Gel for radiotherapy and method for preparing same

Abstract

A radioactive thermogel suspension comprising a thermogel and a plurality of radioactive yttrium phosphate particles suspended in the thermogel. The thermogel is PLGA-g-PEG. The thermogel contains less than 65 ppm stannous octoate. The plurality of radioactive yttrium phosphate particles have a diameter between 0.03 μm and 10 μm. The plurality of radioactive yttrium phosphate particles are generally spherical. The concentration of the YPO4 particles ranges from 3 mg / mL to 100 mg / mL.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This patent application is a continuation-in-part of co-pending U.S. patent application Ser. No. 17 / 740,549, filed May 10, 2022, which is a continuation-in-part of co-pending U.S. patent application Ser. No. 16 / 459,466, filed July 1, 2019, which also claims priority to co-pending U.S. Provisional Patent Application No. 63 / 299,930, filed January 15, 2022.

[0002] [Technical field] The present novel technology relates generally to the field of radio-medicine, and more specifically to gels and methods for their preparation. [Background technology]

[0003] One common approach to treating patients with certain cancers, such as liver cancer, is to introduce radioactive particles into the patient's circulatory system, which are targeted to the site of the cancer. Specifically, precisely measured amounts of radioisotopes are injected into the patient so that they accumulate at the site of the cancer. The particles thus lodged create a predetermined radiation field within or near the location of the cancerous tumor. A particular radioisotope is usually selected according to the type of radiation emitted and its half-life, such that the radiation has a range sufficient to destroy the tumor and adjacent tumor borders, but causes minimal damage to nearby healthy tissues and organs, and the radiation emission lasts only for a short, predetermined duration.

[0004] One commonly used radioisotope is yttrium-90 because it emits nearly 100% beta radiation and has a short half-life of 2.67 days. Yttrium-90 is typically incorporated into glass or resin microspheres that are suspended in a liquid medium and introduced via intravascular injection. However, the properties of the particles and the method of administration have resulted in: a) difficulties in achieving uniform distribution of the particles within the tumor (hence the inability to treat patients with a known and controlled radiation dose); b) difficulties in concentrating all of the radioisotope at the tumor site, resulting in a significant amount of the particles traveling away from the tumor site and delivering radiation to normal healthy tissue.

[0005] Various means have been employed to incorporate therapeutic radioisotopes into microspheres, including those made by coating a resin or crystalline ceramic core with a radioactive material. However, whenever a microsphere comprises a core material with an external surface coating containing a radioisotope, there is a risk that the radioactive coating may separate from the underlying microsphere core. Mechanical failure of the coating may result in the release of unwanted radioactivity to other parts of the patient's body, which is highly undesirable. Further disadvantages are presented by the special handling and precautions required for coating radioisotopes onto crystalline ceramic cores or tagging ion exchange resins.

[0006] In yet another application, microspheres have been prepared that include a ceramic material with a radioisotope incorporated into the ceramic material. Although the inadvertent release of the radioisotope from the radioactive coating to other parts of the body is reduced or eliminated by incorporating the radioisotope into the ceramic sphere, the latter product form is not without its drawbacks. Processing these ceramic particles is hazardous because potentially volatile radioactivity must be added to the ceramic melt and the microspheres must be manufactured and sized while still containing the radioactivity. Such processing steps increase the possibility of accidental exposure of personnel and pose a risk of radioactive contamination of the facility.

[0007] Some of these shortcomings are due to the 89 Y was incorporated in the form of an oxide into glass microspheres, which were then exposed to neutron radiation. 89 Y 90 This has been overcome by activating the microspheres into Y. The microspheres are then injected into the patient through an artery or vein in the tumor, where they remain permanently in the capillary lumen. Over time, the radioactivity of the microspheres 90 The main drawback of these glass microspheres is that 90 The problem with Y is that it emits almost exclusively beta radiation, which is highly desirable for tumor treatment but has a very short range, making it difficult to detect outside the body, and therefore difficult to track and accurately assess where all the microspheres ended up. Summary of the Invention [Problem to be solved by the invention]

[0008] Thus, there remains a need for a radiomedical cancer therapy that is useful in treating cancer or tumor-bearing tissue, but which does not release radioactive coatings or isotopes into distant parts of the patient's body after administration, does not require direct handling of radioactive material by a technician during formation of the microspheres, has a size and density that allows the particles to be suspended in a fluid suitable for direct injection into tumor tissue, and can be easily tracked to ensure precise delivery of the radiation therapy to the desired tumor site. The present invention addresses this need.

[0009] The foregoing and other features and advantages of the present invention will be more readily appreciated as the same become better understood by reference to the following detailed description of preferred embodiments of the invention when considered in conjunction with the accompanying drawings. [Brief description of the drawings]

[0010] [Figure 1]1 shows particle size determined via the claimed process at a pH of 7.35, resulting in a median particle size of 0.2450 μm. [Diagram 2] A yttrium particle suspension with pH 7.4 and a median particle size of 0.1844 μm is presented, which provides efficacy for application in tumor interstitium, extracellular space.

[0011] The foregoing descriptions of specific embodiments of the invention have been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the invention to the precise forms disclosed, and obviously, many modifications and variations are possible in light of the above description and illustrations. The exemplary embodiments have been chosen and described in order to best explain the principles of the invention and its practical application, in order to enable others skilled in the art and in the manufacture of products to best utilize the invention and its various embodiments, with various modifications as may be suited to the particular uses contemplated. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] For the purposes of promoting an understanding of the principles of the novel technology and setting forth its best currently understood mode of operation, reference will now be made to the embodiments illustrated in the drawings and specific language will be used to describe the same, it being understood that no limitation of the scope of the novel technology is thereby intended, and that such changes and further modifications in the illustrated apparatus, and such further applications of the principles of the novel technology as illustrated therein, are contemplated as would normally occur to one skilled in the art to which the novel technology pertains.

[0013] In one embodiment, the new technology relates to a method for preparing a radioactive yttrium particle suspension. Yttrium salts, such as yttrium chloride, yttrium nitrate, yttrium sulfate, yttrium bromide and combinations thereof, are irradiated with neutron radiation to activate the yttrium (reducing it to a stable form). 89 Y is radioactive 90Y). This can be done before or after it is put into stable suspension as follows:

[0014] The yttrium salt is placed in solution and then combined with a solution of a soluble phosphate salt having a stoichiometric excess of the phosphate salt, such as sodium phosphate, lithium phosphate, potassium phosphate, and combinations thereof. The resulting mixture is maintained at a pH in the range of 1.5 to 8. The solution is agitated, typically with continuous stirring, and rapidly heated in a closed vessel to about 150° C. and held for about 1 to about 10 hours to separate the soluble yttrium salt into insoluble YPO. 4 Conversion to YPO of greater than about 99.99% is achieved while achieving the desired particle size distribution, which is typically less than 2 μm (2 microns) in diameter, more typically in the range of 0.03 μm to 10 μm, even more typically in the range of 0.05 μm to 3 μm, and even more typically in the range of 0.1 μm to 2 μm, with a median particle size of about 0.2 μm. By carefully controlling the mixing time, temperature, and concentration of the reactants, the suspended YPO 4 A particular desired particle size distribution and / or particle shape distribution of the particles can be achieved. 4 Once the particles are formed, the solution can be buffered with saline to achieve a neutral pH suitable for direct injection into human or animal tissue.

[0015] Typically, the radioactive particle suspension has an average particle size of less than 2 μm. The radioactive particle suspension is typically characterized by having at least 90 percent of the total particle volume being generally spherical particles in the range of 0.1 μm to 2 μm. Typically, the starting concentration of soluble yttrium in the combined solution is in the range of 0.05 to 1.0 moles / liter, more typically in the range of 0.05 to 0.3 moles / liter, and even more typically in the range of 0.08 to 0.3 moles / liter, and the stoichiometric excess of phosphate is in the range of 10% to 100%. More typically, the starting concentration of soluble yttrium in the combined solution is 0.08 moles / liter, and the stoichiometric excess of phosphate is in the range of 5% to 100%, more typically about 10%, and even more typically about 25%.

[0016] In other embodiments, the radioactive metal cation is selected from members of the lanthanide series, such as Ce, Sm, Ho, Yb, Lu, and combinations thereof. In still other embodiments, the radioactive cation is selected from members of metals and transition metals, such as Ga, In, Sn, Cu, Y, Sc, and combinations thereof, resulting in insoluble or poorly soluble transition metal phosphates. In still other embodiments, the radioactive cation is selected from members of the alkali metal / alkaline earth metals, such as Cs, Ra, Ca, Sr, Ba, and combinations thereof, which may be combined with insoluble inorganic compounds, such as zeolites, because the phosphates may not be sufficiently insoluble. In still other embodiments, the radioactive cation is selected from members of the actinide series, and in still other embodiments, the radioactive cation is selected from members of metals, transition metals, alkali metals, alkaline earth metals, lanthanides, actinides, and combinations thereof. In some embodiments, the phosphate functional group is 32 P and 33 P( 31 It contains one or more radioactive isotopes of phosphorus, such as 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 ...4,15,16,17,18,19,19

[0017] In operation, a particle suspension is formed by preparing a particle precursor solution of an yttrium salt and sodium phosphate to define a mixture. This mixture is then mixed and heated to produce a plurality of YPO4 particles by controlled precipitation. 4 particles. The resulting YPO 4 The particles are rinsed (typically multiple times, more typically three times) with a sterile phosphate buffered saline (PBS) solution, and PBS is removed or added to achieve the final desired volume. The pH of the final solution is adjusted, for example by the addition of sodium hydroxide, and then excess solution is removed or sterile PBS is added to achieve the final desired volume. The YPO 4 The particles are suspended in a phosphate buffered saline solution at neutral pH, suitable for in vivo injection into human or animal tissue.

[0018] The yttrium phosphate particles may, for example, contain a predetermined amount of soluble radioactive 90 The Y isotope was added to the particle precursor solution, which was homogeneously incorporated into the insoluble yttrium phosphate particle matrix, resulting in a solubility of approximately 10 -6 Less than 10 moles / liter, more typically -27 It is radioactive so as to function as a distributed source of therapeutic radiation to treat cancerous tumors and other diseases by being less than Ksp. The amount of radioactive yttrium (or similar cation) is typically about 100 μCi to 300 mCi, with the specific amount required varying with each patient application. Typically, yttrium phosphate particle suspensions are combined in a ratio of about 1:4 to 1:10 by volume with a biocompatible hydrogel or other suitable liquid carrier solution for injection into human or animal tissue, and then dispersed in a 40 mg / mL to 125 mg / mL range of YPO to facilitate imaging by X-ray computed tomography. 4 has a particle concentration.

[0019] It is well known in radiation medicine that certain cancerous tumors can be treated by the local introduction of short-lived radioisotopes at the tumor site. One effective method of delivering such radiation therapy is by introducing to the tumor site a radioisotope that emits gamma or beta radiation at therapeutic levels and intensities and that is suspended or otherwise contained in a thermal gel matrix. 90 Y or a similar radiotherapeutic element is usually introduced in the form of an insoluble stable oxide, phosphate, or the like, and is suspended or dispersed in the thermogel precursor immediately prior to introduction into the patient's body. Typically, a given radiotherapeutic element has a short half-life, such that the radiotherapy is relatively short in duration; more typically, a given element is selected to emit relatively high energy beta particles and / or gamma rays. For example, 90 Y has a half-life of about 64 hours and emits beta particles with a mean energy of about 930 keV, as well as high-energy bremsstrahlung gamma rays. This technique enjoys the advantage of using a thermosetting gel matrix prepared from stable, non-radioactive materials; the non-radioactive thermogel may be safely stored indefinitely and combined with yttrium-90 or a similar radiotherapy therapeutic element immediately prior to introduction into the patient's body.

[0020] Other potential radioisotopes that can be introduced through the thermogel matrix emit high-energy gamma rays. 131 Cs, and 32 P and 186 Contains beta or beta / gamma emitters such as Re.

[0021] radioactive 90 Radiomedical thermogels, such as those containing Y, emit short-range beta radiation of therapeutic intensity and quantity, which can penetrate tissue to depths of up to several millimeters. 90 Y is a commonly used radiotherapeutic isotope. 90 Y is a high-energy beta-emitting isotope with no primary gamma; 90The maximum energy of a Y beta particle is 2.28 MeV, and the average energy is about 0.93 MeV. 90 Y is the half-life (t 1 / 2 ), with 94% of the radiation being delivered in about 11 days. In general, the concentration of the radioisotope in the thermogel and the amount of thermogel introduced into the patient are controlled so as not to emit excessive amounts of unwanted beta or gamma radiation that could damage healthy tissue surrounding the target tumor. Thus, the thermogel composition is typically designed so that the therapeutic radioisotope is the only constituent isotope that emits significant amounts of beta and / or gamma radiation, and the radioisotope has a short enough half-life that the beta and gamma emissions disappear after a relatively short period of time, typically on the order of a few days to a few months. Elements such as yttrium and phosphorus, which form radioisotopes with half-lives greater than about 2 days and less than about 30 days, are typically selected as the constituent elements induced to emit therapeutic radiation.

[0022] Thus, the radiomedical thermogels described above are designed to emit high energy beta particles and / or gamma rays with a relatively short tissue penetration depth. This is desirable to the extent that it optimizes tumor treatment and minimizes collateral tissue damage, but it poses detection problems. Beta rays are not suitable for more precise imaging techniques such as single photon emission computed tomography (SPECT) or positron emission tomography (PET). Therefore, in some cases, it is advantageous to introduce a second amount of radioisotope characterized by an emission compatible with SPECT or PET techniques, which facilitates PET or SPECT imaging of the radiation distribution pattern in the patient and also helps to image the location where the thermogel is deposited to ensure uniform deposition in and around the tumor site.

[0023] As with therapeutic thermogels, the composition of the imaging agent is selected such that the thermogel emits a sufficient amount of positron emission to facilitate PET imaging. In other words, the composition of the imaging agent is typically selected such that its radiation can be tailored to provide a radiation profile suitable for a particular imaging technique. For example, when desired for use with PET imaging, imaging thermogels typically contain 64 Cu (half-life 12.7 hours) or 18 These include short-lived positron emitters such as F (half-life 110 min). 64 Cu and 18 F are particularly attractive positron emitters because they have a short half-life and emit a low-energy positron that annihilates with two 511 keV gamma electrons, facilitating PET imaging. If a longer-lived positron emitter is desired, 89 Zr (half-life 78.4 hours) or 124 I (half-life 4.18 days) may be selected.

[0024] In many cases, ( 86 Y) beta and gamma emitters or ( 90 In addition to high energy beta emitters (such as Y) 64 It may be desirable to use thermogels that incorporate both therapeutic and imaging radioisotopes, such as positron emitters (such as Cu), so that the therapeutic thermogels can themselves be directly imaged and tracked. In one such embodiment, beta-emitters and / or low energy gamma-emitters are incorporated into the thermogel along with positron emitters.

[0025] Therapeutic and imaging thermogels are typically introduced into a patient's body via catheter, injection, etc., where they undergo rapid gelation in vivo and remain in the cancerous or tumor-bearing tissue. Therapeutic and imaging thermogels are typically introduced as liquid media of sufficient density and viscosity such that the thermogel remains liquid during the administration procedure and rapidly gels upon introduction into the relatively warm target tissue.

[0026] Thermogels have a composition that becomes more viscous when heated. Generally, thermogels are more fluid at room temperature and gel and become substantially more viscous at temperatures experienced in vivo, essentially behaving as a solid. In one embodiment, a PLGA-g-PEG polymer was synthesized with a gelation temperature of 26° C. in phosphate buffered saline (PBS). Several batches of polymer were synthesized to narrow down the conditions necessary to obtain a gelation temperature around 26° C. The reaction conditions, polymer composition from NMR, and gelation properties by dynamic rheology are summarized below in Table 1. Rheological data for 30 w% polymer in PBS is shown below. [Table 1]

[0027] Working Example A quantity of thermogel was prepared according to the recipe given above for AMIC1. The EPEG referenced in Table 1 was a catalog product of a particular precursor, EPEG 600, from Polysciences, referenced in the prior art. A contract laboratory, IsoTherapeutics Group (ITG), Angleton, Texas, conducted tests to replicate the polymer described in AMIC1. These tests are summarized below. [Table 2]

[0028] It is clear that the results are not completely reproducible from lab to lab in terms of gelation temperature, MW, LA / GA / EG ratio, and overall polymer yield. Subsequent studies at other contract laboratories have shown further differences in polymer properties and overall yield from the same starting recipe. Subject matter experts noted that the use of EPEG as a thermogelling polymer precursor is unusual and it is not clear that the idealized polymer structures shown in the prior art and subsequently described in the technical literature are actually achieved using this method. The bifunctional structure of EPEG allows each PEG molecule to have two reactive epoxy termini, which may facilitate crosslinking within and between polymer chains, which may have a strong impact on both the water solubility and gelling properties of the polymer.

[0029] Various reaction parameters were tested, but it was quickly realized that stringent steps were necessary to ensure reaction conditions completely water- and oxygen-free to avoid deleterious side effects. Application of such techniques allowed for increased reaction temperatures and the ability to achieve high reaction yields (approximately 90%) compared to previous yields of less than 50%. Examination of reaction stoichiometry revealed that previous recipes conveyed from the prior art, which relied on overfeeding EPEG and controlling specific reaction conditions to achieve the desired product, were neither robust nor highly reproducible in producing the desired product.

[0030] Examples of compositions using different molecular weights and stoichiometric ratios of starting components that will result in desirable gelling properties are as follows: [Table 3]

[0031] The prior art does not teach the importance of solvent selection and purification methods for the final polymer. The type of organic solvent, the relative amount, and the number of dissolution / precipitation cycles were found to be important to obtain the desired final properties. This is due to the observation that these cycles remove low molecular weight fractions of incompletely polymerized material. However, the presence of some of those materials in the final mixture helps to achieve the desired gelling properties. In addition, it is desirable to select a solvent that has the properties of low toxicity and easy removal from the final polymer mixture. This is to ensure that the residual solvent level in the final product meets FDA guidelines for the allowable concentration of solvents in medical products for injection. The solvent may be removed by application of heat and high vacuum, freeze drying, etc., but the stringency of the conditions required to meet the limiting values ​​may be optimized through the selection of solvent and purification conditions.

[0032] Finally, the polymer must be dissolved in an aqueous medium to be suitable for injection into the body and to achieve the desired gelation properties, e.g., gelation temperature and gel strength as measured by rheological parameters. A balance between low viscosity at room temperature for ease of handling and loading into needles, the temperature range over which the gel will form, and the final strength of the gel. For this class of polymers, dissolution in phosphate buffered saline is generally considered adequate to achieve a physiological pH of 7.4. However, it was found that standard buffers are insufficient and result in much lower pH levels. By adjusting the concentration of inorganic buffer ions, the inventors were able to achieve a neutral pH. This may also be achievable with certain organic buffer solutions. The inventors also found that buffering significantly alters the rheological properties, allowing gelation over a wider temperature range, and ultimately resulting in a stronger final gel.

[0033] The above prior art teaches that certain combinations of thermogelling polymer solutions can provide desired properties such as tuning of gelling temperature, gel strength, and even the time required for the polymer to degrade into fragments that can be reabsorbed by the body. Combining different thermogel types to achieve desired properties is not known a priori. Synergistic effects, or conversely, antagonism or inactivation of functions, are not evident from analysis of theoretical polymer structures. Combining radioactive particles with various thermogelling hydrogel compositions to achieve a well-distributed source of radioactivity when injected or placed in tissue is likewise essentially not obvious. The inventors have investigated the combination of radioactive particles with various available thermogelling polymers and the utility of the combination to achieve the desired properties for both interstitial injection as a distributed source of therapeutic radiation and for bolus or planar sources of therapeutic radiation.

[0034] Working Example Approximately 80 mL of anhydrous toluene was weighed into a 100 mL volumetric flask using the following procedure: The flask was sealed with a rubber septum and vacuum purged using an 18 G needle attached to a rubber hose. Once negative pressure was achieved, the needle was removed. One end of a 24 inch double-sided 20 G cannula needle was inserted through the septum seal to the bottom of the bottle of anhydrous toluene. The other end of the cannula was inserted into the rubber septum of the volumetric flask. Argon was pumped into the bottle of toluene using an 18 G needle attached to a rubber hose, transferring the toluene to the flask without contact with air or moisture. The flask was filled to approximately 80% capacity for a total of approximately 80 mL of anhydrous toluene.

[0035] A 2-neck 500 mL round bottom flask (RBF) with a magnetic stir bar that had been rinsed with acetone, dried at 100°C, and cooled in a desiccator was tared. 30.01 g of EPEG was slowly pipetted in. The RBF was re-tared. 3.51 g of mPEG 750 was added to the RBF. Approximately 80 mL of toluene was added to the flask. An argon hose was connected to the stopcock attached to the side neck of the RBF and argon was gently forced through the system (approximately 40 cc / min) while the vacuum distillation apparatus was assembled. A distillation head was connected to the center neck. The condenser temperature on the water recirculator was set to -10°C. A 250 mL 1-neck RBF was attached to the end of the condenser head with a condenser drip tip and a barbed side arm. The argon line was disconnected from the stopcock and attached to a barb on the drip tip adapter; the stopcock was left open to vent the argon. An ice pack was packed around the single port RBF collector. The argon was turned off and the stopcock was closed. Vacuum was applied through a hose attached to the drip tip adapter. The PEG / toluene solution was set to stir at about 200 RPM at 50°C. The PEG was vacuum distilled in this manner until the toluene appeared to be gone (about 1 hour). The heat was then turned off and the system was allowed to cool to room temperature under continuous vacuum. Once cooled, the system was backflushed with argon. Once the pressure in the system was equalized, the stopcock was opened to allow ventilation. Under continuous (about 100 cc / min) argon flow, the distillation assembly was removed with the stopcock still in the side neck. The argon flow was slowed to about 25 cc / min. Through the center-neck funnel, 35.01 g of D,L-lactide and 9.01 g of glycolide were added. 5.0 mL of a 10% stannous octoate / toluene (w:v) solution was pipetted in. The center neck was sealed with a glass stopper and the reaction flask was vacuum purged for approximately 1 hour, then backflushed with argon. Through the center-neck funnel, approximately 100 mL of anhydrous toluene (drawn from the bottle in the same manner as before) was added.The stopcock was moved to the center neck. A 9 inch glass Pasteur pipette was pushed through the thermometer adapter attached to the side neck and the tip of the pipette was threaded approximately 1.5 inches below the surface of the reaction solution. A slow stream of argon was pumped through the pipette (approximately 50 cc / min) and stirred at 300 RPM for approximately 20 minutes. A reflux condenser with a dry trap on top was attached to the center neck. Coolant was circulated through the condenser at -10°C. The stopcock was moved to the side neck and argon was pumped through the stopcock at approximately 50 cc / min for approximately 30 minutes. The stopcock was closed and the heat was set to 130°C for 24 hours with stirring at 300 RPM. The next day the reaction solution was rotary evaporated until all the toluene appeared to be gone. 250 mL of acetone was used to redissolve the polymer. 155 g of the washed granular activated carbon (approximately twice the mass) was weighed into a 1 L bottle, and then the polymer solution was poured over the activated carbon, resulting in substantial removal of the tin. Acetone was used to rinse the residual polymer from the reaction flask into the bottle. The bottle was capped and left overnight in a desiccator chamber. The solution was then drawn through a Büchner funnel under moderate vacuum; copious amounts of acetone were used to rinse as much of the polymer as possible from the granular carbon. The filtrate was passed through a series of polyvinylidene fluoride (PVDF) filters terminating in a 0.1 μm pore size membrane. The filtrate was transferred to a 1 L pear-shaped flask and rotary evaporated to approximately 200 mL before being poured directly into 2 L of stirring hexane. The precipitated material was collected and dried under vacuum at 55° C., giving a yield of approximately 85% with residual tin less than 65 ppm.

[0036] The monomer ratio was optimized for gelling properties. The table below provides the analytical specifications for this example. [Table 4]

[0037] In general, the PLGA-g-PEG gel material produced in this way enjoys the selective optimization of the monomer ratios presented to achieve optimal gel property formation in a highly reproducible manner. The reaction is carried out under selective conditions to maximally remove oxygen and water molecules from the reaction solution before initiation, which is counterintuitive to previous efforts in this field. Purification is achieved via a combination of hexane-based non-solvent precipitation and removal of stannous octoate via activated charcoal soaking followed by filtration, eliminating the need for multiple washes to achieve the desired gelation properties. Removal of stannous from the gel makes it more biocompatible.

[0038] Numerous radioisotopes are suitable for delivery of therapeutic radiation to diseased or unwanted tissues, or for external imaging of source placement, or both. A variety of physical and chemical forms have been described, including insoluble inorganic compounds, organic chelators / complexers, or encapsulation in inert media such as glass microspheres. The specific method of immobilization will necessarily depend on the chemical properties of the desired isotope, and the degree of immobilization required in the in vivo environment. The inventors have created new means of immobilizing isotopes such as P-32, P-33, Re-186, Re-188, Lu-177, Sm-153, Sn-117m, Cs-131, Pd-103, Cu-64, Cu-67, and others. These embodiments are specifically designed to be compatible with PLGA-g-PEG and other hydrogels and hydrogel combinations to provide a localized source for in vivo treatment of cancer and other diseases.

[0039] One advantage of the novel thermogels and thermogelling methods disclosed herein is the ability to utilize additives along with the radioactive source in thermogelling the hydrogel carrier for various purposes. Potential additives include painkillers, anticancer drugs, antibiotics, contrast agents, etc. The inventors have evaluated the usefulness of incorporating such agents, and in particular the use of antibiotics to combat the possibility of infection occurring at the site of administration of the radioactive source material. Important parameters in this regard are the resistance of such agents to degradation upon exposure to radiation and their ability to retain their desired function. Also important is the absence of harmful degradation products to ensure safety of use.

[0040] Working Example In this example, all samples were reconstituted at a concentration of 31.25% w:v hydrogel solution in phosphate buffered saline (PBS) at cold temperature. All three solutions were stored refrigerated.

[0041] Under a laminar flow hood, 8 mL of PLGA-g-PEG and AK097 solution was added to the YPO 4 The particles are injected into separate vials, each containing approximately 1 mL of YPO 4 The vials contained 100% PBS (approximately 59 mg / vial) of hydrogel / YPO4 solution. 1 mL of 0.2 μm filtered PBS was injected into each of the hydrogel / YPO4 solution vials. These vials were each vortexed for approximately 10 seconds. The vials were stored in the refrigerator while the next solution was prepared.

[0042] Under a laminar flow hood, 9 mL of Pluronic F-127 solution was added to approximately 1 mL of YPO 4The solution was then poured into a vial containing the particles. The vials were vortexed for approximately 10 seconds. 5.0 mL of each solution was transferred to a 50 mL Falcon tube (pre-warmed to 37° C.). The tubes were placed in a 37° C. incubator until gelling. 5 mL of 37° C. PBS was pipetted into each tube. The tubes were kept at 37° C. with shaking at 100 RPM for 10 minutes. 4 mL of the supernatant from each tube was transferred to a vial and subjected to yttrium analysis, resulting in the following values ​​for yttrium in the supernatant: Note that this indicates yttrium that was not successfully trapped. [Table 5]

[0043] Using a thermogel to trap yttrium particles is nontrivial, as not all thermogels are useful for this application. In particular, Pluronic F127 was unable to trap these particles. Both PLGA-PEG-PLGA (triblock) and PLGA-g-PEG successfully trapped the particles; PLGA-g-PEG was superior to PLGA-PEG-PLGA in other properties, including reconstitution rate and ease of handling.

[0044] While the present invention has been illustrated and described in detail in the drawings and the foregoing description, these are considered to be illustrative and not restrictive in nature. It is understood that the embodiments have been shown and described in the foregoing specification as the best mode and enabling implementation. It is understood that those skilled in the art can readily make an infinite number of insubstantial changes and modifications to the above-described embodiments, and that it would be impractical to attempt to describe all such variations of the embodiments herein. It is therefore understood that it is desired to protect all changes and modifications that are within the spirit of the present invention.

[0045] [Embodiment] (1) A radioactive thermogel suspension comprising: Thermogel and a plurality of radioactive yttrium phosphate particles suspended in said thermogel; Including, the thermogel is PLGA-g-PEG; The thermogel contains less than 65 ppm stannous octoate; The plurality of radioactive yttrium phosphate particles have a diameter of 0.03 μm to 10 μm; said plurality of radioactive yttrium phosphate particles are generally spherical; The YPO 4 The particle concentrations range from 3 mg / mL to 100 mg / mL of the radioactive thermogel suspension. (2) The radioactive thermogel suspension of claim 1, wherein the radioactive yttrium phosphate is combined with the thermogel to provide a final concentration of thermogelling polymer in the range of about 25 wt% to 30 wt% in an aqueous buffer solution. (3) The radioactive thermogel suspension of claim 1, wherein the radioactive thermogel suspension has a pH of 1.5 to 8.0. (4) The radioactive thermogel suspension of embodiment 1, wherein the thermogel is substantially free of water molecules and oxygen molecules. (5) The radioactive yttrium phosphate suspension of embodiment 1, wherein at least a portion of the yttrium phosphate comprises a radioactive phosphorus isotope.

[0046] (6) A radioactive thermogel suspension comprising: a thermogel, the thermogel being a PLGA-g-PEG containing less than 65 ppm stannous octoate; a plurality of radioactive metal phosphate particles suspended in said thermogel, each metal phosphate particle comprising a metal cation and a phosphate-containing functional group; Including, The plurality of radioactive metal phosphate particles have a diameter of 0.03 μm to 10 μm. (7) The radioactive thermogel suspension of claim 6, wherein the plurality of radioactive metal phosphate particles have a diameter of between 0.1 μm and 2 μm. (8) The radioactive thermogel suspension of embodiment 6, wherein the metal phosphate particles are selected from the group consisting of lanthanide phosphates, alkali and alkaline earth phosphates, transition metal phosphates, and combinations thereof. (9) The metal phosphate particles are 1×10 -6 7. A radioactive thermogel suspension according to embodiment 6, having a solubility of less than moles per liter. (10) The radioactive thermogel suspension of embodiment 6, wherein the metal cation is selected from the group consisting of Y, Ho, Yb, Ce, Sm, Lu, Sc, Ca, Sr, Ba, and combinations thereof.

[0047] (11) The phosphate functional group is 31 P, 32 P, 33 7. The radioactive thermogel suspension of embodiment 6, comprising a phosphorus isotope selected from the group consisting of P, P, and combinations thereof. (12) The radioactive thermogel suspension according to embodiment 6, wherein the concentration of the metal phosphate particles is in the range of 3 mg / mL to 100 mg / mL. (13) The radioactive thermogel suspension of claim 12, wherein the metal phosphate particles provide a dose of between 100 μCi and 300 mCi. (14) The metal cation is selected from the group consisting of Y, La, Ce, Pr, Pm, Sm, Gd, Tb, Ho, Yb, Lu, Ac, Ca, Sr, Ba, Ra, Cs, Cu, Tc, Pd, Sn, Re, Au, and combinations thereof, and the phosphate functional group is 31 P, 32 P, 33 7. The radioactive thermogel suspension of embodiment 6, comprising a phosphorus isotope selected from the group consisting of P, P, and combinations thereof. (15) A radioactive metal phosphate / thermogel suspension comprising: a PLGA-g-PEG thermogel containing less than 65 ppm stannous octoate; a plurality of radioactive metal phosphate particles suspended in the phosphate buffered saline solution, each metal phosphate particle comprising a metal cation and a phosphate-containing functional group; Including, the plurality of radioactive metal phosphate particles have a diameter of 0.03 μm to 10 μm; the metal phosphate particles are selected from the group consisting of lanthanide phosphates, actinide phosphates, alkali and alkaline earth phosphates, transition metal phosphates, and combinations thereof; The metal phosphate particles are 1×10 -6 has a solubility of less than mol / liter, The phosphate functional group is 31 P, 32 P, 33 P, and combinations thereof; The metal phosphate particles provide a dose of 100 μCi to 300 mCi of a radioactive metal phosphate / thermogel suspension.

Claims

1. 1. A radioactive thermogel suspension comprising: Thermogel and a plurality of radioactive yttrium phosphate particles suspended in said thermogel; Including, the thermogel is PLGA-g-PEG; The thermogel contains less than 65 ppm stannous octoate; the plurality of radioactive yttrium phosphate particles have a diameter between 0.03 μm and 10 μm; said plurality of radioactive yttrium phosphate particles are generally spherical; The YPO ４ Radioactive thermogel suspension with particle concentrations ranging from 3 mg / mL to 100 mg / mL.

2. 10. The radioactive thermogel suspension of claim 1, wherein the radioactive yttrium phosphate is combined with the thermogel to provide a final concentration of thermogelling polymer in the range of about 25 wt% to 30 wt% in an aqueous buffer solution.

3. 10. The radioactive thermogel suspension of claim 1, wherein the radioactive thermogel suspension has a pH of 1.5 to 8.

0.

4. 10. The radioactive thermogel suspension of claim 1, wherein the thermogel is substantially free of water molecules and oxygen molecules.

5. 2. The radioactive yttrium phosphate suspension of claim 1, wherein at least a portion of the yttrium phosphate comprises a radioactive phosphorus isotope.

6. 1. A radioactive thermogel suspension comprising: a thermogel that is PLGA-g-PEG containing less than 65 ppm stannous octoate; a plurality of radioactive metal phosphate particles suspended in said thermogel, each metal phosphate particle comprising a metal cation and a phosphate-containing functional group; Including, A radioactive thermogel suspension, wherein said plurality of radioactive metal phosphate particles are between 0.03 μm and 10 μm in diameter.

7. 7. The radioactive thermogel suspension of claim 6, wherein the plurality of radioactive metal phosphate particles are between 0.1 μm and 2 μm in diameter.

8. 7. The radioactive thermogel suspension of claim 6, wherein the metal phosphate particles are selected from the group consisting of lanthanide phosphates, alkali and alkaline earth phosphates, transition metal phosphates, and combinations thereof.

9. The metal phosphate particles are 1×10 －６ 7. The radioactive thermogel suspension of claim 6 having a solubility of less than moles per liter.

10. 7. The radioactive thermogel suspension of claim 6, wherein the metal cation is selected from the group consisting of Y, Ho, Yb, Ce, Sm, Lu, Sc, Ca, Sr, Ba, and combinations thereof.

11. The phosphate functional group is ３１ P. ３２ P. ３３ 7. The radioactive thermogel suspension of claim 6, comprising a phosphorus isotope selected from the group consisting of: P, P, and combinations thereof.

12. 7. The radioactive thermogel suspension of claim 6, wherein the concentration of said metal phosphate particles ranges from 3 mg / mL to 100 mg / mL.

13. 13. The radioactive thermogel suspension of claim 12, wherein the metal phosphate particles provide a dose of between 100 μCi and 300 mCi.

14. The metal cation is selected from the group consisting of Y, La, Ce, Pr, Pm, Sm, Gd, Tb, Ho, Yb, Lu, Ac, Ca, Sr, Ba, Ra, Cs, Cu, Tc, Pd, Sn, Re, Au, and combinations thereof, and the phosphate functional group is ３１ P. ３２ P. ３３ 7. The radioactive thermogel suspension of claim 6, comprising a phosphorus isotope selected from the group consisting of: P, P, and combinations thereof.

15. 1. A radioactive metal phosphate / thermogel suspension comprising: a PLGA-g-PEG thermogel containing less than 65 ppm stannous octoate; a plurality of radioactive metal phosphate particles suspended in the phosphate buffered saline solution, each metal phosphate particle comprising a metal cation and a phosphate-containing functional group; Including, the plurality of radioactive metal phosphate particles have a diameter between 0.03 μm and 10 μm; the metal phosphate particles are selected from the group consisting of lanthanide phosphates, actinide phosphates, alkali and alkaline earth phosphates, transition metal phosphates, and combinations thereof; The metal phosphate particles are 1×10 －６ has a solubility of less than mol / liter; The phosphate functional group is ３１ P. ３２ P. ３３ P, and combinations thereof; A radioactive metal phosphate / thermogel suspension, wherein the metal phosphate particles provide a dose of 100 μCi to 300 mCi.

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