Fast Photodegradable Block Copolymer Micelles for Burst Release

There is increasing interest in designing block copolymer (BCP) micelles of which the assembly state in aqueous solution can be controlled or disrupted by light. This is motivated by the potential application of such BCP micelles as nanocarrier for light-triggered release of guest molecules, which offers the remote-control possibility as well as the temporal and spatial selectivity. The main established approach allowing for photocontrolled dissociation of BCP micelles is to incorporate photochromic groups onto the hydrophobic block of a BCP, whose photoreaction can increase the polarity of the block and thus shift the hydrophilic-hydrophobic balance to render themicellar association of BCP chains thermodynamically unstable. Upon micelle dissociation, loaded hydrophobic guest can be released to aqueous medium. Recently, several groups demonstrated a new approach that is based on using a photocleavable junction linking the hydrophilic and hydrophobic blocks. After micelle formation, light can be applied to breakBCP chains at the junction point. It is easy to imagine that, though interesting, this approach is not ideal for light-triggered release of guestmolecules loaded in the micelle core because the chain aggregation state of the latter would not be loosened due to the removal of the hydrophilic corona. Hereinwe demonstrate a novel BCPdesign strategy. Instead of using a single photolabile junction between the two blocks, photobreakable moieties are positioned repeatedly along the hydrophobic main chain. With this design, the resulting BCP micelle possesses a photodegradable core that, upon photoreaction, can be disintegrated very quickly. The sketch in Figure 1 illustrates the difference between having just one photobreakable junction and having many such units on the main chain of the hydrophobic block. We envision that fast disintegration of the micelle core should lead to a fast release of loaded guest molecules. Scheme 1 shows the one-pot synthesis of an amphiphilic ABA triblock copolymer of which the end block A is water-soluble poly(ethylene oxide) (PEO) and the middle block B is a hydrophobic polyurethane containing nitrobenzyl groups (PEO-bPUNB-b-PEO). The photodegradable PUNB block was first prepared by using condensation polymerization of 2-nitro-1,3benzenedimethanol with tolylene 2,4-diisocyanate in slight excess. It was then terminated withmonomethyl ether PEO to yield the triblock copolymer of PEO-b-PUNB-b-PEO. The size exclusion chromatograph (SEC) result in Figure 2 confirms the successful coupling between PUNB and PEO. As compared with monomethyl ether PEO, the BCP sample has a larger polydispersity index (increased from1.06 to 1.38). This is likely caused by the PUNB block formed via condensation polymerization, with which a broader distribution of molecular weights is generally associated. The possibility of having some PEO-b-PUNBdiblock could not be ruled out, but this does not affect the core-shell micelle formation.With this BCP, fast photoinducedmicelle core disintegration could be expected by having an o-nitrobenzyl unit linked to two methyl ester groups in each repeating unit of the micelle core-forming PUNBblock. Photoinduced degradation of the BCP in dissolved state in THF was first investigated, and the result obtained with SEC is also shown in Figure 2. After irradiation of a BCP solution (3 mL, 0.1 mg/mL) with UV light (300 nm, ∼ 60 mW/cm), the SEC trace shows dominant low molecular weight species while a remaining polymer peak matches the elution peak of PEO, indicating a complete separation of PEO chains from PUNB as well as the severe disintegration of the hydrophobic block into low-molecular-weight species. The continuous photodegradation at a high BCP concentration in THF (10 mg/mL) was also observed from SEC measurements (Figure S4 in Supporting Information). Moreover, the photoreaction of nitrobenzyl units could be monitored from UV-vis spectra that display an increased absorption over a wide range of wavelengths (300-500 nm) as the photoreaction progresses (Figure S5 in Supporting Information). From the BCP design, a variety of degraded nitroand nitrosobenzyl species can be expected due to the randomly occurring photocleavage reaction on the main chain of PUNB. The fast photodegradation of the PUNB block indeed leads to fast disintegration of the BCPmicelle in solution.We first carried out the experiment with BCP micelles in a mixed solvent of dioxane/water (1:1) where the photodegraded molecular species are soluble, which made it possible to monitor the micelle disintegration process through dynamic light scattering (DLS) measurements. In this experiment, micelles were prepared by dissolving theBCP in dioxane (0.2mg/mL), followed first by slow addition of water (35% in volume with respect to dioxane) and then fast addition of water (dioxane/water, 1:1). Figure 3a shows the change in the scattering intensity of the micellar solution (1 mL) upon UV irradiation (300 nm, 250 mW/cm). The intensity of scattered light drops after only 10 s of UV exposure and changes little after 30 s of irradiation even though the photoreaction continues as revealed by the UV-vis spectra (Figure S6 in Supporting Information). This result suggests that the BCP micelles could be disrupted quickly as the PUNB block is broken into pieces upon cleavage of o-nitrobenzyl moieties. Figure 3b shows the change in the volume-averaged size distribution before and after 180 s UV irradiation of the solution. The BCP micelles (hydrodynamic diameter DH ∼ 60 nm) are transformed into smaller species of various sizes after the short time irradiation. The situation after irradiation is understandable because, as mentioned above, the photodegradation of the PUNB block is expected to generate various species including PEO chains. The fast disintegration of BCP micelles is also observable on AFM. Figure 1. Schematic illustration of the difference between placing a photobreakable unit at only the block junction and repeatedly on the hydrophobic block.