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Oslo, Norway

Berg K.,University of Oslo | Nordstrand S.,Synthetica AS | Selbo P.K.,University of Oslo | Tran D.T.T.,University of Oslo | And 2 more authors.
Photochemical and Photobiological Sciences | Year: 2011

Photochemical internalisation (PCI) is a novel technology for release of endocytosed macromolecules into the cytosol. The technology is based on the use of photosensitizers that locate in endocytic vesicles, and that upon activation by light induce a release of macromolecules from the endocytic vesicles. PCI has been shown to stimulate delivery of a large variety of macromolecules and other molecules that do not readily penetrate the plasma membrane. The preclinical evaluation of PCI has been performed with aluminum phthalocyanine disulfonate (AlPcS 2a) as photosensitizer. AlPcS 2a, due to its large number of isomers potentially with batch-to-batch ratio variations, is not an optimal photosenstizer for clinical use. Disulfonated tetraphenyl chlorin (TPCS 2a) has therefore been developed by di-imide reduction of disulfonated tetraphenyl porphine (TPPS 2a). The synthesized TPCS 2a contains 3 isomers as shown by HPLC with low (<4%) inter-batch variation with respect to isomer formation, less than 0.5% (w/w) of the starting material TPPS 2a and absorbs light at 652 nm. As prerequisites for a PCI photosensitizer TPCS 2a was found to localize in intracellular granules assumed to be endocytic vesicles. In cells in culture TPCS 2a-PCI induced activation of gelonin as seen by enhanced cytotoxicity, increased transfection efficacy by an enhanced green fluorescence protein (EGFP)-encoding plasmid, induced gene silencing by siRNA towards EGFP and induced in a synergistic manner tumor growth delay by TPCS 2a-mediated PCI of bleomycin in CT26.CL25 carcinomas growing subcutaneously in athymic mice. TPCS 2a-PCI of bleomycin was found superior to meso-tetraphenyl chlorin-based photodynamic therapy (mTHPC-PDT) with respect to inhibition of tumor growth. The tumor growth delay by PCI of bleomycin was independent of the time of bleomycin administration between 3 h prior to light to immediately after light, while bleomycin administered 24 h prior to or 24 h after the light exposure induced suboptimal or only additive effects on tumor growth delay respectively. TPCS 2a-PDT and -PCI induced indistinguishably strong edema the first 3-4 days after TPCS 2a-administration and only weak erythema the first day after TPCS 2a administration. In contrast, mTHPC-PDT induced moderate edema the first 7 days after mTHPC administration, but strong erythema resulting in open wounds and escar formation the first 2-3 days after mTHPC administration. The pharmacokinetic properties of TPCS 2a were evaluated in athymic mice. The plasma pharmacokinetics was best fit to a 2-compartment model with half-lives of 0.78 and 36 hrs. TPCS 2a was found to be a clinically suitable PCI photosensitizer for photochemical activation of molecules that do not readily penetrate the cellular plasma membrane. © The Royal Society of Chemistry and Owner Societies 2011. Source


Nytoft H.P.,Geological Survey of Denmark | Kildahl-Andersen G.,University of Oslo | Solevic Knudsen T.,University of Belgrade | Stojanovic K.,University of Belgrade | Rise F.,Synthetica AS
Organic Geochemistry | Year: 2014

A C30 pentacyclic triterpane eluting slightly after 18α(H)-oleanane in the m/z 191 mass chromatograms of Late Cretaceous/Tertiary terrigenous oils (peak "J" in the early literature) has been isolated from a Niger Delta oil and identified using NMR spectroscopy as 3β-methyl-24-nor-18α(H)-oleanane. The previous assignment as 18β(H)-oleanane is therefore partly erroneous. 3β-Methyl-24-nor-18α(H)-oleanane affords a larger m/z 412→356 response than the oleananes and the relative contribution of 3β-methyl-24-nor-18α(H)-oleanane to the 412→191 "oleanane peak" can be roughly estimated from comparison of the 412→356/412→191 ratio from the oleanane peak with that of the pure compounds. 3β-Methyl-24-nor-18α(H)-oleanane can be as abundant as 18α(H)-oleanane in oils having a high concentration of early eluting rearranged oleananes. 3β-Methyl-24-nor-19α(H)-taraxastane was also tentatively assigned in the oils on the basis of its mass spectrum as well as its gas chromatography and high performance liquid chromatography retention times. 3β-Methyl-24-nor-gammacerane was tentatively assigned in a similar way in an oil containing gammacerane. All 3β-methyl-24-nor-triterpanes could be formed via dehydration, rearrangement and hydrogenation of triterpenoids having an OH group at C-3. © 2014 Elsevier Ltd. Source

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