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PEGylation of L-asparaginase in microfluidic systems

Grant number: 20/14308-0
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): March 01, 2021
Effective date (End): August 31, 2021
Field of knowledge:Engineering - Chemical Engineering - Chemical Process Industries
Principal Investigator:João Henrique Picado Madalena Santos
Grantee:Mileyde Araujo
Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil


Then enzyme L-asparaginase is responsible for converting the amino acid L-asparagine into L-aspartic acid and ammonium. This enzyme has important applications, mainly in the pharmaceutical industry, where it is used as an antileukemic biopharmaceutical, for the treatment of acute lymphoblastic leukemia (ALL). In order to improve the performance of biopharmaceuticals, in recent years, techniques for improving biopharmaceuticals by bioconjugation have been developed, among these techniques PEGylation stands out. This technique allows a decrease in immunogenicity, an increase in solubility and half-life in plasma, and greater protection against proteolytic attack. Despite the advantages of PEGylated biopharmaceuticals, also called biobetters, some limitations associated with PEGylation reactions need to be addressed, such as: the low conversion rate resulting from the hydrolysis of reactive PEG and the reduced selectivity resulting in a heterogeneity of PEGylated species formed by parallel reactions between reactive PEG and protein functional amino acids. Both the extent of reaction conversion and the selectivity of the protein PEGylation process are highly sensitive to experimental process parameters (i.e. reaction time, PEG molar ratio: protein, agitation and pH). In this way, this innovative study intends to optimize the bioconjugation reactions of L-asparaginase by applying passive microreactors of continuous flow in two geometries (serpentine microchannels and H-shaped microchannels) taking into account the increase in the rate of PEGylation and reaction selectivity. The reactive PEG to be used is methoxy-polyethylene glycol carboxymethyl N-hydroxysuccinimidyl ester (mPEG-NHS) of three molecular weights (10, 20 and 40 kDa). It is intended to compare with the yield of the reactions obtained in microfluidics by passive micromixers with those obtained on a laboratory scale in batch processes by magnetic stirring. It is pretended with this project to expand the knowledge of technologies associated with the reaction processes of bioconjugation of biopharmaceuticals.

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