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Polymerization-Induced Self-assembly of Block Copolymer Nano-objects via Green RAFT Polymerization

Shinji Sugihara

University of Fukui, Graduate School of Engineering, Department of Applied Chemistry and Biotechnology, 3-9-1 Bunkyo, Fukui, 910-8507, Japan

1.1 Introduction

Many biomolecules have specific three-dimensional structures in water or hydrophobic environments, and form higher order structures with high functions. To construct a highly functionalized and higher order structure with a synthetic polymer, it is necessary to examine the fundamental formulation to control the polymer's primary structure and to build the polymers up into a higher order structure. From this point of view, this chapter focuses on block copolymer synthesis as a molecular technology for self-organization. The key technology is in situ "polymerization-induced self-assembly ()."

1.2 Block Copolymer Solution

Self-assembly of AB diblock, ABA, or ABC triblock copolymers to form a variety of macromolecular nanostructures is well known in both the solid state and in dilute solutions, with various prominent functions stemming from the structure [1-21]. In particular, amphiphilic AB diblock copolymers have been demonstrated to form a variety of self-assembled aggregate structures in dilute solutions, where the solvent preferentially solvates one of the blocks. Thus, the basic driving force for solution self-assembly is the solvophobic effect (hydrophobic effect in aqueous solution). These are well documented in other reviews [ 1-5]. For the amphiphilic AB diblock copolymer in a block-selective solvent, the precise nanostructure, i.e. morphology, is primarily a result of the inherent molecular curvature described by its mean curvature H and its Gaussian curvature K, which are given by the two radii of curvatures R1 and R2 in Figure 1.1. The curvature is related to the surfactant packing parameter, P, which is given by Eq. (1.1). The value of P depends on the relative core-block volume (v), the effective interfacial area (a0) at the core-shell/solvent interface, and the chain length normal to the surface per molecule (l0).

Figure 1.1 Various self-assemblies formed by solvophilic block copolymers in a block-selective solvent. The type of structure formed is due to the inherent curvature of the molecule, which can be estimated through calculation of its dimensionless packing parameter, P.

The regions of spherical micelles are favored when P =?0.33, cylindrical micelles are produced when 0.33?< P =?0.50, and vesicles are formed when 0.50?< P =?1.00. Although vesicles are flexible bilayer aggregates, the planar bilayer of lamellae is ideally favored when P = 1. This concept was originally introduced by Israelachvili et al. [22,23] to explain self-assembly of small-molecule surfactants, and was later extended to include diblock copolymer self-assembly by Antonietti and Förster [24].

In practice, morphology is controlled by various factors, especially for small-molecule amphiphiles. Assemblies such as spherical micelles, hexagonals, cubes, and lamellar lyotropic crystallines are highly dynamic with rapid exchange of molecules between micelles and the unimer state in solution. Thus, as shown in Figure 1.2, the packing geometry can be tuned by simply adjusting the surfactant concentration with the same solvent properties, i.e. without additives and at a constant temperature. Figure 1.2 shows an ideal phase sequence, which is only a very generalized picture, and the sequence may be different for some amphiphiles. However, this rapid exchange of molecules is very important to determine the structure and morphology of amphiphilic self-assembled aggregates [4 23-25].

Figure 1.2 The "ideal" sequence of phases from L1 to HI to La observed upon increasing amphiphile concentration, in a binary small-molecular amphiphile-solvent system (ergodic system). Intermediate phases (a and b) are sometimes observed. The normal micellar structure is termed the L1 phase. At higher concentrations, micelles can fill space efficiently to form a cubic phase by packing (a). Upon increasing the concentration further, the micelles change from spherical to rod-like ones. The rod-like micelles then pack into a hexagonal (HI) phase. The HI phase sometimes changes to a bicontinuous cubic or mesh structure phase (b), which is characterized by nonzero mean curvature and negative Gaussian curvature. The phase then changes to bilayers, which tend to stack into a lamellar phase (La). Lamellar phases can be found in different phase states including lamellar crystalline, lamellar gel, and lamellar fluid. When the solvent becomes the minority phase, inverse structures are formed such as the inverse hexagonal phase (HII), inverse micellar liquid phase (L2), and intermediates such as the inverse bicontinuous phase (c), and inverse micellar cubic phase (d).

For many macromolecular amphiphiles, in contrast to small-molecule amphiphiles, the rate of exchange of unimers between colloidal aggregates and individual diblock copolymer chains can be negligible, leading to a range of kinetically frozen, i.e. nonergodic, structures. In other words, most amphiphilic block copolymers have been recognized for their many advantages, such as low critical micelle concentration, robust assemblies, and the ability to trap numerous different structures thanks to their kinetic stability due to slow kinetics [ 4,26]. For example, this stability of the polymeric micelles is a very important issue for a drug (solubilizing substance) carrier for application in drug delivery systems (s). This is because polymeric micelles can retain the loaded drug in the same morphology for a prolonged period of time even in a very diluted condition in the body [19,20,27]. In the early stages of research on DDS, kinetically frozen spherical micelles were used as the drug vehicle. Subsequently, worms (aka cylinders or filomicelles) were found to be better than spherical micelles due to their long circulation time in vivo [28,29] and altered cell internalization pathway compared to spherical constructs [30]. As another example, complex polyprodrug amphiphiles were synthesized from block copolymer amphiphiles, which possess advantages of facile fabrication, high drug loading content and loading stability, active drug protection, blocked premature leakage, and on-demand controlled release [31]. Thus, it is no exaggeration to say that nanoparticles in the biomedical arena are being developed by utilizing the stability of the block copolymer self-organization. Hence, development of the formulation of various self-assemblies is essential and techniques for extracting unstable or metastable assemblies are strongly desired.

1.3 Synthesis of Block Copolymers via RAFT Polymerization

In general, controlled/living polymerization refers to chain polymerization without termination and chain-transfer reaction. Since Szawrc discovered living anionic polymerization in 1956 [32,33], the process has been used in various polymerization mechanisms. In 1962, the first reports on block copolymer self-assembly were published [34]. The advent of controlled/living free-radical polymerization () [35-38] based on the reversible deactivation of the propagating radicals has revolutionized the domain of polymer chemistry and opened the door to the possibility of designing new polymer architectures and creating new materials with targeted properties. A number of fundamental block copolymers for the assemblies mentioned above have been recently synthesized using controlled/living polymerization techniques, especially CRP.

As for CRP, atom transfer radical polymerization () [37-40], nitroxide-mediated polymerization () [41,42], iodine transfer polymerization () [43,44], organotellurium-mediated radical polymerization () [45,46], cobalt-mediated radical polymerization () [47], reversible addition-fragmentation chain-transfer () polymerization [48-50], and reversible chain-transfer-catalyzed polymerization [51,52] are well known. For almost all polymerizations, the abovementioned PISA has been adopted. Examples of these include ATRP [53-55], NMP [56], ITP [57], and TERP [58,59]. However, the vast majority of reports at present have focused on the RAFT process, which results in block copolymer formation and self-assembly. Well-documented reviews of this field have been published by Armes and coworkers [60-62], Pan and coworkers [63], Charleux et al. [64], Lowe [65], etc. Incidentally, the author is also one of the coworkers of Prof....