United States Patent (19)
`Norman et al.
`
`11
`45
`
`Patent Number:
`Date of Patent:
`
`5,038,046
`Aug. 6, 1991
`
`(54)
`
`METHOD AND GENERATOR FOR
`PRODUCING RADIOACTIVE LEAD-212
`
`(75)
`
`Inventors: John H. Norman; Wolfgang A.
`Wrasidlo, both of La Jolla; Karol J.
`Mysels, San Diego, all of Calif.
`
`(73)
`
`(21)
`
`Assignee: Biotechnetics, A Brunswick
`Corporation, San Diego, Calif.
`Appl. No.: 550,468
`
`22
`
`Filed:
`
`Jul. 10, 1990
`
`(51)
`(52)
`58
`
`(56)
`
`Int. Cl. ............................................... G21G 4/06
`U.S. Cl. ................................. 250/432 PD; 423/2;
`423/89; 252/645
`Field of Search .............. 250/432 PD; 423/2, 89;
`252/645, 644
`
`References Cited
`U.S. PATENT DOCUMENTS
`3,801,828 4/1974 Hulit et al. ................... 250/432 PD
`4,663,129 5/1987 Atcher et al. ................ 250/432 PD
`
`OTHER PUBLICATIONS
`Zucchini et al., Int. J. Nucl. Med. Biol., vol. 9, No. 1,
`1982, pp. 83-84.
`Primary Examiner-Jack I. Berman
`Attorney, Agent, or Firm-Pretty, Schroeder,
`Brueggemann & Clark
`(57
`ABSTRACT
`A method and generator for preparing the radioisotope
`of lead, 212Pb, whereby 228Th, in a closed chamber, is
`allowed to decay to gaseous 220Rn which is then readily
`separated from the thorium and other decay products
`by diffusing the 220Rn gas into a second chamber, where
`it decays to 212Pb which can then be collected from the
`second chamber. The 228Th preferably is amorphous,
`such as thorium stearate. Collection of 212Pb occurs in a
`medium of high and open porosity into which the 220Rn
`diffuses so that the decay products recoil into the me
`dium. The 212Pb can be recovered from this medium by
`dissolving the medium or by reacting it with an anti
`body-chelating complex solution to entrap it in the
`antibody-chelating complex.
`
`24 Claims, 1 Drawing Sheet
`
`
`
`
`
`
`
`
`
`
`
`fSS Sy
`N7 SKN SSSZ.
`N<%
`
`N
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`AdvanCell - Exhibit 1007- Page 1
`
`

`

`U.S. Patent
`
`Aug. 6, 1991
`
`5,038,046
`
`24
`
`2Xw3%
`
`SSSSSSSSSSNSSS4
`
`32
`
`2S
`
`
`
`
`
`
`
`
`
`2XYZ
`2/
`2Z.
`N<2 Z2
`N
`
`
`
`AdvanCell - Exhibit 1007- Page 2
`
`

`

`1.
`
`METHOD AND GENERATOR FOR PRODUCING
`RADIOACTIVE LEAD-212
`
`5
`
`This invention relates generally to the production and
`isolation of radioisotopes and more particularly to a
`method and generator for producing lead 212 (212Pb)
`from thorium-228 (228Th).
`BACKGROUND OF THE INVENTION
`Radioactive isotopes have a variety of applications.
`The choice of an appropriate isotope for any particular
`use depends on such factors as its half life and the type
`and energy of the radiation produced. The usefulness of
`certain isotopes may, however, be severly curtailed by
`the difficulty of their production and isolation.
`Radiation therapy has long been used in the treatment
`of cancer and other localized lesions. The development
`of monoclonal antibodies, which can be targeted to
`specific cells with a high degree of specificity, has made
`20
`it possible to selectively deliver radioactive agents pre
`dominantly to specifically targeted cells. The choice of
`an appropriate radioactive isotope is the critical aspect
`in targeting radiation therapy. An appropriate radioac
`tive isotope should, desirably, have a half life which is
`25
`long enough to permit any necessary logistic and phar
`maceutical operations (transport, reaction, sterilization,
`etc.) prior to administration and arrival at the targeted
`cell after administration, without much loss of activity
`and damage in route, but is short enough so that thera
`30
`peutic action proceeds rapidly. Generally one also de
`sires radiation which is highly cytotoxic at short range
`so that the cell to which the antibody is attached is
`killed (as well as immediately adjacent cells that are
`likely to be also pathogenic) but harmless over longer
`distances so as not to injure healthy surrounding tissue.
`Absence of harmful persistent residues is also important.
`Many potential radioactive candidates require a cy
`clotron for production and cannot be seriously consid
`ered for regular therapeutic use because of cost and
`40
`availability reason. Of those possible candidates that do
`not need to be produced in a cyclotron, 212Bi and 212Pb
`have received considerable attention because they have
`acceptable decay form, energy, and half life characteris
`tics.
`45
`While methods for producing both 212Bi and 212Pb
`are known, most require the use of complex equipment
`having a rather short life span. One less complicated,
`long lived generator for producing both 212 Bi and 212Pb
`is shown in the literature by Zucchini et al., Intl. J.
`50
`Nucl. Med. & Bio., Vol. 9, pp. 83 to 84 (June 1982). To
`produce 212Pb in this generator, a bed of sodium titanate
`is maintained in a quartz column in which 228Th in the
`tetravalent state and radium-224 (22'Ra) can be ad
`sorbed above a coarse fritted glass disk sealed in the
`55
`column. When water is passed through the titanate,
`220Rn, which is a decay product of 22Ra, dissolves in
`the water. The water containing the 220Rn passes
`through the fritted disk and is collected in a glass reser
`voir containing 2 cc of water therebelow. Since substan
`tially all of the 220Rn decays within 5 minutes in the
`water to 212Pb, this provides sufficient delay. The water
`containing the 220Rn is passed from the reservoir into a
`column containing a strongly acidic ion exchange resin,
`such as Bio-Rad AG-50 WX18 cation exchange resin
`(Bio-Rad, Richmond, Calif.), which adsorbs 22Pb as
`the water passes through the column. After sufficient
`212Pb has been absorbed, the resin column is removed
`
`5,038,046
`2
`and the 212Pb eluted therefrom using 2N HCl to convert
`the lead isotope to PbCl3. However, residual radioactiv
`ity and contamination was reported when this proce
`dure was used, apparently due to a small amount of
`228Th and 224Raeluted. To reduce the contamination an
`additional ion exchange treatment is required.
`There thus exists a need to provide an apparatus and
`method by which certain useful radioactive isotopes
`can be efficiently and safely produced. The present
`invention satisfies this need and provides related advan
`tages as well.
`SUMMARY OF THE INVENTION
`The present invention provides a method and appara
`tus for producing radioisotopes which are formed as
`decay products from rare gases, which are in turn decay
`products of an element which can be immobilized.
`The invention provides a method of obtaining daugh
`ter isotopes produced from the decay of a parent iso
`tope via a rare gas intermediary by providing the parent
`isotope in gaseous contact with a gas permeable barrier
`impervious to the parent isotope, permitting gaseous
`intermediary isotopes to diffuse through the gas perme
`able barrier into a receiving chamber containing an
`open porosity porous medium, maintaining the gaseous
`intermediary the open porosity porous medium for a
`time sufficient to permit at least a portion of the rare gas
`intermediaries to decay into the daughter isotopes
`which recoil into and are captured by the open porosity
`porous medium and recovering from the open porosity
`porous medium a material whose principal radioactivity
`is that of the daughter isotopes. A generator for per
`forming the process is also provided.
`In one embodiment, the parent isotope is 228Th from
`which the daughter is 212Pb. The open porosity medium
`can be, for example, urea, glucose, inorganic salts, ly
`ophilized antibody or microspheres.
`BRIEF DESCRIPTION OF THE DRAWINGS
`FIG. 1 is a sectional view of a diffusion generator as
`may be utilized in the practice of the process of the
`present invention.
`FIG. 2 is a sectional view of an alternate embodiment
`of the generator as can be utilized in a preferred practice
`of the process of the present invention.
`DETAILED DESCRIPTION OF THE
`PREFERRED EMBODIMENT
`This invention is directed to a simple and inexpensive
`process and a generator for producing radioactive iso
`topes which is rapid, simple and substantially free of
`contamination. An important advantage of the genera
`tor of this invention is that the parent isotope, which
`may be highly radioactive and difficult to handle and
`long lived, is contained in a parental chamber from
`which only the short lived radon isotope can readily
`escape. On the other hand, the receiving chamber can
`be readily loaded with the open porosity porous me
`dium and the latter readily recovered therefrom when
`desired. Thus the generator can be loaded with the
`parent isotope in a facility adapted to handle high radia
`tion levels and then transported and used for a long time
`at a hospital or radio-pharmacy where only the open
`porosity medium needs to be handled.
`In one embodiment, the process and generator of the
`present invention involve the decay of a parent isotope,
`such as 228Th, within a first closed chamber to yield a
`gaseous decay product, such as 220Rn, and then allow
`
`10
`
`15
`
`35
`
`65
`
`AdvanCell - Exhibit 1007- Page 3
`
`

`

`10
`
`15
`
`5,038,046
`4.
`3
`medium is water soluble, the open porosity porous me
`ing the gaseous decay product to diffuse to a second
`closed receiving chamber, thereby effectively separat
`dium can be dissolved in water in order to obtain a
`solution whose principal radioactivity results from the
`ing the gaseous decay product from the parent and from
`daughter isotopes. Alternatively, where the open poros
`other solid decay products. The second closed chamber
`ity porous medium is lyophilized microspheres or anti
`contains an open porosity porous medium, which can be
`body, the material can be removed and utilized directly.
`water soluble, such as a bed of powdered urea or su
`Thus while in some cases the isotopes are extracted or
`crose, into the open porosity of which the radon can
`otherwise removed from the open porosity porous me
`diffuse. Decay of 220Rn to 212Pb (via very short lived
`dium, it is also intended that the porous medium, it is
`polonium-216) causes recoils which tend to embed the
`lead in the open porosity porous medium as well as in
`also intended that the medium itself, or a derivative, can
`be used without separating the isotopes therefrom.
`any other solid exposed to the radon. Because of the
`As used herein, the term "open porosity porous me
`rapid diffusion of the radon and the large fraction of the
`gas phase of the generator being within the pores of the
`dium' refers to a solid of substantial bulkiness so that
`when placed in the receiving compartment the pores
`open porosity porous medium a majority of the 212Pb is
`within this solid form an important part of the gas phase
`deposited on and within this medium. Of course, the
`within the generator and especially of that within the
`212Pb thus deposited undergoes normal radioactive
`receiving chamber. This porosity is "open" in the sense
`decay so that the amount thus made available in the
`open porosity porous medium first increases rapidly but
`that it is interconnected so that the gaseous intermediar
`ies can readily diffuse into it, preferably into most of it.
`then tends to an equilibrium value, after operation for
`Many powders when simply poured into the receiving
`several half lifes of 212pb.
`20
`chamber satisfy these requirements, as do many lyophi
`It should be noted that the amount of 22Pb (and of
`lized materials. The solid itself has sufficient density
`the other isotopes involved) are extremely minute. Thus
`such that substantially all of the recoiling daughter will
`1 mci of 212Pb corresponds to approximately 2x 1012
`be captured by the open porosity porous medium prior
`atoms of this element which is 3.3 x 1012 moles. Hence
`to reaching the side of the container defining the closed
`the handling and reacting of this lead requires special
`25
`chamber. Examples of such open porosity porous media
`precautions and procedures which are, however,
`include powdered urea, glucose or other sugars, or
`known in the art. Thus the open porosity porous me
`inorganic salts; lyophilized antibodies or microspheres.
`dium can be dissolved in the presence of mild complex
`In addition, the open porosity medium must satisfy
`ing agents and of traces of "cold" (i.e. non-radioactive)
`chemical and biological requirements depending on the
`lead, prior to the conjugation reaction with the desired
`use of the daughter isotope, such as being soluble or
`antibody. It may then be removed by dialysis or ultrafil
`dispersible in water, being separable from the antibody
`tration and the retentate sterilized and used. On the
`conjugate, being free of objectionable impurities, partic
`other hand, if the open porosity porous medium is
`ularly other heavy metals, and the like. Such require
`formed by lyophilized fine latex solids, these may be
`ments will vary with the particular utilization desired.
`redispersed in water, conjugated with the antibody and
`Among solids which form suitable open porosity
`injected, with the 212Pb embedded in them.
`porous media are urea, particularly the ultra-pure grade
`As used in the practice of the present invention, the
`228This in a physical form that does not create a major
`obtainable from ICN Biochemicals, of Irvine, Califor
`nia, glucose, and sodium chloride, as well as lyophilized
`barrier to the diffusion of the 220Rn gas formed as the
`228Th decays, and preferably is amorphous or micro
`materials such as proteins, antibodies, latexes and other
`particles.
`crystalline. As the quantity of 28Th required is ex
`Microspheres as used in this invention are spheres of
`tremely small, it will normally be diluted with a carrier
`less than 10 um in diameter and more than about 0.02
`for ease of handling and to dilute radiation damage
`um, generally made from polymers such as polystyrene,
`produced by its decay. Alkaline-earth compounds, par
`polymethyl-methacrylate, available commercially as
`ticularly barium salts are a preferred diluent because of
`45
`aqueous dispersions. Lyophilization is a process by
`their chemical similarity to thorium. Among such salts,
`those of the higher aliphatic acids, particularly stearate
`which solvent, such as water, is removed from a frozen
`solution or dispersion by sublimation of the solvent. In
`and palmitate are preferred as these are known to
`order to facilitate the redispersal of the solute, a wetting
`readily release the radon as it is produced (they have
`high "emanating power”) as described by A. C. Wahl
`agent such as Triton 100 can be added.
`50
`Although the invention can be used to generate vari
`and W. R. Daniels, J. Inorg. Nucl. 6:278-287 (1958),
`ous isotopes as long as they decay through a gas phase
`which is incorporated herein by reference.
`Alternatively, 228Th compounds can be ground into
`intermediary, the invention will be described with par
`ticular reference to producing 212Pb from 228Th. Gener
`super fine particles which are dispersed in a matrix
`ating 212Pb from 228Th as taught by the present inven
`selected from the group consisting of similarly pow
`55
`tion provides a quick, on-site generation and isolation of
`dered graphite, alumina, and inert ceramic.
`a high purity product. The process and generator of the
`As used herein, the term "gas permeable barrier'
`present invention produces 212Pb simply, efficiently,
`refers to a chemical or physical barrier which would
`and economically in a most desirable form that can be
`serve to constrain the immobilized parent isotope but
`used in any desired application.
`which is permeable to the gas phase intermediary. Ex
`The complete sequence of the spontaneous radioac
`amples of such barriers include layers of open-porosity
`tive decay of 228This shown in Table I. For the purpose
`solids such as stainless steel (or other metal) screens or
`sintered powder, ceramic porous discs, porous plastics,
`of this invention this can be simplified to the following
`microporous membranes.
`scheme
`As used herein, "recovering' as it refers to the de
`65
`sired daughter isotopes means obtaining the daughter
`isotopes either with or from the open porosity porous
`medium. For example, where the open porosity porous
`
`*Thys-9Ra in Yi-Pb is
`
`30
`
`35
`
`AdvanCell - Exhibit 1007- Page 4
`
`

`

`5
`-continued
`
`5,038,046
`
`6
`TABLE I-continued
`Half Life
`Radiation
`Alpha
`Alpha
`Beta
`
`3 x 107 Sec.
`3. Minutes
`(Stable)
`
`Energy (Mew)
`gy
`6.05
`8.78
`1.42
`
`Isotope
`p
`
`22 Po
`T
`208Pb
`
`22p;
`Bi
`
`208
`se
`Pb
`stable
`
`5
`
`5
`
`indicating the main isotopes and their approximate half
`lives. During each indicated decay alpha, gamma, and
`in some cases, beta radiations are produced (except in
`the decay of 212Pb which produces only betas and gam
`mas). The therapeutic potential of 212Pb (or its daughter
`10
`212Bi) is due mainly to its providing alpha particles of
`about 6 and 9 MV energy which correspond to some 40
`and 90 um penetration in tissue i.e., killing some 4 to 8
`cells. This characteristic permits reaching not only the
`cancer cells corresponding to the antibody used but also
`other cells which do not respond but are in close vicin
`ity. On the other hand, healthy cells, not in the immedi
`ate vicinity of the target ones, are not affected by these
`alpha particles. While the 10.6 hour half life of 22Pb
`20
`before decaying is perhaps on the short side of ideal for
`uses such as cancer therapy, it is a very acceptable
`length of time to allow for production and purification
`of the therapeutic complex, administration of the com
`plex to the patient, and time of exposure to the cancer
`25
`cells.
`Thorium-228 has a half life of almost two years and is
`available commercially which makes it highly desirable
`as a parent isotope. The raw material for charging the
`parental chamber of the generator of this invention is
`thus readily obtained and once charged, the generator
`could be used for a year or more with only gradual loss
`of productivity.
`Radon-220 being a rare gas will, if allowed, rapidly
`diffuse away from the thorium and other solids of the
`35
`parental chamber. With a half-life of only about a min
`ute, it decays to give the desired 22Pb. In order to
`utilize the radon efficiently it is desirable that as much
`of its decay as practicable occur within the open poros
`ity porous medium. This is facilitated in two ways ac
`cording to the preferred embodiment of this invention.
`1) The thorium is in a matrix having high emanating
`power. The distance between the parent source and the
`receiving open porosity medium is made short. The
`porous membrane separating the two chambers has a
`45
`large area, high porosity and slight thickness.
`2) The volume of the parental chamber is made as
`small as practicable compared to that of the pores of the
`open porosity porous medium. A stable gas will distrib
`ute itself proportionately to the available gas-phase
`volumes. As radon is being generated and is decaying,
`its concentration is decreasing from the source to the
`distal end of the open porosity medium, and diffusion
`continuously proceeds in this direction. Experiments
`showed that little is gained by making the receiving
`chamber much longer than about 1 cm as most of the
`radon would decay before diffusing much longer dis
`tances. By using a shorter column of the open porosity
`medium one can obtain a smaller amount but a higher
`concentration of the daughter isotope and vice versa.
`TABLE I
`Radiation
`Alpha
`Alpha
`Alpha
`Alpha
`Beta
`Beta
`
`A generator which can be utilized in the practice of
`this invention is illustrated in the Figures. The genera
`tor can be remotely manipulated in a closed shielded
`chamber or can be handled in a glove box. As shown in
`FIGS. 1 and 2, the generator comprises a parental
`chamber 10, a receiving chamber 12, and a gas elute
`means such as gas permeable membrane 14 interposed
`between and separating the two chambers 10 and 12.
`The gas permeable membrane 14 must have a pore size
`sufficient to permit the rapid diffusion of the gaseous
`intermediary therethrough while, at the same time,
`preventing the parent isotope from passing into receiv
`ing chamber 12. For safety purposes, diffusion men
`brane 14 preferably comprises a porous support member
`such as a fritted metal disk which can be made from
`stainless steel. The generator shown in FIG. 1 is formed
`by a threaded tubular housing 20 having one end
`thereof closed by end cap 22, which is held in place by
`flanged cap nut 24. The interior portion of tubular hous
`ing 20 has an internal flange 26 at one end thereof which
`encircles the interior cylindrical surface, and against
`which the diffusion membrane 14 is positioned. Diffu
`sion membrane 14 should be spaced from end cap 22 by
`a small distance sufficient to form parental chamber 10
`between end cap 22 and the diffusion membrane 14.
`Parental chamber 10 should be small compared to re
`ceiving chamber 12 as indicated above. The volume of
`receiving chamber should be at least 5 times and prefer
`ably 20 times larger than the volume of the parental
`chamber.
`Bushing 28 is threaded into the other end of tubular
`housing 20 such that its circular inner edge holds diffu
`sion membrane 14 against flange 26, thereby defining
`one end of a smooth interior cylindrical chamber. An
`elongated end cap 30 is slidably inserted into the cylin
`drical chamber within bushing 28 so as to form collec
`tion chamber 12 between diffusion member 14 and the
`inner end of end cap 30. Flanged nut cap 32 is threaded
`onto bushing 28 to hold end cap 30 in place. For safety
`reasons, all of the structural components of generator 8
`are preferably fabricated of a material that will not
`absorb the 220Rn gas or be decomposed by radiation,
`and has a melting point in excess of 1,000 C. for fire
`safety. A particularly preferred material is 316 stainless
`steel.
`In accordance with the preferred practice of this
`invention, the starting material, i.e., 228Th, is used in a
`physical form that does not create a barrier to the diffu
`sion of the 220Rn gas formed as the 228Th decays. For
`example, 228Th can be obtained commercially in the
`form of thorium-228 nitrate (from Isotope Products
`Laboratories in Burbank, Calif.). Wahl and Daniels,
`Supra, teach the coprecipitation of 228Th and barium
`Stearates. Their procedure involves heating aqueous
`solutions of sodium stearate to "60-75' degrees centi
`grade. This causes problems with vapor condensation in
`a usual, unventilated, glove box. Any ventilation must
`insure the decay of 228Rn which is continuously pro
`duced and is not adsorbed by conventional filters.
`Therefore, according to this invention, spiked barium
`
`30
`
`50
`
`55
`
`60
`
`65
`
`Isotope
`228Th
`2-Ra
`220Rn
`216Po
`212Pb
`212Bi
`
`Half Life
`1.9 Years
`3.6 Days
`54.5 Seconds
`0.15 Second
`10.6 Hours
`60.5 Minutes
`
`Energy (Mev).
`8.4
`5.68
`6.28
`6.77
`0.35
`2.24
`
`AdvanCell - Exhibit 1007- Page 5
`
`

`

`10
`
`15
`
`20
`
`5,038,046
`8
`7
`portion thereof. The body is externally threaded on the
`stearate is produced by a metathetical reaction in solu
`upper and lower portions. The gas permeable mem
`tion between barium nitrate and a stearate which is
`brane 14 rests against the lip formed where the cylindri
`soluble at room temperature such as tetramethyl ammo
`nium stearate. The latter is in turn produced by reaction
`cal chamber in body 110 increases in diameter, thereby
`separating the cylindrical chamber into a parental
`of tetramethyl ammonium hydroxide with stearic acid.
`Tetra ethyl ammonium hydroxide or the tetra butyl or
`chamber 10 and a receiving chamber 12. To obtain the
`tetra isopropyl compounds may also be used.
`desired spacing for parental chamber 10, a seal ring 120
`The tetramethyl ammonium stearate solution is pre
`of appropriate thickness may be placed on top of diffu
`pared outside the glove box by heating an excess of
`sion membrane 14. A seal 130 is then slidably inserted
`stearic acid with a tetraethyl annonium hydroxide
`into the upper portion of the body, where it is held in
`solution and adding the latter until phenolphthalein
`place against seal ring 120 by seal cap 140 which is
`indicator turns pink. In the glove box, the 228Th solu
`threaded onto the upper portion of the body. An elon
`tion is added to a barium nitrate solution and the excess
`gated plunger 150 is slidably inserted into the aperture
`nitric acid (accompanying the thorium) is neutralized
`in the bottom portion of the plunger body 110 so as to
`with tetraethyl ammonium hydroxide. Then, with good
`provide collection chamber 12 between the diffusion
`stirring, the stearate solution is added gradually to the
`membrane 14 and the inner end of plunger 150. Plunger
`barium spiked solution. The precipitate flocculates near
`150 is held in place by plunger cap 160 which is
`the equivalence point and near neutrality. It is then
`threaded onto the lower portion of plunger body 110.
`filtered, sucked dry and placed with the filter in the
`As before, all of the structural components of reactor
`parental chamber of the generator and dried over silica
`100 are preferably made from 316 stainless steel. How
`gel. The parental chamber is then closed.
`ever, since seal ring 120 must be compressible in addi
`If the receiving chamber is also closed, i.e., both
`tion to having a high melting point, it is preferred that it
`plungers 22 and 30 are inserted and secured with end
`be made from materials such as gold, copper or nickel.
`caps 24 and 32, the escape of radon from the generator
`While the above described process is specific to the
`is prevented and it can be removed from the glove box
`25
`use of the generator as illustrated, and describes the best
`and stored in any appropriately shielded space or trans
`mode known for the practice of the invention, it should
`ported to another laboratory or hospital.
`be apparent that other procedures could be utilized and
`The generator is ready to produce the daughter iso
`other reactor embodiments fashioned to produce the
`topes whenever the receiving chamber is loaded with
`lead isotope, relying on the same or comparable princi
`the open porosity medium and closed. This can be done
`ples to effect the objects of this invention. For example,
`in a chemical hood or a more sophisticated containment
`while the above described reactor utilizes a diffusion
`as the amount of radon escaping in the short time re
`membrane to separate the two adjacent chambers, it is
`quired, is minimal. Once closed, the generator can be
`apparent that the reactor could be designed such that
`stored in s shielded place. After a time necessary for the
`the two chambers are physically separated from each
`desired amount of 212Pb to accumulate, the reactor is
`35
`other and connected by a passageway through which
`taken back into the hood, the receiving comportment
`the gaseous product could diffuse without permitting
`opened and the open porosity porous medium removed
`transfer of any solid material, e.g., a stopcock. Thus,
`and a material containing the daughter isotope recov
`when the stopcock is opened, the gaseous 220Rn diffuses
`ered, such as by pouring the open porosity porous me
`from parental chamber 10 into the collection chamber
`dium into an aqueous solution of a mild complexing
`12. It is apparent that other such modifications could be
`agent for lead. The receiving chamber is then reloaded
`made to the process and reactor without departing from
`if desired and closed. After a short time, Sufficient for
`the spirit of the invention.
`the radon released upon opening the receiving chamber
`Although the invention has been described with ref.
`(and that contained in the open porosity medium) to
`erence to the presently preferred embodiment, it should
`decay adequately, the solution can be removed from the
`45
`be understood that various modifications can be made
`hood and used for the preparation and administration of
`without departing from the spirit of the invention. Ac
`a therapeutic product.
`cordingly, the invention is limited only by the following
`Alternatively, the 228Th used in the present invention
`claims.
`can be a physical mixture in which a 228Th salt has been
`What is claimed is:
`ground into extremely fine particles to destroy its mac
`50
`1. A method for obtaining daughter isotopes pro
`roscopic crystal structure, and the super fine particles of
`duced from parent isotopes by a chain of spontaneous
`228Th are dispersed within a porous matrix, such as, for
`decay which includes a normally gaseous intermediary
`example, similarly powdered graphite, that will not
`isotope, comprising the steps of:
`absorb the 220Rn gas. The mixture can be compacted so
`(a) providing said parent isotope in gas phase contact
`that the 228This encapsulated within the graphite and
`55
`with a gas permeable barrier impervious to said
`forms a graphite disc 40 as shown in FIG. 2. This em
`parent isotope;
`bodiment gives the 228Th sufficient bulk for handling
`(b) permitting said gaseous intermediary isotope to
`purposes while allowing for the even diffusion of radon
`diffuse through said gas permeable barrier into a
`gas while preventing the formation of thorium crystals.
`chamber containing an open porosity porous me
`Other inert materials which allow free diffusion of the
`20Rn gas therethrough and are not subject to important
`dium;
`(c) maintaining said gaseous intermediate in said me
`decomposition by radiation may be used to form such a
`porous matrix for the 228Th, including but not limited to
`dium for a time sufficient for at least a portion of
`said gaseous intermediate to decay to said daughter
`alumina and inert ceramic.
`isotopes are captured by said open porosity porous
`An alternate embodiment for the reactor of the pres
`65
`medium; and
`ent invention is shown in FIG. 2. The reactor 100 essen
`tially comprises cylindrical body 110 whose cross sec
`(d) recovering said daughter isotopes from said re
`ceiving chamber.
`tion is in the form of a cross which is wider at the upper
`
`30
`
`AdvanCell - Exhibit 1007- Page 6
`
`

`

`5
`
`O
`
`15
`
`30
`
`5,038,046
`10
`9
`which 212Pb recoils into and is captured by the
`2. The method of claim 1, wherein said parent isotope
`open porosity porous medium; and
`s
`is maintained in a first closed chamber.
`(d) recovering the 212Pb from said receiving cham
`3. The method of claim 1, wherein said recovery step
`ber.
`comprises dispersing said medium in water.
`15. The method of claim 14, wherein said parent
`4. The method of claim 1, wherein said recovery step
`isotope is in the form of a long hydrocarbon carboxylic
`comprises dissolving said medium in water.
`acid salt.
`5. The method of claim 1, wherein said open porosity
`16. The method of claim 14, wherein said long hydro
`porous medium is urea.
`carbon carboxylic acid is selected from the group con
`6. The method of claim 1, wherein said open porosity
`sisting of stearic acid, palmitic acid, Sebacic acid, ca
`porous medium is glucose.
`proic acid, lauric acid and myristic acid.
`7. The method of claim 1, wherein said open porosity
`17. The method of claim 14, wherein said immobi
`lized parent isotope is dispersed in a matrix of super fine
`porous medium is an inorganic salt.
`particles comprising charcoal, graphite inert ceramics
`8. The method of claim wherein said open porosity
`porous medium is lyophilized antibody.
`and alumina.
`18. The method of claim 14, wherein said permeable
`9. The method of claim 1, wherein said lyophilized
`barrier is a membrane.
`antibody is conjugated to a chelating agent.
`19. The method of claim 14, wherein said open poros
`10. The method of claim 1, wherein said open poros
`ity porous medium is urea.
`ity porous medium is lyophilized microspheres.
`20. The method of claim 14, wherein said open poros
`20
`11. The method of claim 1, wherein said immobilized
`ity porous medium is glucose.
`parent isotope is in the form of a long hydrocarbon
`21. The method of claim 14, wherein said open poros
`carboxylic acid salt.
`ity porous medium is a chloride.
`12. The method of claim 11, wherein the long hydro
`22. The method of claim 14, wherein said open poros
`carbon carboxylic acid salt is prepared by a metathetical 25
`ity porous medium is lyophilized antibody.
`reaction from a second salt of said long hydrocarbon
`23. The method of claim 14, wherein said lyophilized
`antibody is conjugated to a chelating agent.
`carboxylic acid which is freely soluble in water at room
`24. A generator for preparing radioisotopes produced
`temperature.
`from the decay of a parent isotope via a rare gas inter
`13. The method of claim 12, wherein said second salt
`mediary comprising:
`is selected from the group consisting of tetramethyl,
`a parental chamber for immobilizing the