Water-soluble polymers with hydrolyzable cationic side groups (structure of the monomers are shown in Figure 1) were synthesized and evaluated as DNA delivery systems. The polymers, except for pHPMA-NHEM, were able to condense plasmid DNA into positively charged nanosized particles. The rate of hydrolysis at 37 degrees C and pH 7.4 of the side groups differed widely; the fastest rate of hydrolysis was observed for HPMA-DEAE (half-life of 2 h), while HPMA-DMAPr had the lowest rate of hydrolysis (half-life of 70 h). In line with this, pHPMA-DEAE-based polyplexes showed the fastest destabilization of the polyplexes at 37 degrees C and pH 7.4. Polyplexes based on pHPMA-DEAE, pHPMA-DMAE, and pHPMA-MPPM showed release of intact DNA within 24, 48, and 48 h, respectively, after incubation at 37 degrees C and pH 7.4. PHPMA-DEAE and pHPMA-MPPM based polyplexes showed the highest transfection activity (almost twice as active as pEI). Importantly, the pHPMA-DEAE, pHPMA-MPPM, and pHPMA-BDMPAP polyplexes preserved their transfection activity in the presence of serum proteins. All polymers investigated showed a substantial lower in vitro cytotoxicity than pEI. In conclusion, pHPMA-based polyplexes are an attractive class of biodegradable vectors for nonviral gene delivery.

A reliable routine method for molar-mass characterization of cationic polymers was established. Because standards of known molar masses with narrow distributions are not commercially available for most polymers used in pharmaceutics and biotechnology, the procedure described in this work can also be applied for molar-mass characterization of other water-soluble polymers.

No abstract

Controlled degradability in response to the local environment is one of the most effective strategies to achieve spatiotemporal release of genes from a polymeric carrier. Exploiting the differences in reduction potential between the extracellular and intracellular environment, disulfides are frequently incorporated into the backbone of polymeric drug delivery agents to ensure efficient intracellular release of the payload. However, although to a lesser extent, reduction of disulfides may also occur in the extracellular environment and should be prevented to avoid premature release. Accurate control over the stability of disulfide linkages enables the optimization of polymeric carriers for efficient drug delivery. Bioreducible poly(amido amine)s (PAAs) with varying degrees of steric hindrance adjacent to the disulfide bonds (0, 2 or 4 methyl groups) were prepared in order to obtain carriers with controlled stability. The degradation behavior of these PAA-polymers was evaluated under different reducing conditions and their in vitro toxicities and transfection efficiencies were assessed. Degradation of the PAA-based polyplexes consistently required higher reducing strengths as the steric hindrance near the disulfide bonds increased. Polyplexes based on 2-methyl cystamine disulfide based PAA polymer (PAA) remained stable under extracellular glutathione concentrations (0.001-0.01mM), while degrading within 1h under reducing conditions similar to those in the intracellular environment (1-10mM glutathione). This polymer exhibited excellent transfection capabilities, with efficiencies up to 90% of transfected cells. PAA showed slightly reduced transfection properties compared to PAA, likely due to premature degradation. The severely hindered PAA, however, displayed increased toxicity, accompanied by reduced transfection efficiency, as a result of its exceptional stability. These results demonstrate the feasibility of introducing steric hindrance near the disulfide moiety to tune polyplex stability against bioreduction, and show that PAA is a promising polymer to be further developed for gene therapy.

No abstract

A new RAFT agent leaving group based on a triazole moiety is introduced. The triazole moiety plays an active role in the stabilization of the intermediate radical, comparable to the phenyl group in a benzyl leaving group. The newly developed leaving group allows easy conjugation to a large variety of substrates where the triazole linking group is hydrolytically stable. Good control is reported in the polymerizations of vinyl acetate, N-vinylpyrrolidone, n-butyl acrylate, and styrene. The versatility of the method is exemplified by linking the triazole to a phenyl and to an oligosaccharide substrate. Overall, this new RAFT agent leaving group is a useful addition to the limited set of leaving groups reported in literature.

A ruthenium porphyrin functionalized with a cavity based on diphenylglycoluril is applied as a catalyst in carbenoid transfer reactions using α-diazoesters as substrates. The latter compounds contain a blocking group connected via an α,ω-dioxyalkyl spacer of 3 or 6 carbon atoms. The reaction of an excess of the α-diazoester with the short spacer with the ruthenium porphyrin macrocycle leads to two products, a [2]rotaxane and a maleate ester, which are the result of dimerization reactions at the inside and the outside of the cavity, respectively. A similar reaction using the α-diazoester with the long spacer also yields high molecular weight species. Mass spectrometric and NMR studies suggest that C-H and/or C=C insertion reactions take place on the thread of the initially formed rotaxane. It is proposed that these reactions are favoured by effective molarity effects because of the close proximity of reactive species in the interlocked geometry.

The Prins reaction, an acid‐catalyzed condensation of alkenes with aldehydes, is used extensively in the fragrance industry. This year we celebrate the 100th anniversary of the discovery of this reaction. In honor of this occasion we present an overview of the diverse applications of the Prins reaction in the synthesis of flavor and fragrance ingredients. To pay tribute to the inventor of the Prins reaction, Hendrik Jacobus Prins, we also provide some insight into his life, scientific, and entrepreneurial accomplishments.