Toward Photocontrolled Release Using Light-Dissociable Block Copolymer Micelles

Micellar aggregates (core -shell micelles, vesicles, etc.) formed by amphiphilic block copolymers (BCPs) are being actively investigated as a nanocarrier system for controlled delivery of drugs and other biological substances. 1 Generally speaking, a good nanocarrier of drugs would be (1) stable during the circulation in the blood, allowing no release of encapsulated hydrophobic drugs, (2) able to accumulate specifically in the target site (e.g., tumors), and (3) once on target, able to release the carried drug quickly or in a controlled fashion. Each of these requirements has prompted a great deal of research efforts in the design, synthesis and exploitation of new BCPs. As far as the control of release is concerned, BCP micelles that can be disrupted by external stimuli, thus triggering the release of entrapped agents, are of particular interest. The stimuli studied so far not only include changes that BCP micelles in the body can experience, such as increase or decrease in pH, 2 in temperature 3 and exposure to oxidation reaction, 4 but also include sound 5 and light6-8 that can be applied from outside of the body for remote activation of the disruption of micelles. If the interaction of BCP micelles with light lead to their dissociation, photocontrolled release of encapsulated agents is possible. One obvious, and attractive, feature of stable, lightresponsive polymer micelles is that the release of the carried guest (not limited to drugs) could be started at required time (when light is applied) and at required location (where light exposure is directed to). This offers new perspectives in controlled release that would be difficult to realize using other stimuli. To obtain usable BCP-based nanocarriers for photocontrolled delivery applications, the development of effective designs of BCP structures and fundamental studies of their photoinduced dissociation and release processes are necessary. There are many studies of light-responsive micellar aggregates of small-molecule surfactants, 9-16 but very few reports on lightdissociable polymer micelles. 6-8 We first studied amphiphilic BCPs whose hydrophobic block is an azobenzene-containing side-chain liquid crystalline polymer (Azo-SCLCP). 6,7 We found that their core-shell micelles and vesicles in solution can be dissociated by UV light irradiation and re-formed upon visible light exposure, as a result of the reversible trans -ci photoisomerization of azobenzene side groups of the hydrophobic block. From a study of the mechanism of the reversible micellar dissociation, a general design principle for azobenzene-based light-dissociable BCP micelles has been suggested. 7 The azobenzene moiety should have a small (near zero) dipole moment in the trans form and a high dipole moment in the cis form (determined by the substituents on the azobenzene unit); when this is conjugated with a weakly hydrophilic block (determined by the chemical nature and the length of the block), the increase in polarity of the azobenzene polymer block under UV light (trans-cis isomerization taking place) can alter the hydrophilic/hydrophobic balance which results in dissociation of micelles, while the decrease in polarity upon visible light irradiation (reverse cis -trans isomerization occurring) shifts the hydrophilic/hydrophobic balance in the opposite direction which brings back the micelles. More importantly, these studies suggest that any chromophores whose photoinduced structural rearrangements gives rise to a significant change in dipole moment could be used in designing light-dissociable BCP micelles based on the same principle. If the photoinduced process is reversible, the micellar dissociation is reversible. More recently, we have demonstrated the efficiency of a different, and more general, strategy for designing BCPs whose micelles can undergo irreversible light-induced dissociation. 8