α-Aldehyde Terminally Functional Methacrylic Polymers from Living Radical Polymerization:  Application in Protein Conjugation “Pegylation”

Tao, Lei; Mantovani, Giuseppe; Lecolley, F.R.; Haddleton, David M.

doi:10.1021/ja0456454

Cited by 223 publications

(217 citation statements)

References 21 publications

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“…achievable results in polymers amenable to protein or drug conjugation, 85 as demonstrated for example with lysozyme. 86 Other methacrylate units can be integrated into these structures, including oligopeptide residues such as the RGD sequence that is used widely for cell recognition. 87,88 For conjugation to proteins, and protein-based nanocage assemblies, it should be noted that ''growth-from'' methods are gaining popularity, by functionalization of the proteins with appropriate initiators, followed by polymerization radially outward from the protein.…”

Section: Branched Pegylated Polymer-drug Conjugatesmentioning

confidence: 99%

PEGylated polymers for medicine: from conjugation to self-assembled systems

2010

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Section: Branched Pegylated Polymer-drug Conjugatesmentioning

confidence: 99%

PEGylated polymers for medicine: from conjugation to self-assembled systems

2010

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“…Poly(poly(ethylene glycol) methyl ether methacrylate) polymers of differing MW were prepared by Transition Metal-Mediated Living Radical Polymerization (TMM-LRP) [13,14]. Each polymer (P) was conjugated to the N-terminal cys-1 at of sCT by reductive amination [15].…”

Section: Synthesis Of Sct-poly(poly(ethylene Glycol) Methyl Ether Metmentioning

confidence: 99%

PK/PD modelling of comb-shaped PEGylated salmon calcitonin conjugates of differing molecular weights

Ryan

Frías²,

Wang

et al. 2011

Journal of Controlled Release

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Salmon calcitonin (sCT) was conjugated via cysteine-1 to novel combed-shaped endfunctionalised poly(PEG) methyl ether methacrylate) (sCT-P) comb-shaped polymers, to yield conjugates of total molecular weights (MW) inclusive of sCT: 6.5, 9.5, 23 and 40 kDa. The conjugates were characterised by HPLC and their in vitro and in vivo bioactivity was measured by cAMP assay on human T47D cells and following intravenous (i.v.) injection to rats, respectively. Stability against endopeptidases, rat serum and liver homogenates was assessed. There were linear and exponential relationships between conjugate MW with potency and efficacy respectively, however the largest MW conjugate still retained 70% of E max and an EC 50 of 3.7 nM. In vivo, while free sCT and the conjugates reduced serum [calcium] to a maximum of 15-30 % over 240 min, the half life (T½) was increased and the area under the curve (AUC) was extended in proportion to conjugate MW. Likewise, the polymer conferred protection on sCT against attack by trypsin, chymotrypsin, elastase, rat serum and liver homogenates, with the best protection afforded by sCT-P (40 kDa). Mathematical modelling accurately predicted the MW relationships to in vitro efficacy, potency, in vivo PK and enzymatic stability. With a significant increase in T½ for sCT, the 40 kDa MW comb-shaped PEG conjugate of sCT may have potential as a long-acting injectable formulation.

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“…[1][2][3][4][5][6][7] PEGylation, the covalent attachment of polyethylene glycol, is a versatile means to increase a protein's size, stability and solubility. 2,[8][9][10][11] The increased radius of protein-PEG conjugates leads to a reduction in renal filtration, which together with decreased immunogenicity can result in longer circulation half lives compared to the native protein. 9,10 Such improvements in pharmacokinetics are crucial for the development of cost-effective and patient-friendly protein therapeutics.…”

Section: Introductionmentioning

confidence: 99%

Noncovalent PEGylation via Lectin–Glycopolymer Interactions

et al. 2016

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The full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2 AbstractPEGylation, the covalent modification of proteins with polyethylene glycol, is an abundantly used technique to improve the pharmacokinetics of therapeutic proteins. The drawback with this methodology is that the covalently attached PEG can impede the biological activity (e.g. reduced receptor-binding capacity). Protein therapeutics with "disposable" PEG modifiers have potential advantages over the current technology. Here, we show that a protein-polymer "Medusa complex" is formed by the combination of a hexavalent lectin with a glycopolymer. Using NMR spectroscopy, small angle X-ray scattering (SAXS), size exclusion chromatography and native gel electrophoresis it was demonstrated that the fucose-binding lectin RSL and a fucose-capped polyethylene glycol (Fuc-PEG) form a multimeric assembly. All of the experimental methods provided evidence of noncovalent PEGylation with a concomitant increase in molecular mass and hydrodynamic radius. The affinity of the protein-polymer complex was determined by ITCand competition experiments to be in the µM range, suggesting that such systems have potential biomedical applications.

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α-Aldehyde Terminally Functional Methacrylic Polymers from Living Radical Polymerization: Application in Protein Conjugation “Pegylation”

Cited by 223 publications

References 21 publications

PEGylated polymers for medicine: from conjugation to self-assembled systems

PEGylated polymers for medicine: from conjugation to self-assembled systems

PK/PD modelling of comb-shaped PEGylated salmon calcitonin conjugates of differing molecular weights

Noncovalent PEGylation via Lectin–Glycopolymer Interactions

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