# Light-Responsive Polymeric Micellar Nanoparticles with Enhanced Formulation Stability
## 1 Introduction  
Polymeric micelles have emerged as promising drug delivery systems for cancer treatment because amphiphilic block copolymers enable micelles to improve drug solubility, control drug release, prolong circulation time in body and avoid the elimination of reticuloendothelial system (RES) [1, 2, 3, 4, 5, 6, 7, 8]. Additionally, the prolonged circulation time makes polymeric micellar nanoparticles enhanced accumulation in solid tumors tissue with leaky vasculatures through the enhanced permeability and retention (EPR) effect [9, 10, 11, 12]. Recently, stimulus-responsive polymeric micelles activated by pH, temperatures, redox, ultrasound, and light have been explored to provide spatial or temporal control of release of anti-cancer drugs to tumors [13, 14, 15, 16, 17, 18]. Particularly, light-responsive drug delivery systems are attractive because they allow site-specific release of payload at desired disease sites with precisely controlled wavelength and intensity [19, 20, 21, 22, 23, 24]. Light is already used in clinical practice in phototherapy (e.g., photodynamic and photothermal therapies) and optical imaging (e.g., fluorescence imaging and fluorescence guided surgery) [25, 26].  
In many light-responsive polymeric micelle systems, UV light triggers a change in polarity or a transition from hydrophobicity to hydrophilicity in domains bearing photochromic azobenzene, spiropyran, and 2-diazo-1,2-naphthoquinone (DNQ) [27, 28, 29, 30, 31, 32, 33], which leads to drug release [34, 35, 36, 37, 38]. However, conventional micelle systems have limited drug loading capacity (LC) and relatively high critical micelle concentrations (CMC), which impair particle stability resulting in decreased blood circulation time and release of drugsbefore the micelles accumulate in the tumor sites. To increase drug loading and lower CMC (i.e., to enhance the stability of micelles), micelles have been recently developed by supramolecular interactions such as \(\pi\)-\(\pi\) stacking, hydrogen bonding, stereocomplexation, and electrostatic interaction [39; 40; 41; 42; 43; 44; 45; 46; 47; 48].  
Here, we have developed a light-responsive polymeric micellar nanoparticle with high LC and stability using particularly \(\pi\)-\(\pi\) stacking. The light-responsiveness is imparted by poly(ethylene glycol)-block-poly-l-lysine (PEG-PLL) modified by the light-responsive DNQ group. Upon irradiation by UV or two-photon near infrared (NIR) light, hydrophobic DNQ can be converted to hydrophilic 3-indenecarboxylic acid by the Wolff rearrangement (Supplementary Materials Figure S2). Previously, photo-triggered dye release from micelles comprising a linear amphiphile, DNQ-terminated oligomer, has been reported [36]. However, these micelles had a high CMC (i.e., low stability) of 1.15 mg/mL in phosphate buffered saline (PBS). Alternative DNQ-based drug delivery systems have been developed to lower CMC, reduce the cytotoxicity, and increase biocompatibility, such as linear-dendritic PEO-b-G4 polyester conjugated with 16 DNQs [37], DNQ-modified dextran [34], and Janus-type dendritic polyamidoamine (PAMAM) amphiphiles with DNQ [35]. For in vivo drug delivery, there are still needs to enhance stability of polymeric micelle formulations, increase the drug LC, and develop new stimuli-responsive polymeric nano-sized particles for effective passive tumor targeting by the EPR effect [2; 3; 5]. Herein, we report a light-sensitive polymeric micellar nanoparticle activated under low power density of UV light with enhanced stability, LC, and drug retention by supramolecular hydrophobic and \(\pi\)-\(\pi\) stacking interactions between the copolymers and drugs. The micellar nanoparticles were formulated from the synthesized DNQs-conjugated PEG-PLL amphiphilic copolymers and we successfully obtained burst release of aromatic anticancer drugs, docetaxel (DTX), from the micellar nanoparticles under UV light irradiation.