CA2248076A1 - Polymeric delivery of radionuclides and radiopharmaceuticals - Google Patents

Abstract

Locally deposited polymer depots are used as a vehicle for the immobilization and local delivery of a radionuclide or radiopharmaceutical. Radionuclides are incorporated in their elemental forms, as inorganic compounds, or are attached to a larger molecule or incorporated into the polymer, by physical or chemical methods. Ancillary structure may be employed to control the rate of release. Standard radionuclides which have been used for local radiotherapy may be used, such as radionuclides of iodine, iridium, radium, cesium, yttrium or other elements.

Description

Wo 97l33628 PCT/US97102075 POLYMERIC DELIVERY OF RADIONUCLII)ES
AND RA~IOPHARMACEI~TICALS

Background of the Invention This relates to an improved method of local radiotherapy, and 5 devices and compositions for accompli~hing local radiotherapy.
Radiation has been used for cancer therapy and to control local healing in areas as diverse as preventing excessive scar formation or reducing lymphoid infiltration and proliferation. More recently, radiation has been used to inhibit restenosis following coronary artery or peripheral 10 artery angioplasty. Interstitial radiation by use of radioactivity incorporated into intravascular stents, delivery of radiation dose by use of catheters cont~ining radioactive sources, and external beam radiollleldl)y have been used.
There are disadvantages to each of these approaches. When 15 radiation is delivered by an extracorporeal beam, the usual problems of limiting the exposure only to those tissues inten(lecl to be affected are encountered. Moreover, doses must often be subdivided, requiring more than one visit to the hospital by the patient. If radiation is to be delivered by a catheter or other temporarily-installed medical device, then the rate 20 of delivery of radiation from the device must be high. The active source will normally require careful shielding, even if relatively "soft" radiation, such as beta rays, is used. If ~tlmini.~tered in the same operation as balloon angioplasty or cardiac bypass, extra complications of an already complex and risky procedure are m~gnified Delivery of radiation on a 25 perm~n~oI tly implanted device, or a biodegradable device that n~cess~rily is eroded over a long period of time because it also provides structural ~ support, severely limits the choice of radioisotope because of the need to limit the total delivered dose to the tissue, while simlllt~neously providing sufficient initial dose to achieve the required effect. Moreover, repetition 30 of the ~-lmini~tration, if required, is not readily achieved.

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The object of this invention is to provide an improved-method for localized radiotherapy for the cure or alleviation of medical conditions.

Su~ of the Invention Locally deposited biodegradable polymer depots are used as a vehicle for the immobilization and local delivery of a radionuclide or radioph~ ce~ti~1. Radionuclides are incorporated in their elemental forms, as inorganic compounds, or are att~h~od to a larger molecule or incorporated into the polymer, by physical or çhemi~1 methods.
Ancillary structures may be employed to control the rate of release. The depot is preferably made of a biodegradable material which is selected to degrade at a known rate under conditions encountered at the site of application. The depot is preferably fluent, or capable of being made fluent, so that it may be deposited at a site in a conforming manner by minim~lly invasive means. Examples of such materials are melted polymers which re-solidify at body temperature, and polymerizable materials which are polymerized at the site of deposition. The depot optionally is provided with means for controlling the rate of release of the radioactive compound. These means may include microparticles in which the radioactive compound is incorporated.
The use of the polymeric depots provides a way of irnmobilizing the source of energy from a radioactive source at a remote site within the body, which can be accessible by a less invasive surgical procedure, such as by c~th~ter or laparoscopy. The duration and total dose of radiation can be controlled by a combination of choice of the radionuclide, control of the rate of degradation of the polymer, and control of the rate of release of the radionuclide from the depot. Following polymer degradation and/or release of the radionuclide, excretion from the body in urine and stool can be favored by ~dmini~tering ph~rm~eutir21 agents which favor excre~ion. For example, in the case of iodine radionuclides, excretion can be favored by blocking thyroid uptake of radioactive iodine or iodinated compounds by systemic ~lmini~tration of non-radioactive iodine compounds, such as sodium iodide or Lugol's solution.

Detailed Descl;p~ion of the Invention The polymeric depots provide a method of delivery of a S radioactive agent to a local site of disease for treatm~nt, such as for prevention of restenosis following angioplasty. The method has advantages over other methods of local radiation delivery in all applications, because the duration and illlensily of the exposure can be altered by choosing radionuclides of differing physical half-life, and the biological half-life can be controlled by acceleMting or l~L~fdhlg the rate of release of the radion~c~ e from the polymeric matrix. This provides a way to control local dosage of radiation without the need for physical removal of the implanted radionuclide. Radioactivity can thus be applied at any site in the body that is ~cce~ible by a less invasive procedure or c~thPter, for example, to a coronary artery or a tumor arterial supply.
This also allows the application of inle~ ial, implanted radiotherapy while rninimi7ing the exposure of the opc.~tor to radiation that is som~times n~cçcs~ry when using other currently available methods of providing local radiotherapy.
Polymers Polymers for forming the depot must be biodegradable, i.e., must dissolve into small molecules which can be removed by normal metabolic functions and/or excretion, under the conditions found at the site of application of the depot. In one aspect, the polymers may be slowly soluble under body conditions, for example, certain poloxamers, such as Pluronic ~ F-68 (a polyethylene glycol-polyethylene oxide block copolymer lllal~L~d by BASF), which gel at body temperature and slowly dissolve over several days. In another aspect, the fluidity of the polymers is altered using temperature. For example, polymers can be melted by heating or by cooling (e.g., with PluronicsTM), and applied to the site, where the polymer will re-solidify. Depot formation can also be wo 97/33628 PCT/US97/02075 caused by other known means of coacervation, such as compl-exation of polymers with ions (e.g., alginate with calcium), direct coacervation of polymers (e.g., polyglut~mic acid with polylysine), and exsolvation of polymers by diffusional removal of non-water solvent molecules.
Degradable linkages in the polymers include esters, orthocarbonates, anhydrides, amides and peptides, acetals, phosphazane linkages, and Schiff base adducts. Examples of groups forming suitable ester linkages include hydroxy acids, such as lactic, glycolic, hydroxybutyric, valerolactic and hydroxycaproic. Examples of anhydride-forming groups include oxalic, malonic, succinic, glutaric, adipic, suberic, azelaic sebacic, maleic, fumaric and aspartic. Examples of carbonate-forming ccl.llJoullds include trimethylene carbonate.
In another aspect, the polymers may be cros~lin~hle in situ.
Cros~linking may be by any suitable çh~mir~l means. If chemically crosslin-k-ed~ at least one of the polymer and the linkage formed must be biodegradable. Examples of biodegradable linkages include Schiff bases, anhydrides, ~li.c~lf1~les, and acetals. Examples of other linkages, not nPcess~rily biodegradable, include epoxy (oxirane) groups, uletllalles, ester, ethers, amides, and sulfones. Linkages involving carbon-carbon double bonds may be formed by a variety of means, including the polymerization of ethylenically-unsaLuldted groups. These may include (meth)acryl, vinyl, allyl, styryl, cinnamoyl, and alkenyl groups. Such reactions can be inhi~ted by thermal, rht~mir~l, radiative or photoch~mi~l means. It is known that most ch~omir~lly crosslink~ble groups and molecules will tend to crosslink in the presence of radioactive materials, and are preferably mixed with radioactive materials just before application.
In another aspect, the biodegradable polymer is dissolved in a solvent other than water (an "organic" solvent, broadly construed to include any biocompatible non-aqueous solvent) and deposited at the site, and precipitated as the organic solvent diffuses away from the site, forming a depot. The organic solvent must not cause undue damage to the tissue at the site. This will vary, depçn~ling on the tissue-and on the condition to be treated. In many applications, ethanol, isopropanol, mineral oil, vegetable oil, and liquid silicones may be suitable.
The biodegradable polymer, and any solvent or adjuvant included S in the composition, must further be sufficiently biocompatible for the purposes of the therapy. A biocompatible material is one which arouses little or no tissue reaction to its implantation, and where any reaction is of limited extent and duration. The extent of irritation which is tolerable, or which will be elicited, depends on the site of application. For example, 10 many polymers are minim~lly irritating on the skin, or within the digestive tract, while only a few polymers are acceptable in the peritoneum. Many materials of high biocompatibility (minim~lly irritating) are non-ionic and, after application, contain few reactive or potentially reactive groups. Plefe.lt:d examples of such materials are 15 poly(alkylene oxides), such as polyethylene glycols, poloxamers, meroxapols and the like.
The depot formed by local deposition of an al,pl~liate biodegradable polymer, normally in combination with the radioactive material at the time of deposition, will be structured to release the 20 radioactive material in a known and predictable manner during biodegradation of the depot. The combined effects of radioactive decay and of controlled release will determine the total energy deposited into the target tissue. Numerous means are known for controlling the release rate of a material from a depot. These include diffusion of the material 25 through a solid polymer; diffusion of the material through pores in a polymer, or in a gel formed from the polymer; burst release of a material on rupture of a compalllllent; exposure of material to the environment due to erosion of the polymer; slow dissolution of material from a solid form which is m~int~inP~ in place by the polymer; release of diffusional 30 restrictions on a material by degradation of a solid polymer, a polymeric coating or a gel; release of a material from a degradable linkage to a polymer, or to a carrier material contained in or on a polymer; and ..

de-binding of a reversible association between a material and a polymer, or a carrier material contained in or on a polymer. Combinations of such means may be used to obtain an optimal release profile. For example, a small radiolabelled molecule may be embedded in a degradable 5 microsphere, from which it is slowly released by a combination of diffusion and degradation of the microsphelcs. The microspheres in turn are restrained at the site of therapy by a polymeric gel formed in situ, which itself provides minim~l diffusion bal,itls and further gradually degrades. Selection of the relative degradation rates of the gel and of the 10 microspheres will influence the total radiation dose a-l"~ e,ed to the site of therapy. As used herein, microspheres includes microparticles, microcapsules, liposomes, lipid particles, and other form~ tions of similar size and function.
Radioactive materials Any r2(1io~ctive material may be used. Standard radionuclides which have been used for local radiotherapy may be used, such as radionuclides of iodine, iridium, radium, cesillm, yttrium or other elements.
P,erelred radioisotopes are those which have a particle range in 20 tissue which is concordant with the thirl~n-os~ of the layer of tissue to be treated. Information on particle ranges is readily available. For example, it is known that about 90% of the energy from a 14C (carbon-14) source will be absorbed in about the first 70 microns of tissue, and similar t~nres will be found for sulfur-35 and phosphorous-33, since their 25 emitted particles are of the same kind as 14C (beta particles) and of similar energies. More enelgel-c beta particles would have a longer range, such as those of phosphorous-32, which has a m~ximllm range of about a centimeter and thus can be used to treat thicker tumors, or blood vessels having multi-millimPter thick medial layers. Very high energy emissions, 30 whether of beta particles or of other forms, are generally less pler~llcd because their emissions may exit from the body, thereby causing shielding problems.

The radioisotope must be ar1mini.~tered in a ph~ rel~fir~lly acceptable form. The form must be biocompatible, as described above.
The form must also be capable of rem~ining at the site of application for a controlled length of time, in combination with a means for control of 5 local delivery. For example, the radioisotope could be in the form of an element, an inorganic compound, an organic compound, or ~ rh~d to a larger molecule, such as a polymer. In the last case, incorpoMtion could be into a backbone group; as a side group, preferably covalently bonded;
or as a ligand, bound to a suitable binding group on the polymer. A
10 binding group could be a non-biological binding group, such as a chelator for metal ions; or a biological group for binding, such as avidin for biotin. Likewise, the polymer could be biological, such as a protein, a polysaccharide or a nucleic acid; or it could be ~yllLhtlic, such as a polyalkylene glycol or a poly(meth)acrylate.
Immobilization of Ions in a Gel Radioactive ions can be directly immobilized in a gel. In one embodiment, they may be locally converted to a low-solubility salt form, for example by precipitation with an ap~)lopliate salt, e.g., as calcium phosphate, or as a ligand on a polymer, or as a cofactor bound to a biological molecule.
In a prefe.led embodiment, radioactive ions are immobilized in a gel by chelation. A chelator can be covalently immobilized in a gel. The covalently linked chelator ('host') in turn can immobili_e the m~t~llic ion ('guest').
Polymeri7~hle macromers or small molecules can be synthPsi7ed bearing an aL,~lo~,idLe chelator connected to the backbone. An example of a suitable molecule would be one which has one end(s) of the central backbone (e.g., a polyalkylene oxide, such as polyethylene glycol (PEG) or polypropylene oxide/polyethylene oxide (PPO/PEO) bearing a chelator, optionally a~ .hPd through a spacer group such as a hydroxyacid. The other end(s) of the PEG backbone would carry a polymerizable bond, with or without spacer groups. This ~ uhes a backbone having two or .. .... .. . . . .. . .

more functionalizable ends.~ The presence of the backbone is-optional; a shPl~ting group could be directly coupled to a reactive group, such as an acryl, allyl or vinyl group, which would participate in the formation of a gel.
An example of a chelator ('host') is the polyazamacrocycle cyclam 1,4,8,11-tetra azacyclo tetr~tlec~nr which is know to form thermodyn~mir~lly and kinrtir211y stable complexes with Tc-99m ('guest'), a metal ion used for m~(lir~l applications.
An example of a guest is ter~ el;,.",-99m, a ~-emitter for clinical applications, which emits only ~-radiation, has a low radiation energy and a short half-life of only 6 hrs. Tc-99m can be used for monilu~ g physiological changes using scintigraphy, a highly sensitive y-radiation-based trclmiqlle used in most hospitals.
These chelator-bearing Illaclolllonomers can be delivered as solutions and 'gelled' in the target site using polymerizable crosslinkers (e.g., PEG with acrylate endgroups linked to the PEG by biodegradable spacers)). The degradation and other physical l.lvpelLy of the resl-lting hydrogel can be tailored to desired specifications.
The signifir?nre of such a gel is that:
1. Such hydrogels can be formed in si~u and can bear a y-emitter or other m~flir~lly useful isotope for various mr~ic~l applications.

2. Since databases for various chelators are available from literature, it is strai~h~ vdrd to find an a~ropliate chelator to selectively immobilize a particular metal ion within a hydrogel.
2~ 3. Other possible applications of the concept include localized delivery or immobilization of mrrlic~lly useful nuclides, localized delivery of physiologically beneficial (and therapeutic) metal ions or other charged specles.
Medical Applications Applications of this technology include the local tre~tmPnt of tumors, cancer, and other ullw~ d growths (e.g., atheromae, papillae);
inhibition of scarring or healing to prevent excessive scar formation or keloid forrnation; preservation of surgically-created conduits,-for example inhibition of healing over of the sclera following a filtration procedure for glaucoma; prevention of fibrosis and of capsule formation; and prevention of restenosis following angioplasty.
Methods of Application The local depot can be placed at the site to be treated by any of several methods. For external application, a preformed depot can be applied and secured by a~pro~liate adhesives. An external application would also require al,pro~liate means for prevention of migration of the radioactive material. For internal applications, the depot-forming polymer, preferably in combination with the radioactive material and any required excipients, accessory materials, and drug delivery means, is typically aflm~ le~;d in a fluent form to the site of application by a delivery device, and caused or allowed to solidify at the site. Delivery devices can include pelcuL~Ieous means such as catheters, ç~nm~ , and needles; or means applied through natural or surgically created openings or through temporary oye~lhlgs, such as those created by trocars, using syringes, brushes, pads, or brushes. Similar means are used to apply any stimuli required to form the depot from the fluid polymer materiah For example, light may be brought to a remote site via an optical fiber, or a device similar to a laparoscope, to cause polymerization in a depot, or a chPrnic~ could be applied by means similar to those used for the depot-forming mixture.
Dose control The method provides three ways of controlling the total dose delivered to a site, while simultaneously controlling exposure to other areas of the body. First, the total amount of isotope can be varied.
Second, the half-life of the isotope can be selected; this provides an upper limit of the applied dose. Third, the lifetime of the radioisotope in the local delivery depot can be controlled.
For example, if the radioisotope is a macromolecule, then the depot could be a gel, and the rate of release of the macromolecule from the gel can be controlled by making the gel sufficiently dense-so that the macromolecule is released only as the gel degrades. Such gels are known; for example, the gels described by U.S. Patent No. 5,410,016 to Hubbell et al. are suitable.
If the radioisotope is a small molecule, rather than a macromolecule, its rate of release can be controlled by embedding it in a solid bioerodable material, such as polylactide, polycaprolactone, a polyanhydride, or a polymerized biomaterial, such as protein. Then the small molecule is released by a combination of diffusion through the material, and erosion of the material, each of which is adjustable.
Alternatively, the rate of release of a radioisotope may be regulated by selecting the ~t~ lh of interaction of the molecule with its e~ on,llent.
For example, if both the molecule and the depot are relatively hydrophobic, then the molecule will diffuse out of the depot relatively slowly. If it is not practical to make the depot hydrophobic, then the molecule can be included in more hydrophobic microparticles, such as polymeric miclopallicles~ liposomes, emulsions, etc., which in turn are embedded within a hydrophilic depot.
The present invention will be further understood by reference to the following non-limiting examples.
F.Y~nple 1: Immobilization of a radionuclide in an interfacially fl~p~ite(i gel.
A radionuclide (l25I or ~31I or other radionuclide) is deposited in an interfacial hydrogel following angioplasty, either coronary or peripheral, or intravascular stent placement, or carotid artery stent, or an arterectomy. The incorporated radionuclide is chosen to provide a total of exposure of at least 1500 cGy to the arterial wall. The delivered dose is adjusted by choosing the amount of incorporated radionuclide and is further controlled by choosing a formulation of hydrogel with a dirr~rellL
persistence at the site of deposition. The duration of exposure at the site of deposition can be controlled by adjusting the biodegradable moieties of the hydrogel or by ch~nging the density of crosslink of the polymer at the site.
.Y~ le 2: Local radiotherapy from a polymer ~pr~ l via cath~ lion.
S Local radiotherapy can be applied to any tumor which is a~cessihle by a vascular cathe~er. This technique is particularly applicable to either highly vascularized tumors or tumors which have a single d~
arterial vascular supply. This would provide a method for tre~tm~ont particularly applicable to renal cell carcinoma, hepatoma, sarcomas, cancers of the head and neck, and central nervous system tumors. In this example, radioactive microspheres cont~ining yttrium-90 are incorporated in a hydrogel that is deposited in the artery supplying a tumor. The local tumor volume in the area of deposition is radiated while the microspheres are immobilized at the site of deposition. On degradation of the hydrogel, the microspheres are released and redeposited in the distal microcirculation, where they provide continued radiation treatment. The exposure at the site of an initial deposition can be regulated by controlling the rate of hydrogel degradation, either by adjusting the biodegradable moieties in the hydrogel or the density of cros~linking. The microspheres can be chosen for a longer time of degradation or elimin~tion of greater than 320 hours, when five half-lives of the implanted yttrium-90 have expired and the vast majority of radioactive decay has occurred.

Claims (16)

We claim:

1. A method for administering local radiotherapy at a site in a patient, comprising forming a polymeric depot at a site at which therapy is to be administered by combining one or more radioisotopes with a material capable of polymerizing in vivo to form a biodegradable biocompatible polymeric material;
administering the combination to a site in a patient to which radiotherapy is to be administered; and polymerizing the polymerizable material at the site to form a biodegradable, biocompatible polymeric hydrogel, wherein the material includes a functional group selected from the group consisting of epoxy, urethane, ester, sulfone, and ethylenically unsaturated groups.

2. The method of claim 1, in which the polymerizable material is a polymer containing polymerizable groups applied in a first fluent state and converted to a second less fluent state upon application to tissue and subsequent polymerization.

3. The method of claim 1, wherein the polymerizable material is chemically coupled to the radioisotopes.

4. The method of claim 1, wherein the polymerizable material is conjugated to the radioisotopes via a chelating agent coupled to the material.

5. The method of claim 1, wherein the depot comprises microspheres comprising radioisotopes.

6. The method of claim 6, wherein the microspheres are biodegradable at a different rate than the depot.

7. The method of claim 1, wherein the functional group is an ethylenically unsaturated group.

8. The method of claim 1, wherein the material capable of polymerizing includes degradable linkages selected from the group consisting of ester, orthocarbonate, carbonate, amide, anhydride, peptide, acetal, phosphazene and Schiff base linkages.

9. A composition for local radiotherapy, comprising one or more radioisotopes in combination with a depot-forming material, wherein the depot-forming material is a polymerizable material capable of being polymerized in vivo to form a biodegradable, biocompatible polymer and is formed into a depot in vivo, wherein the depot is a biodegradable, biocompatible polymeric hydrogel and the material includes a functional group selected from the group consisting of epoxy, urethane, ester, sulfone, and ethylenically unsaturated groups.

10. The composition of claim 9, in which the depot is a polymer containing polymerizable groups applied in a first fluent state and converted to a second less fluent state upon application to tissue and polymerization of the polymerizable groups.

11. The composition of claim 9, wherein the polymerizable material is chemically coupled to the radioisotopes.

12. The composition of claim 9, wherein the polymerizable material is conjugated to the radioisotopes via a chelating agent coupled to the material.

13. The composition of claim 9, wherein the composition comprises microspheres comprising radioisotopes.

14. The composition of claim 13, wherein the microspheres are biodegradable at a different rate than the depot.

15. The composition of claim 9, wherein the depot forming material includes degradable linkages selected from the group consisting of ester, orthocarbonate, carbonate, anhydride, amide, peptide, acetal, phosphazene and Schiff base linkages.

16. The composition of claim 9, wherein the functional group is an ethylenically unsaturated group.