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Patent US6117858 - Compositions and methods for altering the biodistribution of biological agents - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inPatentsThe invention relates to a new and improved pharmaceutical composition and method for delivery of therapeutic agents. The methods and composition of the invention can be used with several therapeutic agents and can achieve site specific delivery of a therapeutic or diagnostic substance. This can allow...http://www.google.com/patents/US6117858?utm_source=gb-gplus-sharePatent US6117858 - Compositions and methods for altering the biodistribution of biological agentsAdvanced Patent SearchTry the new Google Patents, with machine-classified Google Scholar results, and Japanese and South Korean patents.Publication numberUS6117858 APublication typeGrantApplication numberUS 09/118,168Publication dateSep 12, 2000Filing dateJul 17, 1998Priority dateJun 28, 1996Fee statusPaidAlso published asCA2258882A1, CA2258882C, DE69727958D1, DE69727958T2, EP0938341A2, EP0938341B1, US5849727, US6537814, US7115583, US7198949, US20040013662, US20040057946, WO1998000172A2, WO1998000172A3Publication number09118168, 118168, US 6117858 A, US 6117858A, US-A-6117858, US6117858 A, US6117858AInventorsThomas R. Porter, Patrick L. IversenOriginal AssigneeThe Board Of Regents Of The University Of NebraskaExport CitationBiBTeX, EndNote, RefManPatent Citations (37), Non-Patent Citations (39), Referenced by (20), Classifications (15), Legal Events (8) External Links: USPTO, USPTO Assignment, EspacenetCompositions and methods for altering the biodistribution of biological agents
FIG. 1 is a Lineweaver-Burke plot of the binding data for PESDA microbubbles with PS-ODN. The equilibrium dissociation constant Km (calculated for the 7 concentrations which were run in duplicate) for the binding to the microbubbles was 1.76×10-5 M. (r2 =0.999; Y-int=0.0566; 7 concentrations). This is nearly within the range observed for binding a 15mer PS-ODN with sequence 5'd(AACGTTGAGGGGCAT)-3' (SEQ ID NO:1) to human serum albumin in solution of 3.7-4.8×10-5M previously reported Srinivasan SK et al, "Characterization of binding sites, extent of binding, and drug interactions of oligonucleotides with albumin. Antisen Res. Dev. 5:131, 1995.
The microbubbles are formed by sonication, typically with a sonicating horn. Sonication by ultrasonic energy causes cavitation within the dextrose albumin solution at sites of particulate matter or gas in the fluid. These cavitation sites eventually resonate and produce small microbubbles (about 7 microns in size) which are non-collapsing and stable. In general, sonication conditions which produce concentrations of greater than about 4×108 m of between about 5 and about 6 micron microbubbles are preferred. Generally the mixture will be sonicated for about 80 seconds, while being perfused with an insoluble gas, in the presence of room air.
A variable flow microsphere scanning chamber was developed for the study which is similar to that we have described previously Mor-Avi V., et al "Stability of Albunex microspheres under ultrasonic irradiation; and in vitro study. J Am Soc Echocardiology 7:S29, 1994. This system consists of a circular scanning chamber connected to a Masterflex flow system (Microgon, Inc., Laguna Hills Calif.) The scanning chamber was enclosed on each side by water-filled chambers and bound on each side by acoustically transparent material. The PS-ODN-labeled PESDA microbubbles (0.1 milliliters) were injected as a bolus over one second proximal to the scanning chamber which then flowed through plastic tubing into a tap water-filled scanning chamber at a controlled flow rate of 100 ml/min. As the bubbles passed through the scanning chamber, the scanner (2.0 Megahertz) frequency, 1.2 Megapascals peak negative pressure) was set to either deliver ultrasound at a conventional 30 Hertz frame rate or was shut off. Following passage through the scanning chamber, the solution was then passed through the same size plastic tubing into a graduated cylinder. The first 10 milliliters was discarded. Following this, the next 10 milliliters was allowed to enter into a collection tube. The collection tube containing the effluent microbubbles was allowed to stand in order to separate microbubbles on the top from whatever free oligonucleotide existed in the lower portion of the sample. Drops from both the upper and lower operation of the effluent were then placed upon a hemocytometer slide and analyzed using a 10× magnification. Photographs of these slides were then made and the number of microbubbles over a 36 square centimeter field were then hand-counted. The upper and lower layers of the remaining effluent were then used for analysis of oligonucleotide content using flow cytometry in the same manner described below.
TABLE 1______________________________________OLIGONUCLEOTIDES BINDING TOALBUMIN OF PESDA MICROBUBBLES       TOP          BOTTOM    RATIO   N   cpm/&#956;l    cpm/&#956;l T/B______________________________________BUBBLES IN THE PRESENCE OF FREE ALBUMINTTAGGG    6     125 ± 6.4 92.3 ± 6.4                                1.35c-myb     6     94.1 ± 17.6                        77.3 ± 1.2                                1.35WASHED BUBBLES (NO FREE ALBUMIN)TTAGGG    6      210 ± 10.8                         126 ± 8.7                                1.67c-myb     6     200.3 ± 37.4                         92.7 ± 15.7                                2.16______________________________________
TABLE 2__________________________________________________________________________DISTRIBUTION OF OLIGONUCLEOTIDE (PS-ODN) BOUND MICROBUBBLESControl PS-ODN  151 nM FITC PS-ODN                       Excess Unlabeled ODNNo.   PE MI     PE  MI      PE  MI__________________________________________________________________________1     99.5    2.38   98.9               2109.8  97.8                           1753.12     99.3    4.07   99.1               2142.3  98.7                           1710.93     99.4    3.52   99.1               2258.5  99.3                           1832.2mean ± SE    3.23 ± 0.50               2170 ± 461                           1765 ± 361,2__________________________________________________________________________ PE = percent events MI = mean intensity SE = standard error 1 indicates this mean is significantly different form control, P &lt; 0.001 2 indicates this mean is significantly different form 151 nM, P &lt; 0.001
Rats were ultimately sacrificed using ethyl ether and microsomes were prepared as described by Franklin and Estabrook (1971). Livers were perfused with 12 ml of 4% saline via the portal vein and then removed from the animal. The livers were minced, homogenized in 0.25 M sucrose (Sigma) and centrifuged at 8000×g for 20 minutes at 4° C. in a Sorvall RC2-B centrifuge (Dupont, Wilmington, Del.). The supernatant was saved and resuspended in a 0.25 M sucrose and centrifuged at 100,000×g for 45 minutes at 4° C. in a Sorvall OTD55B ultracentrifuge (Dupont). The pellet was resuspended in 1.15% KCL (Sigma) and centrifuged at 100,000×g for 1 hour at 4° C. with the final pellet resuspended in an equal volume buffer (10 mM Tris-acetate, 1 mM EDTA, 20% glycerol; Sigma) and frozen at -80° C.
CYP IIB1 content was determined by pentoxyresorufin O-dealkylation (PROD) activity (Burke et al. 1985). For each microsomal sample, 1 mg protein in 1 ml 0.1 M potassium phosphate buffer, 1 ml 2 μM 5-pentoxyresorufin (Pierce, Rockford, Ill.), and 17 μl 60 mM NADPH were mixed and incubated for 10 minutes at 37° C. The mixture was then added to a 2 ml cuvette and read on a RF5000U spectrofluorophotometer (Shimadzu, Columbia, Md.) using an excitation wavelength of 530 nm and emission wavelength of 585 nm. Concentrations of unknowns were calculated from a standard curve of resorufin (Pierce, Rockford, Ill.) standards. Results were recorded in nmol resorufin/mg protein/min.
The perfluorocarbon containing microbubbles (PCMB) used for this study were perfluorocarbon exposed sonicated dextrose albumin. To prepare these microbubbles, one part 5% human serum albumin and three parts 5% dextrose (total of 16 ml) were combined in a 35 ml Monoject syringe (Sherwood Medical, St. Louis, Mo.). This sample was then hand-agitated with 8 ml of fluorocarbon gas (decafluorobutane; MW 238 g/mol). Following the agitation, the sample underwent electromechanical sonication for 80±2 seconds.
The scanning chamber system consisted of a 35 ml cylindrical scanning chamber connected to a peristaltic Masterflex flow system (Microgon, Inc., Laguna Hills, Calif.). Enclosed on both sides of the scanning chamber are cylindrical saline filled chambers, bound by acoustically transparent latex material that is 6.6 microns in thickness (Safeskin, Inc.; Boca Raton, Fla.). Pressure within the scanning chamber during ultrasound exposure was measured with a pressure transducer placed just proximal to the scanning chamber (model 78304A; Hewlett Packard Co., Andover, Mass.), and averaged 7±3 mm Hg throughout all of the trials.
Arterial blood during room air inhalation was taken from four dogs and three healthy pigs just prior to sacrifice. In four of the animals, additional arterial blood was obtained after the animal had inhaled 100% oxygen for a minimum of 10 minutes. The blood was collected in 60 ml heparinized syringes, and kept in a warm water bath at 37° C. until injected into the scanning chamber. Immediately before injection of the blood into the scanning chamber, 0.2 ml of PCMB were injected via a stopcock into the 60 ml syringe of blood, and mixed gently by inverting and rolling the syringe by hand.
Once the PCMB were well-mixed with the blood, the tip cap was removed from the syringe, and the syringe was connected to plastic tubing (3.5 mm in diameter) proximal to the Masterflex flow system. At a flow rate of 50 ml/minute, the contrast filled blood flowed from the syringe into the tubing and then into the scanning chamber. Once the chamber was filled, the closed stopcock connecting the scanning chamber to the plastic tubing distal to the chamber was opened, and ultrasound exposure (intermittent at 1 Hertz frame rate or conventional at 30-45 Hertz) was initiated. The effluent blood after ultrasound exposure flowed out of the scanning chamber into tubing which was connected to a graduated cylinder. The first 10 ml of blood was discarded, and the next 15 ml of blood that flowed from the chamber was collected in three 5 ml aliquots into inverted capped syringes. Three minutes following the collection of the last 5 ml sample, a tuberculin syringe was dipped into the top level of the effluent blood and a drop placed on a hemocytometer slide; this length of time was chose to allow the microbubbles in the effluent blood to rise to the top and be collected. The hemocytometer slide was then examined at 40× magnification with a light microscope (Olympus BH-2, Olympus America Inc., Woodbury, N.Y.) and the field containing the highest concentration of microbubbles was photographed on the hemocytometer field.
Table 3 demonstrates differences in mean microbubble size for PCMB after exposure to ultrasound in arterial blood (room air and 100% oxygen). When PCMB were exposed to 100% oxygenated arterial blood, there was a significant decrease in mean microbubble size after insonation (p=0.01). The smaller microbubble size was seen both after intermittent imaging (7.3±3.7 microns room air vs. 6.4±3.2 microns 100% oxygen) and after conventional imaging (7.5±3.5 microns room air vs. 6.3±3.0 microns 100% oxygen).
TABLE 3______________________________________COMPARISON OF EFFLUENT PESDA MICROBUBBLE SIZEAFTER EXPOSURE TO DIFFERENT ULTRASOUND FRAME RATESIN ROOM AIR AND 100% OXYGENATED ARTERIAL BLOOD    MB size    MB Conc. (No./hpf)    (&#956;m)    Conv    Inter______________________________________Arterial   7.4 ± 3.6  6 ± 8                           16 ± 11&#8224;Arterial +O2      6.3 ± 3.1 11 ± 9                           14 ± 9*______________________________________ Conv = Conventional frame rates (80 to 43 Hz) No./hpf = Number of microbubbles per highpower field MB = microbubble Inter = Intermittent imaging at 1 Hz *p &lt; 0.05 r test compared with arterial samples &#8224;p &lt; 0.05 compared with arterial conv.
TABLE 4______________________________________COMPARISON OF PMVI PRODUCED IN ANTERIOR ANDPOSTERIOR WALL OF LEFT VENTRICULAR SHORT-AXISVIEW AT MID PAPILLARY MUSCLE LEVEL AFTERINTRAVENOUS VEIN INJECTION OF PCMB SONICATED INTHE PRESENCE OF 100% OXYGEN AND ROOM AIR              Microbubble    PMVI (units)    Size     Conc    Ant   Post      (&#956;m)  (No./hpf)______________________________________RA PCMB    54 ± 12              19 ± 9 4.0 ± 2.4                               109 ± 30O2 PCMB      70 ± 6*              31 ± 5*                        3.9 ± 2.3                               108 ± 50______________________________________ Ant = anterior myocardium Conc = microbubble concentration immediately after sonication O2 PCMB = perfluorocarbon microbubbles sonicated in the presence of 100% oxygen PMVI = peak myocardial videointensity Post = posterior myocardium RA PCMB = perfluorocarbon microbubbles sonicated in the presence of room air No./hpf = number of microbubbles per highpower field *p &lt; 0.05 compared with RA PCMB
Two independent observers measured microbubble size and concentration of six different slides exposed to either intermittent or conventional ultrasound frame rates. The coefficient of variation for measurements of microbubble size by two independent observers in six different samples was 8% (r=0.95; p=0.004), while the coefficient of variation for independent measurements of microbubble concentration was 9% (r=0.99; p<0.001). The reported mean difference in peak myocardial videointensity measurements by two independent reviewers for transthoracic imaging is 4±4 units (r=0.94, SEE=5 units; p<0.001; n=24 comparisons), which is well below the 16 unit mean difference in anterior and 13 unit mean difference in posterior peak myocardial videointensity between O2 PCMB and RA PCMB. The two investigators were in agreement of the visual degree of contrast enhancement in 37 of the 44 regions (84%). Five of the discrepancies were in visual grading of RA PCMB myocardial contrast enhancement (0 vs 1+ in two regions, 1+ vs. 2+ in three regions). The three regions where there was disagreement on whether there was 1+ vs 2+ were assigned a 2+ in the statistical analysis.
The in vitro studies confirmed that oxygenated blood reduced PCMB size but did not completely destroy them as has been shown with pure room air containing albumin microbubbles. Wible J. Jr., et al. (1993), Effects of inspired gas on the efficacy of Albunex® in dogs. Circulation 88(suppl):1-401. Abstract. To counter this process, the inventors attempted to reverse this diffusion gradient by removing nitrogen within the microbubbles. It was hypothesized that this would have the opposite effect of that seen with oxygenated blood, resulting in nitrogen diffusion inward. The in vitro and in vivo findings of this study appear to support this hypothesis.
It has previously been shown that PCMB diameter increases after initial exposure to blood at 37° C., most likely from gas expansion from room temperature to body temperature. Although this explains why microbubble size increased in all samples tested, the PCMB exposed to 100% oxygenated arterial blood were significantly smaller in size compared to PCMB exposed to room air blood (Table 3). This observation was seen both following intermittent and conventional imaging. Without wishing to be bound by any theory, it is postulated the one potential explanation for this is the differences in nitrogen diffusion gradients across the microbubble membrane. Since all PCMB in the in vitro study were sonicated in the presence of room air, there was a significant quantity of nitrogen within the microbubble. Mathematical models have suggested that microbubbles containing insoluble gases persist longer if tissue and blood contain nitrogen. (Burkard 1994). In the absence of blood nitrogen (i.e.: 100% oxygenated blood), nitrogen from within the PCMB would have diffused out of the PCMB, reducing their size.
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