Synthesis of Uniform Protein−Polymer Conjugates

Lele, B. S.; Murata, Hironobu; Matyjaszewski, Krzysztof; Russell, Alan J.

doi:10.1021/bm050428w

Cited by 308 publications

(277 citation statements)

References 23 publications

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“…Conjugating polymers with this structure have emerged in recent years as key macromolecular intermediates for the preparation of polymer-(poly)peptide conjugates [20][21][22][23][24] and others. [25][26][27][28] In this study a relatively low molecular weight comb polymer was prepared, in order to facilitate the purification and characterization of the peptide conjugates. Conjugation to Tyrosine-containing peptides.…”

Section: Resultsmentioning

confidence: 99%

“…Again, the conjugate was purified by ion-exchange chromatography (FPLC) affording pure conjugate. Biohybrid materials consisting of protein or peptide conjugates with comb mPEG (meth)acrylates are extremely difficult to characterize by MALDI-ToF mass spectrometry 48 with the only known example reported to date being restricted to conjugates with low Mn. 49 The conjugate sCT-(6) was characterized by cleavage of the diazo linker followed byanalysis of the resulting modified peptide and its tryptic digests (vide infra).…”

Section: Resultsmentioning

confidence: 99%

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Direct Peptide Bioconjugation/PEGylation at Tyrosine with Linear and Branched Polymeric Diazonium Salts

et al. 2012

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Direct polymer conjugation at peptide tyrosine residues is described. In this study Tyr residues of both leucine enkephalin and salmon calcitonin (sCT) were targeted using appropriate diazonium salt-terminated linear monomethoxy poly(ethylene glycol)s (mPEGs) and poly(mPEG) methacrylate prepared by atom transfer radical polymerization. Judicious choice of the reaction conditionspH, stoichiometry, and chemical structure of diazonium saltled to a high degree of site-specificity in the conjugation reaction, even in the presence of competitive peptide amino acid targets such as histidine, lysines, and N-terminal amine. In vitro studies showed that conjugation of mPEG2000 to sCT did not affect the peptide’s ability to increase intracellular cAMP induced in T47D human breast cancer cells bearing sCT receptors. Preliminary in vivo investigation showed preserved ability to reduce [Ca2+] plasma levels by mPEG2000-sCT conjugate in rat animal models.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Direct Peptide Bioconjugation/PEGylation at Tyrosine with Linear and Branched Polymeric Diazonium Salts

et al. 2012

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“…Recently, the direct growth of polymers from proteins has emerged as an alternative to postpolymerization conjugation (10)(11)(12)(13)(14)(15)(16)(17)(18), but these methods do not provide a general method for protein conjugation that meet all of these requirements. Furthermore, they have not been applied to synthesize polymers directly from a protein that improve the pharmacological profiles of proteins, nor have they been evaluated in vivo.…”

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confidence: 99%

In situ growth of a stoichiometric PEG-like conjugate at a protein's N-terminus with significantly improved pharmacokinetics

Gao

Liu

MacKay³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

167

160

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The challenge in the synthesis of protein-polymer conjugates for biological applications is to synthesize a stoichiometric (typically 1:1) conjugate of the protein with a monodisperse polymer, with good retention of protein activity, significantly improved pharmacokinetics and increased bioavailability, and hence improved in vivo efficacy. Here we demonstrate, using myoglobin as an example, a general route to grow a PEG-like polymer, poly(oligo(ethylene glycol) methyl ether methacrylate) [poly(OEGMA)], with low polydispersity and high yield, solely from the N-terminus of the protein by in situ atom transfer radical polymerization (ATRP) under aqueous conditions, to yield a site-specific (N-terminal) and stoichiometric conjugate (1:1). Notably, the myoglobin-poly(OEGMA) conjugate [hydrodynamic radius (R h): 13 nm] showed a 41-fold increase in its blood exposure compared to the protein (Rh: 1.7 nm) after IV administration to mice, thereby demonstrating that comb polymers that present short oligo-(ethylene glycol) side chains are a class of PEG-like polymers that can significantly improve the pharmacological properties of proteins. We believe that this approach to the synthesis of N-terminal protein conjugates of poly(OEGMA) may be applicable to a large subset of protein and peptide drugs, and thereby provide a general methodology for improvement of their pharmacological profiles. drug delivery ͉ living radical polymerization ͉ protein-polymer conjugate

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“…Nevertheless, studies exploring the feasibility of using proteins as macroinitiators to grow directly polymers are still required. [42] Aimed at setting up a suitable protocol to produce therapeutically active polymer-protein bioconjugates according to the growing from concept, the pPEGMA growth on the recombinant human growth hormone (rh-GH) by atom transfer radical polymerization (ATRP) has been explored (Figure 2). [43] ATRP is an advantageous technique for generating polymers with a very wide range of molar masses with good control.…”

Section: Growing From Protein Pegylationmentioning

confidence: 99%

Supramolecular Bioconjugates for Protein and Small Drug Delivery

Salmaso

Bersani

Scomparin

et al. 2010

Israel Journal of Chemistry

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Supramolecular conjugation techniques have been developed to produce novel nanosized systems by assembling materials with diverse physicochemical and biological features. These techniques have been adapted to obtain innovative bioconjugates to deliver drugs with poor biopharmaceutical properties and nano‐devices with potential “theranostic” activity. Supramolecular drug delivery systems include polymer therapeutics such as drug–polymer bioconjugates, and colloidal carriers such as micelles, liposomes, polyplexes, and organic and inorganic nanoparticles. By virtue of their wide array of chemical composition and properties, polymers represent key elements for the construction of novel supramoelcular formulations. Polymer bioconjugation is a fledged technique for fabrication of protein–polymer conjugates. PEGylation, in particular, produces derivatives with enhanced pharmacokinetic, immunological, and stability properties as compared to the parent protein. Over the years, new methods have been set up to obtain site‐directed polymer conjugation. In this review we report few grafting to and growing from PEGylation examples for the preparation of therapeutically effective protein bioconjugates. Supramolecular formulations with unique properties can be also obtained by assembling functional polymers, targeting agents, physicochemical modifiers, and biomodulators. These systems may be designed for disease tissue disposition and cell recognition/penetration. Cyclodextrins, for example, have been functionalized with polyethylene glycol and folic acid to produce tumor‐targeted drug carriers. Interesting results have been obtained with this novel class of drug delivery systems. In addition, responsive polymers have been conjugated to gold nanoparticles to endow a new colloidal platform with triggerable cell disposition properties, which can be exploited either in biomedicine or diagnosis.

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Synthesis of Uniform Protein−Polymer Conjugates

Cited by 308 publications

References 23 publications

Direct Peptide Bioconjugation/PEGylation at Tyrosine with Linear and Branched Polymeric Diazonium Salts

Direct Peptide Bioconjugation/PEGylation at Tyrosine with Linear and Branched Polymeric Diazonium Salts

In situ growth of a stoichiometric PEG-like conjugate at a protein's N-terminus with significantly improved pharmacokinetics

Supramolecular Bioconjugates for Protein and Small Drug Delivery

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