Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
  • A61K51/1217—Dispersions, suspensions, colloids, emulsions, e.g. perfluorinated emulsion, sols

Definitions

• This invention is in the field of diagnostics in radiography and radioimaging and is more particularly concerned with a composition and method of preparing the composition for use in scintigraphy.
• the sentinel node is that lymph node in a given lymphatic basin that first receives lymphatic flow from a primary tumor (Gulec et al. (1997)). As a result the histology of the sentinel node usually reflects the histology of the basin.
• the sentinel node is the best tissue to sample for histophathologic examination (Alazraki et al. (1997)).
• Sentinel node lymphoscintigraphy has made it possible to perform complete lymph node dissection only in those patients with confirmed nodal metastasis. SNL therefore reduces the surgical morbidity associated with such a procedure including: parasthesia, wound infection, seroma, drain discomfort, acute and chorin lymphodema, as well as potential delays in adjuvant therapy (Cox (1998); Hinkle (1998)). Furthermore, lymphatic mapping and sentinel node biopsies direct dissection to all lymph node beds that could have tumors.
• the procedure involves injecting radiopharmaceuticals (specifically radiolabeled colloid of suitable size and properties) at the primary tumor site, which allows the path of lymphatics, for example from a cutaneous melanoma or breast lesion, to the regional node basin to be traced.
• radiopharmaceuticals specifically radiolabeled colloid of suitable size and properties
• gamma probe guided surgery with a hand-held, wand-like instrument that detects gamma rays emitted by the radiocolloid
• successfully locates the sentinel node allowing a directed dissection and minimizing tissue disruption (Alazraki (1998); Pijpers et al. (1995)).
• Tc-S colloids have been used for years to image the reticuloendothelial system. There are three reported methods of making such preparations: (1) 99m TcO " 4 + H 2 S in acid solution;
• Tc-S colloid preparations The major commercial source of Tc-S colloid preparations is the reaction mixture formed from pertechnetate-99m in an acidified solution of sodium thiosulphate (Atkins, H.L., et al. (1966); Stern H.S., et al. (1966)). Such standard preparations result in a final pH on average of between 5.0 and 6.5. Such pH values cause significant irritation in patients often requiring a local anesthetic to accompany the injection.
• the ideal radiocolloid for use in SNL includes ease of labeling; sutiable half life and energy characteristics; permitting quantitative or dynamic measurement and high quality imaging; ease of preparation and good shelf life; physiologically and chemically inert and homogeneous; sterility and pyrogenicity readily established via Quality Control procedures; in vitro and in vivo stability; and optimal mobilization of colloid from injection site.
• rate of colloid transport and movement through lymphatic pathways is most strongly related to the size of the colloid. Those larger than 0.004 ⁇ m to 0.005 ⁇ m are preferred, as smaller particles have been reported to penetrate the capillary membranes and are therefore unavailable to migrate through the lymphatic channels resulting in obscured images.
• Particles smaller than 0.1 ⁇ m show the most rapid disappearance from the interstitial space into the lymphatic vessels and have significant retention in the lymph node.
• Large colloid particles ( ⁇ 0.5 ⁇ m) show a much slower rate of clearance from the interstitial space with significantly less accumulation in the lymph nodes (Alazraki et al. (1997); Bergqvist et al. (1983); Ege G: Lymphoscintigraphy in Oncolgy. Chapter 94 Nuclear Medicine Volume II. Mosby Year Book, St. Louis, Missouri 1504-1523; Eshima et al. (1996); Hung et al. (1995); Nagai et al. (1982)).
• the present inventors have developed a new formulation of Tc-99n ⁇ colloid.
• the new colloid contains a high ratio of perrhenate to thiosulphate, cysteine, and a prepared higher final pH than found previously.
• a "final pH” means the pH of the final formulation and can be between about 5.5 and about 8.0, but is preferably between about 7.0 and about 7.5.
• "high ratio” means from about 0.05 to about 1.2 rhenium:sulfur and in any event, less than rhenium and no sulfur.
• the new colloid has excellent radiochemical purity, and a much smaller particle size distribution than has generally been previously available for sulfur colloid preparations.
• the present invention provides a colloid particle, containing a high ratio of rhenium to sulfur, and containing a source of sulfhydryl groups (-SH), and technetium, preferably wherein the particle is less than about 0. 1 micron in diameter and the technetium is Tc-99w.
• a colloid particle containing a high ratio of rhenium to sulfur, and containing a source of sulfhydryl groups (-SH), and technetium, preferably wherein the particle is less than about 0. 1 micron in diameter and the technetium is Tc-99w.
• the invention also provides a colloid containing a high ratio of rhenium to sulfur, and containing a source of -SH, and technetium wherein a majority of the particles, preferably greater than about 80% of the particles, of the colloid, are less than about 0.1 micron in diameter and the technetium of these particles is Tc-99m.
• the invention provides a method of preparing a colloid containing a high ratio of rhenium to sulfur, and containing a source of -SH, and technetium comprising the steps of: in a container adding a source of sulfur and a source of rhenium; adding a source of technetium; before boiling adding a source of -SH; acidifying the contents of the container; boiling the contents of the container; cooling the contents of the container; raising the pH of the contents of the container to a higher final pH between about 5.5 to about 8.0, preferably between about 7.0 and about 7.5.
• Also provided is a method of detecting sentinel lymph node(s) associated with a tumor comprising administering a sufficient amount of a radiopharmaceutical colloid according to the present invention to an animal, detecting radiation emitted from the animal, and correlating the emissions to locate the associated sentinel lymph node(s).
• Figure 1 is a histogram illustrating percentage of retention on a 0.22 ⁇ m filter and the radiochemical purity of various colloids.
• Figure 2 is a histogram illustrating the effect of increasing amounts of cysteine on retention of sulfur colloid on a 0.22 ⁇ m filter.
• Figure 3 is a histogram illustrating the effect of the added cysteine on particle size of rhenium colloid.
• Figure 4 illustrates the kinetics of boiling time for rhenium colloid.
• Figure 5 is a histogram illustrating percentage of the injected dose retained in a mouse liver for various colloids 20 minutes after intravenous injection.
• Figure 6 is a histogram illustrating the percentage uptake of various colloids by the mouse sternum 20 minutes after intravenous injection.
• Figure 7 is a histogram illustrating the biokinetics of tin colloid in mice 20 minutes after intravenous injection.
• Figure 8 is a histogram illustrating percentage of sulfur colloid in various size ranges for "in-house” sulfur colloid and Amershan TSC colloid (Monday Te99m elution).
• Figure 9 is a histogram illustrating the percentage of colloid smaller than 0.22 microns for three preparations of colloid, with and without cysteine.
• Figure 10 is a histogram illustrating the effect of cysteine addition, before boiling, on the percentage of colloid particles less than 0.22 microns for rhenium colloid versus clinical "in-house” sulfur colloid.
• Figure 11 is a histogram depicting the size distribution of radioactivity comparing "in-house” sulfur colloid with rhenium colloid.
• Figure 12 is a histogram illustrating a comparison of RCP and mouse liver uptake (20 minutes after intravenous injection) between "in-house” sulfur colloid and rhenium colloid.
• Figure 13 is a histogram illustrating a comparison of mouse biodistribution 20 minutes after intravenous injection of "in-house” sulfur colloid versus rhenium colloid.
• Figure 14 is a histogram/graph presentation of results illustrating the changes in radiochemical purity in particles less than 0.22 microns with increasing boiling time.
• Figure 15 illustrates particle size distribution of a commercial sulfur colloid under various conditions.
• Figure 16 is a histogram illustrating size distribution of three colloid preparations with and without cysteine.
• Figure 17 is four histograms illustrating size distribution of TSC colloid with increasing amounts of cysteine.
• Figure 18 is a histogram illustrating the percentage of injected dose after one hour of migration of radioactivity from intradermal injection site in a rabbit.
• Figures 19A and B are a graphs illustrating the migration of radioactive colloid in various lymphatic regions in rabbits for 2 hours after intradermal injection sites by showing amounts left at the injection site.
• Figure 20 is a histogram illustrating entrapment ratios of primary popliteal node to efferent lymphatic channels for radio colloids in a rabbit lymphoscintigraphy model at 2 hours.
• Figure 21 is a histogram illustrating the ratio of primary node to secondary node entrapment of radio colloids at 2 hours in rabbits.
• Figure 22 is a histogram illustrating the ratio of both popliteal nodes to total trunk activity 2 hours post injection in rabbits.
• Figure 23 provides 3 panels illustrating nuclear medicine images showing migration from injection site from melanoma to opposite axilla with Tc-99m-ReC.
• Figure 24 is a composite of nuclear medicine lung scans after inhalation of aerosolized (nebulized) using the ReC of the present invention.
• the present inventors have developed a new technetium colloid which contains a high ratio of perrhenate to thiosulphate, cysteine, and a preferred higher final pH than found previously, and has excellent radiochemical purity, and a much smaller particle size distribution than has generally been previously available for sulfur colloids.
• the present invention provides a colloid particle, containing a high ratio of rhenium to sulfur, preferably greater than about 0.05 and less than about 1.2, preferably about 0.3, and containing a source of -SH, and technetium.
• a source of -SH, and technetium preferably, sodium or potassium perrhenate, perrhenic acid, rhenium chloride, rhenium fluoride, rhenium oxide, preferably, the source of rhenium is perrhenate.
• sources of sulfur are available, preferably, the source of sulfur is thiosulfate.
• the source of -SH is selected from the group consisting of inorganic sulphide, and organic thiols, more preferably the organic thiol is selected from the group consisting of cysteine, glutathione and peptides, and of these preferably cysteine.
• a "high ratio of rhenium to sulfur” means the molar ratio of rhenium to sulfur.
• a "high ratio” means a molar ratio of rhenium to sulfur of about 0.05 to about 1.1, preferably about 0.25.
• the colloid particle size is less than about 0. 1 micron in diameter and for use in the radio imaging field the technetium is Tc- 99m.
• the present invention provides a colloid, containing a high ratio of rhenium to sulfur, preferably greater than about 0.05 and less than about 1.2, preferably about 0.3, and containing a source of -SH, and technetium.
• a source of -SH, and technetium preferably, sodium or potassium perrhenate, perrhenic acid, rhenium chloride, rhenium fluoride, rhenium oxide, preferably, the source of rhenium is perrhenate.
• sources of sulfur are available, preferably, the source of sulfur is thiosulfate.
• the source of -SH is selected from the group consisting of inorganic sulphide, and organic thiols, more preferably the organic thiol is selected from the group consisting of cysteine, glutathione and peptides, and of these preferably cysteine.
• the colloid is one wherein a majority of the particles, and preferable greater than about 80% of the particles, are less than about 0.1 micron in diameter and in these particles of the colloid, the technetium is Tc-99m.
• the colloid has a final pH of about 5.5 to about 8.0, preferably about 7.0 to about 7.5, more preferably 7.4 Preparation of colloids
• a method of preparing a colloid containing a high ratio of rhenium to sulfur, and containing a source of -SH, and technetium comprising the steps of: in a container adding a source of sulfur and a source of rhenium; adding a source of technetium; prior to boiling adding a source of -SH; acidifying the contents of the container; boiling the contents of the container; cooling the contents of the container; raising the pH of the content of the container.
• rhenium a variety of sources for rhenium are available including sodium or potassium perrhenate, perrhenic acid, rhenium chloride, rhenium fluoride, rhenium oxide, preferably, the source of rhenium is perrhenate.
• sources of sulfur are available, preferably, the source of sulfur is thiosulfate.
• the source of -SH is selected from the group consisting of inorganic sulphide, and organic thiols, more preferably the organic thiol is selected from the group consisting of cysteine, glutathione and peptides, and of these preferably cysteine.
• colloid preparations routinely include a gelatin and as such, a colloid and a method of making a colloid according to the present invention includes the incorporation of a gelatin.
• the colloid particle size is less than about 0. 1 micron in diameter and for use in the radio imaging field the technetium is Tc- 99m.
• the amount of cysteine added is sufficient to bring about a reduction in the size of particles, most importantly the source of -SH, for example cysteine, is to be added before boiling.
• the amount of cysteine added is between about 0.5 and about 50 mg, preferably about 6 mg, and preferably the the boiling time is from about six (6) to about ten (10) minutes, most preferably about eight minutes, and the cooling time is from about zero to about ten minutes, preferably about 8 to about 10 minutes.
• the pH is increased to a final pH of between about 5.5 to about 8.0, preferably about 7.0 to about 7.5 using any buffer, preferably a phosphate buffer.
• the method provides a colloid wherein a majority of the particles, preferably greater than about 80% of the particles of the colloid are less than about 0.1 micron in diameter.
• the technetium of the particles which are less than about 0.1 micron in diameter, is preferably Tc-99m and the final pH of the colloid is 7.4.
• Tc-99m the technetium of the particles which are less than about 0.1 micron in diameter
• 196 Tc or 198 Tc may also be used.
• other sources of radioactivity may be employed rather than technetium depending on circumstances in which the colloid is to be utilized.
• a method of preparing a colloid containing a source of sulfur, a source of -SH and a radioactive source comprising adding to a container the source of sulfur and the source of radioactivity, adding the source of -SH prior to boiling, acidifying the contents of the container, boiling the contents of the container, cooling the contents of the container and raising the pH of the contents of the container.
• the source of sulfur is thiosulphate
• the source of radioactivity is Tc-99m
• the source of -SH is cysteine. Acidfication may be brought about with any acid, preferably NCI.
• the pH may be raised with any buffer, preferably phosphate, to a pH of between about 5.5 and about 8.0, preferably about 7.0 to about 7.5, most preferably 7.4.
• the boiling time can be from between about six (6) to about ten (10) minutes, most preferably about eight (8) minutes, and the cooling time is from about zero to about ten minutes, preferably about 8 to about 10 minutes, more preferably 2-4 minutes. With respect to boiling time it is understood that this time can be from 10 seconds to 2 minutes to as much as 1 hour, however, as illustrated in Figure 14, the preferred time is about 8 minutes.
• the method provides a colloid wherein a majority of the particles, preferably greater than about 80% of the particles of the colloid are less than about 0.1 micron in diameter.
• the preparation of a colloid according to the present invention involves the addition of 99m Tc pertechnetate (radioactive label) to a container, such as a vial, containing a chemical or chemicals which forms the bulk of the radioactive colloidal particle (for example, perrhenate as the rhenium source or thiosulphate as a sulfur source).
• a chemical or chemicals which forms the bulk of the radioactive colloidal particle for example, perrhenate as the rhenium source or thiosulphate as a sulfur source.
• a source of sulphydryl groups such as cysteine
• HCI hydrochloric acid
• the source of the 99 Tc per technetate is eluted from a 99 Mo/Tc99m generator, the process of elution/removal is referred to as "milking".
• the length of time between milkings will affect the degree of incorporation of 99 Tc and 99m Tc (delayed elutions have greater quantities of chemical technetium - 99 Tc and 99m Tc).
• the pH of the resultant colloids may be assessed by any standard means including using pH paper or a pH meter. Radiochemical Purity and Stability of Colloids
• the radiochemical purity (RCP) of colloids may be determined by a number of methods well known to those skilled in the art.
• One such method is the use of instant thin layer chromagraphy silica gel (ITLC-SG) chromatography paper as the stationary phase and methyl ethyl ketone (MEK) and saline as mobile phases.
• ILC-SG instant thin layer chromagraphy silica gel
• MEK methyl ethyl ketone
• saline as mobile phases.
• a comparison of RCP obtained for MEK and saline sheds light on the chemical nature of any impurities present in the colloid prepared.
• radiolabeled products are shaken well before withdrawal of the colloid sample. The sample is applied at the origin of the chromatography strip and the paper strip is placed in a chromatography chamber with an approved solvent or mobile phase solvent.
• the solvent is allowed to run a sufficient distance after which the strips may be dried in a convenient manner, typically in air at room temperature.
• the resulting strips may be analyzed using a analyzers well known in the art, for example a Shimadzu ChromatopacTM thin layer chromatogram scanner. Comparing the RCP values obtained at different times, for example 0 and 6 and 24 hours post-production, provides and assessment of a sample's in vitro stability. Size Evaluation of Radiolabeled Colloids
• Radioactive particle size distribution of a colloid may be evaluated by, for examples, ultrafiltration, ultracentrafugation, transmission and electron microscopy.
• a rapid approach which provides meaningful results is membrane filtration with hydrophilic polyvinylidene fluoride micropore filters (eg. MilliporeTM).
• the percentage of radioactivity retained on a filter is expressed as a percentage of the total activity (i.e., filter + filtrate). Filtering may be performed at different times, e.g., 1, 6 and 24 hours after production, in order to determine any temporal changes in particle characteristics.
• the sentinel node is that lymph node in a given lymphatic basin that first receives lymphatic flow from a primary tumor, and consequently the sentinel node usually reflects the histology of the basin: if there is cancer in the sentinel node, there may be metastatic disease in other nodes. If the sentinel node is cancer-free, there is greater than 98% likelihood that the remaining nodes in the basin are negative.
• Sentinel node lymphoscintigraphy SNL has made it possible to perform complete lymph node dissection only in those patients with confirmed nodal metastasis.
• a method of detecting the sentinel lymph node(s) associated with a primary tumor such as in breast cancer comprises administering an effective amount of a radiopharmaceutical colloid according to the present invention to an animal, detecting radiation emitted from the animal, and correlating the emissions to locate the associated sentinel lymph node(s) for further pathology diagnosis and tumor staging.
• This method of detection may be used in connection with any form cancer which is known to metastasize via lymph nodes and includes breast cancer, melanoma, squamous cell carcinoma, and testicular cancer.
• a "radiopharmaceutical colloid” is a colloid according to the present invention which is radioactive, preferably using Tc-99m.
• animal includes all members of the animal kingdom including mammals, preferably humans.
• an "effective amount" of a colloid of the present invention is defined as an amount effective, at dosages and for periods of time necessary to achieve the desired result.
• the effective volume /quantity of radioactivity in the colloid and concentration of colloid amount of a colloid of the invention may vary according to factors such as the disease state, age, sex, and weight of the animal. Dosage procedures may be adjusted to provide the optimum response. For example, several divided doses may be administered or the dose may be proportionally reduced as indicated by the exigencies of the situation.
• the present invention may have a very wide range of radioactivity while maintaining radiochemical purity (RCP), for example, the range may be from 100 ⁇ Ci to 300 mCi.
• the present examples involved testing the effects of altering the standard preparation parameters typically used in the preparation of colloids, specifically: the length of time of boiling, cooling; when the solution is neutralized; the volume of HCI or P0 4 " added; and the length of time since the generator was last milked.
• the pH of the resultant colloids was assessed using pH paper and in some cases a pH meter.
• the in-house SC was composed of the following:
• Solution A potassium perrhenate 1.17 mg gelatin 3.38 mg dipotassium phosphate 10.1 mg sodium thiosulfate 1.5 mg disodium Edetate 1.01 mg, all in 1.5 ml solution.
• Solution B cysteine hydrochloride monohydrate2 mg
• the strips were analyzed using a Shimadzu ChromatopacTM thin layer chromatogram scanner to determine the % of radioactivity remaining at the origin and that migrating to the solvent front.
• the acceptable RCP limit for the colloidal products was arbitrarily set at 95% (for products that were not primarily retained on a 0.22 ⁇ m filter). Comparing the RCP values obtained at 0 and 6 hours post-production assessed the sample's in vitro stability. Size Evaluation of Radiolabeled Colloids The radioactive particle size distribution of the colloids was evaluated by membrane filtration with hydrophilic polyvinylidene fluoride micropore filters (MilliporeTM). 13 mm in diameter with pore sizes of 0.1, 0.22 and 0.45 ⁇ m.
• Biodistribution studies of the radiocolloids prepared were conducted in mature CD-I Swiss white mice weighing approximately 25-30g. An aliquot containing 2 ⁇ Ci 99m Tc was injected into the tail vein of the animals which were euthanized (via C0 2 /cervical dislocation) 20 minutes post injection. The organs (blood, lung, liver, spleen, sternum, femur and in some cases kidney) were quickly removed, made free from adhering tissues and blood then weighed. The radioactivity in each organ was measured and expressed as a percentage of the injected dose per whole organ and per gram. Lymphoscintigraphy For example below, typically, male New Zealand white rabbits with body weight of about 3kg were used.
• Radiopharmaceuticals were injected intradermally using tuberculin syringes and a 27-guage needle into the web space between the second and third toes in both hind legs, each injectate containing 18-20MBq activity in a volume of 0.1ml.
• the injection sites were massaged for three minutes immediately after injection.
• Sequential gamma imaging (using 256 x 256 matrices) from the posterior of the rabbit lying prone on the collimator surface was performed at 0, 5 and 10 minutes post-injection and subsequently at 10 min intervals up to 2 hours by the use of a GE gamma camera connected to a processor. In some cases a 24 hour image was also obtained.
• the images were archived on optical disc.
• Elemental sulfur and preformed sulfur colloid are susceptible to attack by -SH groups where the colloid has already been boiled.
• Inorganic sulfide as well as organic thiols (including cysteine, glutathione, and peptides) will open the S8 ring to form water- soluble polysulfides (Frier et al. (1981)) thus effectively shrinking the sulfur containing particles formed.
• the preponderance of the colloid generating solution is a rhenium source, such as perrhenate, it is not clear if the shrinking effect will still be observed. Neither is there any indication of the effect of adding the -SH source before boiling.
• FIG. 2 illustrates the effect of cysteine on regular SC.
• the effect of increased phosphate buffer (“neutral") was compared with regular quantities("acidic") based on Steigman et al.'s (Steigman et al. (1986)) finding of smaller particles at higher pH.
• 2 mg cysteine did not result in a significant decrease in size from the original SC preparation.
• 6 mg cysteine dramatically reduced the particle size obtained.
• the increased P0 4 slightly reduced the resultant particle size, but in all cases the RCP remained at 100%.
• rhenium colloid (ReC). It is also referred to in the figures as Tc-99m Rhenium Colloid. Without additional cysteine, the 0.22 ⁇ filter retention at 1 hour of the rhenium colloid at acidic pH, 48.3% (Figure 3), was about half of that observed for SC ( Figure 2). The much smaller particle size of Re colloid, 26% ( Figure 3), was even more evident at neutral pH (SC 94% retention Figure 2). A comparison of the size distribution for SC and ReC is provided in Figure 11. EXAMPLE 4
• Figure 4 demonstrates the % retention and RCP as a function of length of time boiling. Note that as the boiling time increases the labeling efficiency approaches 100% (see Figure 14) and the retention also increases. From this study it was concluded that a "safe" boiling time in order to ensure efficient labeling was about eight minutes. Further studies revealed that with cysteine the cooling period did not have a significant effect on the ReC particle sizes obtained by 0.1 ⁇ m or 0.22 ⁇ m filtration analysis. In the upper half of Table 2, for simple comparative purposes, the physical results for the in-house SC versus ReC are listed. EXAMPLE 5
• an antimony colloid kit obtained from the Foothills Radiopharmacy in Calgary, Alberta (not readily commercially available) obtained low retention (1.3% at 1 hour) and high RCP (94% MEK and 100% saline).
• Antimony colloid has been used successfully for general lymphoscintigraphy, but its ability to localize in sentinel nodes has not been firmly established since it appears to migrate passed the sentinel node(s) thereby failing to locate only the sentinel node(s). Lack of commercial availability and a lengthy one hour preparation make it hightly unlikely that it will become widely used unless its imaging capabilities far surpass any of the other colloids.
• the radioactive size distribution (as determined by filtration) of SC and ReC particles are displayed in Figure 6. Note that 70% of the SC radioactive particles are within the 0.22-0.45 ⁇ m range, while only 6% are less than 0.1 ⁇ m in diameter. Compare this with ReC, which has greater than 90% of its particles less than O.l ⁇ m in diameter. ReC is a novel colloidal preparation and as such the exact size and shape of the particles had to be further characterized. A literature review revealed that transmission electron microscopy is the most appropriate technique (Bergqvist, L. et al. (1983); Ercan, M. et al. (1985); Warbick-Cerone, A. (1986)).
• Figure 18 shows the percentage of radioactivity (RA) of the injected dose that has migrated to the popliteal node and to the lymphatic channels of the lower limb.
• the clearance of RA from the injection site in rabbits varied between 13.1% for ReC to 25.3% for filtered TcSC.
• the retention of ReC localized in the popliteal node is not significantly different from the other colloids tested.
• the higher percentage of RA in the lymphatic channels of Eshima's filtered sulfur colloid and lack of preferential retention in the sentinel (popliteal) node may be disadvantageous. Ideally one wants some RA in the lymphatic channels, however not enough that it will obscure the imaging of the sentinel node.
• ReC had the lowest percentage of RA localized to the kidneys and urinary bladder [0.17 ⁇ 0.05% compared with Tc99mSC (0.46 ⁇ 0.10%), filtered TCSC (1.38 ⁇ 0.32%) and antimony (0.58 ⁇ 0.21%)], and the remainder of the body including the liver [(1.12 ⁇ 0.23% compared with Tc99mSC (1.71 ⁇ 0.52%), filtered TcSC (4.9 ⁇ 0.5%) and antimony (2.36 ⁇ 0.43%)] at two hours. This indicates that ReC remains in the lymphatic system for a longer duration of time than the other colloids before entering the blood pool.
• Figure 19 demonstrates the percentage of radioactivity at the injection site
• top graph (19A) distal lymphatic channel, popliteal node and proximal channel (bottom graph (19B)) for ReC for two hours following ID injection.
• the popliteal node is visualized within the first five minutes and the percentage of RA remaining in this sentinel node remains relatively stable for the two hour time period. In fact, 24 hour images revealed that the popliteal (as well as the inguinal nodes) are still easily visualizable. This rapid visualization of the sentinel node and the extended retention of RA have practical significance - allowing the surgical team a large window of time in which to perform the biopsy.
• EXAMPLE 9 Rabbit Lymphoscintigraphy - Entrapment Ratio
• radiolabelled colloid migrates effectively to the first draining lymph node(s). Ideally the radiocolloid does not migrate substantially into further lymphatic channels and further lymph nodes since it will increase background and lead physicians to believe there is more than just the "appropriate" sentinel node. In order to investigate this, a calculation was performed called the entrapment ratio where:
• Entrapment ratio counts in first primary lymph node
• a higher entrapment ratio is indicative of better trapping within the first node and less "leakage" from that lymph node to regions past it. Accordingly, a higher entrapment ratio would lead to less dissection of "non-sentinel nodes" and thereby result in less morbidity to the patient.
• Tc-99m Rhenium Colloid to Filtered (Eshima) and unfiltered Sulfur Colloid(TSC) and Tc-99m antimony colloid was conducted. Methods 3 anaesthetized male rabbits (crossover studies) received two 0.1 ml (18 MBq) intradermal foot injections of Tc-99m colloid and were massaged. Sequential images were performed to 2 hours. Regions of interest (ROI) were drawn over injection sites, lymph nodes, lymphatic channels and body organs. 5 Results
• Isotope SLN mapping was successful in 98% (46/47). The one mapping failure occurred in a patient with a nonpalpable lesion in which the radiocolloid was injected 30 under ultrasound guidance. The mean number of sentinel nodes was 1.7 (range 1-6). Axillary (vs internal mammary) drainage was identified in 93% of patients. In the cases where both blue dye and radiocolloid were found in the axilla, there was 92% blue dye- isotope concordance (uptake of dye and isotope by the same SLN).
• the new Tc-99m rhenium colloid of the present invention is effective in 35 sentinel lymph node mapping for breast cancer.
• SLN localization was successful in 98% of patients and this is comparable to previous studies utilizing sulfur colloid.
• the smaller size eliminates the need for filtration and thereby decreases technologist radiation exposure and product losses. A more neutral pH may induce less pain upon injection.
• EXAMPLE 11 Sentinel Node Biopsy in Melanoma Using Tc-99m Rhenium Colloid
• Tc-99m rhenium colloid of the present invention for sentinel node biopsy in melanoma patients was assessed.
• Methods Consecutive patients with stage lb or 2 melanoma diagnosed between July 1998 and July 1999 underwent preoperative lymphoscintigraphy.
• Intraoperatively, vital blue dye was injected intradermally about the biopsy scar. The gamma probe and blue stained lymphatics aided the dissection.
• follow up ranged from 1 to 13 months. Result
• Tc- 99m sulphur colloid was used in the first 14 patients, and Tc-99m rhenium colloid in the latter 16.
• Figure 23 which illustrates a typical sentinal node identified in the axilla (middle and top panel). Unpredictable drainage patterns compared with classical lymphatic anatomy occurred in 33% of patients. Localization failed in one patient injected with sulphur colloid, for an overall success rate of 97%.
• Ventilation perfusion scintigraphy can be used to provide images of a subject's lungs. It is usually performed using radioactive gases, but can also be carried out using radio aerosols. Aerosols currently used include Tc99m DTPA but suffer from problems of absorption requiring rapid imaging before absorption.
• the radiocolloid of the present invention has distinct advantages over such approaches because the smaller colloid provides better penetration into alveoli with less central deposition in the bronchial tree and is not as rapidly absorbed. Accordingly images can be obtained over a longer period after administration without a charge in biodistribution.
• the methods used to achieve lung inhalation using a radiocolloid of the invention are substantially the same as those described for inhalation of Tc-99m sulfur colloid radioaerosol (see J. Nucl. Med. 24:816-21 (1983); and Vezina et al. Clin. Nucl. Med. 10:759-766 (1985)).
• Tc 15 99m sulfur colloid (TSC) and A 198 colloid (AuC) uptake J. Nucl. Med. 16:532.
• Warbick-Gerone A Radiopharmacology of Colloidal Dispersions. Current Applications in Radiopharmacology 139-147, 1986.

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