CN118647414A - Radiotherapy gel and preparation method thereof - Google Patents

Abstract

A radioactive thermogel suspension comprising a thermogel and a plurality of radioactive yttrium phosphate particles suspended in the thermogel. The thermal gel is PLGA-g-PEG. The thermal gel contains less than 65ppm 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 YPO ₄ particles was 3mg/ml to 100mg/ml.

Description

Radiotherapy gel and preparation method thereof

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is a continuation-in-part of the currently pending U.S. patent application No. 17/740,549 filed on May 10, 2022, which is a continuation-in-part of the currently pending U.S. patent application No. 16/459,466 filed on July 1, 2019; this patent also claims priority to the currently pending U.S. provisional patent application No. 63/299,930 filed on January 15, 2022.

Technical Field

The present novel technology generally relates to the field of radiation medicine, and more specifically, to gel and a method for preparing the same.

Background Art

A common method for treating patients with certain types of cancer (such as liver cancer) is to introduce radioactive particles into the patient's blood circulation system, wherein the radioactive particles target the cancer site. Specifically, a measured amount of radioisotopes is injected into the patient's body so that it accumulates at the cancer site. Therefore, the resident particles generate a predetermined radiation field in or near the location of the cancerous tumor. Specific radioisotopes are usually selected according to the type of radiation emitted and its half-life, so that the radiation has enough range to destroy the tumor and the proximal tumor edge, but only minimal damage is caused to adjacent healthy tissues and organs, and the emission of radiation is only continued for a short predetermined time.

One commonly used radioisotope is yttrium-90, because radioactive yttrium-90 emits nearly 100% beta radiation and has a short half-life of 2.67 days. Yttrium-90 is often incorporated into glass or resin microspheres suspended in a liquid medium and introduced by intravascular injection. However, the glass or resin formulation and administration method result in: a) difficulty in achieving uniform distribution of particles within the tumor (and therefore inability to treat patients with known and controlled radiation doses); and b) difficulty in concentrating all of the radioisotope at the tumor site, resulting in a large number of particles migrating away from the tumor site and delivering radiation to normal healthy tissue.

Various means have been used to incorporate therapeutic radioisotopes into microspheres, such as those made of resin or crystalline ceramic cores and coated with radioactive materials. However, as long as the core material of the microsphere has an outer surface coating containing the radioisotope, there is a risk that the radioactive coating may separate from the underlying microsphere core. Any mechanical damage to the coating may release harmful radioactivity to other parts of the patient's body, which is highly undesirable. Other disadvantages are the need for special handling and precautions to coat the radioisotope on the crystalline ceramic core or the labeled ion exchange resin.

In another application, microspheres have been prepared that include a ceramic material and have a radioactive isotope incorporated into the ceramic material. While the incorporation of the radioactive isotope into the ceramic sphere reduces or eliminates the unintended release of the radioactive isotope from the radioactive coating to other parts of the human body, this subsequent product form is not without disadvantages. Processing these ceramic particles is very dangerous because a radioactive material that may volatilize must be added to the ceramic melt, and the microspheres must be produced and sized in the presence of radioactivity. Such processing steps increase the potential for unintended exposure of personnel and the risk of radioactive contamination of facilities.

Some of these disadvantages have been overcome by incorporating stable ⁸⁹ Y in the form of an oxide into glass microspheres and subsequently exposing them to neutron radiation to activate ⁸⁹ Y to ⁹⁰ Y. The microspheres are then injected into the patient via an artery or vein within the tumor, where they may reside permanently in the capillary space. Over time, the radioactivity of the microspheres decreases as the ⁹⁰ Y decays. The main disadvantage of these glass microspheres is that ⁹⁰ Y emits almost exclusively beta radiation, which, while highly suitable for tumor therapy, has a very short effective range and is therefore difficult to detect in vitro. Therefore, it is difficult to track and accurately assess where all the microspheres ultimately reside.

Therefore, there remains a need for a radiation medicine cancer treatment method that can be used to treat cancer or tumor-bearing tissue but that does not release radioactive coatings or isotopes to distal parts of the patient's body after administration, does not require technicians to directly handle radioactive materials during the microsphere formation process, has a size and density that will allow the particles to be suspended in a fluid suitable for direct injection into tumor tissue, and can be easily tracked to ensure accurate delivery of radiation therapy to the desired tumor site. The present invention addresses this need.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other features and advantages of the present invention will become more apparent and easier to understand through the following detailed description of preferred embodiments of the present invention with reference to the accompanying drawings, in which:

Figure 1 shows the particle size measured by the claimed method at pH 7.35, the median particle size of the particles obtained was 0.2450 um.

FIG. 2 shows that a suspension of yttrium particles having a pH of 7.4 and a median particle size of 0.1844 μm provides efficacy for application to the tumor interstitial, extracellular space.

The above description of specific embodiments of the present invention has been provided for the purpose of illustration and description. They are not intended to be exhaustive or to limit the invention to the exact form disclosed, and obviously various modifications and changes are possible in light of the above description and the accompanying drawings. The exemplary embodiments were chosen and described in order to best explain the principles of the invention and its practical application, so that those skilled in the art and product manufacturers can best utilize the invention and various embodiments with various modifications to suit the specific purpose envisioned.

DETAILED DESCRIPTION

In order to promote an understanding of the principles of the new technology and to provide the best mode of operation currently understood, reference will now be made to the embodiments shown in the drawings and specific language will be used to describe these embodiments. However, it should be understood that the scope of the new technology is not limited thereby and that changes and further modifications to the illustrated devices and further applications of the principles of the new technology illustrated therein will generally occur to those skilled in the art to which the new technology belongs.

In one embodiment, the new technology relates to a method for preparing a suspension of radioactive yttrium particles. Yttrium salts such as yttrium chloride, yttrium nitrate, yttrium sulfate, yttrium bromide and combinations thereof are irradiated with neutron radiation to activate yttrium (converting stable ⁸⁹ Y to radioactive ⁹⁰ Y). This can be done before or after placing them in a stable suspension, as shown below.

The yttrium salt is placed in a solution and then mixed, the solution being one or more soluble phosphates, such as sodium phosphate, lithium phosphate, potassium phosphate, and combinations thereof, and having a stoichiometric excess of phosphate. The pH of the resulting mixture is maintained in the range of 1.5 to 8. The solution is stirred (usually with continuous stirring) and rapidly heated to about 150 degrees Celsius in a closed container for about 1 to about 10 hours to produce greater than about 99.99% conversion of soluble yttrium to insoluble YPO ₄ and obtain a desired particle size distribution, typically less than 2 microns in diameter, more typically in the range of 0.03um to 10um, still more typically in the range of 0.05um to 3um, and still more typically in the range of 0.1um to 2um, with a median particle size of about 0.2um. By carefully controlling the mixing time, temperature, and concentration of the reactants, a specific desired particle size distribution and/or particle shape distribution of the suspended YPO ₄ particles can be achieved. Likewise, once the YPO ₄ particles are formed, the solution can be buffered with saline to achieve a neutral pH suitable for direct injection into human or animal tissue.

Typically, the average particle size of the radioactive particle suspension is less than 2 μm. The radioactive particle suspension is typically characterized by at least 90% of the total particle volume being spherical particles of typically 0.1 um to 2 um. Typically, the starting concentration of soluble yttrium in the combined solution is in the range of 0.05 to 1.0 moles per liter, more typically in the range of 0.05 to 0.3 moles per liter, and still more typically in the range of 0.08 to 0.3 moles per 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 per liter, and the stoichiometric excess of phosphate is in the range of 5% to 100%, more typically about 10%, and still more typically about 25%.

In other embodiments, the radioactive metal cation is selected from members of the lanthanide series, such as Ce, Sm, Ho, Yb, Lu, etc. and combinations thereof. In yet other embodiments, the radioactive cation is selected from members of metals and transition metals, such as Ga, In, Sn, Cu, Y, Sc, etc. and combinations thereof, thereby producing one or more insoluble or slightly soluble transition metal phosphates. In other embodiments, the radioactive cation is selected from members of alkali metals/alkaline earth metals, such as Cs, Ra, Ca, Sr, Ba, etc. and combinations thereof, although its phosphate may not be completely insoluble, these alkali metals/alkaline earth metals can be combined with insoluble inorganic compounds such as zeolites. In yet other embodiments, the radioactive cation is selected from members of the actinide series, and in 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 includes one or more radioactive isotopes of phosphorus, such as ³² P and ³³ P (wherein ³¹ P is a stable isotope).

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

Yttrium phosphate particles are radioactive and can be used as a distributed source of therapeutic radiation for treating cancerous tumors and other diseases, such as by adding a predetermined amount of a soluble radioactive ⁹⁰ Y isotope to a particle precursor solution, which is uniformly incorporated into an insoluble yttrium phosphate particle matrix with a solubility of less than about 10 ^-6 moles/liter, more typically less than 10 ^-27 Ksp. The amount of radioactive yttrium (or similar cation) is typically about 100 uCi to 300 mCi; the specific amount required varies with each patient application. Typically, the YPO ₄ particle concentration of the yttrium phosphate particle suspension is in the range of 40 mg/ml to 125 mg/ml for imaging by X-ray computed tomography after combination with a biocompatible hydrogel or other suitable liquid carrier solution in a volume ratio of about 1:4 to 1:10 for injection into human or animal tissue.

It is well known in radiation medicine that certain types of cancerous tumors can be treated by locally introducing short-lived radioisotopes at the tumor site. An effective method for delivering this radiotherapy is to introduce radioisotopes into the tumor site, which emit gamma or beta radiation at therapeutic levels and intensities and are suspended or otherwise contained in a thermogel matrix. ⁹⁰ Y or similar radiotherapy elements are usually introduced in the form of insoluble stable oxides, phosphates, etc., and are suspended or dispersed in a thermogel precursor shortly before being introduced into the patient's system. Typically, the half-life of the predetermined radiotherapy treatment element is short, so that the duration of radiotherapy is relatively short; more typically, the predetermined element is selected so that it emits relatively high-energy beta particles and/or gamma rays. For example, ⁹⁰ Y has a half-life of 64 hours, emitting beta particles with an average energy of about 930keV and high-energy bremsstrahlung gamma rays. The advantage of this technique is the use of a thermosetting gel matrix made from a stable, non-radioactive material; the non-radioactive thermogel can be safely stored for an indefinite period of time and combined with Yttrium-90 or a similar radiotherapy treatment element shortly before introduction into the patient.

Other potential radioisotopes that can be introduced via the thermogel matrix include131Cs ^, which emits high energy gamma rays, and beta or beta/gamma emitters such ^{as32P and186Re} .

Radiomedical thermal gels (such as those containing radioactive ⁹⁰ Y) emit short-range beta radiation of therapeutic intensity and therapeutic amount, which can penetrate tissue up to a depth of about several millimeters. ⁹⁰ Y is a commonly used radiotherapy isotope. ⁹⁰ Y is a high-energy beta-emitting isotope without primary gamma; the maximum energy of ⁹⁰ Y beta particles is 2.28 MeV and the average energy is about 0.93 MeV. The half-life (t _1/2 ) of ⁹⁰ Y is about 64 hours, and 94% of its radiation is delivered within about 11 days. Generally, the concentration of the radioisotope in the thermal gel and the amount of thermal gel introduced into the patient's body are controlled so that they do not emit excessive amounts of unwanted beta or gamma radiation, which may damage healthy tissue around the target tumor. Therefore, the thermal gel composition is usually engineered so that the therapeutic radioisotope is the only constituent isotope that emits a large amount of beta and/or gamma radiation, and the radioisotope has a sufficiently short half-life that the beta and gamma emissions are extinguished after a relatively short time (usually on the order of days to months). Elements that are induced to emit therapeutic radiation are generally selected that form radioactive isotopes with half-lives greater than about two days and less than about 30 days, such as yttrium and phosphorus.

Therefore, the radiomedical thermal gel discussed above is designed to emit high energy beta particles and/or gamma rays with a relatively short penetration depth in tissue. While this is desirable in optimizing tumor treatment while minimizing collateral tissue damage, it does present a detection problem. Beta radiation is not suitable for more precise imaging techniques, such as single photon emission computed tomography (SPECT) or positron emission tomography (PET). Therefore, it is advantageous in some cases to introduce a second amount of radioisotope characterized by an emission compatible with the SPECT or PET technique, which facilitates PET or SPECT imaging of the radiation distribution pattern in the patient and also aids in imaging the location of thermal gel deposition to ensure uniform deposition in and around the tumor site.

As with the treatment of thermogel, the composition of the imaging agent is selected so that the thermogel emits a sufficient amount of positron emission to facilitate PET imaging. In other words, the composition of the imaging agent is usually selected so that its radiation can be customized to deliver a radiation distribution that is very suitable for a specific imaging technique. For example, when it is needed to be used with PET imaging, the imaging thermogel will usually include a short-lived positron emitter, such as ⁶⁴ Cu (half-life 12.7 hours) or ¹⁸ F (half-life 110 minutes), etc. ⁶⁴ Cu and ¹⁸ F are particularly attractive positron emitters because they have a short half-life and emit low-energy positrons, which produce two 511keV gamma rays after annihilation with electrons, which is conducive to PET imaging. If a positron emitter with a longer life is required, ⁸⁹ Zr (half-life 78.4 hours) or ¹²⁴ I (half-life 4.18 days) can be selected.

In most cases, it is desirable to use a thermogel that combines a therapeutic radioisotope with an imaging radioisotope, such as a positron emitter (e.g., ⁶⁴ Cu) and a beta and gamma emitter (e.g., ⁸⁶ Y) or a high-energy beta emitter (e.g., ⁹⁰ Y), so that the therapeutic thermogel itself can be directly imaged and tracked. In one such embodiment, a beta emitter and/or a low-energy gamma-emitting nuclide is incorporated into the thermogel along with the positron emitter.

Therapeutic and imaging thermal gels are usually introduced into the patient's body through a catheter, injection, etc., where they rapidly gel and allow the gel to reside in cancerous or tumor-laden tissues. Therapeutic and imaging thermal gels are usually introduced as a liquid medium with sufficient density and viscosity so that the thermal gel remains liquid during the administration process and rapidly gels after being introduced into relatively warm target tissues.

Thermogels have a composition that becomes more viscous when heated.

Typically, thermogels are more fluid at room temperature, while gels become more viscous and essentially behave as solids at in vivo temperatures. In one embodiment, a PLGA-g-PEG polymer is synthesized, and its gelation temperature in phosphate buffered saline (PBS) is 26°C. Several batches of polymers are synthesized to narrow the conditions required to obtain a gelation temperature of about 26°C. The reaction conditions, polymer composition obtained by NMR, and gelation characteristics obtained by dynamic rheology are summarized in Table 1 below. The rheological data of 30w% polymer in PBS are shown below.

Table 1.

Example

A certain amount of thermogel was prepared according to the above formulation for AMIC 1. The EPEG cited in Table 1 is a specific precursor catalog item EPEG600 from Polysciences, Inc. mentioned in the prior art. IsoTherapeutics Group (ITG), a subcontracted laboratory located in Angleton, Texas, conducted tests to replicate the polymer described in AMIC 1. Their tests are summarized as follows.

It is clear that the results are not completely reproducible between different laboratories in terms of gelation temperature, MW, LA/GA/EG ratio and overall polymer yield.

Subsequent work by other contract laboratories indicated further differences in polymer properties and overall yields from the same starting formulation. Experts in the technical field noted that the use of EPEG as a thermogelling polymer precursor is unusual and that it is not clear that the idealized polymer structures present in the prior art and subsequently described in the technical literature are actually achieved using this approach. Due to the bifunctional structure of EPEG, each PEG molecule has two reactive epoxy termini, which are likely to promote crosslinking within and between polymer chains, strongly affecting the water solubility and gelling properties of the polymer.

We tested various reaction parameters but soon realized that rigorous procedures were required to ensure completely anhydrous and oxygen-free reaction conditions to avoid deleterious side effects. Applying such techniques allowed for increased reaction temperatures and enabled high reaction yields (~90%) to be achieved, compared to <50% previously. Examination of the reaction stoichiometry showed that previous formulations transferred from prior art techniques, which relied on supplying excess EPEG and controlling specific reaction conditions to obtain the desired product, were not stable or highly reproducible in producing the desired product.

Examples of compositions that produce desired gelling properties using starting components of varying molecular weights and stoichiometric ratios are shown below:

210719mPEG 750, reduced EG – repeat 0628

The prior art does not teach the importance of solvent selection and purification methods for the final polymer. Studies have found that the type of organic solvent, relative volume and number of dissolution/precipitation cycles are very important for achieving the desired final properties. This is because it is observed that these cycles remove the lower molecular weight portion of the incompletely polymerized material. However, having some of these materials present in the final mixture helps to achieve the desired gelation properties. In addition, it is desirable to select a solvent with low toxicity and the properties of being easy to remove from the final polymer mixture. This is to ensure that the residual level of solvent in the final product meets the FDA's guidelines on the allowable concentration of solvents in injectable medical products. The solvent can be removed by heating and high vacuum, freeze drying, etc., but the stringent conditions required to meet the restrictions can be optimized by selecting solvents and purification conditions.

Ultimately, the polymer must be dissolved in an aqueous medium to be suitable for injection into the body and achieve the desired gelation properties, such as gelation temperature and gel strength measured by rheological parameters. This is a balance between low viscosity at room temperature for easy handling and loading into the needle and the temperature range of gel final strength and gel formation. It is generally assumed that the dissolution of such polymers in phosphate buffered saline is sufficient to reach a physiological pH of 7.4. However, it was found that standard buffers were not sufficient to produce such low pH levels. By adjusting the concentration of inorganic buffer ions, we were able to achieve a neutral pH. This can also be achieved with certain organic buffer solutions. We found that the buffer also significantly changed the rheological properties, allowing gelation over a wider temperature range and ultimately allowing a higher strength of the final gel.

The above prior art teaches that certain combinations of thermogelling polymer solutions can provide desired properties, such as gelling temperature, gel strength, and the time required to tailor the degradation of the polymer into fragments that can be resorbed in the body. It is not clear whether combinations of different thermogel types can achieve the desired properties. By analyzing the theoretical polymer structures, synergistic effects or conversely antagonistic effects or functional inactivation are not significant. Similarly, it is not significant in nature to combine radioactive particles with various thermogelling hydrogel compositions to achieve good distribution of the radioactive source when injected or placed in tissue. We have studied the utility of combining radioactive particles with various available thermogelling polymers and combinations to achieve the desired properties for interstitial injection as a distributed source of therapeutic radiation and for bolus or planar sources of therapeutic radiation.

Example

Measure about 80mL of anhydrous toluene into a 100mL volumetric flask using the following procedure: seal the flask with a rubber septum and use an 18G needle connected to a rubber hose for vacuum purge. When negative pressure is reached, remove the needle. Insert one end of a 24-inch double-sided 20G sleeve needle through the sealed septum into the bottom of the anhydrous toluene bottle. Insert the other end of the sleeve into the rubber septum of the volumetric flask. Use an 18G needle connected to a rubber hose to pump argon into the toluene bottle so that the toluene is transferred to the flask without contact with air or moisture. Fill the flask to about 80% capacity, a total of about 80mL of anhydrous toluene.

A double-necked 500 mL round bottom flask (RBF) rinsed with acetone, dried at 100°C, cooled in a desiccator and equipped with a magnetic stirring bar was calibrated weight. 30.01 g EPEG was slowly transferred in. The RBF was calibrated weight again. 3.51 g mPEG 750 was added to the RBF. About 80 ml of toluene was added to the flask. The argon hose was connected to the piston attached to the side neck of the RBF, and argon was gently pushed into the system (about 40 cc/min) when the vacuum distillation apparatus was assembled. The distillation head was connected to the middle neck. The condenser temperature on the water recirculator was set to -10°C. A 25 mL single-necked RBF was connected to the end of the condenser head along with a condenser dripper and a threaded side arm. The argon line was removed from the piston and connected to the thread (barb) of the dripper adapter; the piston was opened to exhaust the argon. Ice packs were filled around the single-necked RBF collector. The argon was turned off and the piston was closed. A vacuum was applied through a hose connected to the dripper adapter. Set to stir the PEG/toluene solution at about 200RPM at 50°C. In this way, PEG is vacuum distilled until toluene almost disappears (about 1 hour). Then, stop heating and allow the system to cool to room temperature under continuous vacuum. After cooling, backflush the system with argon. Once the pressure in the system reaches equilibrium, open the piston to facilitate ventilation. Under a continuous (about 100cc/minute) argon flow, remove the distillation assembly and keep the piston at the side neck. Slow down the argon flow to about 25cc/minute. Add 35.01g of D,L-lactide and 9.01g of glycolide through the funnel of the middle neck. Draw 5.0mL of 10% Sn octanoic acid/toluene (w:v) solution. Seal the middle neck with a glass stopper, and vacuum purge the reaction flask for about 1 hour, then backflush with argon. Add about 100mL of anhydrous toluene (drawn from the bottle in the same way as before) through the funnel of the middle neck. Move the piston to the middle neck. A 9" glass Pasteur pipette was pushed into the thermometer adapter attached to the side neck so that the tip of the pipette penetrated about 1.5 inches below the surface of the reaction solution. A stream of argon (about 50 cc/min) was slowly pumped through the pipette and stirred at 300 RPM for about 20 minutes. A reflux condenser with a dry-trap on top was attached to the middle neck. A coolant was circulated through the condenser at -10°C. The piston was moved to the side neck and argon was pumped through the piston at about 50 cc/min for about 30 minutes. The piston was closed and set to 130°C for 24 hours with stirring at 300 RPM. The next day, the reaction solution was rotary evaporated until all toluene appeared to be gone. The polymer was redissolved using 250 mL of acetone. Measure 155 grams of washed activated granular carbon (about 2 times the mass) into a 1L bottle, then pour the polymer solution on top of the activated carbon, followed by substantial removal of the tin. Use acetone to rinse the residual polymer from the reaction flask into the bottle. Cap the bottle and let it sit overnight in a desiccator chamber. The solution is then passed through a Buchner funnel with a moderate vacuum; use plenty of acetone to wash as much polymer as possible from the granular carbon. Pass the filtrate through a series of polyvinylidene fluoride (PVDF) filters, ending with a 0.1um pore size membrane. The filtrate is transferred to a 1L pear-shaped bottle, rotary evaporated to about 200mL, and then poured directly into 2L of stirred hexane. The precipitated material is collected and vacuum dried at 55°C with a yield of about 85% and less than 65ppm of residual tin.

The monomer ratios were optimized for gelation properties. The following table provides an analytical description of this example.

In general, the PLGA-g-PEG gel material produced in this way can selectively optimize the monomer ratio, thereby realizes the formation of optimal gel properties in a highly reproducible manner. The reaction is carried out under selective conditions, to remove oxygen and water molecules in the reaction solution to the greatest extent before the reaction begins, which is different from previous attempts in this field. Purification is completed by combining non-solvent precipitation based on hexane and removing stannous octanoate (stannous octanoate) by activated carbon soaking and then filtering, without the need for multiple washings to realize the required gelling properties. Removing tin from the gel makes the gel more biocompatible.

Many radioisotopes are suitable for delivering therapeutic radiation to diseased or unwanted tissue or for external imaging of source placement, or both.

A variety of physical and chemical forms are described, including encapsulation in insoluble inorganic compounds, organic chelating/complexing agents, or inert media such as glass microspheres. The specific method of immobilization must depend on the chemical properties of the desired isotope and the degree of immobilization required for the in vivo environment. We have developed new methods for 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, etc. These embodiments are specifically designed to be compatible with PLGA-g-PEG and other hydrogels and combinations of hydrogels to provide local sources for in vivo treatment of cancer and other diseases.

The advantage of the novel thermogel and thermogelation method disclosed herein is that additives with radioactive sources can be utilized in thermogelation hydrogel vehicles for various purposes. Additives considered include analgesics, anticancer agents, antibiotics, imaging agents, etc. We have evaluated the effectiveness of incorporating such agents, especially the use of antibiotics to counter the possibility of developing infections at the site of application of radioactive source materials. In this regard, important parameters are the resistance of such agents to degradation caused by radiation exposure and the ability to maintain their desired functions. It is also beneficial that there are no harmful degradation products to ensure the safety of use.

Example

In this example, all samples were resuspended at low temperature in phosphate buffered saline (PBS) at a concentration of 31.25% w:v hydrogel solution. All three solutions were kept refrigerated.

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

Under a laminar flow hood, 9 mL of Pluronic F-127 solution was injected into a vial containing approximately 1 mL of YPO ₄ particles. The vial was vortexed for approximately 10 seconds. 5.0 mL of each solution was transferred to a 50 mL Falcon tube (pre-heated to 37° C.). The tubes were placed in a 37° C. incubator until gelled. 5 mL of 37° C. PBS was moved into each tube. The tubes were maintained at 37° C. and vibrated at 100 RPM for 10 minutes. 4 mL of supernatant from each tube was transferred to a vial and analyzed for yttrium, yielding the following values for yttrium in the supernatant. Note that this indicates that yttrium was not successfully captured.

Using thermogels to capture yttrium particles is not obvious, as not all thermogels are suitable for this application. Notably, Pluronic F127 failed to capture the particles.

Although PLGA-PEG-PLGA (triblock) and PLGA-g-PEG successfully captured particles; PLGA-g-PEG had advantages over PLGA-PEG-PLGA in other properties, including speed of resuspension and ease of handling.

Although the present invention has been illustrated and described in detail in the drawings and the foregoing description, these illustrations and descriptions should be considered illustrative rather than restrictive. It should be understood that the foregoing description has shown and described embodiments that meet the best mode and implementation requirements. It should be understood that a person of ordinary skill in the art can easily make a nearly unlimited number of non-substantial changes and modifications to the above-mentioned embodiments, and it is impractical to attempt to describe all of these changes in the present description. Therefore, it should be understood that all changes and modifications within the spirit of the present invention need to be protected.

Claims (15)

1. A radioactive thermogel suspension comprising:

Thermal gelation; and

A plurality of radioactive yttrium phosphate particles suspended in the thermal gel; wherein the thermal gel is PLGA-g-PEG;

Wherein the thermal gel contains less than 65ppm stannous octoate;

wherein the plurality of radioactive yttrium phosphate particles have a diameter of 0.03 μm to 10 μm;

wherein the plurality of radioactive yttrium phosphate particles are generally spherical; and

Wherein the concentration of YPO ₄ particles is 3mg/ml to 100mg/ml.

2. The radiothermal gel suspension of claim 1, wherein said radioactive yttrium phosphate is combined with said thermal gel to produce a thermal gel polymer having a final concentration of about 25 to 30w% in an aqueous buffer solution.

3. The radiothermal gel suspension according to claim 1, wherein the pH of said radiothermal gel suspension is from 1.5 to 8.0.

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

5. The radioactive yttrium phosphate suspension according to claim 1, wherein at least some of the yttrium phosphate comprises a radioactive phosphorus isotope.

6. A radioactive thermogel suspension comprising:

A thermogel, wherein the thermogel is PLGA-g-PEG containing less than 65ppm stannous octoate; and

A plurality of radioactive metal phosphate particles suspended in the thermal gel, wherein each metal phosphate particle comprises a metal cation and a phosphate bearing functional group; and

Wherein the plurality of radioactive phosphate particles have a diameter of 0.03 μm to 10 μm.

7. The radiothermal gel suspension of claim 6, wherein the plurality of radiometal phosphate particles have a diameter of from 0.1 μιη to 2 μιη.

8. The radiothermal gel suspension according to claim 6, wherein said 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 radiothermal gel suspension of claim 6, wherein said metal phosphate particles have a solubility of less than 1 x 10 ^-6 moles/liter.

10. The radiothermal gel suspension according to claim 6, wherein said metal cations are selected from the group consisting of: y, ho, yb, ce, sm, lu, sc, ca, sr, ba and combinations thereof.

11. The radiothermal gel suspension of claim 6, wherein said phosphate functionality comprises a phosphorus isotope selected from the group consisting of: ³¹P、³²P、³³ P and combinations thereof.

12. The radiothermal gel suspension of claim 6, wherein said concentration of metal phosphate particles is from 3mg/ml to 100mg/ml.

13. The radiothermal gel suspension of claim 12, wherein said metal phosphate particles provide a dose of 100 to 300 mCi.

14. The radiothermal gel suspension according to claim 6, wherein said metal cations are 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 wherein the phosphate functionality comprises a phosphorus isotope selected from the group consisting of: ³¹P、³²P、³³ P and combinations thereof.

15. A radioactive metal phosphate/thermal gel suspension comprising:

PLGA-g-PEG thermogel containing less than 65ppm stannous octoate; and

A plurality of radioactive metal phosphate particles suspended in a phosphate buffered saline solution, wherein each metal phosphate particle comprises a metal cation and a phosphate bearing functional group;

Wherein the plurality of radioactive metal phosphate particles have a diameter of 0.03 μm to 10 μm;

wherein 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;

Wherein the metal phosphate particles have a solubility of less than 1 x10 ^-6 moles/liter;

Wherein the phosphate functional group comprises a phosphorus isotope selected from the group consisting of: ³¹P、³²P、³³ P and combinations thereof; and

Wherein the metal phosphate particles provide a dose of 100 to 300 mCi.