RAFT Synthesis of Acrylic Copolymers Containing Poly(ethylene glycol) and Dioxolane Functional Groups: Toward Well-Defined Aldehyde Containing Copolymers for Bioconjugation

Abstract

Copolymers of poly(ethylene glycol) methyl ether methacrylate (PEGMA) and one of two dioxolane-containing monomers, (2,2-dimethyl-1,3-dioxolane)methyl acrylate (DDMA) and (2,2-dimethyl-1,3-dioxolane)methyl acrylamide (DDMAA), were successfully synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. RAFT copolymerization was performed in dimethylformamide (DMF) at 70°C for 24 h using 4,4′-azobis(4-cyanovaleric acid) as initiator and N-(sodium ethane sulfonic acid)-2-((thiobenzyl)sulfanyl)proprionamide (CTA 1), 4-cyano-4-((thiobenzoyl)sulfanyl)pentanoic acid (CTA 2), or S,S′-bis(R,R′-dimethyl-R′′-acetic acid)trithiocarbonate (CTA 3) as the chain transfer agent (CTA). Control over molecular weight and composition was achieved by altering the CTA concentration and the monomer feed ratio respectively. The resulting copolymers had narrow molecular weight distributions (polydispersity indices typically between 1.2 and 1.3), while monomer conversions were typically 60%. Kinetic studies revealed that PEGMA was consumed at a higher rate than the comonomers over a given time. The molecular weight of the copolymer increased linearly with conversion, while a low polydispersity was maintained throughout. The copolymerization reactivity ratios were determined using the Mayo-Lewis method. After copolymerization, the dioxolane functional groups were deprotected to form 1,2-diol groups and subsequently oxidized with HIO 4 to form reactive aldehyde groups. Subsequent chemical modification of the dioxolane moieties to aldehyde groups showed no adverse effects in terms of degradation of the copolymer (specifically ester linkages). The advantage of the current synthesis over direct copolymerization of aldehyde-based monomers is the stability of the 1,2-diol moiety compared to the corresponding aldehyde copolymer. The availability of the aldehyde groups along the polymer backbone to form stable conjugates with amine containing molecules was confirmed via a reaction with the iron chelating drug desferrioxamine (DFO). Conjugation was achieved via an aldamine reaction, followed by a reduction of the resulting Schiff base to a secondary amine. Full characterization of the copolymers was performed using NMR spectroscopy and GPC-MALLS, while UV-vis absorption spectroscopy was used to determine the efficiency of DFO conjugation.

Living Radical Polymerization by the RAFT Process - A Second Update

“…BMA [139] MAA [140] MMA [64,141] AEMA [90,142] DEGMA [141] DMAEMA [143] DPAEMA [144] MAA [145] PEGMA [144,[146][147][148] 383 [149] DMAM [150] NIPAM [151] 274 [152,153] 325 [154] 326 [154] APMAM-b-NIPAM [89,152] AEMAM [153] St [155] 274 [153] 275 [153] 285 [156] 286 [156] 289 [157] 292 [158] 304 [140] 305 [140] 331 [159] 329 [140] 327 [157] 380 [160] 391 [161,162] 389 [104] (390) [104] 416 [163,164] MAA-b-280 [145] BMA-b-MPC [139] PEGMA/ 320 [165] PEGMA/344 [165] DEGMA-b-384 [141] MMA-b-384 …”

“…PEGA [204] St [205] 357 [206] 362 [207] St/EVE [208] (St/MAH) [208] 50 [209] NAM [47] 52 [210] S S Si(OCH 3 ) 3 -C 53 [210] E Poly(silsesquioxane) macro-RAFT agent PSSQ S S MMA [210] MA [210] DMAM [210] St [210] MMA/312 [210] 54 [211] NAM [211] (Continued) [165] 56 [211,212] [47,211] NAM/342 [212] …”

“…In the case of bis-RAFT agents sequential polymerization of two monomers will yield a triblock. [269] BA [270] MA [270] NIPAM [269,[271][272][273] 420 [274] BA [281] DA [281] St [71,275] 2VP [276] NVP [103] NIPAM/274 [153] DEHEA [280] MA [281] TMAPMA/PEGMA/NIPAM [277] (PEGMA/320) [165] tBA [280] BA/AA [279] (PEGMA/344) [165] 331 [159] AEMA/325/328 [278] DEHEA-b-ODA [280] DMAM-b-331 [159] DMAM-b-331-b-NIPAM [159] DEHEA-b-tBA [280] NIPAM-b-DMAM [272] 2VP-b-EA [276] tBA-b-DEHEA [280] AEME/328/342 [278] 105 [282] [282] PEGA-b-St [282] 106 [188] [188] EHA-b-MA [188] S S S…”

“…319 [352] O [165] O O O O 321 [374] [185] 324 [210] O O O Table 19. Methacrylamide derivatives subjected to RAFT polymerization 325 [154] 326 [154] 327 [157] OH [278] 329 [140] HN Table 20.…”

“…339 [319] O NH HO 2 C [312] NH O B OH OH 344 [165] O HN O O 345 [99] N N NH O 346 [358] O NH HN O 347 [101] O HN N HN O Table 22. Styrene derivatives subjected to RAFT polymerization 348 [100,199] O 349 [138] O N N N 350 [158,309] N VBTAC 351 [159] Cl Ϫ Nϩ 352 [459] HN O 353 [321] O F F F F 354 [313] O F F F F 355 [313] [244] VBTPC 359 [34] Cl Ϫ P ϩ 360 [244] 361 [250] O N O 362 [207] O O O 363 [134] O O O Fe 364 [102] N 365 [102] N Table 23.…”