Drug delivery by polymeric micelles: an in vitro and in vivo study to deliver lipophilic substances to colonocytes and selectively target inflamed colon.

Colitis is the term used for chronic inflammatory bowel diseases at substantially increased risk of developing a form of colorectal cancer (CRC) known as colitis-associated cancer. In our study we synthesized core-shell polymeric micelles obtained by self-assembly of block copolymers for high efficiency delivery of anti-inflammatory and anti-cancer compounds to colonocytes and colon mucosa. We achieved an efficient intracellular delivery of these hydrophobic compounds (prednisone, retinoic acid and doxorubicin) to cultured colonocytes without cellular toxicity. The efficacy of retinoic acid and doxorubicin administration was significantly increased using these nanosized carriers. Moreover, these polymeric micelles have been shown to overcome the multidrug resistance efflux mechanism effectively delivering doxorubicin to multidrug-resistant colon cancer cells. These nanocarriers are also suitable for selective in vivo delivery of lipophilic drugs by enema administration to the inflamed colon tissue, specifically targeting the inflamed mucosa. FROM THE CLINICAL EDITOR: This team of investigators studied polymeric micelles as highly efficient drug delivery systems enabling intracellular delivery of hydrophobic compounds (prednisone, retinoic acid, and doxorubicin) to cultured colonocytes without cellular toxicity, also demonstrating beneficial in vivo effects.

Universal (switchable) RAFT agents.

The polymerization of most monomers that are polymerizable by radical polymerization can be controlled by the reversible addition-fragmentation chain transfer (RAFT) process. However, it is usually required that the RAFT agent be selected according to the types of monomer being polymerized. Thus, RAFT agents (dithioesters, trithiocarbonates) suitable for controlling polymerization of "more activated" monomers (MAMs; e.g., styrene, acrylates, methacrylates, etc.) tend to inhibit polymerization of "less activated" monomers (LAMs; e.g., vinyl acetate, N-vinylpyrrolidone, etc.). Similarly RAFT agents suitable for polymerizations of LAMs (xanthates, certain dithiocarbamates) tend to give little or poor control over polymerizations of MAMs. We now report a new class of "switchable" RAFT agents, N-(4-pyridinyl)-N-methyldithiocarbamates, that provide excellent control over polymerization of LAMs and, after addition of 1 equiv of a protic or Lewis acid, become effective in controlling polymerization of MAMs, allowing the synthesis of poly(MAM)-block-poly(LAM) with narrow molecular weight distributions.

On the actual EPR detection of thioacyl radicals.

The direct EPR detection of thioacyl radicals has been reported only once, while thioacyl nitroxides remain an elusive species. We failed to detect the thioacyl radicals from two thioaldehydes and from phosphoryldithioformates but have obtained EPR evidence that thioacyl radicals react with 2-methyl-2-nitrosopropane to give thiocarbonyloxyaminyls rather than thioacyl nitroxides. The results of DFT calculations support this unexpected reactivity of thioacyls, while making questionable their previous EPR identification.

New biocompatible polymeric micelles designed for efficient intracellular uptake and delivery.

New amphiphilic block copolymers are easily synthesised by post-polymerisation modifications of poly(glycidyl methacrylate) chain derivatives. The obtained material, upon dispersion in water, is capable of self-assembling into robust micelles. These nanoparticles, which are also characterised by adaptable stability, were loaded with different thiophene based fluorophores. The photoluminescent micelles were administered to cultured cells revealing a high and rapid internalisation of structurally different fluorescent molecules by the same internalisation pathway. Appropriate pairs of chromophores were selected and loaded into the micelles to induce Förster resonance energy transfer (FRET). The disappearing of the FRET phenomenon, after cell uptaking, demonstrated the intracellular release of the nanoparticle contents. The studied nanomaterial and the loaded chromophores have also shown to be biocompatible and non toxic towards the tested cells.

Hydrogen abstraction ability of different aromatic nitroxides.

Indolinonic aromatic nitroxides have been shown to efficiently inhibit free radical mediated oxidation reactions in biological systems. Since all antioxidants also possess pro-oxidant activity, possibly through a hydrogen abstraction process from suitable substrates, the relative hydrogen abstraction abilities of these compounds were evaluated. Different hydrogen donors were reacted with an indolinic and two indolinonic nitroxides and the rates of hydrogen abstraction were determined using UV-Vis spectroscopy. From the data obtained, a structure-activity relationship was found. In addition, the hydrogen abstraction ability of these compounds was found to be much greater than that of the aliphatic nitroxide TEMPO, despite existing reports indicating that these two classes of compounds show similar antioxidant activities in biological systems.

A new facile synthesis of tertiary dithioesters.

Thermal decomposition of tertiary azo compounds in the presence of a triphenylmethyl dithioester results in the formation of the corresponding tertiary dithioesters. This procedure is especially useful for the synthesis of tertiary phosphoryldithioformates, but also represents an easy synthetic methodology of general applicability.