# Biodegradable Polymeric Architectures via Reversible Deactivation Radical Polymerizations
## 2 Biodegradable Polymeric Architectures  
### Well-Defined Star-Shaped Structures  
Well-defined polymeric structures, e.g., star polymers, are of particular significance in biological applications such as drug delivery and bio-therapeutics [39]. Generally, star polymeric structures can be synthesized via \"arm-first\" or \"core first\" methodologies. The \"arm-first\" methodology can be used to generate multi-armed structures by either cross-linking the linear polymeric chains or post-polymerization conjugation of linear functionalized polymeric chains to a multi-functional core via chemo-selectively covalent coupling or non-covalent interactions, e.g., metal ion mediated coordination [40; 41; 42; 43; 44; 45; 46; 47; 48]. The \"core first\" strategy is more straightforward, and therefore has attracted an increasing interest for generating multi-armed polymeric architectures in a more controllable mode using multi-functional chain transfer agent [49; 50; 51; 52; 53; 54]. Star polymers consisting of miktoarms have also been tailored to achieve different properties [10; 42; 55; 56]. Multi-armed star polymeric architectures have attracted increasing interest due to their potential applications in a number of areas, e.g., encapsulation, sensing, catalysis, electronics, optics, biological engineering, coatings, additives, and drug and gene delivery [57; 58]. In recent studies, [PERSON] and coworkers successfully demonstrated the synthesis of three-armed star polymeric architectures using both \"core first\" and \"arm first\" methodologies to generate three-armed architecture containing biodegradable disulfide linkages. When \"arm first\" method was adopted, the linear polymer chain was tailored with thiol-reactive pyridyl disulfide groups, through which the linear chains were attached onto a tri-thiol functional core to afford three-armed star polymeric structure. At the same time, the \"core first\" technique was also utilized to generate the same three-armed star polymers from RAFT controlled polymerization using a trifunctional RAFT agent (Figure 2a). Gel permeation chromatography (GPC) and electrospray ionization (ESI) mass spectroscopy analysis evidenced the well-controlled RAFT polymerization which yielded well-defined three-armed star structures with polydispersity index (PDI) less than 1.28. The R group was designed at the end of the RAFT agent, through which the as-prepared polymer chains would sit outside of the RAFT active centers, that is, at the end of each arm. Further modification of the RAFT cores would risk polymeric chain loss. This design would compromise the application when modification of the trithiocarbonate or dithioster RAFT cores is required. To overcome this drawback, [PERSON] and coworkers designed a three-armed RAFT agent via a condensation reaction between the \(R\)-group of the RAFT agent and a trifunctional core to afford a trifunctional RAFT agent with \(Z\)-groups at the end of each arm. The subsequent polymerizations of styrene and PEG-A using this RAFT agent generated three-armed polymeric structures with trithiocarbonate cores at the end of each arm, endowing the potential for further modifications through the RAFT cores (Figure 2b) [59]. Anninolysis of the trithiocarbonate cores and further reaction with dithiolpyridine (DTDP) yielded sulfhydryl groupsand subsequently pyridyldisulfide (PDS) terminal groups, available for further reactions with any free thiol-tethered precursors. When the ends of the star polymers were modified with cholesterol groups, \(\alpha\)-cyclodextrintrin (\(\alpha\)-CD) groups were attached successfully via inclusion complexation. The generated architecture can be easily degraded in the presence of DTT due to the introduction of disulfide linkages. The methodology presented here can be a prototype research for post-polymerization modifications of various polymeric architectures prepared by RAFT mechanism.