## 2 Synthetic Approaches to Miktoarm Star Polymers
### In-Out Synthesis  
Synthesis of miktoarm polymers using \"in-out\" methodologies does not strictly fall into either core-first or arm-first methods. In-out syntheses typically involve the preparation of polymeric macroinitiators, and subsequently crosslinking them using small molecules, such as those containing divinyl functionalities. Miktoarm polymers prepared in this manner form densely core-crosslinked star (CCS) A\({}_{\text{x}}\)B\({}_{\text{y}}\) architectures, comprised of two different arm variants. The first known example of such a miktoarm polymer involved the synthesis of vinylbenzyl terminated PS and PI by coupling living anionic PS and PI with \(p\)-chloromethylstyrene. These macroinitiators were then copolymerized in benzene with n-BuLi as an initiator to yield A\({}_{\mathrm{x}}\)B\({}_{\mathrm{y}}\) (A = PS, B = PI) miktoarm stars. The latter were reported to undergo microphase separation, with individual domains being smaller than those observed with the analogous diblock copolymers [108]. While this study did not use polymeric arms compatible with drug delivery, such microdomain sizes suggest potentially beneficial micelle sizes and properties for such architectures. An example of a typical in-out methodology involved modification of PCL with 2-bromoisobutyryl bromide to form PCL-Br, a macroinitiator for ATRP, which was subsequently core-crosslinked with divinylbenzene (DVB) to give a PCL star polymer with ATRP-active ends. The latter were then used for the polymerization of styrene to yield an A\({}_{\mathrm{x}}\)B\({}_{\mathrm{y}}\) (A = PCL, B = PS) CCS polymer. The PCL chains in this miktoarm star were able to undergo biodegradation through hydrolysis in alkaline conditions (Scheme 5) [109]. Using a poly(butyl acrylate) (PBA) macroinitiator for ATRP, [PERSON]'s group was similarly able to demonstrate ATRP-enabled core crosslinking using DVB. This was followed by using the resulting Br-capped ends to initiate polymerization of PS. A biodegradable miktoarm polymer was similarly synthesized by exchanging a few components from their earlier miktoarm polymer. Poly(methyl methacrylate) (PMMA) polymerization was initiated using 2-bromoisobutyrate and CuBr/2,2'-bipyridine (bpy) as a catalyst. The resulting chain was then core crosslinked using bis(2-methacryloyloxyethyl) disulfide, a divinyl molecule containing a degradable disulfide linkage. Subsequent ATRP of BA led to the formation of a biodegradable A\({}_{\mathrm{x}}\)B\({}_{\mathrm{y}}\) (A = PBA, B = PMMA) miktoarm polymer. Reduction, and the resulting degradation of the miktoarm polymer, was triggered by its incubation in 0.08 M Bu\({}_{3}\)P/THF solution, and complete cleavage was seen in 40 h [110]. While not carried out under biological conditions, a comparison can be made to the reductive power of intracellular glutathione (GSH), present at roughly 10 mM concentrations, which can cleave disulfide functional groups [111; 112; 113]. A similar study approached the idea of biodegradable CCS polymers, which included arm-degradable A\({}_{\mathrm{x}}\), partially arm-degradable A\({}_{\mathrm{x}}\)B\({}_{\mathrm{y}}\), and core-degradable B\({}_{\mathrm{y}}\) (A = PCL, B = PS/PMMA). Beginning with a bifunctional core, 2-hydroxyethyl 2'-methyl-2'-bromopropionate, which had both ROP and ATRP active ends, arm-degradable polymers were synthesized by the sequential ROP of CL, and core-crosslinking using DVB. This resulted in a PCL-CCS polymer, which could be degraded through hydrolysis. A non-degradable analogue was synthesized by using the initiator for the ATRP of MMA/St first, followed by DVB crosslinking. Most interestingly, however, was the capacity to make partially arm-degradable A\({}_{\mathrm{x}}\)B\({}_{\mathrm{y}}\) polymers using this approach [114]. This opens up the possibility of synthesizing miktoarm polymer-based drug delivery systems with tuned biological responses that can be adjusted to provide a good sustained release of drug cargo.