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Synthesis of Cleavable Amphiphilic Block Copolymers Deepak Vishnu Dharmangadan, Liying Wang, Qiuying Zhang, Mario * Gauthier Institute for Polymer Research, Department of Chemistry, University of Waterloo Introduction Synthesis of Novel Redox-Sensitive Initiator Synthesis of Redox Sensitive Block Copolymers (PLA-b-PEG) b Amphiphilic block copolymers in solution can self-assemble into different nanostructures such as micelles, wormlike structures, and polymeric vesicles (polymersomes).1 One important potential application of amphiphilic block copolymers is as drug carriers,2,3 to help prevent the deactivation of therapeutic drugs such as proteins, antibodies and nucleic acids during their travel in the blood stream.4 Depending on the types of functional groups used and the external stimuli present, different response mechanisms may come into play including pH-sensitive, thermosensitive, redox-sensitive, enzyme-sensitive, photosensitive, and so on.5 Herewith we describe the synthesis of a novel redox-sensitive initiator for the metal-free ring opening polymerization (ROP) of lactide. A series of redox-sensitive amphiphilic block copolymers of polylactide (PLA) with polylysine (PLys) or poly(ethylene glycol) (PEG) segments were also obtained using the PLA macroinitiator. c d *e f a OH c',d' e' b' * 9 8 a' OH 7 6 5 NH ppm 4 3 2 1 0 Synthesis of Redox-Sensitive Block Copolymers (PLA-b-PLys) PEG-OH PEG-COOH PEG-b-PLA Why Lactide, Lysine and Poly(ethylene glycol)? a b Lactide: Serves as monomer for the hydrophobic block. Polylactide (PLA)based materials are highly biocompatible, biodegradable by enzymes, can hydrolyze under physiological conditions. a Lysine: Serves as monomer for the hydrophilic block. Lysine is an amino acid that the human body does not produce on its own, but it plays a key role in the makeup of body proteins. b 8 a Poly(ethylene glycol): Is highly soluble in organic solvents and, therefore, end-group modifications are relatively easy. PEG is also soluble in water and has a low intrinsic toxicity making it ideally suited for biological applications. d Why Metal-Free Ring Opening Polymerization? Conventional ROP uses metal complexes with organic ligands Drawbacks: High PDI, metal ions cannot be removed completely, high price 8 d e,f f a NH3 Br c 6 * 5 Normalized intensity Allows the synthesis of PLA with low PDI and targeted molecular weights 2 1 0 0.6 Polymer Target Mn [g/mol] Mn [g/mol] PDI PLA-Boc 2500 2800 1.08 PLA-Boc 5000 5600 1.05 PLA(2.5K)-b-PLys (1:2) 20300 22500 1.18 0.4 MW Data from NMR 0.2 0.0 5 10 15 20 Retention time (min) 25 2 1 0 30 Mn determined from 1H NMR and GPC are close to the target Mn Prepared redox sensitive PLA-b-PLyz and PLA-b-PEO block copolymers with low polydispersity indices 0.8 0 ppm 3 Synthesized polylactide with low polydispersity index by metal-free ring-opening polymerization using the novel redox-sensitive initiator b,e * MW Data from GPC PLA-b-PLys PLA-Boc PLA-NH2 1.0 4 Successfully synthesized a novel redox-sensitive initiator * b,e 4 ppm 3 1.2 System6 d d c a 7 5 Conclusions b c - 6 e,f a + 7 g c Ph The DBU/BA b d c Polymer Target Mn [g/mol] Measured Mn [g/mol] PLA-Boc 2500 2480 PLA-Boc 5000 4500 PLA(2.5K)-b-PLys (1:2) 20300 22100 References 1. Li, X.; Chen, G. Polym. Chem. 2015, 6, 1417–1430. 2. Chen, H.; He, S. Mol. Pharm. 2015,12, 1885–1892. 3. Bensaid, F. et al. Biomacromolecules 2013, 14, 1189–1198. 4. Ge, Z.; Liu, S. Chem. Soc. Rev. 2013, 42, 7289–7325. 5. Tong, R. et al. J. Chem. Soc. Rev. 2014, 43, 6982–7012. 6. Coady, D. J. et al. Chem. Commun. 2011, 47, 3105–3107.