Improvement in the therapeutic index of doxorubicin, a cytotoxic molecule, has been sought through its chemical conjugation to short (15-23 amino acid) peptide sequences called Vectocell peptides. Vectocell peptides are highly charged drug delivery peptides and display a number of characteristics that make them attractive candidates to minimize many of the limitations observed for a broad range of cytotoxic molecules. The studies reported here characterized the in vitro and in vivo efficacy of a range of Vectocell peptides conjugated to doxorubicin through different linkers. These studies show that the in vivo therapeutic index of doxorubicin can be improved by conjugation with a specific Vectocell peptide (DPV1047) through an ester linker to C14 of doxorubicin, in both colon and breast tumor models. This conjugate was also shown to have significant in vivo antitumoral activity in a model resistant to doxorubicin, suggesting that this conjugate is able to circumvent the multidrug resistance (MDR) phenotype. These experiments therefore provide support for the use of the Vectocell technology with other cytotoxic agents.

Glycosides, acylated glycosides, and sulfates of quercetin ( 3,3',4',5,7-pentahydroxyflavone; 1), which is, together with its derivatives, among the most common polyphenols found in plants and in the human diet, were prepared and quantitatively investigated for their ability to bind metal ions (Al III , Fe II , Fe III ), enhance and vary natural colours (anthocyanin copigmentation), and trap potentially damaging radicals (antioxidant activity).Introduction. ± Flavonoids and other polyphenols are ubiquitous secondary metabolites in plants [1] which, as food components, enjoy increasing interest from researchers, food manufacturers, and consumers. Indeed, polyphenol-rich diets (e.g., the regular consumption of fruits, vegetables, red wine, and tea) have been repeatedly correlated with a low risk of developing cardiovascular diseases and cancers [2], the two major causes of mortality in occidental countries. Because of their antioxidant properties and their ability to bind to a wide range of proteins including enzymes [1] [3], polyphenols may be partially responsible for these protective effects.Besides phenolic acids (benzoic and cinnamic acid derivatives), flavonols (3-hydroxyflavones) are one of the main classes of dietary polyphenols [1]. Their antioxidant properties essentially stem from their ability to trap reactive O-species (ROS) and bind transition-metal ions, which, if not suitably complexed, could enter redox cycles that produce ROS [3]. This work focuses on quercetin (3,3',4',5,7-pentahydroxyflavone; 1), the most representative dietary flavonol (abundant in onions, apples, and tea) and a potent antioxidant. In most naturally occurring flavonols, at least one of the OH groups of the polyphenolic nucleus (aglycone) is glycosylated by monoand oligosaccharides involving neutral sugars such as d-glucose, d-galactose, lrhamnose, and d-xylose. Quercetin b-d-glucopyranosides are particularly interesting because their biodisposability, irrespective of the location of the sugar moiety on the polyphenolic nucleus, is better than that of quercetin and other quercetin glycosides, possibly as a consequence of a facilitated intestinal absorption via glucose transporters [4]. Moreover, quercetin sulfates deserve particular attention, not only because of their natural occurrence [1] [5], but also because the quercetin conjugates found in the plasma of human volunteers after consumption of a meal rich in plant products are actually glucuronides and sulfates [6].

BCLIS was well tolerated and safe over 14 days of treatment and significantly improved postprandial BG vs LIS when administered at mealtime.

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Funding informationAdocia sponsored this study.We investigated the pharmacodynamics (PD) and pharmacokinetics (PK) of BioChaperone insulin Lispro (BCLIS), faster insulin aspart (FIA) and insulin aspart (ASP) in patients with type 1 diabetes using an insulin pump. In this randomized, double-blind, three-way crossover glucose clamp study, 43 patients received a bolus dose of each insulin (0.15 U/kg) in addition to a basal rate (0.01 U/kg/h), delivered via an insulin pump. With BCLIS, the AUC-GIR,0-60 minutes (primary endpoint) was improved compared to ASP (least square means ratio, 1.63; 95% CI, 1.44-1.88; P < 0.0001) and was similar compared to FIA (least square means ratio, 1.06; 95% CI, 0.94-1.18; P = 0.4609). BCLIS showed faster-on PD (t early0.5GIRmax ) than ASP and faster-off PD (t late0.5GIRmax ) than both FIA and ASP. BCLIS also demonstrated significantly higher early exposure (AUCins, 0-60 minutes) and lower late exposure (AUCins,120-600 minutes) than both other insulins. In patients with type 1 diabetes using an insulin pump, BCLIS better mimics prandial insulin secretion and action than ASP and shows a faster off-PD than FIA.insulin analogs, insulin pump therapy, pharmacodynamics, pharmacokinetics, type 1 diabetes This clamp study demonstrated earlier insulin absorption of 10 to 20 minutes and earlier onset of action with BCLIS compared to ASP when administered via CSII. Onset of action was similar with BCLIS and FIA, but offset appeared to be faster with BCLIS. No safety concerns emerged with BCLIS.Data concerning the earlier absorption and shorter duration of action of BioChaperone Lispro in comparison with conventional insulin lispro have been presented previously. 2,3 The present study confirms these earlier absorption characteristics of BCLIS compared to the rapid-acting mealtime insulin analog aspart in the setting of CSII. This is the first study to compare BCLIS and FIA, two ultra-rapidacting mealtime insulin analogs. Faster aspart was recently marketed for type 1 and type 2 diabetes in the EU, and in the USA and EU also for use in insulin pumps. 11-13 Whether the possibly faster offset of action observed with BCLIS prevents the increase in post-meal hypoglycaemia seen with FIA in some of these trials needs to be investigated in appropriately designed head-to-head comparative studies. 11,12 The faster offset of action could be a particular advantage in the setting of the artificial pancreas, in which the basal rate is in fact replaced by multiple small insulin boli. Faster offset of action would shorten the feedback cycle for basal glucose control 14 and potentially facilitate mealtime glucose control as well.A limitation of this study is that possible differences in insulin absorption over the lifetime of the insulin catheter were not investigated, for example, by repeating the studies on Day 3 after catheter insertion. 9,15,16 In conclusion, this study showed improved overall PK and PD properties of BCLIS compared to ASP, as well as improved early and late PK and late PD properties of BCLIS com...