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PEGylation is a process in which one or more units of chemically activated polyethylene glycol reacts with a biomolecule, usually a protein, peptide, small molecule or oligonucleotide, creating a putative new molecular entity possessing physicochemical and physiological characteristics that are distinct from its predecessor molecules. In recent years, PEGylation has been used not only as a drug delivery technology but used also as a drug modification technology to transform existing biopharmaceuticals clinically more efficacious than before their PEGylation. PEGylation bestows several useful properties upon the native molecule, resulting in improved pharmacokinetic and pharmacodynamic properties, which in turn enable the native molecule to achieve maximum clinical potency. In addition, PEGylation results in sustained clinical response with minimal dose and less frequency of dosing, leading to improved quality of life via increased patient compliance and reduced cost. During the course of development of various pegylated protein therapeutics, several new insights have been gained. This review article focuses on the approaches, strategies and the utilization of modern PEGylation concepts in the design and development of well-characterized pegylated protein therapeutics.

An injectable formulation of rapamycin was prepared using amphiphilic block co-polymer micelles of poly(ethylene glycol)-b-poly(epsilon-caprolactone) (PEG-PCL). Drug-loaded PEG-PCL micelles were prepared by a co-solvent extraction technique. Resulting PEG-PCL micelles were less than 100 nm in diameter and contained rapamycin at 7% to 10% weight and >1 mg/mL. PEG-PCL micelles released rapamycin over several days, t50% 31 h, with no burst release; however, physiological concentrations of serum albumin increased the release rate 3-fold. Alpha-tocopherol, vitamin E, was co-incorporated into PEG-PCL micelles and increased the efficiency of rapamycin encapsulation. The addition of alpha-tocopherol also slowed the release of rapamycin from PEG-PCL micelles in the presence of serum albumin, t50% 39 h.

A biodegradable polymer network hydrogel system with both hydrophilic and hydrophobic components was synthesized and characterized. The hydrophilic and hydrophobic components were dextran and poly(D,L)lactic acid (PDLLA), respectively. These two polymers were chemically modified for incorporating unsaturated groups for subsequent UV crosslinking to generate a hydrogel with a three-dimensional network structure. The effects of the reaction conditions on the synthesis of a dextran derivative of allyl isocyanate (dex-AI) were studied. All newly synthesized materials were characterized by Fourier transform infrared and NMR. The swelling property of the hydrogels was studied in buffer solutions of different pHs. The results of this study showed that a wide-range swelling property was obtained by changes in the dex-AI/PDLLA composition ratio, the type and degree of unsaturated groups incorporated into dextran, and the UV photocrosslinking time. The solvent extraction effect on the swelling property of the hydrogels was also studied. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 2392–2404, 2000

A new class of biodegradable hydrogels, consisting of hydrophobic poly(D,L)lactic acid (PDLLA) and hydrophilic dextran segments with a polymer network structure, was synthesized with UV photopolymerization. Unsaturated vinyl groups first were introduced onto the PDLLA and dextran polymer backbones, then followed by a crosslinking reaction of diacrylate-terminated PDLLA and dextran acrylate. The chemical crosslinking forced the hydrophobic PDLLA and hydrophilic dextran segments to mix with each other in the network hydrogels. The new polymers were characterized by standard polymer characterization methods such as NMR, Fourier transform infrared spectroscopy, and gel permeation chromatography. The effects of reaction time, temperature, and molar ratio of the reactants on the incorporation of acrylate onto the polymer backbone were examined. A series of hydrogels with different dextran/PDLLA composition ratios was prepared, and their swelling behaviors were studied. These new bicomponent network hydrogels had a wide range of hydrophilicity to hydrophobicity that was difficult to achieve in totally hydrophilic hydrogels. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 4554–4569, 1999

A polysaccharide-based hydrogel was prepared by photocrosslinking of modified dextran. Dextran was first bromoacetylated by bromoacetyl bromide and was subsequently reacted with sodium acrylate for incorporating a vinyl group. The acrylated dextran was then irradiated by a long-wave UV lamp for photocrosslinking. Reaction products (bromoacetyl dextran, acrylated dextran, and hydrogel) were characterized by elemental analysis, FT-IR, 1H-NMR, and 13C-NMR. The prepared dextran hydrogels showed a wide range of swelling behavior in different pH media, depending on the degree of substitution in bromoacetyl dextrans.

Novel water-soluble unsaturated poly(ether amide)s (PEAs) were synthesized by low-temperature polycondensation of fumaryl chloride and amine-terminated poly(ethylene glycol) (Jeffamine®). The unsaturated copolymers were further chemically modified with thiols to provide reactive pendant functional groups. Hydrogels based on these copolymers were prepared by copolymerization of the PEA with N-vinyl pyrrolidone exposure to ultraviolet (UV) irradiation. The resulting hydrogels exhibited a high swelling ratio, and the magnitude of swelling depended on the molecular weight of Jeffamine®. The swelling ratio and equilibrium water content tended to increase with increasing chain length of the Jeffamine® used in copolymer synthesis.

The objective of this study was to examine the reactivity of superoxide ion as an oxygen nucleophile towards biodegradable biomaterials having an aliphatic polyester structure, such as poly(D,L-Lactide) (PDLLA). The changes in molecular weights and thermal properties of PDLLA were studied as a function of the superoxide ion concentration, hydrolysis time, and hydrolysis temperature. The superoxide ion induced fragmentation of PDLLA yielded a mixture of various species with different chain length. A combined size exclusion chromatography (SEC) method with a chemical tagging by phenyl isocyanate revealed that the structure of the oligomer species with the lowest molecular weight formed in the superoxide ion induced degradation mixture was linear. The significant reduction in Tg was consistent with the significant reduction in the molecular weight of PDLLA. The linear low molecular fragments (dimers and trimers) in the reaction mixture could act as an internal plasticizers to enhance the Tg reduction by increasing the free volume of chain ends. The relationship of Tg with molecular weight of PDLLA followed the general theory of Fox–Flory. The mechanism of simple hydrolysis of ester by superoxide ion proposed by Forrester et al. was modified to interpret the data obtained from the synthetic biodegradable polymers. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 3558–3567, 1999

A new class of hydrogel precursor, dextran-maleic acid (Dex-MA), was synthesized by the reaction of dextran with maleic anhydride in the presence of the catalyst triethylamine. The effects of temperature, time, catalyst amount, and reactant concentration on the degree of substitution (DS) by MA was studied to establish an optimum reaction condition. The new hydrogel precursor had excellent solubility in various common organic solvents. The hydrogels based on Dex-MA precursor were made by the irradiation of Dex-MA with a long wave UV lamp. The Dex-MA hydrogels showed a very high swelling ratio in water, and the magnitude of swelling depended on the pH of the medium and the DS by MA. The Dex-MA hydrogels exhibited the highest swelling ratio in neutral pH, followed by acidic (pH 3) and alkaline pH (10). The most distinctive characteristic of Dex-MA hydrogels was that a carboxylic acid group was generated by the reaction of dextran with maleic anhydride. As a result, the swelling ratio increased with an increase of the DS of the MA segment (ionizable moiety that affects swelling ratio) in the Dex-MA hydrogel.

The purpose of this research was to synthesize new regular poly(ester amide)s (PEAs) consisting of nontoxic building blocks like hydrophobic α-amino acids, α,ω-diols, and aliphatic dicarboxylic acids, and to examine the effects of the structure of these building block components on some physico-chemical and biochemical properties of the polymers. PEAs were prepared by solution polycondensation of di-p-toluenesulfonic acid salts of bis-(α-amino acid) α,ω-alkylene diesters and di-p-nitrophenyl esters of diacids. Optimal conditions of this reaction have been studied. High molecular weight PEAs (Mw = 24,000–167,000) with narrow polydispersity (Mw/Mn = 1.20–1.81) were prepared under the optimal reaction conditions and exhibited excellent film-forming properties. PEAs obtained are mostly amorphous materials with Tg from 11 to 59°C. α-Chymotrypsin catalyzed in vitro hydrolysis of these new PEA substrates was studied to assess the effect of the building blocks of these new polymers on their biodegradation properties. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 391–407, 1999

A new biodegradable poly( l -aspartic acid-co-poly(ethylene glycol)) having pendant amine functional groups was synthesized by the melt polycondensation reaction of prepolymer prepared from N-(benzyloxycarbonyl)- l -aspartic acid anhydride (N-Z- l -aspartic acid anhydride) and poly(ethylene glycol). The synthesized polymer was characterized by FTi.r., 1H n.m.r., d.s.c., g.p.c. and solubility. The weight-average molecular weight of the prepolymer increased about 11 times via melt polycondensation at 160°C in a vacuum for

The melt polycondensation reaction of the prepolymer prepared from N-(benzyloxycarbonyl)-L-aspartic acid anhydride (N-CBz-L-aspartic acid anhydride) and low molecular weight poly(ethylene glycol) (PEG) using titanium isopropoxide (TIP) as a catalyst produced the new biodegradable poly(L-aspartic acid-co-PEG). This new copolymer had pendant amine functional groups along the polymer backbone chain. The optimal reaction conditions for the preparation of the prepolymer were obtained by using a 0.12 mol % of p-toluenesulfonic acid with PEG 200 for 48 h. The weight-average molecular weight of the prepolymer increased from 1,290 to 31,700 upon melt polycondensation for 6 h at 130°C under vacuum using 0.5 wt % TIP as a catalyst. The synthesized monomer, prepolymer, and copolymer were characterized by FTIR, 1H- and 13C-NMR, and UV spectrophotometers. Thermal properties of the prepolymer and the protected copolymer were measured by DSC. The glass transition temperature (Tg) of the prepolymer shifted to a significantly higher temperature with increasing molecular weight via melt polycondensation reaction, and no melting temperature was observed. The in vitro hydrolytic degradation of these poly(L-aspartic acid-co-PEG) was measured in terms of molecular weight loss at different times and pHs at 37°C. This pH-dependent molecular weight loss was due to a simple hydrolysis of the backbone ester linkages and was characterized by more rapid rates of hydrolysis at an alkaline pH. These new biodegradable poly(L-aspartic acid-co-PEG)s may have potential applications in the biomedical field. © 1998 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 36: 2949–2959, 1998

Inulin polysaccharide was esterified with N-protected α-amino acids (N,N′-di-benzylocarbonyl-L-lysine and N-benzylocarbonyl-glycine) under a mild condition (room temperature) and within short reaction times (6 h). The esterification reactions were conducted in the presence of dicyclohexylcarbodiimide and 4-(dimethylamino)pyridine as a catalyst. The optimal reaction time (6 h) was determined by monitoring the concentration of free carboxylic acid of the N-protected amino acids during the reaction. The degree of substitution per fructose unit was 0.95 for inulin-lysine and 1.01 for inulin-glycine. The resulting biopolymer was deprotected by catalytic transfer hydrogenation method using 1,4-cyclohexadiene as an effective hydrogen donor. The structures, molecular weight, and thermal properties of the amino acid esters of inulin were determined by Fourier transform infrared spectroscopy, 1H and 13C NMR, UV, viscosity, and dicyclohexylcarbodiimide. This new modified inulin polysaccharide would have the potential as a biomaterial for biomedical applications. © 1998 John Wiley & Sons, Inc. J. Appl. Polym. Sci. 70: 953–963, 1998

A novel hormone conjugate has been prepared by a coupling reaction between modified estrone and dextran. In order to provide a suitable reactive estrone derivative for coupling with dextran and a spacer between the drug carrier and the hormone, the steroidal sex hormone was succinylated by reaction with succinic anhydride. Subsequently, the carboxylic acid terminal of succinylated estrone was further reacted with thionyl chloride to replace the hydroxy group with chlorine to make a better leaving group. The ester bond was employed as labile linkage between the hormone and the biopolymer carrier backbone so that the coupled estrogen could be released from the conjugate via ester hydrolysis. Structures of the modified estrone and dextran–estrone conjugate were determined by elemental analysis and by FTIR, 1 H and 13 C NMR spectroscopies. The degree of substitution (D.S.) per anhydroglucose (AHG) unit was 0.33 (11.0 mol-% of estrone moieties), as calculated from the 1 H NMR spectrum. In vitro hydrolysis of the conjugate in aqueous phosphate buffer/ethanol solutions at pH 8.0 and 7.4 and 37°C released estrone was completed within a few days and followed zero-order kinetics.

The objective of this study was to provide new synthetic route to prepare starch as a potential carrier for controlled release of drugs. A starch was modified with bromoacetyl bromide in order to provide more reactive sites for coupling of bioactive estrone and a suitable spacer between the drug carrier and the hormone. The degree of substitution (D.S.) per anhydroglucose (AHG) unit was calculated from the bromine content and ranged from 0.11 to 2.29, depending on the ratio of bromoacetyl bromide to starch. The starch-estrone conjugate was then synthesized by reacting bromoacetylated starch with the sodium salt of estrone. The structures of bromoacetylated starch and starch-estrone conjugate were determined by means of FTIR,1H NMR,13C NMR and UV. Additionally, X-ray diffraction patterns showed the amorphous character of the bromoacetylated starches.

A novel biodegradable polyester having pendant amine functional groups was snythesized from N-(benzyloxycarbonyl)-L-aspartic anhydride (2) and 1,4-cyclohexanedimethanol (3) by polycondensation reaction using p-toluenesulfonic acid as a catalyst. The synthesized polymer 4 shows the characteristic ester carbonyl absorption peak at 1732 cm−1 in the IR spectrum, and the NMR spectra were consistent with the IR data. Also, the elemental analysis showed that the experimental and calculated values were very close to each other. The weight-average molecular weight of the polymers ranged from 1140 to 5050 and increased with increasing reaction time. This new polymer would have the potential of a drug delivery biomaterial.

A solvent and Cremephor free formulation of the anticancer chemotherapeutic geldanamycin was prepared using amphiphilic block co-polymer micelles of poly(ethylene glycol)-b-poly(epsilon-caprolactone) (PEG-b-PCL). Although geldanamycin was not solubilized by PEG-b-PCL micelles, fatty acid prodrugs of geldanamycin were encapsulated in PEG-b-PCL micelles by a co-solvent extraction technique. Resulting PEG-b-PCL micelles were120 nm in diameter and solubilized20% w/w geldanamycin prodrugs increasing aqueous solubility to2 mg/mL. PEG-b-PCL micelles released the geldanamycin prodrugs over several days, t(1/2) 2.2 to 9.6 days. The free prodrugs hydrolyzed rapidly, t(1/2)6 h, into the geldanamycin analogue 17-beta-hydroxyethylamino-17-demethoxygeldanamycin, which has high activity against MCF-7 breast cancer cells, IC(50) 240 nM.

A New heterobifunctional poly(ethylene glycol) (PEG) having a polymerizable acryloyl group at one end and an isocyanate group at the other end was prepared in three efficient steps from commercially available t-Boc-PEG-NH 2 . The end groups were characterized by 'H NMR and MALDI-TOF-MS spectroscopy. Conjugation of the resulting PEG onto dextran via stable urethane linkage gave the PEG graft polymer with an acryloyl group at the free end of the graft chain.

Plastic waste recycling is beneficial because it can lead to a reduction in the amount of waste generated, a decreased need for landfills, and a more rational utilization of resources. An important source of polyethylene terephthalate (PET) for recycling is physically cleaned post-consumer bottles which are ground to form flake, depolymerized, purified, and repolymerized to form recycled resin bottles. Caustic treatment of polyester scrap involves cleavage of the ester linkages. The reaction of aqueous sodium hydroxide (8–10% by weight) with waste material in an autoclave at 210–250°C and elevated pressure goes to completion in about 3–5 hours1. The rate of hydrolysis may be enhanced by the presence of accelerants2,3. Terephthalic acid and ethylene glycol may be recovered from the solution. Hall3 used cetyl trimethylammonium bromide and lauryl dimethylbenzylammonium chloride as accelerants for the caustic reduction of PET.