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|Publication number
|Publication type
|Application number
|Publication date
|Mar 22, 2005
|Filing date
|May 9, 2001
|Priority date
|Apr 10, 1998
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|Richard E. Weller, Michael A. Lind, Darrell R. Fisher, Anna Gutowska, Allison A. Campbell
|Original Assignee
|Battelle Memorial Institute
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|Patent Citations (41), Non-Patent Citations (18), Referenced by (16), Classifications (13), Legal Events (4)
|External Links: USPTO, USPTO Assignment, Espacenet
This application is a Continuation Application of application Ser. No. 09/058,712 filed Apr. 10, 1998, now U.S. Pat. No. 6,296,831.
This invention was made with Government support under Contract DE-AC06 76RLO 1830 awarded by the U.S. Department of Energy. The Government has certain rights in the invention.
The present invention relates generally to a stimulus sensitive gel containing a radioisotope or radionuclide and method of making. As used herein, the term "stimulus sensitive gel" is a polymer solution that gels upon a change in stimulus. A stimulus includes but is not limited to temperature, pH, ionic strength, solvent composition, sheer stress or a combination of these factors. The preferred gel is generally a reversible gel, more specifically; the gel is a random copolymer of an [meth-]acrylamide derivative with a hydrophilic comonomer. As used herein, the term [meth]-acrylamide denotes methacrylamide, acrylamide, or combinations thereof. As used herein, the terms "radioisotope" and "radionuclide" are synonymous.
Radiolabelling as a method of diagnosis or treatment has been in use for many years. The continuing challenge has been to maximize concentration of the radioisotope in the area or region of interest, diseased tissue or tumor, while minimizing the concentration of the radioisotope in other areas and thereby minimizing damage to healthy tissues.
The paper by S. Ning, K. Trisler, D. M. Brown, N. Y. Yu, S. Kanekal, M. J. Lundsten, S. J. Knox: "Intratumoral radioimmunotherapy of a human colon cancer xenograft using a sustained-release gel", Radiotherapy and Oncology, 39, 179-189, 1996 discusses an intratumoral injectable gel drug delivery system for local administration of radio-immunotherapy. The injectable gel was a collagen-based drug delivery system designed for intratumoral administration. The study demonstrated that intratumoral delivery of radiolabeled antibodies using the collagen gel system markedly increased the retention of radioisotope in the tumors, enhanced the antitumor efficacy, and reduced the systemic toxicity compared to systemic administration of the radiolabeled antibody. Ning et al. teach the use of injectible collagen gels that are not stimuli-sensitive. Moreover, these collagen gels neither fully perfuse tumor tissue nor do they hold the radioisotope within the collagen gel matrix. Thus, the radioisotope is attached to an antibody for perfusing and binding to the tumor tissue. Lack of perfusion of the collagen gel and limited range of radioisotope decay products require that the radioisotope leave the collagen gel matrix to achieve close proximity with tumor tissue to achieve the therapeutic effect.
In the paper PRELIMINARY EXPERIENCE OF INFUSIONAL BRACHYTHERAPY USING COLLOIDAL 32P, S E Order, J A Siegel, R Principato, L S Zieger, E Johnson, P Lang, R Lustig C Kroprowski, P E Wallner, Annals Academy of Medicine, May 1996, Vol. 25, No. 3, an infusion by a needle into a tumor was done without the need for an arterial catheter and eliminating the need for hospitalization. This paper reports using dexamethasone (Decadron) to overcome intratumoral resistance followed by macroaggregated albumin then colloidal chromic phosphate 32P followed by more macroaggregated albumin injected into the tumor. Sufficient radiation emitted by the radioisotope leads to tumor cell killing and remission of solid cancers. However, disadvantages of this method include the serial injections and leakage of 32P from the tumor.
There is need in the art for a method of introducing a radioisotope into a localized area with a single or multiple injection(s) as well as a need for a local delivery system with little or reduced leakage of the radioisotope.
Stimulus-sensitive reversible hydrogels are herein defined as copolymer-solvent systems that undergo a transition between a solution and a gel state in response to the external stimuli such as temperature, pH, ionic strength, solvent composition, sheer stress or a combination of these factors. A reversible stimuli-sensitive gel is one in which the transition is reversed upon reversal of the stimulus. A well known example of a reversible hydrogel is an aqueous solution of gelatin that is in a solution state at high temperatures (e.g. 80� C.) and forms a gel at lower temperatures (e.g., 20� C.). Other examples of reversible gels involve aqueous solutions of agarose and kappa-carrageenan that gel in response to the temperature change, and aqueous solutions of alginate that gel in response to the increased concentration of calcium ions. Reversible hydrogel systems are used in food and pharmaceutical industries as thickeners and suspending agents.
Some specific reversible gelling copolymers were also investigated as drug delivery systems and tissue engineering polymer matrices. High viscosity aqueous solutions containing 20 (or more) wt % of block copolymers of polyethylene oxide and polypropylene oxide, e.g. Poloxamer 407 and Pluronic F68 (Poloxamer 188) exhibit reverse thermal gelation. Solutions of Poloxamer 407 have been investigated for intraocular administration. Solutions containing 25 and 30 wt % of Poloxamer 407 have been prepared and the force needed to inject them through a 25 GA needle was investigated. It was concluded that a liquid-gel transition occurred inside the needle, due to the heat transfer between the needle walls and the surroundings. [J. Juhasz, A. Cabana, A. Ait-Kadi, EVALUATION OF THE INJECTION FORCE OF POLOXAMER 407 GELS FOR INTRAOCULAR ADMINISTRATION, Pharm.Res., 13, No.9, 1996, Symposium Supplement, S-276].
In another example, 25 wt % aqueous solution of Pluronic F68 was mixed with articular chondrocyte cells suspension at 4� C. and injected subcutaneously in nude and immunocompetent rabbit. In both cases, the cells entrapped in the copolymer formed tissue with histological appearance of hyaline cartilage. It was concluded that thermally reversible Pluronic F68 gel can serve as an effective injectable matrix for tissue engineering. [C. A. Vacanti, et al., Proceedings of Tissue Engineering Society, Orlando, Fla., 1996].
An example of a pH-reversible hydrogel, investigated as an in situ gelling system for ophthalmic use is the aqueous solution of, a poly(acrylic acid)polymer, which undergoes a pH-mediated phase transition at concentrations above 0.1 wt %. The solution also contains hydroxypropyl methylcellulose, a viscosity enhancing agent. [Pharm.Res., 13, No.9, 1996, Symposium Supplement].
A new vehicle for topical and mucosal delivery, based on reversible gelation, was developed as an interpenetrating polymer network (IPN) of poly(acrylic acid) and a block copolymer of poly(ethylene oxide)/poly(propylene oxide). When heated from ambient to body temperature the network exhibited a significant viscosity increase from a viscous liquid to a gel-like consistency. It was concluded that at higher temperature, reduced release rates of active ingredients from the network were observed due to the increased viscosity of the IPN. [E. S. Ron, et al., A NEW VEHICLE FOR TOPICAL AND MUCOSAL DRUG DELIVERY, Pharm.Res., 13, No.9, 1996, Symposium Supplement, S-299].
All gels containing the copolymers of poly(ethylene oxide)/poly(propylene oxide), i.e., Poloxamer 407, Pluronic F68 (Poloxamer 188), an IPN of poly(acrylic acid) and a block copolymer of poly(ethylene oxide)/poly(propylene oxide), and combinations thereof exhibit a limited, concentration dependent, stability of the gel state. The gels formed from these copolymers become liquids upon dilution (as for example due to the dilution with body fluids after peritoneal injection). Additionally, all the above examples of reversible hydrogels exhibit high initial viscosity in a liquid state, i.e., before the gelling transition.
Accordingly there is a need for a reversible gel that only reverses when a specific stimulus is reversed and does not reverse upon introduction of a different stimulus (e.g. dilution). Moreover, there is a need for a reversible gel that has a lower initial viscosity.
The U.S. Pat. No. 5,262,055 to Bae et al. discusses an artificial pancreas utilizing reversible gels based on NiPAAM and its copolymers. These polymers and copolymers do not reverse upon dilution and they have a lower initial viscosity. However, the NiPAAM homopolymer described in Example 1 of Bae et al. forms a dense gel with minimal water content (i.e. exhibits substantial syneresis).
Accordingly, there remains a need for a thermally reversible gel without substantial syneresis.
Polymers exhibiting phase transitions in water have many potential uses for drug delivery as stated in GRAFT COPOLYMERS THAT EXHIBIT TEMPERATURE-INDUCED PHASE TRANSITIONS OVER A WIDE RANGE OF pH, G. Chen, A S Hoffman, Nature, Vol 373, 5 Jan. 1995 (pp49-52). In this paper, the authors further describe a temperature sensitive polymer that phase separates with a change in temperature or pH. Chen and Hoffman use graft copolymers having side chains of a temperature sensitive homopolymer, the oligo-N-isopropylacrylamide, grafted onto a pH sensitive backbone homopolymer of acrylic acid. The authors describe the phase separation of the graft copolymer investigated by a cloud point determination in dilute solutions. However, a dilute solution cannot produce a reversible gelation of these graft copolymers. Chen and Hoffman also mention random copolymers of N-isopropylacrylamide and acrylic acid as exhibiting a phase separation, however, there is no description of the intention to study the possibility of reversible gelation in more concentrated solutions of these random copolymers.
Thus, there is a need for a stimulus sensitive gel with radioisotope that is useful in infusional brachytherapy.
The present invention is a radioisotope carrier made by combining a stimulus sensitive gel with either an aqueous insoluble or confined radioisotope. A preferred stimulus sensitive gel is a thermally reversible gel or thermally reversible gelling copolymer that is preferably a random copolymer of an [meth-]acrylamide derivative and a hydrophilic comonomer, wherein the random copolymer is in the form of a plurality of linear chains having a plurality of molecular weights greater than or equal to a minimum gelling molecular weight cutoff. The thermally reversible gelling copolymer is enhanced by either combining it with a therapeutic agent in an aqueous solution containing the thermally reversible gelling copolymer, and/or by grafting the thermally reversible gelling copolymer to a biodegradable backbone. The stimulus sensitive gel may also be selected from biodegradable polymers, for example polysaccharides, polypeptides and combinations thereof; cellulose derivatives including but not limited to hydroxypropylmethyl cellulose; other polymers such as agar, gelatin, chitosan, alginate in combination with a slow gelling agent for example calcium sulfate and combinations thereof.
The method of the present invention for making a radioisotope carrier has the steps of:
Aqueous non-soluble radioisotope is a radioisotope in a colloidal or precipitate form, for example radioisotope insoluble salt, e.g. yttrium phosphate, radium sulfate, and combinations thereof. Confined radioisotope is radioisotope in a chelator, glass particle, polymer particle or other binding compound.
A preferred stimulus-sensitive gelling polymer is a thermally reversible gelling copolymer, preferably made according to the steps of:
It will be apparent to one of skill in the art of radiotherapy that an image enhancer or contrast agent may be added to the stimulus sensitive gelling polymer, for example as used in nuclear medicine imaging, ultrasonic imaging, and magnetic resonance imaging (MRI).
Advantages of the present invention include (1) the stimuli-sensitive gel of the present invention exhibits a thermodynamic stability, and when geled, will not reverse to the liquid state upon dilution but may reverse to the liquid state only in response to a stimulus change. Moreover, the stimuli-sensitive gel of the present invention in a solution state has lower initial viscosity more suitable for tissue perfusion.
It is an object of the present invention to provide a radioisotope carrier.
It is a further object of the present invention to provide a method of making a radioisotope carrier.
It is a further object of the present invention to provide a biodegradable stimuli-sensitive polymer useful for a radioisotope carrier.
The subject matter of the present invention is particularly pointed out and distinctly claimed in the concluding portion of this specification. However, both the organization and method of operation, together with further advantages and objects thereof, may best be understood by reference to the following description taken in connection with accompanying drawings wherein like reference characters refer to like elements.
The present invention is a radioisotope carrier having a stimulus-sensitive gelling polymer mixed with aqueous solvent and with a radioisotope that is either aqueous non-soluble or confined as the radioisotope carrier.
The radioisotope is preferably an alpha and/or beta emitter with a short half life. More specifically, the radioisotope is selected from the group of yttrium-90, indium-111, radium-223, actinium-225, bismuth-212, bismuth-213, scandium-47, astatine-211, rhenium-186, rhenium-188, iodine-131, iodine-124, lutetium-177, holinium-166, samarium-153, copper-64, copper-67, phosphorus-32 and combinations thereof.
In a preferred embodiment, the radioisotope carrier further has a radioisotope confine. The purpose of the radioactive confine is to minimize or prevent migration of the radioisotope to healthy tissue areas. The radioisotope confine may be for example chelators or complexing agents, capsules and combinations thereof. Preferred isotope/chelator combinations are yttrium-90 or indium-111 with 1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid (DOTA), derivatives of DOTA; radium-223 with tetra-t-butyl-calix[4]arene-crown-6-dicarboxylic acid (TBBCDA), derivatives of TBBCDA; actinium-225 with 5,11,17,23-tetra-t-butyl-25,26,27,28-tetrakis(carboxymethoxy)-calix[4]arene (TBTC), derivatives of TBTC; and bismuth-212, bismuth-213 with 5,11,17,23,29,35-hexa-t-butyl-37,38,39,40,41,42-hexakis(carboxymethoxy)-calix[6]arene (HBHC), derivatives of HBHC, diethylenetriamine-pentaacetic acid (DTPA), or ethylenediaminetetraacetic acid (EDTA), derivatives of DTPA, and combinations thereof.
The radioisotope confine may be glass beads and/or polymer beads.
The stimulus-sensitive gelling polymer may be selected from biodegradable polymers, for example polysaccharides, polypeptides and combinations thereof; cellulose derivatives including but not limited to hydroxypropylmethyl cellulose; other polymers such as agar, gelatin, collagen, chitosan, alginate with a slow gelling agent for example calcium phosphate, gelling copolymer and combinations thereof. A preferred polymer is a polymer that is useful as a gel that forms without substantial syneresis when the stimulus-sensitive polymer is in an aqueous solution. Syneresis is defined as water expelled from a polymer matrix upon gelation. Substantial syneresis is more than about 10 wt % water expelled from the polymer matrix. According to the present invention, it is preferred that the syneresis be less than about 10 wt %, more preferably less than about 5 wt % and most preferably less than about 2 wt %. Substantially no syneresis is syneresis of less than about 2 wt %, preferably 0 wt %.
The thermally reversible copolymer is a linear random copolymer of an [meth-]acrylamide derivative and a hydrophilic comonomer wherein the linear random copolymer is in the form of a plurality of linear chains having a plurality of molecular weights greater than or equal to a minimum gelling molecular weight cutoff. According to the present invention, the minimum gelling molecular weight cutoff is at least several thousand and is preferably about 12,000. The presence of a substantial amount of copolymer or polymer chains having molecular weights less than the minimum gelling molecular weight cutoff results in a milky solution that does not gel. Further, the amount of hydrophilic comonomer in the linear random copolymer is preferably less than about 10 mole %, more preferably less than about 6 mole % and most preferably about 2-5 mole %. The structure of linear chains is not cross linked. Moreover, the linear random copolymer structure is one in which a linear chain 100 is shared by randomly alternating portions of the [meth-]acrylamide derivative 102 and the hydrophilic comonomer 104 as depicted in FIG. 1.
The [meth-]acrylamide derivative is an N,N′-alkyl substituted [meth-]acrylamide including but not limited to N-isopropyl[meth-]acrylamide, N,N′-diethyl[meth-]acrylamide, N-[meth-]acryloylpyrrolidine, N-ethyl[meth-]acrylamide, and combinations thereof.
The hydrophilic comonomer is any hydrophilic comonomer that co-polymerizes with the [meth-]acrylamide derivative.
Preferred hydrophilic comonomers are hydrophilic [meth-]acryl-compounds including but not limited to carboxylic acids, [meth-]acrylamide, hydrophilic [meth-]acrylamide derivatives, hydrophilic [meth-]acrylic acid esters. The carboxylic acid may be, for example, acrylic acid, methacrylic acid and combinations thereof. The hydrophilic acrylamide derivatives include but are not limited to N,N-diethyl[meth-]acrylamide, 2-[N,N-dimethylamino]ethyl[meth-]acrylamide, 2-[N,N-diethylamino]ethyl[meth-]acrylamide, or combinations thereof. The hydrophilic [meth-]acrylic esters include but are not limited to 2-[N,N-diethylamino]ethyl[meth-]acrylate, 2-[N,N-dimethylamino]ethyl[meth-]acrylate, and combinations thereof.
According to the present invention, the stimulus-sensitive polymer may be mixed with an aqueous solvent to form a stimulus-sensitive gelling solution, or reversible gelling solution. The aqueous solvent includes but is not limited to water and aqueous salt solutions. The salt solution is preferably a phosphate buffered saline solution for medical use.
The method of making the thermally reversible polymer according to the present invention has the steps of:
The alternatives for the [meth-]acrylamide derivative and the hydrophilic comonomer have been set forth above and are not repeated here.
The reaction solvent may be aqueous or non-aqueous. The preferred aqueous solvent is simply water. Alternatively, the aqueous solvent is a salt solution. The non-aqueous solvent may be a hydrocarbon including but not limited to oxygenated hydrocarbon solvent, for example dioxane, chlorinated hydrocarbon solvent, for example chloroform, an aromatic hydrocarbon, for example benzene. Precipitation of the polymer occurs during polymerization in benzene. Dioxane is the preferred solvent because there is no precipitation during copolymerization thereby imparting greater uniformity of composition of the random copolymer (NiPAAM/AAc).
The amount of aqueous solvent with respect to [meth-]acrylamide derivative is preferably about 80 wt %, but may range from about 30 wt % to about 98 wt %. The amount of non-aqueous solvent with respect to the [meth-]acrylamide derivative is preferably about 80 wt % but may range from about 30 wt % to about 98 wt %.
The initiator may be any free radical initiator compatible with the [meth-]acrylamide derivative. The preferred initiator is 2,2′-azobis-isobutyrolnitrile (AIBN). The amount of the initiator with respect to the reaction mixture of solvent and polymer is preferably about 0.1 wt % but may range from about 0.01 wt % to about 2 wt %.
A reversible gelling solution is made by mixing the thermally reversible polymer with an aqueous solution. The amount of aqueous solution with respect to polymer is from about 70 wt % to about 99 wt %, preferably about 98 wt % for NiPAAm/AAc to achieve a nonresorbable reversible gel with substantially no syneresis. The aqueous solution is preferably a salt solution.
In addition to the nonresorbable reversible gel composed of a linear random copolymer of N-isopropyl[meth-]acrylamide and [meth-]acrylic acid described in this invention, a biodegradable (resorbable) copolymer exhibiting similar gelation properties is obtained by grafting of the oligo [meth-]acrylamide derivative side chains on a biodegradable homopolymer backbone of, e.g., poly(amino acid). Preferred oligo [meth-]acrylamide derivative side chains include N,N-alkyl substituted [meth-]acrylalmide derivatives, linear random copolymer of [meth-]acrylamide derivative and hydrophylic comonomer, and combinations thereof. Techniques of grafting of oligo-N-isopropyl[meth]acrylamide side chains on a nonbiodegradable pH-sensitive homopolymer backbone are described (Chen and Hoffman). The technique(s) of Chen and Hoffman were used herein to graft the oligo-N-isopropyl[meth-]acrylamide side chains on an alternative biodegradable homopolymer backbone such as poly(amino acid). The first step of the synthesis is either the free-radical homopolymerization or the random copolymerization of the oligo-N-isopropyl[meth-]acrylamide side chains by free radical homopolymerization using an amino-terminated chain transfer agent, for example 2-aminoethanethiol hydrochloride. The next step is the coupling of the amino-terminated macromer to the carboxyl moieties of the biodegradable backbone using the activation reagent, e.g., dicyclohexyl carbodiimide. Other biodegradable backbones such as poly(phosphazenes) and poly(caprolactone) may also be grafted with the oligo-N-isopropyl[meth-]acrylamide side chains using similar synthetic techniques. The reaction solvent is non-aqueous, preferably a hydrocarbon, for example chloroform, dichloromethane, N,N′-dimethylformamide or combinations thereof.
The resorbable and/or non-resorbable stimulus-sensitive gel(s) of the present invention is/are useful as a radioisotope carrier for infusional brachytherapy.
One or more contrast or imaging agents may be added to the stimulus sensitive gelling polymer. For nuclear medicine imaging, any gamma-emitting radioisotope may be added to the gel polymer as an imaging agent or contrast agent. The common types of gamma source imaging systems are gamma-cameras (Anger cameras), single-photon emission computed tomography (SPECT), and positron-emission tomography (PET). Preferred imaging agents for gamma cameras would be technetium-99m (and any of the standard chemical forms of Tc-99m, such as pertechnetate). The preferred chemical form of Tc-99m may be an insoluble material, such as Tc-99m-sulfur colloid (a common liver scanning agent). Other gamma emitters include but are not limited to indium-111, rhenium-186, rhenium-188, thallium-201, gallium-67, yttrium-91, and iodine-131, and combinations thereof. Positron-emission tomography systems use positron-emitting radioisotopes and detect the twin 0.511 keV photons that accompany radioactive decay. Examples of radioisotopes that could be added for positron-emission tomography include fluorine-18, copper-64, arsenic-74, and zirconium-89, ioding-124, and yttrium-86. A typical amount of photon-emitter added is one that will provide approximately 500,000 counts per two-minute imaging time (0.3 to 10 millicuries).
For ultrasonic imaging, any ultrasound contrast-enhancement agent could be added to render the gel polymer more imageable using ultrasonic detection. Examples include commercially available echocontrast products such as Albunex� (registered trade mark, Molecular Biosystems) and Optison™ (trade mark of Molecular Biosystems), which are manufactured for and distributed by Mallinckrodt Medical, St. Louis, Mo. Albunex� is an ultrasound contrast agent prepared by sonicating 5% human serum albumin to produce stable, air-filled, albumin-coated microspheres. It is an effective ultrasound contrast agent for use during echocardiography and other ultrasound radiological procedures. Optison™ is an ultrasound contrast agent containing human serum albumin with octofluoropropane. Each milliliter of echocontrast agent contains about 700 million microspheres. The amount of contrast agent added could be approximately 1 to 5 percent by weight of the gel polymer.
For magnetic resonance imaging (MRI), any paramagnetic material used for contrast-enhancement may be used. An example includes a relaxation agent gadolinium-chelate (gadolinium-DTPA or gadolinium-EDTA). The stable (nonradioactive) form of gadolinium is preferred. The amount of gadolinium contrast agent added would be a few parts per thousand by weight (millimolar concentrations).
An experiment was conducted to demonstrate synthesis and thermoreversible gel formation of poly(N-isopropylacrylamide-co-acrylic acid)(NiPAAm/AAc). The linear high molecular weight NiPAAm/AAc copolymers containing different amounts of AAc were synthesized by a free radical copolymerization.
The [meth-]acrylamide derivative was N-isopropylacrylamide (NiPAAm) (Fisher, Co.) that was recrystallized from hexane before use. The initiator 2,2′-azobis-isobutyronitrile (AIBN) (Eastman Kodak, Co.) was recrystallized from methanol. The hydrophilic comonomer was acrylic acid (AAc) (Aldrich Co.) that was purified before use by vacuum distillation at 39� C./10 mmHg. The reaction solvent, dioxane, HPLC grade (Aldrich Co.) was used as received. The mixture of [meth-]acrylamide derivative, initiator, hydrophilic comonomer, and solvent formed the reaction mixture.
The molar feed ratio of NiPAAm to AAc was varied as 99:1, 98:2 and 97:3. The copolymerization was carried out in dioxane (80 wt %), with the amount of AIBN initiator of 1.219�10−3 mols/L. The reaction proceeded at 60� C. for 18 hours. The resulting copolymer solution was diluted with fresh dioxane and added dropwise to a ten-fold excess of diethyl ether producing copolymer precipitation. The precipitated copolymer was isolated by filtration and drying. The isolated copolymer was redissolved in acetone and reprecipitated into ten-fold excess diethyl ether. The final, essential step of purification involved dialysis of aqueous copolymer solution through 12,000-14,000 molecular weight cut off (MWCO) dialysis membrane. Dialysis removed the residual unreacted monomer and all copolymer fractions with molecular weights smaller than the MWCO of the dialysis membrane, resulting in a purified copolymer product. The purified copolymer product was further freeze dried.
The removal of molecular weights below 12,000 from the synthesized copolymers was confirmed by gel permeation chromatography. The removal of unreacted monomers was confirmed by nuclear magnetic resonance.
The lower critical solution temperature (LCST) of the synthesized copolymers was evaluated by the cloud point determination method. In this method, 1 wt % solutions of synthesized copolymers in phosphate buffered saline were heated from 20 to 50� C. in 2-deg increments every 10 min. and the absorbance at 450 nm was measured. The cloud point, corresponding to the LCST was determined as the temperature at the inflection point in the absorbance versus temperature curve. NiPAAm homopolymer exhibited an LCST at 32� C. Copolymerization with hydrophilic comonomers shifted the LCST to the physiological temperature range of 36-38� C. NiPAAm/AAc copolymer containing 2 mol % of AAc exhibited the LCST at 37� C.
Thermally reversible gel formation was studied at 37� C. The freeze dried copolymer was dissolved in phosphate buffered saline (PBS) at different copolymer concentrations (0.5, 1.0, 1.5, 2.0, 2.5, and 5.0 wt %) forming copolymer solutions. The PBS was specifically 0.15M NaCl, 0.01 M phosphates KH2PO4, and Na2HPO4. The copolymer solutions were thermally equilibrated at 37� C. for 24 hours. The syneresis (amount of water expelled from the gel) was measured gravimetrically. Syneresis of thermoreversible hydrogels of N-isopropylacrylamide (NiPAAm) and its copolymers with acrylic acid (AAc) was affected by copolymer composition (0, 1, 2 mol % of AAc) and polymer concentration as shown in FIG. 2. In
An experiment was conducted to confirm the necessity of the minimum gelling molecular weight cutoff. A gelling polymer solution was made as in Example 1, but the solution was not dialyzed so that no low molecular weight species were removed. The result was a solution, milky in appearance, that did not form a gel.
A further experiment was conducted to demonstrate the behavior of the gel during tissue perfusion in lymph nodes. A freeze dried copolymer of N-isopropylacrylamide with acrylic acid (2 mol %) NiPAAm/AAc)] was dissolved in PBS as in Example 1. A dye Naphthol blue-black, electrophoresis reagent, from Sigma was added to the copolymer solution. In all solutions, the dye was physically mixed by dissolving into the solutions, but was not covalently bonded to the copolymer.
Canine lymph nodes were freshly isolated and equilibrated at 37� C. PBS for 30 min.
A 5 wt % solution of NiPAAm/AAc in PBS, containing also a small amount (>0.01%) of the blue dye was prepared and cooled in an ice bath. Small aliquots (0.2-0.3 ml) of the cold polymer solution were injected into the freshly isolated canine lymph nodes. After the injection, lymph nodes were kept at 37� C. PBS for 10-15 min permitting the thermal gelation of the injected copolymer solution. The injected lymph nodes were then cut open with a razor blade to evaluate the extent of tissue perfusion. As shown in
As a control, dye solution in PBS only was injected into another lymph node 304 without mixing the dye into the gelling solution. Dye 306 was not contained locally within the lymph node but diffused throughout and beyond the lymph node as illustrated in
An experiment was conducted to demonstrate containment of a radioisotope in a gel. A non-radioactive stable isotope proxy was used. Specifically, in vitro experiments were performed to evaluate the ability of the poly(NiPAAm-co-AAc) copolymer gel to entrap stable isotope forms of barium and yttrium salts within the gel matrix at 37� C.
The poly(NiPAAm-co-AAc) copolymer containing 2 mol % of acrylic acid was used for the experiments. This copolymer exhibited the gelling transition at 37� C. The following salts of barium and yttrium were tested: yttrium chloride, barium chloride and barium sulfate.
Yttrium Chloride (YCl3)
Polymer solution (1) was prepared by dissolving 5.0 g of poly(NiPAAm-co-AAc) copolymer in 95.0 g of phosphate buffered saline (PBS). YCl3 colloidal suspension was prepared by mixing 0.11 g of YCl3 with 10 ml of PBS. An amount of 0.1 ml of the colloidal suspension was added to 0.9 ml of polymer solution (1) and mixed thoroughly. The mixed polymer solution was then placed in a test tube and incubated at 37� C. for 20 min. Formation of an opaque gel was observed. The amount of YCl3 in the gel was 1100 μg.
After 20 min. of incubation, a 10 ml of PBS prewarmed to 37� C. was added to the test tube on the top of the gel. The gel layer stayed intact for the time of the experiment, and the added PBS did not mix with the gel layer.
The concentrations of YCl3 in the PBS were tested after 33 min. and 24 hours by ICP/AES analysis. Detected concentrations were 0.12 μg/ml after 30 min. and 0.03 μg/ml after 24 hr. These correspond to 0.12% and 0.03% of total yttrium present in the gel. In conclusion, the poly(NiPAAm-co-AAc) copolymer gel localized YCl3 very efficiently.
Barium Chloride (BaCl2)
To prepare a BaCl3 stock solution, 0.497 g of BaCl2 was mixed with 5 ml PBS. Next, 0.1 ml of the stock solution was added to 0.9 ml of polymer solution (1) and mixed thoroughly. The mixed polymer solution mixture was then placed in a test tube and incubated at 37� C. for 20 min. Formation of an opaque gel was observed. The amount of BaCl2 in the gel was 9036 μg.
After 20 min. of incubation, a 10 ml of PBS prewarmed to 37� C. was added to the test tube on the top of the gel. The gel layer stayed intact for the time of the experiment, and the added PBS did not mixed with the gel layer.
The concentrations of BaCl2 in the PBS were tested after 33 min. and 24 hours by ICP/AES analysis. Detected concentrations were 30.95 μg/ml after 30 min. and 17.73 μg/ml after 24 hr. These correspond to 3.76% and 2.16% of the total barium present in the gel. In conclusion, the poly(NiPAAm-co-AAc) copolymer gel localized BaCl2 less efficiently than YCl3. The difference was due mainly to a higher water solubility of the BaCl2 salt.
Barium Sulfate (BaSO4)
BaSO4 exhibits very low solubility in water. In order to prepare a BaSO4/polymer suspension, 10.1 mg of BaSO4 was added directly to 0.99 ml of polymer solution (1) and mixed thoroughly. The mixed polymer solution was then placed in a test tube and incubated at 37� C. for 20 min. Formation of an opaque gel was observed. The amount of BaSO4 in the gel was 10,100 μg.
After 20 min. of incubation, a 10 ml of PBS prewarmed to 37� C. was added to the test tube on the top of the gel. The gel layer stayed intact for the time of the experiment, and the added PBS did not mixed with the gel layer.
The concentrations of BaSO4 in the PBS were tested after 33 min. and 24 hours by ICP/AES analysis. Detected concentrations were 0.34 μg/ml after 30 min. and 0.28 μg/ml after 24 hr. These correspond to, respectively, 0.04% and 0.03% of the total barium present in the gel. In conclusion, the poly(NiPAAm-co-AAc) copolymer gel localized BaSO4 equally efficiently as YCl3.
An experiment was conducted to demonstrate the in vivo containment of a radioisotope carrier in a cancerous tumor. A preliminary study was conducted in mice to demonstrate administering therapeutic levels of polymer composite (gel) containing yttrium-90 to tumors growing in mice. The purpose of this study was to show that (1) Y-90 was contained within the polymer composite at the site of the injection, and that (2) cancer cells in the tumors were killed by the intense beta-particle radiation from the Y-90 in the polymer. It is well known that beta particle radiation is useful for treating cancer cells. However, the melanoma cell line is a radiation-resistant cancer requiring very high radiation doses for effective therapy. Very high radiation doses (greater than 1000 Gy, or 100,000 rads) would be needed for complete cell killing in melanoma. Therefore, the main objective of this study was to demonstrate the feasibility of safely delivering very high radiation absorbed doses to live mice. It is believed that this study was the first in which a radioisotope-polymer composite was administered as a therapeutic agent against solid tumors in live animals.
Twelve normal, six-to-eight-week old C57BL/6 female mice were obtained from Charles River Laboratories, were acclimatized on standard shredded pine-chip bedding in plastic laboratory cages, and were provided standard rodent chow and water ad libitum. All procedures and experiments were approved in advance by the Institutional Animal Care Committee.
Each of the 12 mice was inoculated with melanoma cells 12 days prior to the scheduled therapy injection. The cell line used was B16-F1 mouse melanoma from the 331 building stock. Approximately 50,000 viable tumor cells in 0.05 mL of cell culture medium (a concentration of about 1 million cells per mL) were administered subcutaneously into the inner anterior thigh/abdomen area.
Yttrium-90 chloride (YCl3) was prepared as a solution in 0.05M HCl. Colloidal Y-90 was formed upon mixing with polymer solution in phosphate buffered saline. Approximately 2.6 mCi Y-90 were placed in each of six heavy shielded (beveled glass) vials (0.1 mL Kimax) stored in shielded aluminum overpack.
The polymer composite used was a thermally reversible copolymer gel composed of poly(N-isopropylacrylamide-co-acrylic acid) [NA2 polymer], as a 5 wt % solution in phosphate buffered saline (PBS). This thermally sensitive polymer is liquid at room temperature (22� C.). It solidifies at body temperature (37� C.). Approximately 0.1 mL of polymer was drawn by syringe and place into the Kimax vial containing the 2.5 mCi Y-90, and mixed prior to injection into a mouse tumor.
Approximately 0.1 mL Dexamethasone sodium phosphate U.S.P. (Dex), 3 mg/mL (Steris Laboratories, Inc., Phoenix) was administered to some of the tumors by needle injection. The purpose of the Dex was to reduce the intratumoral pressure. Fifteen minutes elapsed between injection of Dex and injection of Y-90 polymer composite.
Rubber-shielded syringes (0.5 to 1.0 cc) fitted with micro-fine needles (27 gauge) were used to administer the radioisotope composite solution to the mouse tumors.
Radioisotope Polymer Composite Injection
Ten mice were anesthetized, one at a time, with methoxyflurane (Pitman-Moore, N.J.). The mice were kept intermittently under an infra-red heating lamp to keep their body temperature at or above 37� C.
Each of these ten mice was injected with dexamethasone, NA2 polymer, or Y-90 solutions according to the treatment regimen summarized in Table E5-1.
Mice were sacrificed on day two after the therapy injection by CO2 asphyxiation, and their tumor, liver, kidneys and spleen were excised and preserved for further examination and radiological counting for Y-90. The amount of Y-90 in the excised tissues (liver, kidney and spleen) was determined using a planar beta counter. The histopathology of the tumors was also examined.
Injection regimes and survival
Injection regime (total)
Injection volume 100 μl
Dexamethasone + polymer + Y-90
Alive on day 2,
some skin burning
observed on
periphery of tumor
Dexamethasone + polymer + Y-90
Alive on day 2
Dexamethasone + polymer + Y-90
Alive on day 2
Polymer + Y-90
Alive on day 2
Polymer + Y-90
Died on day 1, 2
large tumors
Polymer + Y-90
Alive on day 2
Dexamethasone + polymer
Died on day 2
Dexamethasone + polymer
Died on day 1
Alive on day 2
Died on day 1
No treatment
Died on day 2
No treatment
Died on day 2
Weights of the excised tumors and organs on day 2 (necropsy)
TABLE E6-3 Isotope containment within the tumors Activity per sample on day 2 after injection (microcuries, decay-corrected Total Y-90 to time of injection), and percent of activity administered activity Mouse administered Kidney Liver Spleen number (microcuries) μCi % μCi % μCi % 1 2600 17.1 0.658 8.29 0.319 0.44 0.017 2 2600 40.0 1.538 16.9 0.650 — — 3 2600 6.76 0.260 3.40 0.131 0.092 0.034 4 2600 18.8 0.723 19.4 0.746 0.71 0.027 5* 2600 — — — — — — 6 2600 9.91 0.381 3.33 0.128 0.11 0.004 *Mouse 5 died before necropsy
Pathology Report
Formalin fixed specimens from 7 mice were submitted in individual vials. The specimens were trimmed, inserted in plastic cassettes, and submitted to Our Lady of Lourdes Hospital in Pasco for the preparation of paraffin sections stained with hematoxylin and eosin.
The following information was provided: the mice had been injected subcutaneously with a melanoma cell line; the resulting tumors from 5 of the 7 mice (specimens labeled 1, 2, 3, 5, and 6) were injected with a soluble matrix of yttrium-90; the mice were killed 2 days after Y-90 injection; a high radiation dose from the Y-90 was delivered to the tumors; the specimens were stored for several weeks to allow for the decay of the Y-90; tumors from mice #1, 2, 3, and 7 were also injected with a corticosteroid; mice #7 and 9 were not injected with Y-90.
The purpose of the histopathologic examination was to determine whether the Y-90 had an effect on the tumors, and how that effect could be altered with corticosteroids.
Pathology Discussion
The tumors produced by the injected cell cultures resembled malignant melanomas. The necrosis observed was compatible with tumors of a high level of malignancy and also with the effect of high-dose irradiation and cell death. There were no clear difference in the necrosis between the Y-90 injected tumors and the tumors not injected with Y-90. It should be noted that the measurements provided were for only one sample from each specimen and are not intended to imply quantitative differences between the specimens.
The short (2-day) time period between therapy injection of Y-90 polymer composite and sacrifice would not have been sufficient for manifestation of extensive cell-killing. The tumors were well-advanced and necrotic, which made it difficult to isolate the radiotoxic effects of high-dose irradiation. In general, the mice treated with Y-90 appeared to be more healthy and active, even with large tumor burdens on day 2 after the injection, just before necropsy, than did the mice that were not treated with Y-90. The notable exception was mouse No. 5 with two large tumors. Mouse No. 5 died of causes apparently related to melanoma tumor burden on day 1.
Radiation Absorbed Dose Estimates
The Y-90 equilibrium dose constant is 1.99 g-rad/μCi-hr. The cumulated hours in the tumor for two days is 21.1 hrs (the integral of the time-activity curve for 100% retention in the tumor). Therefore, the radiation absorbed dose to a tumor of 3.5 g would be
1.99�2600�21.1/3.5=31,200 rads (312 Gy).
For a 1.7 g tumor, the dose would be 64,200 rads (642 Gy).
Actual doses to tumors would be less than this amount, because some of the activity was excreted, and a fraction translocated to normal tissues. We do not have sufficient information on uptake and retention of Y-90 activity in normal organs for dose estimates.
Summary and Conclusions
This experiment showed the feasibility of administering a radioisotope polymer composite to solid tumors in animals. The experiment clearly demonstrated the ability of the gelling NA2 polymer to contain Y-90 radioisotope mostly at the injection site. The tumors remained very radioactive after administration, showing that most of the injected activity was retained at the injection site. Normal-tissue uptake was minimal (a few percent or less). Histopathology did not show a significant melanoma cell death from radiation because of the short time between injection and necropsy; however, the efficacy of treatment may have been obscured by the short time between injection and necropsy, and the advanced stage of the tumor development (extensive coagulative necrosis).
An experiment was conducted to demonstrate placement of Yttrium-90/technetium-99m-polymer composite into prostate tissue of two young, healthy beagle dogs.
Y-90/Tc-99m-polymer Composite
Yttrium-90 was prepared as a solution of YCl3 in 0.05 N HCl. Colloidal Y-90 was formed upon mixing with polymer solution in phosphate buffered saline. The total amount administered to each dog prostate was approximately 1.1 mCi in a volume of 1.5 to 2.0 mL. Technetium-99m sulfur colloid (Mallincrodt Medical) (600 μCi, or 22 MBq, 100 μL by volume) was added to and mixed with the Y-90-polymer solution immediately prior to injection to facilitate in vivo gamma-camera imaging of the injected material.
Reversibly gelling copolymers of N-isopropylacrylamide and acrylic acid, poly(NiPAAm-co-acrylic acid), were tested as delivery vehicles for the Y-90 and Tc-99m radioisotopes. Two copolymers with different gelling temperatures were tested: NA-2 Sept. 97, with gelling temperature at 37� C. and NA-1.8 Feb. 2, 1998 that gels at 36� C.
Polymer solutions were prepared as follows: 5 wt % of poly(NiPAAm-co-acrylic acid) was dissolved in phosphate buffered saline. A 50 μL solution of YCl3 (stable yttrium) suspension was added to obtain a diluted YCl3 suspension with total stable yttrium concentration of 55 μg/mL. The suspension was steam-sterilized in an autoclave for 15 min. Directly before injection, an appropriate amount of this suspension was added to the vial containing the Y-90 radioisotope and mixed thoroughly.
Two beagle dogs were anesthetized for this study. Anesthesia given was injected Pentothal (15 mg/kg), with 0.625 Acepromazine and the same amount of Atropine plus Isoflurane gas and oxygen. The dogs' rectal temperatures were measured before and after the injections. The dogs were placed in a supine position on the operating table, and were immobilized. The hind legs were tied upward to facilitate the polymer injections. The ultrasound probe was placed in the rectum. The parallel grid template was affixed to the ultrasound probe.
Injection Procedure
The Y-90/Tc-99m-polymer composite was injected using two to four needles inserted through a parallel grid template.
Gamma Imaging
Portable gamma camera was used to image the localization of technetium-99m gamma rays from the polymer composite.
Dog 1 Procedure and Results
The initial rectal temperature was 38.0� C., and the final temperature was 36.3� C.
The surgeons had difficulty identifying/defining the position of the prostate due to a large pubic arch and small gland size (2.5 cm wide, 1.5 cm int.-post.), volume approx. 7 cm3.
The amount and polymer batch injected was 1.6 mL of NA-2 September 1997, having a gelling temperature 37� C.
The Y-90/Tc-99m-polymer composite was maintained on ice before injection. Two needles were used, and four squirts of 0.2 mL (200 μL) were administered through each needle.
Gamma-camera imaging was performed immediately after the polymer composite was administered to the prostate gland. The images showed liver uptake (approx. 20% within 10 min. after the injection). A possible cause for early liver uptake may have been a direct injection into the vasculature and trauma to the prostate after multiple needle puncture. The polymer may not have had an opportunity to gel completely because the dog body temperature was slightly below the polymer gelation point (36.3 vs. 37� C.).
Dog 2 Procedure and Results
The initial rectal temperature was not measured. The final rectal temperature was 36.6� C. The prostate of Dog 2 was easier to locate. There was no pubic arch problem. The prostate gland was slightly larger, with an estimated volume of 10 cm3 (4�3 cm).
The amount and polymer batch administered were 2.0 mL of NA-1.8 Feb. 2, 1998, having a gelling temperature 36� C. The Y-90-polymer composite was maintained at room temperature prior to injection into Dog 2. Four needles were used to administer the polymer composite. Injections consisted of 0.5 mL (500 μL) per needle as three squirts per needle of about 0.17 mL per squirt. Each squirt was given after withdrawing the needle approximately 1 cm.
Gamma-camera imaging was conducted immediately after the injections, acquiring approximately 200,000 counts. The images showed no specific liver uptake within 10 min. after the injection.
It appears that the polymer did gel completely in Dog 2 because the dog body temperature was slightly above the polymer gelation point (36.6 F. vs. 36� C.).
Post Injection Procedures for Dog 1 and 2
Animals were sacrificed on day 9 after the injection of the Y-90/Tc-99m-polymer composites. Samples of the prostate, liver, lung, heart, kidney, and spleen tissues were collected and the activity of Y-90 in the tissues was determined in pCi/gm per unit wet weight. The results are summarized in Table E7-1. As shown, after nine days in vivo, the concentrations of Y-90 in the prostate of Dog 2 were significantly higher than concentrations of Y-90 in other tissues of the animal. Tissue counts for Dog 1 demonstrate no specific localization of Y-90 in the prostate tissue. These results are consistent with gamma imaging results showing that the surgeions completely missed the target tissue (prostate) during their injection procedure. There was also significant liver uptake of Tc-99m in Dog 1 and no liver uptake in Dog 2. The results are also consistent with the fact that polymer used for Dog 1 had a higher gelling transition temperature (37� C.) and did not gel during the injection because Dog 1 body temperature was below 37� C. (36.3� C.). Therefore radioisotope localization did not occur in Dog 1. However, localization did occur in Dog 2.
TABLE E7-1 The Y-90 activities measured in tissue samples collected on day 9 post injection. Y-90 Activity Wet Weight (g) (pCi/gm) Dog 1 Heart 0.6475 11.4 Kidney 0.4712 211 Liver 0.6510 214 Lung 0.3587 342 Spleen * 0.0704 51.5 Prostate 1.2450 37.7 Dog 2 Heart 2.1700 4.44 Kidney 0.7028 112 Liver 1.1765 104 Lung 1.6691 362 Spleen 0.6935 50.4 Prostate 1.7588 13650
The results of Y-90 counts and gamma imaging are consistent with the fact that gelling temperatures of the injected polymers were different and that polymer used for the Dog 1 procedure did not completely gel (the Dog 1 body temperature was slightly below the polymer gelation point: 36.3 vs. 37� C.). Hence, the results presented clearly illustrate the importance of gelling polymer in localization of the injected radioisotopes.
This experiment showed excellent localization of radioisotope polymer composite in the target tissue (prostate) of Dog 2 with minimal radionuclide activity in other non-target tissues at 9 days post injection subsequent autoradiography of Dog 2 prostate showed uniform distribution of the Y-90 polymer composite throughout the prostate gland.
While a preferred embodiment of the present invention has been shown and described, it will be apparent to those skilled in the art that many changes and modifications may be made without departing from the invention in its broader aspects. The appended claims are therefore intended to cover all such changes and modifications as fall within the true spirit and scope of the invention.
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Owner name: BATTELLE MEMORIAL INSTITUTE, WASHINGTON
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TBI Hosts Lecture on Immigration
Inside USD -- "Human rights don't stop at borders."
Ev Meade, PhD, of the USD Trans-Border Institute welcomed community members to the 18th Annual Sister Sally Furay Lecture this May with these powerful words. Featuring keynote speaker Mary Meg McCarthy, executive director of Heartland Alliance's National Immigrant Justice Center (NIJC), the lecture explored the current state of U.S. immigration policy. Throughout the lecture, McCarthy constantly returned to the main question at hand: "What Does Justice Mean for Migrants and Refugees?" For many immigrants and refugees, McCarthy answered, "Justice has become a moving target, and far too often one that is moving in the wrong direction." (Full Story)
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The Mackie SRM 450 V2 delivers live sound that sounds like it should!
The SRM 450 V2 Active loudspeaker combines superior quality with innovative technology to bring ultimate performance - and reliability - to Mackie's legendary Sound Reinforcement Monitor (SRM) series. The SRM 450 V2 retains the best of the original SRM design, including Mackie signature Active architecture and its renowned rugged durability.
With ultra-efficient switching power supplies, a lightweight neodymium woofer, an upgraded compression driver and Class-D Fast Recovery amplification (300W LF/100W HF), the SRM 450 V2 packs way more power, clarity and punch. And its wide dispersion, outstanding bass extension and ultra-low distortion mean the SRM 450 V2 delivers pure studio monitor fidelity at full-on loudspeaker levels. Thanks to the SRM 450 V2, live has never sounded so good.
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What started as a simple string and pedal sales catalog has grown exponentially over the past thirty years. The early days were a time where catalogs didn't have much of a presence in the industry, but what began as a college dorm room operation grew rapidly. In 1986 we moved to a full product offering and 64-page catalog, which over the years has grown to 162 pages. Join the AMS family and get your free catalog now!
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GraphicRiver Toaster 8696518
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GraphicRiver Toaster 8696518
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Kitchen \ Toaster \ Vector \ Illustration \ Housework \ Bread \ Cook \ Food \ Graphic
Stock Vector - Toaster 8696518 by barbulat @ GraphicRiver
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Red toaster. he image is a vector illustration and can be used for different compositions. The image is an .eps file and you will need a vector editor to use this file, such as Adobe Illustrator.
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Jamaica Urban Transit Company (JUTC) will be rolling out school buses for the new school year which begins today September 3, 2012. As Jamaica continues to improve there infrastructure to ensure the country will increase there competitive edge in the 21st century, they elected the best practice approach which is to investment in the children.
As a result, 350 buses are expected to be on the street by next week. While the buses are set to operate in Kingston, St. Andrew and parts of St. Catherine and St. Thomas, it's a great start. Our hope is for JUTC to extend the services to rest of the island. See article


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I really don't understand what for ....
sorry, i'd be interested but am busy.....
Hahahahaha ... does anyone know how far is Zibo, and how may hours is the train ride?
I'll be doing much the same all week.
Hahahaha ... and here's 单独子儿's wardrobe for the week ...
to the Inferior Alex:
Hahahahaha ... Alex ... your right hand fighting with your left hand again?
@Edward M., I actually have worked as a contributor for WLIB, many, many moons ago, and I can assure you that they don't pay shit. They never even gave me drink coupons. You're a conspiranoid wanker. Go cuddle a cactus.
@Alex F., OH LAWD! Witness the oppression! This site is disorganized and fucked up because it is an ongoing public beta test. When the mods delete something critical of the site, it should be taken as a positive sign that our Norwegian masters actually read it closely enough to provoke a response. Thank you, citizen!
@DD, It was not a top-knot which I had cut off, but a mohawk.
tick tock tick tock, how long before everyone sees this and knows the truth...!!?? YOURE IN A RACE AGAINST TIME MODS!!
Someone better remove it asap!! Before the secret get out! No word fights or there'll be bitchin! LOL
Cant wait till someone proves my point for me.
单独子儿 (随便叫兽): "When the mods delete something critical of the site, it should be taken as a positive sign that our Norwegian masters actually read it closely enough to provoke a response."
Case closed.
单独子儿 - youre either retarded or insane or both.
@DD, The second "suit" is holding the hair of what was his Qing-era top-knot in his right hand. On the contrary, I was considerably more 非主流 before I landed in the Jing.
@Alex F. Indeed. Run along now, children. There's nothing to see here.
I'm grateful to the Nordic Administrati of these sacred hunting grounds wherein we Gentlemen may wile away the hours stalking wyld foxes as well as bores.
(continued) ... 单独子儿 ... those "paper clothes" were found on a page about Bruce Lee, those were his outfits in some of his movies ...
A former friend of mine went to something similar in Beijing, same rate, and he got paid just to show up in a suit being in the background of some business meeting for a few hours. This seems to be quite normal in China for companies with Chinese staff only to give important people an impression that they are indeed international. I don't think any bigger companies has any problem paying 700 rmb to some foreigners now and then as long as they can pay Chinese salaries only.
And what's up with people actually believing that we pay for forum activity? That's the LAST thing we'd have to pay for with people like you guys ;-)
Hahahahaha ... for the record, as the rumored CEO ... I dont get paid ... hell, these guys dont even listen to me :)
Scott wrote:
I love when the fresh meat steps off the boat to China and thinks the hottest shit ever just arrived in town.
lol. Youre classy scott, I can tell by your avatar. FYI Ive been in and out of this beech for nigh on 10 years so there aint nothing FOB about this produce, sorry to disappoint.
Alex F Who gives a damn about your wordfight with Erik? You're utterly retarded for screencapping and posting that.
You have (unsurprisingly) missed the point entirely, which is that posts (which contravene none of the forum or site rules and regulations) are deleted and censored. This conversation took place on my profile page then disappeared because the bitch "isnt supposed to get into word fights or he gets bitched at" - surely he shouldnt have visited my profile and posted provocative messages in the first place? Or did that not cross your numbskull?
I love every cat who comes here to sling weak flames at the site itself, the admins, and frequent users
weak flames....? ooooooor simply stating the facts that this site is not what it claims to be, doesnt follow its own rules and resorts to petty threats, bans and censorship at times when the idiotic staff are publicly shown to be...well...idiots.
all because.... they're not getting the pussy they expected?
lol. Clealy projection.
They're not the hot shit in China they wanted to be?
As above.
Why? I don't know.
You dont know because you have the IQ of a dried apricot and the charisma of a mollusc.
I can't explain why desperate pathetic tools do the infantile things they do.
Me neither, I mean...your dad boned your mom and all.
But thanks for giving us a laugh
The pleasure is all mine.
and reminding the rest of us that our lives aren't so bad
....I think they are.
when bottom-feeders like yourselves are still managing to eat and shit.
...and make a mockery of social invalids such as yourself with minimal effort.
@ Erik
So why did you post that? And then all of the following junk? I dont know you, I never met you and have never slighted you in any way - untill your BS.
Enlighten me as to your reasons for visiting my profile and posting stalk, publicly, on it. I would love to hear your reasoning behind this, other than to provoke me.
And the reason you provoked me is because I asked a simple question in the forums about whether or not members were paid for contributions - and why certain members had multiple aliuses?
Pray tell, why was that thread deleted?
@Alex: Yea this was in Beijing somewhere. If you could do this 10-20 times a month, you'd manage to make a living out of it ;-) But it'd be slightly weird if people started recognize you across companies ;)
I just have to point out how funny it is watching Alex F trying to win over Erik when knowing what I know ;-)
*picturing Erik down at the Café laughing his butt off in malicious delight*
Ole - one thing I know is that information I have shared with certain members of this site has mysteriously crossed over to be in the posession of others members. So really, I have a pretty good idea of whats going on.
(continued) ... such strange logic ... looks kind of familiar ...
HAHHAHAH! I'm DYING here!
Too bad I have to restrain myself in respect of users privacy ;-) Now I gotta get back to work.
Happy trolling :-)
...[br] [br] (continued) ... leaving so soon?
knowing what I know
... I am officially BORED now ... so what do you know? ... spill ...
"Oh wow. Oh wow. Oh wow."
- Steve Jobs
I think 700 RMB is not too bad. I mean you dont need to have any other skills that being a long nose. If I were a language student I would be happy to have such an opportunity.
@Scott ** your attempts to rattle my cage are about as successful as your attempts to come off as anything other than a wheezing subhuman cretin.
Alex F's blueballs - you have serious got to stop with the projection..way too blatent.
@Scott Dude, you're not James Bond and I'm not Goldfinger.
Ironically, I look quite similar to James Bond and you look quite similar to fatbastard from goldmember.
We're all just laughing at you.
Enjoy :)
Please, continue posting all your beefs with this free site rather than acting like a rational human being and going away.
A rational human being....like you? Or just a cretin? (Like you.)
You've accused me of "projecting" more than once now. Did you just learn that from your foreign English teacher or something?
Yes. More than once, because it applied more than once. Here's a freebie - English is my native language.
News flash: projection is 90% of mocking and ridiculing retards.
I don't actually take heavy notes on those with Down's Syndrome, I just glance at them for a few seconds and then makes some projections.
Ahhhh....yes. Now I understand. People with Down's Syndrome illicit a response from you because they appear to be easy targets. Its good to know that "glacing at" these folk and "makes some projections" gives you a feeling of some kind of self worth. Im happy for you, really.
And those who call out "projection" are basically affirming that my projection was indeed correct.
......Or they are just calling you out for projecting...one of the two.
Now stop acting like a nut thinking this site is stealing all your "precious" private information
Anything I post electronically I do not automatically assume will be private. And certainly nothing I have ever posted on this site, privately or otherwise was "precious". I just wanted to know why my posts which contravened no site rules were deleted. Thats all.
pull your head out of your ass, grow some balls, and I'll be happy to meet you in Sanlitun and show you how to get laid.
Ide be happy to meet you in sanlitun.....were it not for the fact that I do not associate myself with subhuman cretins that I can probably smell before I catch sight of. I cant think of anything that would cramp my game more than being within 10 feet of you in RL.
Yeah. Ain't it, Tempura, puddin'?
It's as if OP thinks he's doing us crackers a favor with this "Free trip to Shandong" vacation package horseshit.


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All lifts which carry goods or people should be checked on a regular basis, 12 monthly for those lifts carrying goods and 6 monthly for those which carry people. These tests are required by law and must be completed – they're known as statutory tests.
Burghley House Preservation Trust Limited in Stamford employed Arthur Mellar as a butler and he was crushed to death by a lift in July 2014 when it became stuck after one of the bags became jammed.
The lift had not been fitted with a slack rope detector and this was identified by the competent person after its examination. Had the lift been examined by a competent person earlier the engineer should have identified that this needed to be fitted.
The Trust pleaded guilty to a breach of Section 2 (1) of the Health and Safety at Work etc. Act 1974 and were today fined £266,000 and ordered to pay costs of £16,863.
Speaking after the sentencing, HSE inspector Alison Ashworth said:
"Arthur Mellar was killed when a luggage lift descended on him while he was trying to free an item of luggage. This was a completely avoidable incident, and Burghley House admitted its role in it, but of course that will be little comfort for Mr Mellar's family.
I would urge any business using lifts, particularly older lifts such as the one in this case, watching this case to ensure correct measures are taken in relation to maintenance of lifts and that competent lift engineers are employed when necessary to identify defects."
Contact us on 01453 800100 if you need expert help with health and safety for a fixed cost or use contact us above or the form below to request a proposal;


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Fruit Baskets to Afghanistan ›
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Cooking Grill Tips
Summertime is rapidly approaching. This means it's time to begin preparing meals without heating the home whenever achievable. In case, you haven't considered the value of cooking on the grill previously, perhaps now is a superb time to adjust your way of thinking.
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Short Film Profile
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Barcelona en dos Colors
Italy | 2011 | 29:00 | Documentary, Live Action
All information | Synopsis | Credits | Reviews | Details
Barcelona, July 2010. The Constitutional Court refuses Catalonia's instance of autonomy: the political, linguistic and national aspirations of Catalans are drastically resized. Around the streets of Gaudì's city explodes the euphoria of independence: on July 10th there will be a huge protest in defence of self-determination. In those same days, the Spanish national soccer team walks along its triumph in South Africa World Cup. The goal of a catalan, Carles Puyol, states the final match conquest against Holland, that will take place on July 11th.
Film notes
The director takes the public through a travel made of differences, contradictions and hidden intolerances of a city in two colors.
Film details
Aspect ratio
Additional details, including film categories, dialogue/subtitle languages and technical details are available to members.
Production country
Running time
29 min
Film type
User rating
All enquiries
Information on this profile is provided by the film owners and/or compiled from available sources | Profile updated 25 Jul 2012


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David Ramsey is an American Film Actor is born to Jeraldine and Nathaniel Ramsey on 17 November, 1974 at Detroid, Michigan, United States. He is well known for his role as John Diggle in TV series Arrow and Anton Briggs in Dexter. He graduated from Mumford high school. Black belt in Jeet Kune do, also study boxing and tae kwon do. Let's see some personal detail, family detail, height, weight, biceps, triceps, body type, body statistics and measurement.
David Ramsey Personal Detail:
Name: David Ramsey
Born: Novemeber 17, 1972
Age: 44 Years Old (2016)
Born Place: Detroit, Michigan, USA
Occupation: Actor
Debut with Movie: Scared Stiff as George Masterson
Active Year: 1987-Present
Education: Wayne State University
Origin: American
Ethnicity: Afro-American
Religion: Non-religious
Net Ramsey Earn: 4 Million $
Salary: 0.2 Million
Car Own: Mercedes Benz C-Class
Relationship Status: Married
Sexuality: Straight
David Ramsey Family Detail:
Parents: Nathaniel Ramsey, Jeraldine Ramsey
Spouse: Mary McKeon Ramsey
Children: Jamal, Keira, Janett
David Ramsey Height,Weight,Body Statistics and measurements:
David Ramsey Height: 188 cm
David Ramsey Weight: 86 kgs
Hair Color: Brown/Black
Eye Color: Dark Brown
Have a Tatoo: No
Smoke?: No, Never
David Ramsey Filmography:
1987 Scared Stiff
1996 The Nutty Professor, A Very Brady Sequel
1997 Con Air
1998 A Short Wait Between Trains
1999 Three to Tango
2000 Pay It Forward
2001 Mr. Bones
2004 Hair Show
2005 Resurrection: The J.R. Richard Story, Bathsheba
2007 The Death and Life of Bobby Z
2008 The Coverup
2009 The Rub Cam, Mother and Child
2014 Draft Day
2015 Accidental Love
1995: Murder One
1996: Deutschlandlied, Space: Above and Beyond, Her Costly Affair
1997-98: Good News
1998: CHiPs '99, Mama Flora's Family
1999: Mutiny
2002: Ali: An American Hero
2000-01: For Your Love
2001: Girlfriends, Thieves
2002: For the People, Romeo Fire, The Guardian
2002-03: One on One
2003: The Flannerys, Strong Medicine, NCIS
2004: Crossing Jordan, CSI: Miami, Charmed, Second Time Around
2005: Huff, All of Us, Jane Doe: The Wrong Face
2005-08: Ghost Whisperer, Hello Sister, Goodbye Life, The WestWing
2006: Fatal Contact: Bird Flue in America, CSI: Crime Scene Investigation
2007: Criminal Minds, Journeyman, Hollywood Residential, Wildfire
2008-09: Dexter
2009: Castle
2010: Grey's Anatomy, Outlaw
2011-Present: Blue Bloods
2012-Present: Arrow
2014-Present: The Flash
Featured Image taken from Image Source: www.tvnz.co.nz