Polymer Sequences DOI: 10.1002/anie.201103076 Precision Synthesis of Biodegradable Polymers** Christophe M. Thomas* and Jean-FranÅois Lutz* biocompatible materials · biodegradable polymers · polymerization · polymers · primary structure The design of bioapplicable polymers and materials is a true dilemma for todays synthetic chemists. Indeed, modern bioapplicable materials have to fulfill antinomic criteria: on one hand, they should exhibit advanced properties and functions, [1] while on the other hand they have to comply with increasingly stringent regulations on sterilization, bio- compatibility, and in vivo clearance. Consequently, there nowadays is a huge gap between promising options reported in the scientific literature and real bioapplicable systems. For instance, the overall number of approved polymers for human use is relatively low. Biodegradable aliphatic polyesters such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA) and poly(lactic-co-glycolic acid) (PLGA) are widely used poly- mers in life sciences. [2] These polymers can be hydrolyzed in vitro and in vivo within weeks to years. In addition, PLA, PGA, and PLGA and their degradation products have been shown to be nontoxic and biocompatible. [3] Therefore, in the past few decades, many homopolymers and copolymers based on lactic and glycolic acid have been used in a variety of bioapplications as diverse as controlled drug release, gene therapy, regenerative medicine, or implants. [4] In particular, the copolymer PLGA that contains both (S,S)- or rac-lactic and glycolic units is the most widely used material for drug- release systems. Several parameters have been reported to influence the degradation behavior of PLGA; the most important factors are the copolymer composition, the molecular weight and molecular-weight distribution, the crystallinity, and the struc- ture of the copolymer. [5] Other important properties of the polymer matrix that depend on the copolymer composition, such as the glass transition temperature (T g ), have additional indirect effects on degradation rates. [5d] For instance, PLGAs with diverse material properties and degradation rates can be produced by incorporating various monomer ratios. Indeed, PLGA degrades by hydrolysis of its ester linkages and it has been shown that the ester linkages in glycolic units are more sensitive to hydrolysis than their lactic counterparts. [6] How- ever, the simple adjustment of the overall copolymer compo- sition is not necessarily optimal for all applications. For instance, demanding applications such as controlled and sustained drug delivery may require very specific degradation kinetics. Major problems encountered in time-controlled delivery of drugs from biodegradable PLGA matrices are the overall bioavailability of the released drugs and the fast initial release from the polymer matrix (“burst release”). [7] This initial hydrolysis is typically followed by a slow degradation of the residual material. Thus, the preparation of micro- or nano- particles is usually accompanied by an important loss in activity of the drugs. [8] Therefore, there is still a great need for a safe and effective delivery system for labile and/or large molecules to be delivered to specific targets. Possible alter- natives to PLGA are extensively studied and reported every week in specialized journals. However, as mentioned above, the approval of a new biocompatible polymer is a tedious process, which may require years to be completed. In this context, it is sometimes wiser and certainly more straightfor- ward to optimize existing structures rather than to develop new ones. For instance, a finer control of the PLGA structure would allow the proper selection of the rates of both the drug release and the biodegradation of particles. There is an increasing interest in methods that allow for the preparation of PLGAs in a reproducible and controlled fashion. Current methods to synthesize PLGAs include direct condensation from lactic acid, glycolic acid, and light condensates (i.e. small oligomers) or ring-opening polymer- ization (ROP) of the related cyclic dimers, namely, lactide and glycolide) in bulk, initiated with metal alkoxides. [9] However, in such ring-opening processes, the number and types of sequences that can be prepared are limited by the dimeric form of the ROP monomers. Moreover, poly(rac-lactic acid- co-glycolic acid) (rac-PLGA) obtained from these dimers has broad composition ranges and a random block nature because of the much higher reactivity of glycolide and the drastic polymerization conditions. [10] Current PLGAs are therefore far from being optimal and tailor-made structures are certainly needed. However, in the case of simple aliphatic polyesters, the available options for molecular optimization are relatively limited. Indeed, only a [*] Prof. Dr. C. M. Thomas Chimie ParisTech, UMR CNRS 7223 11 rue Pierre et Marie Curie, 75005 Paris (France) E-mail: christophe-thomas@ens.chimie-paristech.fr Dr. J.-F. Lutz Precision Macromolecular Chemistry Institut Charles Sadron, UPR22-CNRS 67034 Strasbourg (France) E-mail: jflutz@unistra.fr [**] C.M.T. is grateful to the ENSCP, the CNRS, and the French Ministry of Higher Education and Research for financial support. J.F.L. gratefully acknowledges the CNRS, the University of Strasbourg, the International Center for Frontier Research in Chemistry (FRC, Strasbourg), and the European Research Council (Project SE- QUENCES—ERC grant agreement 258593) for financial support. Highlights 9244  2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2011, 50, 9244 – 9246