A series of well-defined poly[(ethylene oxide)-block-2-(dimethylamino)ethyl methacrylate-block-2-(diethylamino) methacrylate] (PEO−DMA−DEA) triblocks were synthesized by successive ATRP polymerization of DMA and DEA monomers using PEO-based macroinitiators of different molecular weights. These triblock copolymers dissolved molecularly in aqueous solution at low pH; on addition of NaOH, micellization occurred at pH 7.1 to form three-layer “onionlike” micelles comprising DEA cores, DMA inner shells, and PEO coronas. Above pH 7.3, dynamic light scattering studies indicated unimodal, near-monodisperse populations, with mean micelle diameters of 27−84 nm depending on block compositions (for PEO113 triblock copolymers) and polydispersities typically less than 0.10. The average hydrodynamic diameter 〈D h〉 of the micelles decreased as the solution pH was increased from pH 7.3 to pH 9.0, indicating that the micelles become more compact due to deprotonation of the tertiary amine residues in the DMA and DEA blocks. 1H NMR studies supported a three-layer micelle structure and also revealed changes in the hydrophilicity of the DMA chains in the inner shell during cross-linking, which was achieved by adding the bifunctional alkyl iodide, 1,2-bis(2-iodoethoxy)ethane (BIEE). Selective quaternization of the DMA residues by the BIEE leads to increased hydrophilicity and colloid stability for the shell cross-linked (SCL) micelles. The minimum amount of BIEE required to “lock-in” the micellar structure depended on the thickness of the PEO corona:  shorter PEO chains led to enhanced cross-linking efficiency. At pH 8.5, the hydrodynamic diameter of un-cross-linked micelles increased rapidly above 40−50 °C due to the LCST behavior of the neutral DMA chains in the inner shell. In contrast, the dimensions of the SCL micelles in dilute aqueous solution are independent of temperature. These SCL micelles exhibit reversible swelling on varying the solution pH. At low pH, the DEA cores become protonated and hence hydrophilic. The effect of varying the block composition and the target degree of cross-linking on the structural stability and pH-dependent (de)swelling of the SCL micelles was systematically studied. Longer DEA blocks and lower target degrees of cross-linking led to increased swellability, as expected.

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2-Methacryloyloxyethyl phosphorylcholine (MPC) is commonly used to prepare biocompatible copolymers that have delivered clinically proven benefits in various biomedical applications. Recently, we reported that MPC could be homopolymerized to high conversions with good control via atom transfer radical polymerization (ATRP) in protic media. In the present study we describe the synthesis of a wide range of well-defined MPC-based block copolymers using either near-monodisperse macroinitiators or sequential monomer addition. With the former approach, the macroinitiators were based on either poly-(alkylene oxides) or poly(dimethylsiloxane). With the latter approach, suitable comonomers included a wide range of methacrylic and other monomers, including 2-(dimethylamino)ethyl methacrylate (DMA) and its quaternized derivatives, 2-(diethylamino)ethyl methacrylate (DEA), 2-(diisopropylamino)ethyl methacrylate (DPA), methyl methacrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, and glycerol monomethacrylate. Polymerization of MPC using the three macroinitiators yielded novel PEO-MPC, PPO-MPC, and PDMS-MPC diblock copolymers. The PPO-MPC diblock copolymer proved to be thermoresponsive: molecular dissolution occurred in cold water, with colloidal aggregates being formed reversibly at elevated temperatures due to the inverse temperature solubility behavior of the PPO block. For the sequential monomer addition syntheses, the MPC monomer was generally polymerized first under optimized conditions, followed by the second monomer. High conversions were obtained for both stages of polymerization, and where applicable, aqueous GPC analyses indicated reasonably low polydispersities and good blocking efficiencies. Above pH 8, the MPC-DMA diblock copolymers also exhibited thermoresponsive behavior, forming DMA-core aggregates at elevated temperature. Spontaneous dissociation occurred on cooling to ambient temperature as the hydrophobic DMA block became hydrophilic again. The MPC-DMA, MPC-DEA, and MPC-DPA diblock copolymers proved to be pH-responsive polymeric surfactants at ambient temperature: molecular dissolution occurred in dilute acidic solution with well-defined, near-monodisperse micelles being formed at around neutral pH. In each case, the MPC block formed the biocompatible micelle coronas and the tertiary amine methacrylate block formed the hydrophobic micelle cores. In the case of the MPC-DPA diblock copolymer, the pyrene partition constant for the DPA-core micelles at pH 9 was similar to that reported previously for polystyrene-core micelles. These new MPC-based diblock copolymers are being evaluated as new nonviral vectors for DNA condensation and "stealthy" nanocapsules for the delivery of hydrophobic drugs and also for the synthesis of biocompatible shell cross-linked micelles.

Two micellar states are possible for a novel PPO–PDEA diblock copolymer synthesized by atom‐transfer radical polymerization. Subtle variation of the solution pH value and temperature is all that is needed to form both conventional micelles (with the PDEA block in the core) and reverse micelles (with the PPO block in the core) in aqueous media (shown schematically). DEA=2‐(diethylamino)ethyl methacrylate, PO=propylene oxide.

The branching copolymerization of 2-hydroxypropyl methacrylate (HPMA) with either ethylene glycol dimethacrylate (EGDMA) or bisphenol A dimethacrylate (BPDMA) as the branching agent has been carried out using atom transfer radical polymerization (ATRP) in methanol at 20 °C. With EGDMA, soluble branched copolymers were obtained provided that less than one branching agent was incorporated per primary chain:  higher levels of EGDMA led to gelation, as expected. Analysis of the changes in the molecular weight and polydispersity of the polymers shows that the formation of highly branched chains occurs only at high (>90%) conversions. Chain coupling is close to the ideal behavior predicted by the Flory−Stockmayer theory, suggesting that all double bonds are equally reactive and that there is no significant cyclization, in contrast to conventional free radical polymerization. This analysis is confirmed by comparison of the consumption of the EGDMA branching agent with predictions from both theory and simulation. With BPDMA as the branching agent, similar results are obtained although branching is slightly less efficient.