Laboratoire de catalyse et synthese organique

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Core-shell Structured Chitosan-polyethylenimine Nanoparticles for Gene Delivery: Improved Stability, Cellular Uptake, and Transfection Efficiency

Sandrine Gerber, Laura Camille Louise Nicolle, Perrine Agnes Edith Robin

Gene therapy emerged as a promising treatment option for acquired and inherited diseases. The delivery of nucleic acids relies on vectors that condense and encapsulate their cargo. Especially non-viral gene delivery systems are of increasing interest. However, accomplishing therapeutic transgene expression levels and limited tolerability of these systems remain a challenge. Therefore, we investigate in the improvement of nucleic acid delivery using depolymerized chitosan – polyethylenimine DNA complexes (dCS-PEI/DNA). These core complexes are further entrapped into chitosan-based shells, functionalized with polyethylene glycol and cell penetrating peptides. This modular approach allows to evaluate the effect of functional shell components on physico-chemical particle characteristics and biological effects. The optimized ternary complex combines a core-dCS-LPEI/DNA complex with a shell consisting of dCS-PEG-COOH, which resulted in improved nucleic acid encapsulation, cellular uptake, transfection efficiency, and transfection potency in human hepatoma HuH-7 cells and murine primary hepatocytes. Effects on transgene expression are confirmed in wild-type mice following retrograde intrabiliary infusion. After administration of only 100 ng complexed DNA, ternary complexes induce a high reporter gene signal for three days. We conclude that ternary core-shell structured particles comprising functionalized chitosan are a promising gene delivery technology for both in vitro as well as in vivo applications.

2022

Copper-Catalyzed Alkynylation of Hydrazides: An Easy Access to Functionalized Azadipeptides

Julien Aymeric Borrel, Eliott Hugo Joran Le Du, Jérôme Waser

We report a copper-catalyzed alkynylation of azadipeptides using ethynylbenziodoxolone (EBX) reagents. Nonsymmetrical ynehydrazides could be obtained in 25–97% yield using azaglycine derivatives as nucleophiles. The transformation is compatible with most functional groups naturally occurring on amino acid side chains and allows the transfer of silyl-, alkyl-, and aryl-substituted alkynes. The obtained α-alkynyl azaglycine products could be further functionalized by nucleophilic attack or cycloaddition on the triple bond.

2022

H-1 Hyperpolarization of Solutions by Overhauser Dynamic Nuclear Polarization with C-13-H-1 Polarization Transfer

David Lyndon Emsley, Pinelopi Moutzouri, Yu Rao, Amrit Venkatesh

Dynamic nuclear polarization (DNP) is a method that can significantly increase the sensitivity of nuclear magnetic resonance. The only effective DNP mechanism for in situ hyperpolarization in solution is Overhauser DNP, which is inefficient for H-1 at high magnetic fields. Here we demonstrate the possibility of generating significant H-1 hyperpolarization in solution at room temperature. To counter the poor direct H-1 Overhauser DNP, we implement steady-state C-13 Overhauser DNP in solutions and then transfer the C-13 hyperpolarization to H-1 via a reverse insensitive nuclei enhanced by polarization transfer scheme. We demonstrate this approach using a 400 MHz gyrotron-equipped 3.2 mm magic angle spinning DNP system to obtain H-1 DNP enhancement factors of 48, 8, and 6 for chloroform, tetrachloroethane, and phenylacetylene, respectively, at room temperature.

AMER CHEMICAL SOC2022