## 3 Amphiphilic Miktoarm Star Polymers: Self-Assembly
### Micelle Drug Loading and Release  
As mentioned earlier, most pharmaceutical agents have poor water-solubility and low bioavailability [2, 3]. Loading drugs into self-assembled polymeric micelles can help resolve this issue by providing solvation, enabling prolonged gradual release, and through the EPR effect, facilitate passive targeting to disease sites [7, 12, 117]. Owing to their tailorable architecture, superior CMCs, improved drug loading, and sustained drug release, there has been much recent interest in miktoarm star polymer-based assemblies for drug delivery [21, 25, 26]. Drug incorporation into micelles has been shown to have varied effects on the size of miktoarm micelles, where it can lower, increase,or have a negligible effect upon drug encapsulation [24; 47; 48; 49; 24]. Though generally, a decrease in size has been attributed to good polymer-drug compatibility [47; 49; 57]. One of the beneficial effects of including multiple branching arms as in miktoarm stars, is in increasing drug loading content into their self-assemblies. For example, AB\({}_{3}\) (A = PMMA, B = PNIPAM) self-assembled miktoarm polymers were used to load prednisone acetate with encapsulation efficiencies of 50%, compared to 11% with the corresponding linear diblock copolymers [31; 125]. Improved drug loadings were also seen in AB\({}_{2}\) type miktoarm stars with A = PNIPAM, B = poly(undecylenic acid) (PUA), and A = PEG, B = poly(trimethylene carbonate) (PTMC) [27; 32; 133].  
Micellar drug retention has generally been associated with more sustained drug release and dampening burst release [32; 48; 55; 70], which has the benefit of increasing drug bioavailability. This could be the result of strong interactions and more sites of association between the encapsulated drug and multiple hydrophobic chains [27; 52; 70; 133]. In a study of A(AB)\({}_{3}\), A(2A)\({}_{2}\), and A\({}_{3}\)(AB) (A = PEG, B = PCL) miktoarm stars, camptothein loading percentages ranged from 3.6 to 10.8%, with higher loadings in assemblies of miktoarm stars with more PCL blocks [57]. A higher degree of branching in polymer-based nanocarriers is imperative in improving their therapeutic efficiency.  
It has been argued that the branching architecture of miktoarm stars has favourable effects on drug loading and release properties, and increasing hydrophobic chain length can lead to an increase in drug encapsulation and prolonged drug release [32; 48; 62]. However, long hydrophobic segments may also prohibit micellar hydrophilic surface coverage [13; 52; 134]. This has been mainly a concern for diblock copolymers, and it can be lessened by making use of the branched architectures. For example, in a study of AB\({}_{2}\) (A = poly(lactide-co-glycolide) (PLGA), B = PEG) miktoarm stars, increasing the length of PLGA arms was shown to result in total cumulative ibuprofen release to be between 10 and 60% [75]. In another study (using AB\({}_{2}\) (A = PCL, B = PEG) miktoarm stars), nimodipine loading efficiencies, scaled between 23 and 70%, with variations in PCL length in PEG775\({}_{2}\)-PCL5800 and PEG775\({}_{2}\)-PCL19000. However, the drug release was found to be between 93 and 85% of their loaded cargo, respectively, showing that PCL size or drug loading efficiency had little effect on drug release [24]. Interestingly, increasing the hydrophilic chain length of a miktoarm star polymer can also promote drug loading, as was shown for a miktoarm star with two hydrophilic PNAM chains and hydrophobic poly(L-lactide) (PLLA) arm [72].