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SPECIFIC AIMSAccording to folk wisdom, milk intake improves sleeping or has a calming role, a belief supported by some scientific studies. As caseins contain peptides with physiological roles, we hypothesized that one of their peptides can carry this anxiolytic activity. In this study, ␣ s1 -casein tryptic hydrolysate (␣ s1 -CnTH) was tested in vitro on benzodiazepine (BDZ) receptors and checked in vivo for its anticonvulsant and anxiolytic effects in the rat. PRINCIPAL FINDINGS ␣ s1 -CnTH inhibits pentylenetetrazole (PTZ) -induced seizures in Wistar ratBovine ␣ s1 -CnTH was injected intraperitoneally (i.p.) in a Wistar rat 30 min before an i.p. injection of 60 mg/kg of PTZ to evaluate anticonvulsant activity. Crisis severity parameters, crisis latency, and clonus duration were determined after 45 min observation of behavior. The i.p. injection of 1 mg/kg of ␣ s1 -CnTH reduced crisis severity (PϽ0.02). Other parameters were not significantly different from the control. The i.p. injection of 3 mg/kg of ␣ s1 -CnTH increased crisis latency (PϽ0.005), decreased crisis severity (PϽ0.002), and decreased clonus duration (PϽ0.005) of PTZ-induced seizures. The anticonvulsant action of the ␣ s1 -CnTH was underestimated because of a sensitization of animals to PTZ during successive experiments. ␣ s1 -CnTH displays an anxiolytic activity in the elevated plus maze paradigmElevated plus maze test was used to evaluate the anxiolytic effect of the ␣ s1 -CnTH. Diazepam (1 mg/kg) and ␣ s1 -CnTH (3 mg/kg) enhanced (PϽ0.02) the percentage of entries in the open arms whereas general activity, represented by entries in closed arms, was not modified (Fig. 1). ␣ s1 -CnTH displays an anxiolytic activity in the conditioned defensive burying (CDB) experimentWhen a rat is shocked once through an electrical probe mounted on a wall of a test cage, it returns to the probe and buries it with bedding material from the floor of the cage. This CDB response is reduced by anxiolytic drugs. Some behavioral sequences such as exploratory approaches to the probe and escape movements from the probe are needed to differentiate agonists from partial inverse agonists. Similar to diazepam, the ␣ s1 -CnTH, administrated at 3 mg/kg i.p., decreased the duration of probe burying (PϽ0.005) (Fig. 2). The ratio of the retreats to the approaches decreased in rats treated with ␣ s1 -CnTH or diazepam. The CDB paradigm indicates that the ␣ s1 -CnTH exerts an anxiolytic activity over rats. A peptide (␣-casozepine) of the ␣ s1 -CnTH binds on the BDZ site of the GABA A receptorAffinity for the BDZ site of the GABA A receptor from bovine cerebral cortex membranes was measured in competition with [methyl-3 H]-flunitrazepam. ␣ s1 -CnTH competed with the radioligand for binding on the BDZ site of the GABA A receptor with an IC 50 of 72 1 To read the full text of this article, go to http://www. fasebj.org/cgi/doi/10.1096/fj.00 -0685fje; to cite this article, use FASEB J.

Photodynamic therapy (PDT) has drawn great interest in recent years mainly due to its low side effects and few drug resistances. Nevertheless, one of the issues of PDT is the need for oxygen to induce a photodynamic effect. Tumours often have low oxygen concentrations, related to the abnormal structure of the microvessels leading to an ineffective blood distribution. Moreover, PDT consumes O2. In order to improve the oxygenation of tumour or decrease hypoxia, different strategies are developed and are described in this review: 1) The use of O2 vehicle; 2) the modification of the tumour microenvironment (TME); 3) combining other therapies with PDT; 4) hypoxia-independent PDT; 5) hypoxia-dependent PDT and 6) fractional PDT.

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Photodynamic therapy (PDT) is an emerging theranostic modality for various cancer as well as non-cancer diseases. Its efficiency is mainly based on a selective accumulation of PDT and imaging agents in tumor tissue. The vascular effect is widely accepted to play a major role in tumor eradication by PDT. To promote this vascular effect, we previously demonstrated the interest of using an active- targeting strategy targeting neuropilin-1 (NRP-1), mainly over-expressed by tumor angiogenic vessels. For an integrated vascular-targeted PDT with magnetic resonance imaging (MRI) of cancer, we developed multifunctional gadolinium-based nanoparticles consisting of a surface-localized tumor vasculature targeting NRP-1 peptide and polysiloxane nanoparticles with gadolinium chelated by DOTA derivatives on the surface and a chlorin as photosensitizer. The nanoparticles were surface-functionalized with hydrophilic DOTA chelates and also used as a scaffold for the targeting peptide grafting. In vitro investigations demonstrated the ability of multifunctional nanoparticles to preserve the photophysical properties of the encapsulated photosensitizer and to confer photosensitivity to MDA-MB-231 cancer cells related to photosensitizer concentration and light dose. Using binding test, we revealed the ability of peptide-functionalized nanoparticles to target NRP-1 recombinant protein. Importantly, after intravenous injection of the multifunctional nanoparticles in rats bearing intracranial U87 glioblastoma, a positive MRI contrast enhancement was specifically observed in tumor tissue. Real-time MRI analysis revealed the ability of the targeting peptide to confer specific intratumoral retention of the multifunctional nanoparticles.

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