Synthesis of Copolymers Containing an Active Ester of Methacrylic Acid by RAFT:  Controlled Molecular Weight Scaffolds for Biofunctionalization

Abstract

We report the controlled radical copolymerization of N-(2-hydroxypropyl)methacrylamide (HPMA) with a monomer containing an active ester, N-methacryloyloxysuccinimide (NMS), by reversible addition fragmentation chain transfer (RAFT). The large difference in the reactivity ratios of HPMA and NMS resulted in significant variations in copolymer composition with increasing conversion during batch copolymerization. The use of a semi-batch copolymerization method, involving the gradual addition of the more reactive NMS, allowed uniformity of copolymer composition to be maintained during the polymerization. We synthesized polymers in a wide range of molecular weights (M(n) = 3000-50,000 Da) with low polydispersities (1.1-1.3). The effect of the ratio of monomer to chain transfer agent (CTA) on the molecular weight of the polymer was investigated. Given the numerous applications of poly(HPMA)-based conjugates in designing polymeric therapeutics, these controlled molecular weight activated polymers represent attractive scaffolds for biofunctionalization. As a demonstration, we attached a peptide to the activated polymer backbone to synthesize a potent controlled molecular weight polyvalent inhibitor of anthrax toxin.

Living Radical Polymerization by the RAFT Process - A Second Update

“…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. Vinyl derivatives subjected to RAFT polymerization 366 [380] N 367 [380] N 368 [380] N 369 [390] N O O G. Moad, E. Rizzardo, and S. H. Thang [111,135] 370 [135,146] 375 [136] 376 [195] 377 [150] 378 [410] O O (H 3 C) 3 Si 372 [338,346,347] 373 [201] 374 [459] O [466] NAS 380 [160,299,317,345,347] 381 [178] 382 [222] [149,…”

Living Radical Polymerization by the RAFT Process—A First Update

“…[135] [61] S/VBSC [62] 8* AN [63] (DBI) [64] DMAEMA [65] 9* (DBI) [64] DMAEMA [68] GMA [68] HPMAM/NMS [66] MMA [67] HEMA [68] (MA) [69] MMA [46,70,71] NIPAM [72] PFMA [73] (S) [44,74] S [75] S [76] S/AN [68] S/MAH [68] S S CN S S CN…”

“…[12,30,66,[183][184][185] Free radical reducing agents can be used to replace the thiocarbonylthio group with hydrogen. These reducing agents comprise a free radical source and a hydrogen atom donor such as tributylstannane, [12,30] tris(trimethylsilyl)silane, [30] hypophosphite salts, [183] or isopropyl alcohol [186] and reduction takes place by a free radical chain reaction for which the propagation steps are shown in Scheme 11.…”

“…Incomplete end group removal (∼95%) reaction was observed for polystyrene with trithiocarbonate ends [30] but the process is effective for HPMAM/NMS with dithiobenzoate ends. [66] S S Z P n S S Z P n X S S Z X X ϩ ϩ P n P n H H X X ϩ Scheme 11. H-X is a hydrogen atom donor.…”

“…[244] Copolymers of N-(meth)acryloyl succinimide or pentafluorophenyl methacrylate (these monomers, NAS, NMS, and PFMA are referred to as active esters of (meth)acrylates) have been produced by RAFT polymerization and served as substrates for biofunctionalization or other grafting reactions using grafting-to processes. [66,73,245,246] Recent examples include poly(t-butyl acrylamide-block-poly(Nacryloylmorpholine-co-NAS) [245] poly(DMA-co-NAS), [246] PFMA-block-PNAM, [73] and PFMA-block-PMMA. [73] …”