CONTROLLED SYNTHESIS OF POLYGLUTAMATES WITH LOW POLYDISPERSITY AND VERSATILE ARCHITECTURES

摘要

The present invention relates to the control of the polymerization of N-carboxyanhydrides (NCAs) of alpha-amino acids via the use of non-nucleophilic salts in order to obtain highly versatile polymeric architectures with low polydispersity indexes (homopolymers, diblock polymers, triblock polymers or multiblock sustems), and also to processes for the preparation therof and the use thereof of pharmaceutical compositions. Reference is specifically made to the production of functional polyglutamates with a defined structure, adjustable molecular weight and low polydispersity (D = Ms / Mn < 1.3) by means of the ring-opening polymerization of N-carboxyanhydrides. Also, the acid groups of the polymeric chain of the polyglutamates may be activated with 4- (4,6-dimethoxy-1,3,5-trizin-2-yl)-4-methylmorpholine, which allows the incorporation of various functionalities by "post-polymerization modification", thereby forming different reactive groups in the side chains of the polymer. The remaining reagents, such as azides, maleimides, thiles or (linear or cyclic) alkynes offer the opportunity for specific conjugation and can be used for drugs, directing units or markers. Futhermore, this functionalization strategy has also been used as a polyglutamate PEGylation mechanism, which reduces possible interactions arising from the carboxyl group load and therefore allows adjustment of the pharmacological properties of each case to the use therof in drugs or molecular imaging agents with therapeutic and/or diagnostic applications.