## 4 Drug Delivery  
Aqueous self-assembly of amphiphilic asymmetric branched architectures has intrigued the scientific community, due to its potential in tuning core-corona architectures in the resulting aggregates. It has been demonstrated that, compared to linear diblock copolymers, which have been extensively employed in drug delivery, the branching architecture of miktoarm star polymers affords enhanced micellar stabilities, lower CMCs, and could encapsulate hydrophobic drugs with much higher efficiencies and loading capacities [21; 22; 23; 25; 54; 67]. Asymmetric arm build-up of miktoarm stars has promoted the development of several unique systems that take advantage of having multiple polymer arms, each with specific effects. For example, using high yield reactions and a combination of ring-opening and stitching methodologies, a variety of AB\({}_{2}\) (A = PCL and B = PEG) and ABC (A = PCL, B = PEG, and C = PS) type miktoarm polymers have been prepared through the design of cores on which orthogonal reaction sequences could be easily carried out [24; 39]. Using imaging studies, intracellular localization into lipid droplets has also been demonstrated, and the niacin conjugated nanostructures suppressed bacterial endotoxin stimulated nitric oxide production in microglia [41]. In another study, tetraiodofluorescein (TIF), a fluorescent dye, containing ABC (A = PEG, B = PCL, C = TIF) miktoarm star was synthesized, by sequential click coupling of mPEG and propargylatedTIF to a central core, and ROP of caprolactone on the third junction [49]. The miktoarm star polymers formed micelles in an aqueous medium with a diameter of about 115 nm and a CMC of 0.43 mg/L. These micelles showed a cumulative release of 66% over seven days. When macrophages were treated with them and imaged using fluorescence microscopy after labeling them with Hoechst 33342, the nanocarriers were clearly visible upon uptake into the cells (Figure 6). The nano-delivery system was found to decrease LPS-induced nitric oxide release in stressed macrophages, demonstrating their anti-inflammatory properties. A series of mitochondria-targeting ABC (A = PEG, B = PCL, C = triphenylphosphonium bromide (TPBr)) miktoarm star polymers were developed for coenzyme Q10 (CoQ10) delivery [42]. The star polymers with molar masses ranging from 6000 to 12,000, formed micelles with a size range of 26.7-43 nm, and encapsulation efficiencies of 83-85%. Fluorescein isothiamate (FITC) labeled miktoarm stars-based micelles with the TPPBr functionalities at the corona surface showed significant localization in mitochondria in neurons and glia cells, compared to polymers without any mitochondria targeting moiety. Furthermore, MTT assays and confocal micrographs showed that miktoarm stars carrying CoQ10 improved mitochondrial metabolic activity within 24 h and reduced mitochondrial damage from reactive oxygen species (ROS) in primary hippocampal cultures. Miktoarm polymers could also be designed to lead to more stable self-assembled micelles by including stereochemically opposing arms as hydrophobic segments [35]. In this regard, AB\({}_{2}\) and ABC-type miktoarm star polymers were synthesized based on cyclic carbonate-functionalized PEG, on which ring-opening of the carbonate was carried out with an amine-functionalized silyl protecting  
Figure 6: Fluorescent micrographs of macrophages treated with (**A**) curcumin-loaded PEG-PCL-TIF micelles, (**B**) unloaded PEG-PCL-TIF micelles, and (**C**) TIF control. Relative fluorescence intensities of macrophages treated with control media, TIF-loaded PEG-PCL micelles, curcumin-loaded PEG-PCL-TIF micelles, unloaded PEG-PCL-TIF micelles, free TIF, and free curcumin as a function of (**D**) treatment time and (**E**) dose concentration. Scale bar = 20 μm, inset scale bar = 10 μm. Statistically significant differences are represented by **(\(p\) < 0.01), and *** (\(p\) < 0.001). Reprinted with permission from reference [49]. Copyright 2014 John Wiley and Sons. groups.