The reversible addition−fragmentation chain transfer (RAFT) polymerization of acrylamide (AM) was studied in order to establish reaction conditions which would provide optimal rates of monomer conversion and to determine reasons for deviation of theoretical and experimental molecular weights, the former predicted from current models. To this end, chain transfer agents (CTAs) and initiators were selected and experiments performed in water and in dimethyl sulfoxide (DMSO) at specified CTA/initiator ratios and temperatures. Higher apparent rates of polymerization were achieved utilizing CTAs with higher intermediate fragmentation rates, larger initiator concentrations, and higher temperatures. For RAFT polymerization of acrylamide under these experimental conditions, a continuing supply of radicals was required in order to achieve reasonable conversions. The deviations of experimentally measured molecular weights from those theoretically predicted are a function of the CTA utilized and parallel the extent of rate retardation. The deviations are, at least in part, consistent with significant early radical coupling of stable intermediate species during the preequilibrium period (or the recently proposed CTA “initialization” period). These effects are apparent in both aqueous buffer and DMSO. The retardation effects and eventual loss of linearity of the first-order kinetic plots at extended times are also consistent with termination processes although these experiments alone do not rule out alternative mechanisms of reversible termination or slow fragmentation of intermediate species. For RAFT polymerizations in DMSO mediated by the trithiocarbonate CTA, reaction rates are significantly faster, and near quantitative conversions can be reached with proper initiator choice.

Poly(N-(2-hydroxypropyl)methacrylamide) (PHPMA) is a nonimmunogenic, neutral-hydrophilic polymer currently employed in the delivery of anticancer drugs. Herein, we report conditions that facilitate the direct, controlled RAFT polymerization of HPMA in aqueous media. We demonstrate that the use of 4-cyanopentanoic acid dithiobenzoate and 4,4'-azobis(4-cyanopentanoic acid) as the chain transfer agent (CTA) and initiating species, respectively, in the presence of an acetic acid buffer solution at 70 degrees C is a suitable condition leading to controlled polymerization. The "living" nature of these polymerizations is demonstrated via chain-extension of an HPMA macroCTA to yield the corresponding poly(HPMA-b-HPMA) "homopolymer".

Controlled radical polymerization (CRP) combines the benefits of the robust nature of conventional radical polymerization with the ability to prepare advanced macromolecular architectures common to living polymerization techniques. Of the major CRP techniques, the reversible additionfragmentation chain transfer (RAFT) technique appears to be the most tolerant of aqueous reaction conditions and a variety of monomer functionalities. To date, however, there have been no reports of the RAFT polymerization of a cationic (meth)acrylamido monomer directly in aqueous media. Herein we report the polymerization of N- [3-(dimethylamino)propyl]methacrylamide (DMAPMA) directly in aqueous media utilizing 4-cyanopentanoic acid dithiobenzoate (CTP) as the chain transfer agent (CTA). Polymerization in water at neutral pH allowed a moderate level of control over the polymerization up to 50% conversion. Polymerization in an aqueous buffer (pH ) 5), on the other hand, afforded excellent control up to 98% conversion (M n ) 38 000, Mw/Mn ) 1.12). Purification of the poly(DMAPMA) macro-CTA under conditions that minimize the exposure of the macro-CTA to an unbuffered aqueous environment was necessary for the retention of functional chain ends. Block copolymers of DMAPMA and N,Ndimethylacrylamide (DMA) or (ar-vinylbenzyl)trimethylammonium chloride (VBTAC) were successfully prepared from a macro-chain-transfer agent (macro-CTA) of poly(DMAPMA). † Paper no. 110 in a series entitled Water Soluble Polymers.

The complexation of small interfering ribonucleic acid (siRNA) with a series of specifically designed block copolymers consisting of the hydrophilic, nonimmunogenic monomer N-(2-hydroxypropyl)methacrylamide (HPMA) and the cationic monomer N- [3-(dimethylamino)propyl]methacrylamide (DMAPMA) has been investigated for potential siRNA stabilization and delivery applications. Specific compositions of poly(HPMAb-DMAPMA) copolymers were synthesized via aqueous reversible addition-fragmentation chain transfer (RAFT) polymerization and characterized using aqueous size exclusion chromatography with multiangle laser light scattering (SEC-MALLS) and 1 H NMR spectroscopy. The degree of soluble complex formation between a model siRNA and the polymers was determined by centrifugal membrane filtration experiments and quantitated by scintillation counting of 32 P ATP-labeled siRNA to determine complex solubility and to estimate the degree of complexation relative to cationic and neutral block lengths. Dynamic and static light scattering methods were employed to determine the hydrodynamic radii, molecular weights, and second virial coefficients of the complexes and to demonstrate their unimodal size distributions. In vitro enzymatic degradation studies of selected siRNA/block copolymer complexes were conducted to demonstrate the enhanced stability of the siRNA/poly(HPMA-b-DMAPMA) complexes. Furthermore, the siRNA/polymer complexes dissociate slowly under gel electrophoresis conditions. Therefore, the siRNA/polymer complexes demonstrate some highly desirable properties for potential applications in therapeutic siRNA stabilization and delivery.

A novel pH-and salt-responsive carboxybetaine monomer, 4-(N,N-diallyl-N-methylammonio)butanoate (2), was prepared and cyclocopolymerized with the cationic monomer N,N-diallyl-N,Ndimethylammonium chloride (3) in 0.5 M NaCl aqueous solution (pH ) 7.0) using 2-hydroxy-1-[4-(hydroxyethoxy)phenyl]-2-methyl-1-propanone (Irgacure 2959) as the free-radical photoinitiator. The molar feed ratio of 2:3 was varied from 100:0 to 0:100 with the total monomer concentration held constant at 2.5 M. Cyclopolymerization to five-membered ring structures common to diallylammonium salts was confirmed by 13 C NMR spectroscopy. Reactivity ratio studies indicate that 2 and 3 copolymerize in a nearly ideal fashion (r1 ) 0.86, r2 ) 0.99). Weight-average molecular weights and second virial coefficients vary from (6.0 to 12.8) × 10 4 g mol -1 and (1.62 to 5.36) × 10 -4 mL mol g -2 , respectively. Dilute solution viscosity behavior depends on copolymer composition, ionic strength, and pH. Copolymers with a large excess charge exhibit typical polyelectrolyte behavior, while those with balanced charge exhibit "antipolyelectrolyte" behavior reported for zwitterionic (co)polymers. The polymers studied here are closely analogous cyclocopolymers we prevoiusly reported containing sulfobetaine mer units. 25 Unlike solutions of sulfobetaine-containing polymers, soltuions of poly(2-co-3) remain soluble at very low ionic strength even up to 100% incorporation of 2. Additionally, while the sulfobetaine systems are insensitive to pH, solutions of poly(2-co-3) exhibit a pH-dependent viscosity. All the copolymers have an apparent pKa of ∼3.6. Copolymers with 2 incorporations of 28 mol % and above have viscosity responsiveness between pH values of 2.5 and 4.5. The maximum pH response was achieved for solutions of poly(2-co-3) containing 37 and 56 mol % of the carboxybetaine monomer 2. † Paper No. 98 in a series entitled "Water-Soluble Polymers".