Macromolecular Cobalt Carbonyl Complexes Encapsulated in a <i>Click</i>-Cross-Linked Micelle Structure as a Nanoparticle To Deliver Cobalt Pharmaceuticals

Block copolymers poly(trimethylsilyl propargyl methacrylate)-block-poly(poly(ethylene glycol) methyl ether methacrylate) (P(TMS-PAMA)-b-P(PEGMA)) were synthesized using reversible addition−fragmentation chain transfer (RAFT) polymerization. Subsequent removal of the trimethylsilyl protective groups on the P(TMS-PAMA)24-b-P(PEGMA)40 polymer with tetra-n-butylammonium fluoride hydrate lead to the polymer P(PAMA)24-b-P(PEGMA)40 with pendant alkyne groups, which self-assembled in aqueous solution into micelles with hydrodynamic diameters of less than 20 nm. The alkyne groups in the core took on two functions, acting as a ligand for Co2(CO)8 to generate a derivative of the antitumor agents based on (alkyne)Co2(CO)6 as well as an anchor point for the cross-linking of micelles via click chemistry. The click process was shown to be highly efficient with the two types of cross-linker employed: 1,2-bis-(2-azidoethoxy)ethane and bis-(azidoethyl)disulfide, with almost all of the cross-linker reacting with the micelle at room temperature. The cross-linking density was influenced by the amount of added cross-linker leaving a well-defined amount of alkyne groups that were utilized in the formation of the cobalt complexes. The successful complexation was confirmed via UV/vis and FT-IR spectroscopy. With the formation of (alkyne)Co2(CO)6 moieties in the core, the un-cross-linked and cross-linked micelles were found to almost double in size. The resulting Co-loaded un-cross-linked micelles were observed to be highly toxic to L929 fibroblast cells, while the cross-linking of the micelle was shown to reduce the toxicity

Shell-Cross-Linked Micelles Containing Cationic Polymers Synthesized via the RAFT Process: Toward a More Biocompatible Gene Delivery System

Block copolymers poly(2-(dimethylamino) ethyl methacrylate)-b-poly(polyethylene glycol methacrylate) (PDMAEMA-b-P(PEGMA)) were prepared via reversible addition fragmentation chain transfer polymerization (RAFT). The polymerization was found to proceed with the expected living behavior resulting in block copolymers with varying block sizes of low polydispersity (PDI <1.3). The resulting block copolymer was self-assembled in an aqueous environment, leading to the formation of pH-responsive micelles. Further stabilization of the micellar system was performed in water using ethylene glycol dimethacrylate and the RAFT process to cross-link the shell. The cross-linked micelle was found to have properties significantly different from those of the uncross-linked block copolymer micelle. While a distinct critical micelle concentration (CMC) was observed using block copolymers, the CMC was absent in the cross-linked system. In addition, a better stability against disintegration was observed when altering the ionic strength such as the absence of changes of the hydrodynamic diameter with increasing NaCl concentration. Both cross-linked and uncross-linked micelles displayed good binding ability for genes. However, the cross-linked system exhibited a slightly superior tendency to bind oligonucleotides. Cytotoxicity tests confirmed a significant improvement of the biocompatibility of the synthesized cross-linked micelle compared to that of the highly toxic PDMAEMA. The cross-linked micelles were taken up by cells without causing any signs of cell damage, while the PDMAEMA homopolymer clearly led to cell death

Kinetic Investigations of Reversible Addition Fragmentation Chain Transfer Polymerizations: Cumyl Phenyldithioacetate Mediated Homopolymerizations of Styrene and Methyl Methacrylate

A previously published simulation and data fitting procedure for the reversible addition fragmentation chain transfer (RAFT) process using the PREDICI simulation program has been extended to cumyl phenyldithioacetate mediated styrene and methyl methacrylate (MMA) bulk homopolymerizations. The experimentally obtained molecular weight distributions (MWDs) for the styrene system are narrow and unimodal and shift linearly with monomer conversion to higher molecular weights. The MMA system displays a hybrid of conventional chain transfer and living behavior, leading to bimodal MWDs. The styrene system has been subjected to a combined experimental and modeling study at 60 °C, yielding a rate coefficient for the addition reaction of free macroradicals to polymeric RAFT agent, kβ, of approximately 5.6 × 105 L mol-1 s-1 and a decomposition rate coefficient for macroradical RAFT species, k-β, of about 2.7 × 10-1 s-1. The transfer rate coefficient to cumyl phenyldithioacetate is found to be close to 2.2 × 105 L mol-1 s-1. The MMA system has been studied over the temperature range 25−60 °C. The hybrid behavior observed in the MMA polymerizations has been exploited (at low monomer conversions) to perform a Mayo analysis allowing the determination of the temperature dependence of the transfer to cumyl phenyldithioacetate reaction. The activation energy of this process is close to 26 kJ mol-1. In contrast to the styrene system, the PREDICI simulation procedure cannot be successfully applied to cumyl phenyldithioacetate mediated MMA polymerizations for the deduction of kβ and k-β. This inability is due to the hybrid nature of the cumyl phenyldithioacetate−MMA system, leading to a significantly reduced sensitivity toward kβ and k-β