Yann Sibiril

Numerous diseases affect the respiratory tract and the aerosol administration has been widely considered as an adapted and non-invasive method for local delivery. This pathway induces a lung concentration and thus also limits, systemic side effects. However, aerosol delivery of active pharmaceutical ingredients represents a real challenge, due to numerous obstacles such as the specific respiratory movement, the presence of mucus or surfactant, mucociliary clearance. Nanomedicines, such as liposomes, micelles or nanoparticles, offer the possibility to increase bioavailability and favor intracellular penetration of specific drugs into lung tissue. This review focuses on the description of aerosol formulations and cellular barriers including design, characteristics and progressive adaptation to airways anatomy. Then, aerosolized formulations currently clinically approved, or in clinical trial are summarized according to the encapsulated drug. In a final section, promising aerosol formulations in pre-clinical studies are detailed.

The objective of lung gene therapy is to reach the respiratory epithelial cells in order to deliver a functional nucleic acid sequence. To improve the synthetic carrier’s efficacy, knowledge of their biodistribution and elimination pathways, as well as cellular barriers faced, depending on the administration route, is necessary. Indeed, the in vivo fate guides the adaptation of their chemical structure and formulation to increase their transfection capacity while maintaining their tolerance. With this goal, lipidic fluorescent probes were synthesized and formulated with cationic lipophosphoramidate KLN47 (KLN: Karine Le Ny). We found that such formulations present constant compaction properties and similar transfection results without inducing additional cytotoxicity. Next, biodistribution profiles of pegylated and unpegylated lipoplexes were compared after systemic injection in mice. Pegylation of complexes led to a prolonged circulation in the bloodstream, whereas their in vivo bioluminescent expression profiles were similar. Moreover, systemic administration of pegylated lipoplexes resulted in a transient liver toxicity. These results indicate that these new fluorescent compounds could be added into lipoplexes in small amounts without perturbing the transfection capacities of the formulations. Such additional properties allow exploration of the in vivo biodistribution profiles of synthetic carriers as well as the expression intensity of the reporter gene.

In vitro haematotoxicity assays are thought to have the potential to significantly reduce and refine the use of animals for haematotoxicity testing. These assays are used successfully in all types of studies — however, their use is not so common in human toxicology studies in the preclinical setting, as they are not required for regulatory testing in this case. Furthermore, these assays could play a key role in bridging the gap between preclinical toxicology studies in animal models and clinical investigations. In previous studies, the Colony Forming Unit-Granulocyte Macrophage (CFU-GM) assay has been validated for testing drug haematotoxicity (with both mouse bone-marrow and human cord blood) and for predicting the in vivo human maximal tolerated dose (MTD) by adjusting in vivo data on mouse toxicity. Recently, a Colony Forming Unit-Megakaryocyte (CFU-MK) assay has also been prevalidated for testing drug toxicity toward megakaryocytes. The rat CFU-GM assay has been used by many researchers for its ability to evaluate in vitro haematotoxicity. Although it is not yet available, a standardised procedure for data comparison could be very important, since the rat is the most widely-used species for the in vivo testing of toxicants. This report presents the results of the prevalidation study developed to analyse the intra-laboratory and inter-laboratory variability of a standardised operating procedure for this assay and its performance for the in vitro determination of the inhibitory concentration (IC) values of drugs on rat myeloid progenitors (CFU-GM). The results demonstrate that the CFU-GM assay can be performed with cryopreserved rat bone-marrow cells (rBMC). The assay represents a useful tool for evaluating the toxicity of a compound, in terms of both relative toxicity (when different molecules are compared) and the prediction of the degree of in vivo toxicity. The use of this assay could greatly reduce the number of rats used in experimental procedures, and could also contribute to the accumulation of more toxicity data on compounds to be registered according to the criteria established by the European Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) programme.

In this study, di‐n‐butyltin(IV) oxide was reacted with the amino glucose analog, cis‐4‐[N‐(1′,3′,4′,6′‐tetra‐O‐benzoyl‐2‐deoxy‐glucopyranosyl)imido]‐4‐oxo‐2‐butenoic acid (1a) and o‐[N‐(1′,3′,4′,6′‐tetra‐O‐benzoyl‐2‐deoxy‐glucopyranosyl) carbamoyl] benzoic acid (2a) to give the complexes bis‐{cis‐4‐[N‐(1′,3′,4′,6′‐tetra‐O‐benzoyl‐2‐deoxy‐glucopyranosyl)imido‐4‐oxo‐2‐butenoic acid]‐di‐n‐butyltin} carboxylate (1) and bis‐{o‐[N‐(1′,3′,4′,6′‐tetra‐O‐benzoyl‐2‐deoxy‐glucopyranosyl) carbamoyl‐benzoic acid]‐di‐n‐butyltin}carboxylate (2). These two compounds were then characterized by IR, NMR and MS. In vitro tests showed that both compounds have high cytotoxicity in four tumor cell lines (P388, HL‐60, A549 and BEL‐7402). Clonogenic assays demonstrated that both compounds 1 and 2 have hematopoietic cell toxicity at 10⁻⁶ m.