowered blood glucose levels for a period of 8 h when compared to 2 h for insulin alone. PEOZ, like PEG, was also able to successfully attenuate the immunogenic properties of BSA. The POZ polymers (10 and 20 kDa) are safe when administered intravenously to rats, and the maximum tolerated dose (MTD) was greater than 2 g/kg. Blood counts, serum chemistry, organ weights, and the histopathology of key organs were normal. These results conclude that POZ has the desired drug delivery properties for a new biopolymer.
Hyaluronic acid (HA) has currently several therapeutic applications: in ophthalmology, osteoarthritis, wound healing, tissue regeneration, postoperative anti-adhesion and anesthetic medicine. In the last ten years, it has also been successfully investigated in the field of drug delivery, in the form of conjugates or hydrogel depot systems. HAylation, the covalent conjugation of HA to bioactive molecules, allows the overcoming of disadvantages associated with some pharmaceuticals, such as insolubility, instability and fast kidney clearance. These issues can be addressed also by covalent attachment of polyethylene glycol (PEGylation), but HA has the relevant advantages of biodegradability, high loading and specific targeting. In this review, the novel HA derivatives and the latest advances in HA-based drug delivery with a particular focus on the chemistry of conjugation will be discussed. Although, so far, there are no HA-drug conjugates on the market, several derivatives are presently under clinical investigation, and the promising results encourage further investigations and the exploitation of this versatile polysaccharide.
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