A new approach to bioconjugates for proteins and peptides (“pegylation”) utilising living radical polymerisation

Lecolley, F.R.; Tao, Lei; Mantovani, Giuseppe; Durkin, Ian; Lautru, Sylvie; Haddleton, David M.

doi:10.1039/b407712a

Cited by 154 publications

(161 citation statements)

References 19 publications

(2 reference statements)

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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%

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

confidence: 99%

“…injection to rats. Whilst increased polymer MW generally improves peptide stability and lengthens the T½, it may interfere with biological functions at the receptor level due to steric hindran2e [13]. Therefore, an appropriate polymer MW should be selected to balance pharmacodynamics (PD) and PK.…”

Section: Introductionmentioning

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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“…Besides controlling polymer microstructure, the alkoxyamine initiator fragment can permit functionalization and derivatization, such as using an initiator bearing an activated ester moiety. N-hydroxysuccinimidyl (NHS) esters readily react with nucleophiles in single-step reactions [34] and precursors functionalized by NHS have been reported for ATRP [35] and RAFT [36] to yield α-functional polymers. Vinas et al synthesized the first NHS-functionalized initiator for NMP using BlocBuilder [37].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Stimuli-responsive, Water-soluble Poly[2-(dimethylamino)ethyl methacrylate/styrene] Statistical Copolymers by Nitroxide Mediated Polymerization

Zhang

Marić

2011

Polymers

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Abstract:2-(Dimethylamino)ethyl methacrylate/styrene statistical copolymers (poly(DMAEMA-stat-styrene)) with feed compositions f DMAEMA = 80-95 mol%, (number average molecular weights M n = 9.5-11.2 kg mol −1 ) were synthesized using succinimidyl ester-functionalized BlocBuilder alkoxyamine initiator at 80 °C in bulk. Polymerization rate increased three-fold on increasing f DMAEMA = 80 to 95 mol%. Linear M n increases with conversion were observed up to about 50% conversion and obtained copolymers possessed monomodal, relatively narrow molecular weight distributions (polydispersity = 1.32-1.59).Copolymers with f DMAEMA = 80 and 90 mol% were also cleanly chain-extended with DMAEMA/styrene mixtures of 95 and 90 mol% DMAEMA, respectively, confirming the livingness of the copolymers. Copolymer phase behavior in aqueous solutions was examined by dynamic light scattering and UV-Vis spectroscopy. All copolymers exhibited lower critical solution temperature (LCST)-type behavior. LCST decreased with increasing styrene content in the copolymer and with increasing solution concentration. All copolymers were completely water-soluble and temperature insensitive at pH 4 but were more hydrophobic at pH 10, particularly copolymers with f DMAEMA = 80 and 85 mol%, which were water-insoluble. At pH 10, LCST of copolymers with f DMAEMA = 90 and 95 mol% were more than 10 °C lower compared to their solutions in neutral, de-ionized water. Block copolymers with two statistical blocks with different DMAEMA compositions exhibited a OPEN ACCESSPolymers 2011, 3 1399 single LCST, suggesting the block segments were not distinct enough to exhibit separate LCSTs in water.

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“…Thus, an activated bromocompound, SI-Br, was prepared from 2-bromopropionyl bromide and NHS by following a literature protocol. [69] For attachment of the 2-bromopropionyl group to the amine groups present on the antibodies, anti-IgG or antipoly-His was incubated with SI-Br for 48 h. Subsequently, the antibodies were incubated in a sodium azide solution for another 48 h for the substitution reaction between the azide and bromide groups to occur (Scheme 2).…”

Section: Resultsmentioning

confidence: 99%

Photoinducedin situformation of clickable PEG hydrogels and their antibody conjugation

Kahveci

Çiftçi

Evran

et al. 2014

Designed Monomers and Polymers

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A simple approach for the preparation of a clickable poly(ethylene glycol)-based hydrogel as a polymeric support for protein immobilization via photoinitiated free radical polymerization of poly(ethylene glycol) diacrylate and propargyl acrylate is established. Bioconjugation to the obtained gels was achieved by azide-alkyne click reaction with azidofunctionalized anti-immunoglobulin G (anti-IgG) and anti-His tag antibodies. Evaluation of the affinities of the PEG hydrogels to the corresponding substrates (IgG and His-tagged YFP, respectively) indicates their specific binding capability.

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A new approach to bioconjugates for proteins and peptides (“pegylation”) utilising living radical polymerisation

Abstract: The synthesis of protein-polymer bioconjugates is reported using N-succinimidyl ester functionalised polymers from transition metal mediated living radical polymerisation.

Cited by 154 publications

References 19 publications

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

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

Synthesis of Stimuli-responsive, Water-soluble Poly[2-(dimethylamino)ethyl methacrylate/styrene] Statistical Copolymers by Nitroxide Mediated Polymerization

Photoinducedin situformation of clickable PEG hydrogels and their antibody conjugation

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