pH-responsive micelles and vesicles nanocapsules based on polypeptide diblock copolymers F. Che ´cot, J. Rodrı ´guez-Herna ´ndez, Y. Gnanou, S. Lecommandoux * Laboratoire de Chimie des Polyme `res Organiques (LCPO-UMR5629), CNRS, ENSCPB, University Bordeaux 1, 16 Avenue Pey Berland, 33607 Pessac-Cedex, France Abstract The self-assembly of well-defined polypeptide-based diblock copolymers into micelles and vesicles is presented. The stimuli-responsive behavior of polypeptides to pH and ionic strength is used to produce stimuli-responsive nanoparticles with controlled size and shape. Results focusing on micelles and vesicles obtained from polypeptide-based diblock copolymers that are particularly promising for biomedical applications are detailed by means of static and dynamic light scattering analysis, UV circular dichroism, NMR and small angle neutron scattering experiments. Also systems able to form vesicles with a narrow size distribution at basic and acid pH going through a single molecule intermediate state are presented. These nanoparticles are particularly interesting for encapsulation and delivery purpose at a controlled pH. # 2006 Elsevier B.V. All rights reserved. Keywords: Self-assembly; Block copolymers; Polypeptide; Vesicle 1. Introduction Block copolymers are a well-known and representative class of macromolecules that have been synthesized in laboratory during the last 50 years. Moreover, the recent progresses in the synthetic strategies that can be applied to vary the chemical composition and architecture of block copolymers open new areas of development. One main reason of the current interest in these systems is related to the wide variety of micro and nanostructures that can be obtained. It is now well established, both from a theoretical (Leibler, 1980; Bates, 1991; Fredrickson and Bates, 1996) and an experimental (Ciferri, 2000; Hamley, 1998) point of view, that linear AB diblock copolymers composed of immiscible blocks undergo microphase separation. They can form micellar aggregates when dissolved in a selective solvent for one of the blocks (Riess, 2003), and phase separate into a variety of organized structures in the bulk state (Ciferri, 2000; Hamley, 1998; Klok and Lecommandoux, 2001). The corresponding morphologies (shape and size) depend on the total degree of polymerization N, which is proportional to the molecular weight, and on the chemical composition of the copolymer f A , corresponding to the volume fraction of the block A( f B =1 À f A ). The thermodynamic interaction between the two blocks is given by the dimensionless Flory-Huggins interaction parameter x AB (or x), which is inversely proportional to the temperature. Over the past few years, increasing attention has been given to the supramolecular organization of water- soluble block copolymer surfactants and to their potential use in applications such as coatings, drug delivery systems, nanopar- ticles or nanoreactors (Graff et al., 2002; Nardin et al., 2001; Chiu et al., 1999; Kataoka et al., 2001; Lavasanifar et al., 2002; Kabanov et al., 2002). An important issue towards making these self-assembled systems useful for specific applications is their capability to respond to external stimuli such as temperature and/ or pH (Sauer and Meier, 2001; Gohy et al., 2001). The few water- soluble stimuli-responsive systems investigated so far were essentially based on the electrostatic repulsion between charged polyelectrolyte blocks (typically poly(2-vinylpyridine) and polyacrylamide), but such systems are not completely reversible owing to the formation of salt with each cycle of pH variation. Finally, another important factor in the design of a self- assembled material is its stability. In fact, most aggregates are only stable within a certain range of concentration, temperature or pH. A suitable approach to improve the stability of self- assembled structures is to cross-link one of the blocks (Won et al., 1999; Stewart and Liu, 1999; Thurmond et al., 1999; Armes, 1998; Rodrı ´guez-Herna ´ndez et al., 2005). Recently, block copolymers comprised of polypeptide segments have been shown to provide significant advantages in controlling both the function and supramolecular structure of bio-inspired www.elsevier.com/locate/geneanabioeng Biomolecular Engineering 24 (2007) 81–85 * Corresponding author. Tel.: +33 54000 22 41; fax: +33 54000 84 87. E-mail address: lecommandoux@enscpb.fr (S. Lecommandoux). 1389-0344/$ – see front matter # 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.bioeng.2006.05.015