Dual electrochemical and chemical control in atom transfer radical polymerization with copper electrodes.

In Atom Transfer Radical Polymerization (ATRP), Cu0 acts as a supplemental activator and reducing agent (SARA ATRP) by activating alkyl halides and (re)generating the CuI activator through a comproportionation reaction, respectively. Cu0 is also an unexplored, exciting metal that can act as a cathode in electrochemically mediated ATRP (eATRP). Contrary to conventional inert electrodes, a Cu cathode can trigger a dual catalyst regeneration, simultaneously driven by electrochemistry and comproportionation, if a free ligand is present in solution. The dual regeneration explored herein allowed for introducing the concept of pulsed galvanostatic electrolysis (PGE) in eATRP. During a PGE, the process alternates between a period of constant current electrolysis and a period with no applied current in which polymerization continues via SARA ATRP. The introduction of no electrolysis periods without compromising the overall polymerization rate and control is very attractive, if large current densities are needed. Moreover, it permits a drastic charge saving, which is of unique value for a future scale-up, as electrochemistry coupled to SARA ATRP saves energy, and shortens the equipment usage.

Catalytic Halogen Exchange in Supplementary Activator and Reducing Agent Atom Transfer Radical Polymerization for the Synthesis of Block Copolymers.

Synthesis of block copolymers (BCPs) by catalytic halogen exchange (cHE) is reported, using supplemental activator and reducing agent Atom Transfer Radical Polymerization (SARA ATRP). The cHE mechanism is based on the use of a small amount of a copper catalyst in the presence of a suitable excess of halide ions, for the synthesis of block copolymers from macroinitiators with monomers of mismatching reactivity. cHE overcomes the problem of inefficient initiation in block copolymerizations in which the second monomer provides dormant species that are more reactive than the initiator. Model macroinitiators with low dispersity are prepared and extended to afford well-defined block copolymers of various compositions. Combined cHE/SARA ATRP is therefore a simple and potent polymerization tool for the copolymerization of a wide range of monomers allowing the production of tailored block copolymers.

Near infrared light-triggered nanoparticles using singlet oxygen photocleavage for drug delivery systems.

Drug delivery systems (DDSs) have showed a reduced systemic toxicity and enhanced therapeutic efficacy over conventional cancer treatments. However, after reaching the damaged tissue, DDSs should present a trigger release of the encaged therapeutics. Among all methodologies for a controlled release system, the use of light in NIR window (650-900 nm) shows the most appropriate characteristics for biological applications (e.g. biocompatibility with tissues). This review is focused on NIR responsive approaches for DDSs intermediated by a photosensitizer (PS) using nanoparticles (NP) that possess oxidation sensitive segments. After excited by light, the PS generates singlet oxygen species which interact with a sensitive segment, causing bond cleavage or hydrophobicity change in NP followed by the release of entrapped therapeutics. The most relevant sensitive segments addressed in this work are: olefin (lipid, vinyl ether, vinyl disulfide, and aminoacrylate), thioketal, selenium and hydrophobicity changeable polymers (tellurium, poly(propylene sulfide), imidazole and nitroimidazole). The chemical structure of the sensitive segment, the available strategies for nanoparticle formation and DDSs in vitro and in vivo studies are also critically discussed. These NIR responsive DDSs have enormous potential as a tool for a controlled spatial-temporal drug release with capacity to overcome the drawbacks of the others specificity target DDSs (such as pH, temperature and ROS). In order to reach the pharmacological market, the light sensibility of the labile segments should increase for the range of wavelengths used and more biological test should be addressed.

Preparation of well-defined brush-like block copolymers for gene delivery applications under biorelevant reaction conditions.

Well-defined oligo(ethylene glycol) methyl ether methacrylate (OEOMA) based block copolymers with cationic segments composed by N,N-(dimethylamino) ethyl methacrylate (DMAEMA) and/or 2-(diisopropylamino) ethyl methacrylate (DPA) were developed under biorelevant reaction conditions. These brush-type copolymers were synthesized through supplemental activator and reducing agent (SARA) atom transfer radical polymerization (ATRP) using sodium dithionite as SARA agent. The synthesis was carried out using an eco-friendly solvent mixture, very low copper catalyst concentration, and mild reaction conditions. The structure of the block copolymers was characterized by size exclusion chromatography (SEC) analysis and 1H nuclear magnetic resonance (NMR) spectroscopy. The pH-dependent protonation of these copolymers enables the efficient complexation with plasmid DNA (pDNA), yielding polyplexes with sizes ranging from 200 up to 700 nm, depending on the molecular weight of the copolymers, composition and concentration used. Agarose gel electrophoresis confirmed the successful pDNA encapsulation. No cytotoxicity effect was observed, even for N/P ratios higher than 50, for human fibroblasts and cervical cancer cell lines cells. The in vitro cellular uptake experiments demonstrated that the pDNA-loaded block copolymers were efficiently delivered into nucleus of cervical cancer cells. The polymerization approach, the unique structure of the block copolymers and the efficient DNA encapsulation presented can open new avenues for development of efficient tailor made gene delivery systems under biorelevant conditions.

Aqueous SARA ATRP using Inorganic Sulfites.

Aqueous supplemental activator and reducing agent atom transfer radical polymerization (SARA ATRP) using inorganic sulfites was successfully carried out for the first time. Under optimized conditions, a well-controlled poly[oligo(ethylene oxide) methyl ether acrylate] (POEOA) was obtained with <30 ppm of soluble copper catalyst using tris(2-pyridylmethyl)amine (TPMA) ligand in the presence of an excess of halide salts (e.g. NaCl). Inorganic sulfites (e.g. Na2S2O4) were continuously fed into the reaction mixture. The mechanistic studies proved that these salts can activate alkyl halides directly and regenerate the activator complex. The effects of the feeding rate of the SARA agent (inorganic sulfites), ligand and its concentration, halide salt and its concentration, sulfite used, and copper concentration, were systematically studied to afford fast polymerizations rates while maintaining the control over polymerization. The kinetic data showed linear first-order kinetics, linear evolution of molecular weights with conversion, and polymers with narrow molecular weight distributions (D ~1.2) during polymerization even at relatively high monomer conversions (~80%). "One-pot" chain extension and "one-pot" block copolymerization experiments proved the high chain-end functionality. The polymerization could be directly regulated by starting or stopping the continuous feeding of the SARA agent. Under biologically relevant conditions, the aqueous SARA ATRP using inorganic sulfites was used to synthesize a well-defined protein-polymer hybrid by grafting of P(OEOA480) from BSA-O-[iBBr]30.

Copper-mediated controlled/"living" radical polymerization in polar solvents: insights into some relevant mechanistic aspects.

The field of transition-metal-mediated controlled/"living" radical polymerization (CLRP) has become the subject of intense discussion regarding the mechanism of this widely-used and versatile process. Most mechanistic analyses (atom transfer radical polymerization (ATRP) vs. single-electron transfer living radical polymerization (SET-LRP)) have been based on model experiments, which cannot correctly mimic the true reaction conditions. We present, for the first time, a determination of the [Cu(I)Br]/[L] (L=nitrogen-based chelating ligand) ratio and the extent of Cu(I)Br/L disproportionation during CLRP of methyl acrylate (MA) in dimethylsulfoxide (DMSO) with Cu(0) wire as a transition-metal catalyst source. The results suggest that Cu(0) acts as a supplemental activator and reducing agent of Cu(II)Br(2)/L to Cu(I)Br/L. More importantly, the Cu(I)Br/L species seem to be responsible for the activation of SET-LRP.