A new conceptual design for an accelerator-based boron neutron capture therapy (ABNCT) facility based on the high-current low-energy proton beam driven by the linear accelerator at SARAF (Soreq Applied Research Accelerator Facility) incident on a windowless forced-flow liquid-lithium target, is described. The liquid-lithium target, currently in construction at Soreq NRC, will produce a neutron field suitable for the BNCT treatment of deep-seated tumor tissues, through the reaction (7)Li(p,n)(7)Be. The liquid-lithium target is designed to overcome the major problem of solid lithium targets, namely to sustain and dissipate the power deposited by the high-intensity proton beam. Together with diseases conventionally targeted by BNCT, we propose to study the application of our setup to a novel approach in treatment of diseases associated with bacterial infections and biofilms, e.g. inflammations on implants and prosthetic devices, cystic fibrosis, infectious kidney stones. Feasibility experiments evaluating the boron neutron capture effectiveness on bacteria annihilation are taking place at the Soreq nuclear reactor.

Cyclisation of diethyl 3-allyloxy-1-propynylphosphonates with Mo(CO)(6) under PK conditions to give 3-substituted-5-oxo-3,5,6,6a-tetrahydro-1H-cyclopenta[c]furan-4-ylphosphonate, 2a-h, in 45-88% isolated yields was done. The R groups are always syn with H(b)(where applicable). The stereochemistry was determined via both NMR and crystal X-ray analysis.

Zirconacyclopropenylboronates can be stabilized to dimerization by complexation with tributylphosphine; the phosphine stabilized zirconacycle boronates react with aliphatic and aromatic ketones and aldehydes at C2 of the triple bond to give the previously unknown 3-hydroxyvinylboronates in 61-80% isolated yields.

The bioluminescence of the marine bacterium Vibrio harveyi is controlled by quorum sensing. This effect is mediated by production, accumulation, and auto-detection of the species-specific autoinducer 1 (AI-1), autoinducer 2 (AI-2), and the V. cholerae autoinducer 1 (CAI-1). The V. harveyi AI-2 was recently identified as furanosyl borate diester. We synthesized several oxazaborolidine derivatives that chemically resemble the structure of AI-2. Five oxazaborolidine derivatives (BNO-1 to BNO-5) were tested, however only BNO-1 (3,4-dimethyl-2,5-diphenyl-1,3,2-oxazaborolidine), and BNO-5 (2-butyl-3,4-dimethyl-5-phenyl-1,3,2-oxazaborolidine) strongly induced V. harveyi bioluminescence in V. harveyi mutant (BB170) lacking sensor 1. A dose-dependent relationship between those oxazaborolidine derivatives and bioluminescence induction was observed with this V. harveyi strain (BB170). BNO-1 and BNO-5 did not affect V. harveyi BB886 lacking sensor 2. Using a mutant strain which produces neither AI-1 nor AI-2 (V. harveyi MM77) we showed that the presence of spent medium containing AI-2 is essential for BNO-1 and BNO-5 activity. This effect was similar when introducing the spent medium and the BNOs together or at a 3-h interval. A comparable induction of bioluminescence was observed when using synthetic DPD (pre-AI-2) in the presence of BNO-1 or BNO-5. The mode of action of BNO-1 and BNO-5 on bioluminescence of V. harveyi is of a co-agonist category. BNO-1 and BNO-5 enhanced AI-2 signal transduction only in the presence of AI-2 and only via sensor 2 cascade. BNO-1 and BNO-5 are the first oxazaborolidines reported to affect AI-2 activity. Those derivatives represent a new class of borates which may become prototypes of novel agonists of quorum sensing mediated by AI-2 in V. harveyi.

PURPOSE: Locoregional recurrence is the most common complication after adenocarcinoma resection in the colon, despite adjuvant chemotherapy. Therapy efficacy could be improved if designed to target malignant cells by incorporating specific recognition factors in the drugs or the drug vehicles. The aim of this study was to elucidate whether the overexpression of sialic acid (SA) on colonic malignant tissues could be utilized for drug targeting by cationic polymers. MATERIALS AND METHODS: Cell lines (IEC-6, SW-480 and SW-620) and colon polyps and normal adjacent tissues harvested from dimethylhydrazine (DMH) induced rats were used as in vitro and in vivo models of different metastatic stages of colon cancer. SA expression was identified by fluorescent wheat germ agglutinin (WGA), and verified by pretreatment with neuraminidase. The role of mucus in the mucosal binding experiments was explored by pretreatment with dithiothreitol (DTT). The binding of FITC labeled cationic polymers of various degrees of cationization to normal and malignant colonic cells and tissue was measured. RESULTS: SA was overexpressed on malignant colonic cells and tissues, and its expression correlated to the metastatic stage in vitro. The binding of the cationic copolymers to the cell lines and tissues correlated with the charge density of the polymer and with the metastatic stage of the cell line. The interaction between the malignant colonic cells and tissues with the polymers was SA dependent and increased after mucus removal. CONCLUSION: Cationic polymers could be used as a targeting tool to colonic malignant epithelium, to be implemented in drug delivery and diagnosis.

Brachytherapy has many potential roles in cancer therapy. However, major constraints are associated with placement and removal procedures of the brachytherapy machinery. An attractive approach would be the use of a biodegradable implant loaded with a radioisotope, thus enabling targeted radiotherapy, while reducing the need for surgical procedures for the removal of brachytherapy hardware. In this study, crosslinked chitosan (Ct) hydrogels were prepared and loaded with (131)I-norcholesterol ((131)I-NC). The radioactive hydrogels ((131)I-NC-Ct) were implanted adjacent to 4T1 cell-induced tumors in two different xenograft mice models either as primary therapy or surgical adjuvant therapy of breast cancer. Non-treated mice and mice implanted with naive (non-radioactive) hydrogels served as control groups. In the primary therapy model, the progression rate of the tumor was delayed by two weeks compared with the non-treated and the naive-implant control animals, resulting in a one-week extension in the survival of the treated animals. In the adjuvant therapy model, for the treatment of minimal residual disease,(131)I-NC-Ct implants were able to prevent 69% of tumor recurrence, and to prevent metastatic spread resulting in long-term survival, compared with 0% long-term survival of the non-treated and the naive control groups. Imaging of the hydrogel's in vivo elimination revealed a first order process with a half-life of 14 days. The degradation was caused by oxidation of the Ct as was assessed by in vitro H&E stain. Biodegradable radioactive implants are suggested as a novel platform for the delivery of brachytherapy. This radiotherapy regimen may prevent locoregional recurrence and metastatic spread after tumor resection.

Reaction of diethyl 5-chloro-1-pentynylphosphonate with primary and secondary amines produces novel 2-amino-1-cyclopentenylphosphonates, 1, in excellent isolated yields (79-88%). Calculations supported by experimental facts point to a two-step mechanism: an initial amine addition to give a zwitterionic intermediate followed by cyclization and proton transfer. Calculations rule out the formation of an enamine as an intermediate.

The aim of the present study was to evaluate the toxicity of biodegradable hydrogels in the rat with a future aim of utilizing this hydrogel as a vehicle for brachytherapy delivery in cancer patients. Two types of chitosan hydrogels: fast degrading and slow degrading; were prepared and surgically implanted in rats. The adjacent tissue response to the gels after subcutaneous and intraperitoneal implantation was examined histologically and found to be identical to typical foreign body response and was milder than the response to absorbable surgical sutures (Vicril(R)). Neither tissue damage nor gel fragments could be detected in distant organs (brain, heart, lungs, liver, spleen, kidney, and sternal bone marrow) after implantation of the hydrogels. The degradation mechanism of the gels was studied invivo, and it was deduced that an oxidative process degraded the chitosan. Loading the hydrogels with a radioisotope ((131)I-norcholesterol) caused a severe tissue response and necrosis in adjacent tissues only at a distance of several microns. It is concluded that crosslinked chitosan implants could serve as alternative, biocompatible, and safe biodegradable devices for radioisotope delivery in brachytherapy for cancer.(c) 2007 Wiley Periodicals, Inc. J Biomed Mater Res, 2007.