Short peptide sequences that are able to transport molecules across the cell membrane have been developed as tools for intracellular delivery of therapeutic molecules. This work describes a novel family of cell-penetrating peptides named Vectocell peptides [also termed DPVs (Diatos peptide vectors)]. These peptides, originating from human heparin binding proteins and/or anti-DNA antibodies, once conjugated to a therapeutic molecule, can deliver the molecule to either the cytoplasm or the nucleus of mammalian cells. Vectocell peptides can drive intracellular delivery of molecules of varying molecular mass, including full-length active immunoglobulins, with efficiency often greater than that of the well-characterized cell-penetrating peptide Tat. The internalization of Vectocell peptides has been demonstrated to occur in both adherent and suspension cell lines as well as in primary cells through an energy-dependent endocytosis process, involving cell-membrane lipid rafts. This endocytosis occurs after binding of the cell-penetrating peptides to extracellular heparan sulphate proteoglycans, except for one particular peptide (DPV1047) that partially originates from an anti-DNA antibody and is internalized in a caveolar independent manner. These new therapeutic tools are currently being developed for intracellular delivery of a number of active molecules and their potentiality for in vivo transduction investigated.

In order to study the role played by the fetoplacental unit in providing the human fetus with arachidonic acid, Δ⁵- and Δ⁶-desaturase activities were studied in microsomes from human fetal liver and placenta after 18 and 22 weeks of gestation. We evidenced for the first time Δ⁵- and Δ⁶-desaturase activities in fetal liver microsomes. As in adult liver, Δ⁶-desaturation is the rate-limiting step of arachidonic acid synthesis. No activity was found in the placenta. Arachidonic acid concentrations were higher in fetal serum than in maternal serum while the opposite was observed for linoleic acid. The fetal liver microsomal content in arachidonic acid was low. Taken together the data suggest that arachidonic acid is supplied to the fetus through a preferential transfer across the placenta.

Purpose: Irinotecan is a prodrug converted to the active cytotoxic molecule SN38 predominantly by the action of liver carboxylesterases. The efficacy of irinotecan is limited by this hepatic activation that results in a low conversion rate, high interpatient variability, and dose-limiting gastrointestinal toxicity. The purpose of this study was to evaluate a novel peptidic prodrug of SN38 (DTS-108) developed to bypass this hepatic activation and thus reduce the gastrointestinal toxicity and interpatient variability compared with irinotecan. Experimental Design: SN38 was conjugated to a cationic peptide (Vectocell) via an esterase cleavable linker.The preclinical development plan consisted of toxicity and efficacy evaluation in a number of different models and species. Results: The conjugate (DTS-108) is highly soluble, with a human plasma half-life of 400 minutes in vitro. Studies in the dog showed that DTS-108 liberates significantly higher levels of free SN38 than irinotecan without causing gastrointestinal toxicity. In addition, the ratio of the inactive SN38-glucuronide metabolite compared with the active SN38 metabolite is significantly lower following DTS-108 administration, compared with irinotecan, which is consistent with reduced hepatic metabolism. In vivo efficacy studies showed that DTS-108 has improved activity compared with irinotecan. A significant dose-dependent antitumoral efficacy was observed in all models tested and DTS-108 showed synergistic effects in combination with other clinically relevant therapeutic agents. Conclusions: DTS-108 is able to deliver significantly higher levels of SN38 than irinotecan, without the associated toxicity of irinotecan, resulting in an increased therapeutic window for DTS-108 in preclinical models. These encouraging data merit further preclinical and clinical investigation.Irinotecan is an effective chemotherapeutic agent that is widely prescribed for advanced colorectal cancer as a first-or secondline treatment. Irinotecan has also been shown to be active in gastric cancer, non -small cell lung cancer, and small-cell lung cancer, alone or in combination with other cytotoxic agents (1). Currently, irinotecan is used in combination with 5-fluorouracil (5-FU) in first-line treatment for metastatic colorectal cancer (2). Irinotecan is also used with other agents, including the anti -vascular endothelial growth factor antibody bevacizumab (Avastin; refs. 3,4). Following administration of irinotecan, the active metabolite SN38 (7-ethyl-10-hydroxycamptothecin) is formed by the action of carboxylesterases that are predominantly present in the liver (5, 6). SN38 is a topoisomerase I inhibitor with an activity a thousand times greater than irinotecan, but that cannot be administered directly as it is highly insoluble (1).Several limitations to the clinical use of irinotecan arise due to its mechanism of activation, metabolism, and elimination. The first limitation is caused by the complexity of irinotecan metabolism, which results in high interpatient variabil...

(R)-Roscovitine, a pharmacological inhibitor of kinases, is currently in phase II clinical trial as a drug candidate for the treatment of cancers, Cushing's disease and rheumatoid arthritis. We here review the data that support the investigation of (R)-roscovitine as a potential therapeutic agent for the treatment of cystic fibrosis (CF). (R)-Roscovitine displays four independent properties that may favorably combine against CF: (1) it partially protects F508del-CFTR from proteolytic degradation and favors its trafficking to the plasma membrane; (2) by increasing membrane targeting of the TRPC6 ion channel, it rescues acidification in phagolysosomes of CF alveolar macrophages (which show abnormally high pH) and consequently restores their bactericidal activity; (3) its effects on neutrophils (induction of apoptosis), eosinophils (inhibition of degranulation/induction of apoptosis) and lymphocytes (modification of the Th17/Treg balance in favor of the differentiation of anti-inflammatory lymphocytes and reduced production of various interleukins, notably IL-17A) contribute to the resolution of inflammation and restoration of innate immunity, and (4) roscovitine displays analgesic properties in animal pain models. The fact that (R)-roscovitine has undergone extensive preclinical safety/pharmacology studies, and phase I and II clinical trials in cancer patients, encourages its repurposing as a CF drug candidate.

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