# Biodegradable Polymeric Architectures via Reversible Deactivation Radical Polymerizations
## 2 Biodegradable Polymeric Architectures
### Cross-Linked (Highly Branched) Structures  
RAFT polymerization can be a convenient tool for generating functionalized and biodegradable macro-monomers via wisely tailored RAFT agent. [PERSON] and coworkers synthesized a novel AB\({}_{2}\) macro-monomers bearing \(\alpha\)-dithiobenzoate and \(\omega\)-double pyridyl disulfide end-groups through a straightforward synthetic approach [72]. These monomers were prepared by RAFT polymerization, after which the \(\alpha\)-dithiobenzoate functionality was aminolyzed to yield thiols that were simultaneously subjected to an exchange reaction with pyridyl disulfide at the chain ends, resulting in the formation of hyperbranched structures, which could proceed disulfide mediated degradation in the presence of reducing agent such as DL-Dithiothreitol (DTT), Tris(2-carboxyethyl)phosphine (TCEP) or glutathione. Biodegradable hyperbranched cationic polymers, poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA), have also been synthesized via RAFT mechanism for DNA binding and delivery [73]. In addition to the biodegradable linkages, when the biodegradable polymers such as poly(lactide) (PLA) or polycaprolactone (PCL) are incorporated into cross-linked or self-assembled polymeric architectures, biodegradability can also be achieved. [PERSON], [PERSON] and coworkers synthesized a well-defined biodegradable macro-monomer, oligo(2-ethyl-2-oxazoline) methacrylate by direct end-capping of living oligo(2-ethyl-2-oxazoline) chains with in situ formed triethylammonium methacrylate, followed by homopolymerization via RAFT mechanism and then copolymerization using the homopolymer as macro-RAFT agent to achieve comb-like biodegradable architectures [74]. Despite the same combined polymerization techniques being used, different polymerization sequence may afford completely different polymeric structures. In research by [PERSON] and coworkers, RAFT polymerization and ROP were used to synthesize both hyperbranched and microgel particles [75]. The core-first method afforded the hyperbranched core-shell structure, whereas the arm-first method gave core-cross-linked shell particles (Figure 5). In addition to RAFT polymerization, ATRP was also used as a convenient tool for the synthesis of highly branched biocompatible poly(2-hydroxyethyl methacrylate), which was then used to prepare biocompatible fibers. The incorporation of partial disulfide-based dimethacrylate monomer in the polymerization conferred the biodegradability to the highly branched polymers [76]. [PERSON] and coworkers described a new functional lactone containing a pendant acrylate group that can be of great interest for the design of new cross-linked biodegradable materials using combined ATRP and ROP techniques [77]. Similarly, [PERSON] et al. reported the generation of comb-shaped copolymers composed of biocompatible hydroxypropyl cellulose backbones and cationic poly(2-dimethylamino)ethyl methacrylate) side chains for gene delivery. The generated complex exhibited a stronger ability to bind with DNA, due to the increased surface cationic charges [78]. Comb-like and biodegradable supramolecular architectures can also be prepared using amphiphilic copolymer, poly(lactide)-_b_-poly(2-hydroxyethyl methacrylate) (PLA-_b_-PHEMA) with partially biodegradable PLA block and PHEMA biocompatible one using an orthogonal polymerization strategy via ROP and ATRP [79]. Likewise, the same methodology was also adopted to prepare ABA and star amphiphilic block copolymers composed of polymethacrylate bearing a galactose fragment and biodegradable poly(epsilon-caprolactone) [80]. Series of degradable branched poly(dimethylaminoethyl methacrylate) (PDMAEMA) copolymers were investigated by [PERSON]'s group. The branched PDMAEMA copolymers were synthesized by controlled radical cross-linking copolymerization. Efficient degradation processes were experimented for all of the copolymers. The degree of branching exhibited a big impact on the performance of transfection when tested on different cell types.