Controlled Synthesis of Polyglutamates with Low Polydispersity and Versatile Architectures

摘要

Polyglutamates are well known to be highly biocompatible, biodegradable and multifunctional polymers, which have been already used as building blocks in polymer drug conjugates and polymeric micelles. Those systems have been applied to various medical applications ranging from therapy to molecular imaging. Furthermore a polyglutamic acid (PGA) paclitaxel conjugate has already entered clinical studies (Opaxio™ PGA-PTX conjugate currently in phase III of Clinical trials).;In this context, a synthetic pathway to a plethora functional polyglutamates (homopolymers, block-co-polymers, triblocks) with well-defined structure, adjustable molecular weight (Mw) and low dispersity (D=Mw/Mn<1.2) applying the ring opening polymerization (ROP) of N-carboxyanhydrides (NCA) has been developed. Additionally, the acid moieties of the polyglutamates can be activated with 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium (DMTMM) and various functionalities can be easily introduced by “post-polymerization modification” yielding a set orthogonal reactive attachment sides. The reactive moieties, such as azides, maleimides, thiols, alkynes (linear or cyclic) offer the opportunity of specific conjugation of the drugs, targeting moieties or markers. Besides introducing reactive groups the functionalization strategy was also used for PEGylation of PGA reducing charge induced interactions and therefore pharmacological properties, such as blood circulation time may be adjusted.;In summary, a tool kit of various polyglutamates has been developed enabling the synthesis of a variety of polymer drug conjugates or polymer based imaging agents. The functional polymeric precursors developed will allow us to functionalize and therefore adjust the polymer properties to a desired application.

主权项

1. Process for obtaining polyglutamates by means of controlled polymerization of N-carboxyanhydrides (NCAs) of alpha-amino acids using non-nucleophilic salts as initiator: tetrafluoroborate, according to formula:wherein:
R represents an alkyl group with Defined C-terminal attachment group (alkyne, azyde, thiols, halydes, activated thiols, alkenes, activated esters, activated alcohols, protected amines, maleimide groups, acetals, activated carboxylic acids), ethylenglycol (EG) of different molecular weights including polyethylenglycol (PEG, from 100 to 20000 g/mol); and n represents number of units of γ-benzylglutamate in the polymer, from 1 to 1000.