Intramolecular [4+2] cycloaddition in presence of a dimer of cholic acid: from dia to enantioselectivity

International audienc

Efficient isomerization of methyl arabinofuranosides into corresponding arabinopyranosides in presence of pyridine

International audienceFisher glycosylation, the oldest but efficient reaction towards alkyl glycosides, suffers nonetheless from lack of selectivity, especially when dealing with pentoses. In this case, a mixture of the four isomers, namely the furanosides and the pyranosides, is formed. According to previous studies, the rate and selectivity of the reaction depend greatly on the reaction time and the temperature. In this report, another factor was evaluated, the introduction of a weak nucleophilic base. Interestingly, addition of pyridine few hours after the reaction has started allowed rapid isomerization of the methyl pentofuranosides into its pyranoside counterparts. The reaction proceeds with great diastereoselectivity using arabinose, ribose, xylose and lyxose as starting pentoses. Corresponding methyl pyranosides were obtained as the sole isomers with yields ranging from 65% to 75%. © 2016 Elsevier Lt

Time-dependent phase diagram of bolaamphiphile molecules presenting various lamellar structures

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Evaluation of enantioselectivity of monohydroxy per-O-methylated -cyclodextrin derivatives by gas chromatography

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Polyurethanes prepared from cyclocarbonated broccoli seed oil (PUcc): New biobased organic matrices for incorporation of phosphorescent metal nanocluster

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Synthesis of a novel archaeal tetraether-type lipid containing a diorthoester group as a helper lipid for gene delivery

International audienceAs an alternative to recombinant virus, synthetic carriers are widely developed for providing efficient and safe DNA delivery. To reach the nucleus where nucleic acid (NA) constructs are transcripted, chemical complexes have to overcome serious cellular traps such as endosomal escape and intracellular trafficking. Here, the design and the multi-step synthesis of a stabilizing tetraether lipid analogue of archaeal counterparts containing a diorthoester moiety in the middle of the bridging chain were described. The key step involved a double coupling reaction between two diether alcohols and a diketene acetal. Under aqueous acidic conditions, the diorthoester function of the tetraether lipid can be hydrolysed to yield two monopolar diether lipids. Applied to gene delivery in association with a cationic lipid, this new helper bipolar tetraether lipid led to lipid-DNA complexes with sizes and potential zeta values depending on the charge ratios (+/-). In addition, preliminary in vitro transfection assays supported the interest of these novel bipolar lipid-based lipoplex formulations compared to standard Lipofectamine-based formulations. © 2016 Elsevier Ltd. All rights reserved

Synthesis of a trimannosylated-equipped archaeal diether lipid for the development of novel glycoliposomes

International audienceAn archaeal diether lipid possessing a tri-antenna of α-D-mannopyranoside linked via an oligoethylene spacer to a (2S)-2-(phytanyloxy)-3-(hexadecyloxy)propanoic acid backbone (TriMan-Diether) was designed and synthesized. This new mannosylated lipid inserted in liposomes would show both DC-targeting and adjuvant properties thanks to the TriMan structure and the diether tail part, respectively

Aerosol-mediated non-viral lung gene therapy: The potential of aminoglycoside-based cationic liposomes

Aerosol lung gene therapy using non-viral delivery systems represents a credible therapeutic strategy for chronic respiratory diseases, such as cystic fibrosis (CF). Progress in CF clinical setting using the lipidic formulation GL67A has demonstrated the relevance of such a strategy while emphasizing the need for more potent gene transfer agents. In recent years, many novel non-viral gene delivery vehicles were proposed as potential alternatives to GL67 cationic lipid. However, they were usually evaluated using procedures difficult or even impossible to implement in clinical practice. In this study, a clinically-relevant administration protocol via aerosol in murine lungs was used to conduct a comparative study with GL67A. Diverse lipidic compounds were used to prepare a series of formulations inspired by the composition of GL67A. While some of these formulations were ineffective at transfecting murine lungs, others demonstrated modest-to-very-efficient activities and a series of structure-activity relationships were unveiled. Lipidic aminoglycoside derivative-based formulations were found to be at least as efficient as GL67A following aerosol delivery of a luciferase-encoding plasmid DNA. A single aerosol treatment with one such formulation was found to mediate long-term lung transgene expression, exceeding half the animal’s lifetime. This study clearly supports the potential of aminoglycoside-based cationic lipids as potent GL67-alternative scaffolds for further enhanced aerosol non-viral lung gene therapy for diseases such as CF

Aerosol-mediated non-viral lung gene therapy: The potential of aminoglycoside-based cationic liposomes

International audienceAerosol lung gene therapy using non-viral delivery systems represents a credible therapeutic strategy for chronic respiratory diseases, such as cystic fibrosis (CF). Progress in CF clinical setting using the lipidic formulation GL67A has demonstrated the relevance of such a strategy while emphasizing the need for more potent gene transfer agents. In recent years, many novel non-viral gene delivery vehicles were proposed as potential alternatives to GL67 cationic lipid. However, they were usually evaluated using procedures difficult or even impossible to implement in clinical practice. In this study, a clinically-relevant administration protocol via aerosol in murine lungs was used to conduct a comparative study with GL67A. Diverse lipidic compounds were used to prepare a series of formulations inspired by the composition of GL67A. While some of these formulations were ineffective at transfecting murine lungs, others demonstrated modest-to-very-efficient activities and a series of structure-activity relationships were unveiled. Lipidic aminoglycoside derivative-based formulations were found to be at least as efficient as GL67A following aerosol delivery of a luciferase-encoding plasmid DNA. A single aerosol treatment with one such formulation was found to mediate long-term lung transgene expression, exceeding half the animal’s lifetime. This study clearly supports the potential of aminoglycoside-based cationic lipids as potent GL67-alternative scaffolds for further enhanced aerosol non-viral lung gene therapy for diseases such as CF. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Preclinical evaluation of mRNA trimannosylated lipopolyplexes as therapeutic cancer vaccines targeting dendritic cells

International audienceClinical trials with direct administration of synthetic mRNAs encoding tumor antigens demonstrated safety and induction of tumor-specific immune responses. Their proper delivery to dendritic cells (DCs) requires their protection against RNase degradation and more specificity for dose reduction. Lipid-Polymer-RNA lipopolyplexes (LPR) are attractive mRNA delivery systems and their equipment with mannose containing glycolipid, specific of endocytic receptors present on the membrane of DCs is a valuable strategy. In this present work, we evaluated the capacity of LPR functionalized with a tri-antenna of α-d-mannopyranoside (triMN-LPR) concerning (i) their binding to CD209/DC-SIGN and CD207/Langerin expressing cell lines, human and mouse DCs and other hematopoietic cell populations, (ii) the nature of induced immune response after in vivo immunization and (iii) their therapeutic anti-cancer vaccine efficiency. We demonstrated that triMN-LPR provided high induction of a local inflammatory response two days after intradermal injection to C57BL/6 mice, followed by the recruitment and activation of DCs in the corresponding draining lymph nodes. This was associated with skin production of CCR7 and CXCR4 at vaccination sites driving DC migration. High number of E7-specific T cells was detected after E7-encoded mRNA triMN-LPR vaccination. When evaluated in three therapeutic pre-clinical murine tumor models such as E7-expressing TC1 cells, OVA-expressing EG7 cells and MART-1-expressing B16F0 cells, triMN-LPR carrying mRNA encoding the respective antigens significantly exert curative responses in mice vaccinated seven days after initial tumor inoculation. These results provide evidence that triMN-LPR give rise to an efficient stimulatory immune response allowing for therapeutic anti-cancer vaccination in mice. This mRNA formulation should be considered for anti-cancer vaccination in Humans