## 3 Amphiphilic Miktoarm Star Polymers: Self-Assembly
### Polymersomes  
While micellar systems have been the main focus of miktoarm star-based formulations for drug delivery, polymersomes remain an interesting and valuable option. This is due to the fact that they can load both hydrophilic and hydrophobic drugs as a result of their unique morphologies. Part of the reason why polymersomes have been more seldom explored in drug delivery is that amphiphilic polymers, including miktoarm polymers, are synthesized with hydrophilic/hydrophobic ratios that favour micelle formation upon self-assembly. As stated earlier, hydrophilic fractions of \(0.35\pm 0.1\) generally favor the formation of polymersomes [120; 121]. Such approximations are difficult to apply universally, especially when considering the variably branched architectures of miktoarm polymers. A comparison of AB and AB\({}_{2}\) (A = PEG, B = PLLA) polymers with varying hydrophilic PEG volume fractions revealed that self-assembly of miktoarm star polymers into polymersomes, is much more tolerant of more varied volume fractions. Polymersome formation was observed for PEG volume fractions of \(f\) = 0.2-0.7, much broader than the range of 0.2-0.4 for the linear diblock counterparts [34]. In another example, an AB\({}_{3}\) (A = PAzo, B = PEG) miktoarm star polymer with an azobenzene-containing 4-isobutyloxyazobenzene side chain on the polymethacrylate arm, had a 78/22 hydrophobic/hydrophilic ratio, slightly outside the typical range for polymersome formation, yet it was still well suited for polymersome assembly. Although their spherical nature can be easily established using electron microscopy or a combination of DLS and SLS, it is often necessary to specifically distinguish them from spherical micelles. To this end, TEM and cryo-TEM micrographs can determine whether particles are polymersomes, due to the visual presence of thin outer membranes (Figure 5) [43; 53]. Figure 5: Cartoon schematic (**left**) and comparative TEM micrograph (**right**) of a polymersome assembled from a PEG-PHis\({}_{2}\) miktoarm star polymer with emphasis on its hydrophobic bilayer. Reprinted with permission from reference [43]. Copyright 2012 Royal Society of Chemistry. An AB\({}_{2}\) (A = PEG, B = PCL) miktoarm polymer-based polymersome was used for the dual loading of both hydrophobic curcumin and hydrophilic methotrexate HCl, with encapsulation efficiencies of 14.13 and 10.93%, respectively. The nanocarriers showed a large burst release of methotrexate HCl unless co-loaded with curcumin. Curcumin was found to have an additional effect in combating multidrug resistance, as a small loading of it had a significant effect on enhancing methotrexate cytotoxicity [71]. Thus far, there has not been enough research to determine whether miktoarm architectures promote drug encapsulation, specifically in polymersomes. However, in one study, linear AB and miktoarm star AB\({}_{2}\) and A(BA)\({}_{2}\) A = PEG, B = PCL) polymer-based assemblies were used to load rhodamine B isothiamate-Dextran (RhDex), with encapsulation efficiencies of roughly 45 and 40% for their AB and AB\({}_{2}\) polymers based systems, respectively. It showed good consistency between the two architectures, but with higher loading in the diblock. On the other hand, complete drug release occurred at 9 and 14 days for the AB and AB\({}_{2}\) polymers, respectively, suggesting enhanced drug retention conferred by branching [40]. Trends relating to the physical properties of polymersomes do show some differences to those in micelles. For example, an increase in hydrophobic block size had the effect of hindering drug release, even in the case of those loaded in the hydrophilic core [34]. In comparing polymersomes of AB and AB\({}_{2}\) (A = PEG, B = PLLA) type architectures, CACs were found to be consistently lower for polymersomes assembled from miktoarm polymers, and were also found to decrease with hydrophobic block size [34].