Centro De Investigacion Principe Felipe

Fundacion De La Comunidad Valenciana “Centro De Investigaciones Principe Felipe”

Fundacion De La Comunidad Valenciana Centro De Investigacion Principe Felipe

Aroa Duro Castaño

María Jesús Vicent Docón

Vicent Josep Nebot Carda

Matthias Barz

Fabiana Canal

Inmaculada Conejos Sanchez

Maria Jesus Vicent Docon

Richard Mark England

Inmaculada Conejos SÁNCHEZ

María Jesús Vicent DOCÓN

The invention relates to 3-arms star-shaped polypeptides derivatives which are able to self-assemble to form bioresponsive nanometric globular structures with controllable size and shape. These multivalent constructs also present the ability of disassemble under specific physiological conditions and of linking to at least one active agent so that they can be used as carries in biomedical applications.

Cross-linked star-shaped self-assembled polypeptides and its use as carriers in biomedical applications

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&#x2122; 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, tribocks) with well-defined structure, adjustable molecular weight (Mw) and low dispersity (D=Mw/Mn&#x3c;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, akynes (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.

Controlled synthesis of polyglutamates with low polydispersity and versatile architectures

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Valencia, Spain

Aroa Duro Castaño