## 3 Amphiphilic Miktoarm Star Polymers: Self-Assembly  
As discussed earlier, most pharmaceutical agents have inadequate bioavailability when administered directly [2; 3], and thus, polymeric nanocarriers provide an important tool for drug delivery. Amphiphilic block copolymers and lipids have been extensively studied as potential platforms for loading and delivering drug cargo to targeted diseased sites within the body [7; 117]. When introduced into aqueous media, the exposure to the newly polar environment forces amphiphilic polymers to undergo microphase separation, during which chains segregate into distinct polar and non-polar phases [118]. The overall assembly that results from the sequestering of chains, is generally guided by the total fraction of each polar/non-polar chain segment within the amphiphilic polymer, as well as its overall topology [119]. Although conditions vary, it is commonly accepted that for micelle formation, an amphiphilic polymer must have a hydrophilic fraction \(f>0.45\), and for polymersomes, \(f=0.35\pm 0.1\) (Figure 4) [120; 121]. While micelles are characterized by their hydrophobic cores and hydrophilic coronae, polymersomes distinctly have a hydrophilic core, surrounded by a hydrophobic layer, enclosed within a hydrophilic corona. These domains make such nanostructures suitable for the physical encapsulation, prolonged retention, and delivery of poorly-water-soluble drugs, thus increasing their bioavailability and overall therapeutic efficiency. Some of the important parameters typical of nanocarriers used for drug delivery applications include their size, CAC/CMC, biocompatibility, drug loading, and drug release [8; 25; 122]. While much of the familiarity surrounding the effects of polymer self-assembly on drug delivery is derived from work on amphiphilic linear diblock copolymers, miktoarm star polymers with asymmetric branching polymer segments have increasingly been shown to possess superior micelle properties, while also being more tunable, due to their varied syntheses and number of unique constituent segments [21; 122]. As discussed earlier, micelle diameters below 200 nm are necessary to improve their biological distribution and disease site accumulation, commonly through the EPR effect [12]. Self-assembled structures from miktoarm star polymers can, in general, have similar sizes to those from linear block copolymers [52], and scale similarly with increasing hydrophobic segment size relative to hydrophilic blocks [24; 56; 62]. The branched architecture of miktoarm stars offers potential for tuning, and this was explored in a study of three copolymers using biocompatible PEG and PCL arms, with different AB, BAB, and AB\({}_{2}\) (A = PEG, B = PCL) diblock, triblock, and miktoarm topologies, but with similar hydrophilic/hydrophobic ratios [60]. XRD was used to study PEG and PCL crystallinities, and it was found that the relative crystallinity of PCL chains decreased in the sequence AB \(>\) BAB \(>\) AB\({}_{2}\), as the arms became more sterically restricted. PEG crystallinity was found to be severely limited in the BAB triblock as a result of the adjacent PCL arms, and it was similar in AB and AB\({}_{2}\) copolymers. This was further evidenced by the measurement of C=O vibrations using FTIR at 1726 and 1736 cm\({}^{-1}\), for crystalline and amorphous PCL regions, respectively. Such variations in crystallinity accounted for the differences in micellar diameters, where AB, BAB, and AB\({}_{2}\) copolymers had sizes of 43, 74, and 53 nm, respectively. On the other hand, one can design miktoarm star polymers to have a larger proportion of hydrophilic to hydrophobic arms, so that the relatively large volumes of the hydrophilic groups force a constricted micellar curvature, resulting in smaller diameters [123; 124]. An AB\({}_{3}\) (A = PMMA, B = PNIPAM) miktoarm star for prednisone acetate delivery was designed for this purpose, and it formed spherical micelles of roughly 50 nm, considerably lower than the 190 nm diameters of the equivalent linear diblock analogues [31; 125].