## 2 Synthetic Approaches to Miktoarm Star Polymers
### Arm-First Synthesis  
Arm-first syntheses generally comprise methodologies in which polymer chains are individually prepared, and then attached to a single core. In fact, the chlorosilane-based miktoarm polymers described above belong to the arm-first methodology. This approach is advantageous due to the great control over the properties of individual chains, and the freedom to use reaction conditions that would normally be incompatible in the presence of other polymers. The most important aspect of these syntheses is the necessity to use a coupling or conjugation reaction to link a completed polymer chain to the core. This can generally be achieved using (i) a condensation reaction between a terminal alcohol/amine and acid; and (ii) \"click\" coupling chemistry. Due to the unlikelihood of complete reaction between polymer terminal ends, which can generally be associated with steric factors, condensations are conducted using catalysts. For example, [PERSON] famously described an esterification procedure that uses a combination of dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) as a coupling reagent and catalyst, respectively [104]. Depending on the reaction conditions, necessary workup, and catalyst solubility, a variety of combinations of coupling reagents have been employed, including, but not limited, to: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), \(N\),\(N^{\prime}\)-Diisopropylcarbodiimide (DIC), DCC, N-Hydroysuccinimide (NHS), 1,4-Dimethylpyridinium p-toluenesulfonate (DPTS), and DMAP. For example, an AB\({}_{2}\) miktoarm polymer was prepared with two PEG segments conjugated to a benzyl core using click chemistry, and niacin was coupled to the benzyl alcohol on the core using EDC/DMAP coupling chemistry. The niacin conjugated structure was seen to localize within cellular lipid droplets (LD), and inhibit the activity of the LD-localized enzyme, DGAT2 [41]. Another AB\({}_{2}\) (A = PEG,  
Figure 3: Core-first synthesis of an AB\({}_{2}\) miktoarm polymer (A = PLLA, B = PNAM) from a multifunctional core using ring-opening polymerization (ROP) and reversible addition-fragmentation chain transfer (RAFT). B = PLLA) miktoarm polymer was synthesized by first activating an acid-terminated PEG with NHS/DCC, to couple it with the free amine of serinol, thereby providing a PEG-core structure where the core has two free hydroxy groups available for ROP. L-Lactide was subsequently polymerized using these terminal alcohols as initiators to give the final miktoarm polymer [34]. Click coupling is the other widely used form of chemical conjugation applied in developing miktoarm polymer architectures. The term \"click chemistry\", while having older roots, is now widely used to refer mainly to the copper-catalyzed alkyne-azide cycloaddition (CuAAC) coupling reaction, first demonstrated by [PERSON] [105]. Due to this reaction's atom economy, tendency to only form the 1,4 isomer, complete or near-complete reaction progression, tolerance of other functional groups, and capacity to be adapted into an immense variety of reaction conditions, it has found significant usage in polymer coupling, in general [81]. An example of its use in miktoarm polymer synthesis can be found in one of the first miktoarm polymers used in drug delivery. An \(\alpha\)-methoxy-\(\omega\)-epoxy poly(ethylene glycol) was exposed to sodium azide in the presence of ammonium chloride in order to produce a methoxy PEG-core structure with primary azide and hydroxy functional groups. A propargyl alcohol-initiated PCL chain was then combined with this PEG, and reacted in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and CuI, to \"click\" the two polymers together. The remaining hydroxy functional group was used for the ROP of 2-Ethoxy-2-oxo-1,3,2-dioxaphospholane (EEP), thus forming an ABC (A = PEG, B = PCL, C = polyphosphoester (PPE)) miktoarm star [106]. Most researchers rarely limit themselves to one type of conjugation or even only arm-first syntheses.