Synthesis of new versatile functionalized polyesters for biomedical applications Ve ´ronique Nadeau, Gre ´goire Leclair, Shilpa Sant, Jean-Michel Rabanel, Richard Quesnel, Patrice Hildgen * Laboratoire de nanotechnologie pharmaceutique, Faculte ´ de pharmacie, Universite ´ de Montre ´al, CP 6128, succursale Centre Ville, Montre ´al, Que., Canada H3C 3J7 Received 12 May 2005; received in revised form 16 September 2005; accepted 22 September 2005 Available online 24 October 2005 Abstract A new family of branched polymers was synthesized for different biomedical applications such as the preparation of targeted nanoparticulate drug carriers. They are new copolymers of hydroxy-acids and allyl glycidyl ether. The functional groups (allyl-, hydroxyl- and carboxyl-) to which various groups will be grafted are linked to the polymer backbone. The resulting polymers were characterized by 1 H NMR, 13 C NMR, size exclusion chromatography (SEC), elemental analysis and differential scanning calorimetry (DSC). In vitro cytotoxicity assays were also conducted to ensure biocompatibility of the polymers. In order to obtain some structural evidences, different molecules have been grafted on the pendant groups. The method allows a rapid and easy synthesis of allyl-, hydroxyl- and carboxyl-branched degradable polymers for grafting various bioactive molecules. q 2005 Elsevier Ltd. All rights reserved. Keywords: Branched polymer; Biocompatible; Bioadhesive 1. Introduction Biodegradable polymers have had a remarkable impact in the field of controlled drug delivery. Over the past two decades, poly-(L-lactic acid) (PLLA) and its copolymers with D-lactic acid or glycolic acid or 3-caprolactone (CL) or polyethylene glycol (PEG) have been extensively studied as controlled drug delivery carriers. Such carriers offer various advantages such as controlled drug release rate, improved therapeutic efficiency, prolonged biological activity and decreased administration frequency [1]. With the in-depth understanding of the pathophysiology and cellular mechanisms of the disease, targeted or cell specific drug delivery is the focus of the current research. Block and graft copolymers of PLA and PEG have opened new avenues to the field of targeted drug delivery by prolonging the circulation time of the polymeric colloidal drug carriers. To target specific cell type in the body (as in case of tumour cells), the presence of specific ligands is necessary on the surface of the colloidal carriers. This would reduce the systemic side effects of the drug by improving the receptor- mediated uptake by the targeted cells. For instance, targeted doxorubicin delivery could be achieved by folate conjugated mixed micelles of the PLGA-b-PEG-folate polymer [2]. In other words, targeted drug delivery has generated a great need for biomaterials with bioadhesive and/or specific recognition properties. Thus, the ability to impart bioadhesivity, cell specificity or other specific characteristics to the existing biocompatible polymers represents an important synthetic challenge as well as holds the promise for better therapeutic protocols. Indeed, the availability of functional pendant groups is highly desirable for the fine tuning of the above- mentioned properties. Various efforts are directed towards achieving this goal [3,4]. However, chemistry involved in the synthesis of the functional monomers is complex and/or tedious, whereas the subsequent polymerization is generally out of control. For example, Bizzarri et al. have synthesized functionalized malolactonate polymers and copolymers, where the synthesis of monomers itself was long with low yields (12–45%) and polymerization reactions were very slow (over 4–30 days) [3]. Similarly, Ouchi et al. have reported the synthesis of PLA- grafted polysaccharides, however, their method required protection/deprotection steps [5]. Thus, there are very few reports on the efficient and easy synthesis of functionalized polyesters. Amongst them, Finne et al. have reported very Polymer 46 (2005) 11263–11272 www.elsevier.com/locate/polymer 0032-3861/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.polymer.2005.09.079 * Corresponding author. Tel.: C1 514 343 6448. E-mail address: patrice.hildgen@umontreal.ca (P. Hildgen).