Catalytic chain transfer polymerisation based on cobalt II or III chelates is a free radical technique which allows the synthesis of functional oligomers with a terminal α-substituted acrylate group. This paper will review the applications of such oligomers in the design of low molecular weight, graft and block copolymer emulsions and dispersions for waterborne, two-component polyurethane paints. Such emulsions and dispersions have a composition and molecular weight control and offer unique properties when compared with binders prepared via conventional techniques.

Poly-[N-(2-hydroxyethyl)-L-glutamine] (PHEG) prodrugs of the cytotoxic agent Mitomycin C were synthesized using peptidyl spacers to link the drug to the polymeric carrier. The influence on the length and detailed structure of the oligopeptide on the rate of drug release was investigated in buffer, in the presence of lysosomal enzymes (tritosomes, cathepsin B and D) and metalloprotease type IV collagenase. It was observed that tetra- and hexapeptide based conjugates generally release Mitomycin C (MMC) more effectively than tripeptide derivatives. The gly-phe-ala-leu conjugate released MMC very rapidly both in presence of lysosomal enzymes and collagenase IV. Only in the presence of the aspartic protease cathepsin D, the gly-phe-leu-gly-phe-leu derivative turned out to be a better substrate. In vivo studies against C26 solid tumour bearing mice suggest that PHEG-spacer-MMC conjugates act as prodrugs of MMC: antitumour efficacy of the macromolecular prodrugs was better than free MMC both in inhibition of tumour growth and increasing survival.

The synthesis and in vitro biodegradation of poly(ethylene glycol) modified poly[N-2-hydroxyethyl)L-glutamine] are described. Poly(ethylene glycol) (PEG) with terminal amino endgroup was coupled onto 4-nitrophenyl chloroformate activated poly[N-2-hydroxyethyl-L-glutamineI (PHEG). The influence of the degree of substitution and the molecular weight of PEG side groups on the degradability of the PHEG backbone exposed to isolated rat liver lysosomal enzymes was determined. These data indicate that substitution of PHEG with PEG side-chains only slightly alters the degradability of the carrier. The PEG-grafted polymers showed potential tensioactive properties. DSC analysis demonstrated phase separation of the PEG side-groups in solid state.

Prodrugs of mitomycin C (MMC) based on soluble poly-[N-(2-hydroxyethyl)-L-glutamine] (pHEG) polymers have been evaluated as tumour-targeted drugs. These materials are designed to exploit the enhanced permeability of tumour vasculature, combining a passive tumour tropism with decreased systemic liberation of free MMC. A tri- or tetrapeptide linkage (e.g. Gly-Phe-Ala-Leu) between pHEG and the aziridine nitrogen of MMC can combine good hydrolytic stability with rapid cleavage by lysosomal enzymes, releasing free MMC. The conjugates showed decreased systemic toxicity and could be administered to mice at a total MMC dose of 15 mg/kg i.v., compared with just 6 mg/kg for free MMC. Conjugates also showed better activity against animal models of established tumours, achieving up to 77% increased life span (ILS) against solid P388 leukaemia, compared with only 23% for free MMC, and up to 121% ILS against solid C26 colorectal carcinoma, compared with no activity for the free drug. Improving the therapeutic index of anticancer drugs by combining tumour tropism with decreased systemic toxicity is a versatile approach that should produce a new generation of improved anticancer agents.

Poly-[N-(2-hydroxyethyl)-L-glutamine] (PHEG) prodrugs of the antitumour antibiotic mitomycin C (MMC) were synthesised using peptidyl spacers, tri- and tetrapeptides, to link the drug to the macromolecular carrier. The relationship between the length and composition of the oligopeptide spacer and the rate of drug release was studied by incubation in buffers, serum and in the presence of enzymes (lysosomal enzymes and collagenase IV). It was observed that tetrapeptide-based conjugates generally release MMC more effectively than tripeptide derivatives. Conjugates having a terminal glycine in the spacer are less stable to hydrolysis than those with a terminal hydrophobic amino acid both in buffer and in serum. The gly-phe-ala-leu conjugate released MMC very rapidly in the presence of both lysosomal enzymes and collagenase IV. Biological experiments indicate that PHEG-MMC conjugates act as prodrugs of MMC: cytotoxicity was observed after hydrolytic release of the active compound in vitro. In vivo studies of P388 solid tumour-bearing mice suggest that conjugates which release MMC slowly may be more effective in inhibiting tumour growth and prolonging animal lifespan. Preliminary in vivo bone marrow toxicity studies indicate that PHEG-MMC prodrugs are less myelosuppressive than free MMC.

Poly-α,β-[N-(2-hydroxyethyl)-d,l-aspartamide] (PHEA) and poly-α,β-[N-(2,3-dihydroxypropyl)-d,l- aspartamide] (PDHPA) are suitable as macromolecular drug carriers. In order to introduce amine- containing drug moieties onto these polymers, partial conversion of the hydroxyl side groups is required. This paper describes the 4-nitrophenyl chloroformate activation of PHEA and PDHPA. It is shown that, during the course of the activation of PHEA, only linear aromatic carbonate structures were formed. However, during the activation reaction of PDHPA, conversion of 4-nitrophenyl carbonates into cyclic carbonate structures could be observed. The relative amount of the two types of carbonate moieties could be controlled by addition of the appropriate catalyst. During the activation reaction of both polymers, the total content of carbonate groups could, for a given set of reaction conditions, be controlled by the amount of chloroformate added. The 4-nitrophenyl carbonate groups easily reacted with amines. However, the conversion of the cyclic carbonate moieties into urethane-bound derivatives was only possible with highly reactive amines. This could be an interesting property for the introduction of different types of amine- containing derivatives onto the polymer backbone. The results of this study demonstrate the feasibility of the described activation methods to prepare macromolecular prodrugs.

In the present paper, we report the competition for the mannose-specific lectin of mononuclear phagocytes between two potential drug carriers, namely dextran and poly-alpha,beta-[N(2-hydroxyethyl)-D,L-aspartamide] (p-HEA) both modified by either alpha-D-mannose or beta-L-fucose residues, and glucose oxidase (G.O.) following intravenous coinjection into mice.Native dextran or p-HEA did not influence the plasma half-life time of G.O. On the other hand, coinjection of an excess of either alpha-D-mannosylated or beta L-fucosylated dextran of comparable sugar content did increase the circulation half-life time significantly. The extent by which the T1/2 of G.O. was prolonged, depended on sugar loading and the amount of competing polymer. Comparison between beta-L-fucosylated and alpha-D-mannosylated dextran revealed a slightly more efficient receptor inhibition by mannose.The effect of the macromolecular carrier nature was clearly demonstrated by comparison between dextran and p-HEA conjugates. All glycosylated p-HEA derivatives retarded the blood clearance of G.O. less than the dextran analogues. Further competition experiments revealed a rather peculiar in vivo behaviour of modified dextrans, probably due to adsorption phenomena on blood cell membranes.

Macromolecular Rapid CommunicationsVolume 15, Issue 9 p. 697-704 Article Synthesis and characterization of poly(oxyethylene) modified dextrans Katty Hoste, Katty Hoste Department of Organic Chemistry, Biomaterial & Polymer Research Group, University of Gent, Krijgslaan 281, B-9000 Gent, BelgiumSearch for more papers by this authorDorine Bruneel, Dorine Bruneel Department of Organic Chemistry, Biomaterial & Polymer Research Group, University of Gent, Krijgslaan 281, B-9000 Gent, BelgiumSearch for more papers by this authorAnne De Marre, Anne De Marre Department of Organic Chemistry, Biomaterial & Polymer Research Group, University of Gent, Krijgslaan 281, B-9000 Gent, BelgiumSearch for more papers by this authorFrans De Schrijver, Frans De Schrijver Department of Chemistry, Laboratory for Molecular Dynamics and Spectroscopy, Catholic University of Leaven, Celestijnenlaan 200F, B-3001 Heverlee, BelgiumSearch for more papers by this authorEtienne Schacht, Corresponding Author Etienne Schacht Department of Organic Chemistry, Biomaterial & Polymer Research Group, University of Gent, Krijgslaan 281, B-9000 Gent, BelgiumDepartment of Organic Chemistry, Biomaterial & Polymer Research Group, University of Gent, Krijgslaan 281, B-9000 Gent, BelgiumSearch for more papers by this author Katty Hoste, Katty Hoste Department of Organic Chemistry, Biomaterial & Polymer Research Group, University of Gent, Krijgslaan 281, B-9000 Gent, BelgiumSearch for more papers by this authorDorine Bruneel, Dorine Bruneel Department of Organic Chemistry, Biomaterial & Polymer Research Group, University of Gent, Krijgslaan 281, B-9000 Gent, BelgiumSearch for more papers by this authorAnne De Marre, Anne De Marre Department of Organic Chemistry, Biomaterial & Polymer Research Group, University of Gent, Krijgslaan 281, B-9000 Gent, BelgiumSearch for more papers by this authorFrans De Schrijver, Frans De Schrijver Department of Chemistry, Laboratory for Molecular Dynamics and Spectroscopy, Catholic University of Leaven, Celestijnenlaan 200F, B-3001 Heverlee, BelgiumSearch for more papers by this authorEtienne Schacht, Corresponding Author Etienne Schacht Department of Organic Chemistry, Biomaterial & Polymer Research Group, University of Gent, Krijgslaan 281, B-9000 Gent, BelgiumDepartment of Organic Chemistry, Biomaterial & Polymer Research Group, University of Gent, Krijgslaan 281, B-9000 Gent, BelgiumSearch for more papers by this author First published: September 1994 https://doi.org/10.1002/marc.1994.030150906Citations: 22AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume15, Issue9September 1994Pages 697-704 RelatedInformation

This paper describes the synthesis of poly[N5-(2-hydroxyethyl)-l-glutamine] (PHEG) by the aminolysis of poly(γ-benzyl-l-glutamate) (PBG) with 2-aminoethanol. The effects of the temperature and addition of the bifunctional catalyst, 2-hydroxypyridine (2-HP), on the kinetics of aminolysis were studied. The results suggest that the aminolysis reaction takes place much faster with increasing temperature and an increasing amount of added catalyst. Moreover, chain scission, due to aminolysis of the amide bonds of the polymer backbone, can be minimized by the addition of the appropriate amount of 2-hydroxypyridine. These data demonstrate the feasibility of the described method to prepare PHEG derivatives with well controlled molecular weights.

A series of polymeric prodrugs of Mitomycin C (MMC) were prepared by coupling the drug via a tri- or tetrapeptide spacer onto poly-[5N-(2-hydroxyethyl)-L-glutamine] (PHEG). In the first step MMC was linked to the peptide spacer. For preparing the oligopeptide-MMC derivatives N-Fmoc protected oligopeptide was activated as the pentafluorophenyl ester. After coupling with MMC the N-protective group can be removed under mild conditions. The spacer-MMC derivatives were finally coupled to 4-nitrophenyl chloroformate activated PHEG.

The cytostatic agent Mitomycin C (MMC) was coupled to a polymeric carrier, poly-[N-(2-hydroxyethyl)-l-glutamine] (PHEG), via peptide spacers. The influence of the amino acid sequence of the spacer on the hydrolytic and enzymatic stability of the macromolecular drug conjugate was investigated under different conditions. Accordingly the conjugates were incubated at neutral and slightly acid pH, and in presence of lysosomal enzymes or in serum. It was observed that tetrapeptide-based conjugates generally release MMC more effectively than tripeptide derivatives. Conjugates having a terminal glycine in the spacer are less hydrolytically stable than those with a terminal hydrophobic amino acid both in buffer and in serum. Gly-Phe-Leu-Gly, Gly-Phe-Ala-Leu and Ala-Leu-Ala-Leu derivatives released MMC very rapidly in the presence of lysosomal enzymes.

Poly[N-(2-hydroxyethyl)-L-glutamine] (PHEG) is a suitable carrier for the design of macromolecular prodrugs, A method is described for partial conversion of hydroxyl side groups into reactive carbonate esters. Activation is achieved through the reaction with 4-nitrophenyl chloroformate. It is shown that during the course of the activation no intra- or intermolecular carbonate esters are formed. The content of reactive carbonates can, for a given set of reaction conditions, be controlled by the amount of chloroformate added. The activated polymer easily reacts with numerous amines. Reaction with a melphalan prodrug and amino-terminated glycosides demonstrated the feasibility of the presently described activation method to prepare macromolecular prodrugs.

Dextran fractions with a narrow molecular weight distribution were modified using the 4-nitrophenyl chloroformate activation method. The activated polymers were subsequently reacted with a small amount of L- tyrosinamide and a number of selected peracetylated ω-amino glycosides of D- mannose, D-galactose, L-fucose and L-rhamnose and including some cluster de rivatives. All monosaccharides were linked to the polymer chain via a carbon C-6 spacer. The number of L-tyrosinamide units introduced could be accurately deter mined by UV absorption spectroscopy. On the other hand, the degree of substi tution by a glycoside ligand was calculated from 1H NMR data.