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mPEG–NHS carbonates: Effect of alkyl spacers on the reactivity: Kinetic and mechanistic insights
Author(s) -
Vaillard Victoria A.,
Menegon Malen,
Neuman Nicolás I.,
Vaillard Santiago E.
Publication year - 2019
Publication title -
journal of applied polymer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.575
H-Index - 166
eISSN - 1097-4628
pISSN - 0021-8995
DOI - 10.1002/app.47028
Subject(s) - pegylation , reactivity (psychology) , chemistry , reagent , alkyl , combinatorial chemistry , hydrolysis , macromolecule , organic chemistry , polyethylene glycol , medicine , biochemistry , alternative medicine , pathology
Nowadays, the chemical conjugation to mPEG, also known as PEGylation, is a well‐recognized technology used to improve the pharmaceutical properties of the therapeutic proteins. Over the last 20 years, more than 10 PEGylated macromolecules reached the market with tremendous success, whereas various other bioconjugates are under advanced clinical trials. mPEG– N ‐hydroxysuccinimidyl carbonate is an important reagent of widespread application for the PEGylation of biomacromolecules. One of the most important challenges in this technology is the development of more selective PEGylation reagents aimed to provide more consistent polymer–protein conjugates. One approach followed to improve the selectivity of PEGylation reagents is the design of less reactive derivatives, for example, by incorporation of alkyl spacers between the polymer chain and the terminal reactive group. In this work, we prepared a family of mPEG– N ‐hydroxysuccinimidyl carbonates bearing spacers of up to 6 carbon atoms. The kinetics of hydrolysis of the carbonates was studied under different experimental conditions, as a straight measure of the influence of the length of the spacer on the reactivity. By DFT calculations, we propose a detailed mechanism for the hydrolysis reaction. The influence of the length of alkyl spacer on the reactivity of the carbonates and related esters is studied and discussed in detail. Finally, to further evaluate the reactivity, selected N ‐hydroxysuccinimidyl carbonates were studied in the conjugation reaction of bovine lactoferrin. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136 , 47028.