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This is why our patent and Radiogel is so valuable! Brachytherapy seed with fast dissolving matrix for optimal delivery of radionuclides to cancer tissue

A system, method and device for treating tumor cells utilizing a resorbable therapy seed made up of microspheres containing a beta- or alpha-particle-emitting radiation source and a resorbable polymer matrix.

http://www.google.com/patents/US8821364 TAKE A LOOK!

Beta or Alpha Particle!

A recent article on Alpha Emitters. Alpha Emitters are the future and with our Y-90 products (Beta emiter) ADMD has an extremely valuable patent and product. Below the Alpha Emitters article is a writeup on the technology that shows that it includes both Alpha and Beta emitters and explains why this technology is so valuable and will get FDA approval in time. Do your due diligence. Do your research on Alpha Emitters and study the patent,

Alpha therapy targets metastatic disease

Modern radiotherapy approaches based on precision delivery of photon or proton beams provide sophisticated tools with which to treat tumours. But despite continuing advances in these technologies, survival rates for some cancer types have not improved in decades. Speaking at the recent IUPESM World Congress in Toronto, Canada, Eva Bezak from the University of Adelaide in Australia discussed how targeted radiation therapies could help.

Eva Bezak
Eva Bezak
"Challenges in cancer management can be divided into treatment of local and disseminated disease," Bezak explained. "We have to ask how we can improve outcomes in both of these branches." Treatments for localized cancers are reasonably successful, she said, though with highly site-dependent outcomes. But there are few effective options available to successfully manage advanced metastatic cancer. "So can we come up with new strategies that can deliver more benefit for a limited increase in cost?"

Bezak proposed that short-range, targeted, high-LET (linear energy transfer) radiation may provide a means to destroy disseminated micrometastases. She introduced the concept of targeted alpha therapy (TAT) – a type of radio-immunotherapy. TAT works by labelling a tumour-specific antibody with an alpha-emitting radioisotope. This radio-immunoconjugate then attaches to antigens on the cancer cells, delivering a highly targeted radiation dose to the tumour while minimizing irradiation of surrounding healthy tissue.

Alpha particles are particularly suited for this approach as they have a short range (20–80 µm, which encompasses 2–4 surrounding cells), and a high LET of around 100 keV/µm. Potential alpha-emitting isotopes include: bismuth-213, with a half-life of 46 minutes; astatine-211, with a half-life of 7.2 hours; radium-223 with a half-life of 11.4 days; and thorium-227, which has a half-life of 18.7 days.

The antibodies used for tumour targeting, meanwhile, must be chosen for each particular cancer type. Example monoclonal antibodies include 9.2.27 for treating melanoma or glioblastoma, WM-53 for leukaemia, C595 for pancreatic and prostate cancers, C30.6 for colorectal cancer, and Herceptin for breast and ovarian tumours. "It's a major task to find a tumour-specific antigen and create the radio-immunoconjugates," said Bezak, noting that alpha-emitting drugs are already being developed for several solid cancers and leukaemia.

There are also phase 1 clinical trials of TAT in place, mostly for treating leukaemia and lymphomas, with a couple of studies looking at melanomas and glioblastomas. "Radium-223 chloride has been approved in the US for palliative therapy of advanced prostate cancer," Bezak told the delegates. "Recent clinical trials have been positive."


Addressing hypoxia
Next, Bezak introduced a new concept: "necrotic TAT", which uses a radio-immunoconjugate that specifically targets necrotic cells. The aim here is to deliver alpha emitters directly to radioresistant hypoxic tumour cells, by exploiting the observed spatial correlation (co-location) between necrotic tumour regions and regions of hypoxia. Using the emitted alpha particles to kill hypoxic tumour cells should help reduce the likelihood of recurrence and metastasis.

Bezak described an investigation performed by her research team at the University of Adelaide and the Royal Adelaide Hospital. In this study, mice with Lewis lung tumours were treated with the murine monoclonal antibody DAB4 (which targets an antigen that is overexpressed in necrotic tissue) radiolabelled with thorium-227. Each mouse received about 18 kBq of Th-227-DAB4 and some were also given cisplatin beforehand.

Images of tumour sections from treated mice
Images of tumour sections from treated mice
After therapy, the researchers performed autoradiography using a Timepix detector to monitor Th-227-DAB4 uptake and distribution in excised tumour sections. The results showed that the radio-immunoconjugate accumulated in the tumour, and that the density of detected alpha particles increased four-fold after chemotherapy, due to an increase in necrotic tissue volume following chemotherapy.

"TAT will play an important role in the treatment of disseminated, chemoresistant and radioresistant metastatic disease," Bezak concluded. "When combined with other therapies, TAT is likely to improve survival." The next step in the evolution of this approach, from a physics point of view, will be to develop appropriate techniques to monitor and quantify radio-immunoconjugate uptake and local dose deposition using novel microdosimetry detectors.

Here is the writeup

The Polymer Sphere has no Peer!

Why is this technology worth so much?

Brachytherapy seed with fast dissolving matrix for optimal delivery of radionuclides to cancer tissue

A system, method and device for treating tumor cells utilizing a resorbable therapy seed made up of microspheres containing a beta- or alpha-particle-emitting radiation source and a resorbable polymer matrix. These seeds are implanted within the tumor and then rapidly dissolved so as to release the microspheres from the polymer matrix. These microspheres then spread within a preselected target area and provide radiation therapy in a predetermined amount and at a preselected rate according the specific needs and necessities of the users. The configuration of the microspheres, the types of radiation provided and the location and use of these microspheres provides desired localized treatment to target cells while preferentially avoiding or minimizing undesired damage to surrounding tissue.

Treatment of cancerous tissue by exposure to radiation-emitting material is now a well established and accepted practice. Generally, the aims of such a practice include targeting exposure of radiation to the tissue surrounding or adjacent to a radiation source while keeping the radiation effects on neighboring healthy tissue to a minimum. A major advantage of this form of treatment is that it concentrates the emitted radiation at the site where the treatment is needed, e.g. within or adjacent to a tumor, while keeping the amount of radiation transmitted to the healthy tissue far below what it otherwise would be if the radiation were beamed into the body from an external source, using other forms of teletherapy.

Prior art forms of brachytherapy typically include various processes such as placing the source(s) typically small metallic capsules, approximately 4.5 mm long and 0.8 mm in diameter, called seeds containing a radiation sources such as iodine-125, cesium-131, or palladium-103, which are placed within the tissue to be treated, i.e. interstitial therapy. In various embodiments of the construction, the capsule is typically designed to allow the rapid and facile insertion of the seed into the organ or body part being treated, with minimal trauma to the targeted and surrounding tissues. These devices are many times inserted into the body percutaneously using a hollow needle which is preloaded with the desired number of therapy seeds. When the needle is in the desired location in the tissue, a stylet is used to hold the seeds in place while the needle is withdrawn from around them, leaving the seeds in the desired location. The use of such small radiation sources is a common way of practicing interstitial brachytherapy.

In many such methods it is typically considered necessary and in some cases crucial to enclose the radioactive material with an encapsulating material so as to contain the radioactive material and preventing it from becoming systemically distributed within the patient or escaping into the environment where it could contaminate medical personnel, medical facilities or the general environment. Various types of encapsulating devices and materials have been utilized and are presently contemplated. Typically these materials contain the radioactive material while allowing photon radiation (Auger x-rays) to irradiate cancerous tissues while the radioactive source decays to negligible activity. Typically, the metallic seed remains permanently implanted. A further polymer embodiment containing the radioactive source may gradually dissolve in the body after the radioactive source has decayed to negligible activity.

Another major drawback for metal-encapsulated seeds is that the encapsulating metal absorbs a significant fraction of the low-energy beta and photon radiation emitted by the contained radioisotope, for example about 14% of the iodine-125 x-rays and 40% of the palladium-103 x-rays are absorbed in the encapsulating metal in the current commercial seeds. As a consequence, to obtain the desired radiation dose rate on the exterior of the seed, an additional amount of relatively costly radioisotope activity must be added to overcome the losses in the encapsulating metal. Also, because it is typically necessary to seal (or weld). the ends of the capsules, the effective thickness of the metal is not the same in all directions resulting in a radiation field around the seed which is not uniform, a fact that complicates treatment planning and raises the possibility of the existence of areas within the treatment volume in which the radiation dose is non-uniform or below that required to kill all tumor cells present.

Thus the current practice of brachytherapy based on the use of discrete encapsulated sources is limited by: the need to associate groups of discrete seeds together by some means so that they can be placed into tissue in a predetermined array and held in that array throughout the therapeutic life of the sources, the need for complex treatment planning that takes into account the discrete nature of the seeds and the shape of the radiation field around each seed with the assumption the field shape around each seed is uniformly the same, the need to add excess radioactivity to compensate for the radiation absorption in the encapsulating metal, and the creation of a nonuniform radiation field around the source because the geometry and effective thickness of the encapsulating metal is not the same in all directions, and the radiation field about a source is not precisely spherical. The present invention as disclosed herein, significantly reduces each of these limitations and furthermore allows a more complete realization of the potential benefits of brachytherapy. The present invention includes a device, method and system for implementing brachytherapy and creating devices for use in such methods and systems. The present invention provides substantial advantages over the devices taught in the prior art.

Additional advantages and novel features of the present invention will be set forth as follows and will be readily apparent from the descriptions and demonstrations set forth herein. Accordingly, the following descriptions of the present invention should be seen as illustrative of the invention and not as limiting in any way.

SUMMARY

The present invention is a method, system and device for treating tumor cells utilizing a resorbable therapy seed comprising microspheres containing alpha or beta emitting radiation source and a resorbable polymer matrix containing the microspheres. In use, these seeds are implanted within the target tissue, such as a prostate carcinoma tumor, and then dissolved so as to release the microspheres so that they are not encumbered by a surrounding, energy-absorbing material. These microspheres then slightly spread within a preselected target area and provide radiation therapy in an amount and at the rate of radioisotope decay according the specific needs and necessities of the users. The configuration of the microspheres, the types of radiation provided and the location and use of these microspheres provide desired localized treatment to target cancer cells while preferentially avoiding undesired damage to surrounding tissue. Because beta radiation is defined by a distinct energy-range cutoff, this method combined with the materials and methods for production of these materials provides a significantly more effective and less expensive therapy alternative than other methods taught in the prior art.

In one embodiment of the invention the resorbable therapy seed contains a plurality of microspheres preferably of a generally uniform size, and having a diameter of less than 50 microns. While these preferred descriptions are provided it is to be distinctly understood that that the invention is not thereto but may be variously alternatively embodied according the respective needs and necessities of the individual user. Each of these individual microspheres contains a beta particle emitting material such as yttrium-90 preferably bound up in an insoluble chemical form. While yttrium-90 has been provided as an example of one material, it is to be distinctly understood that the invention is not limited thereto but may be variously embodied and configured to include a variety of materials including but not limited to phosphorus-32, copper-64, copper-67, iodine-131, lutetium-177, samarium-153, holmium-166, rhenium-186, and rhenium-188. It also includes the alpha-emitters that are usually considered for interstitial radiation therapy, including but not limited to actinium-225, bismuth-213, bismuth-212, thorium-227, radium-223, astatine-211, and terbium-149. This chemical binding of radioisotope within an insoluble form prevents dissolution and release of the radioactive material in body fluids leading to translocation to other parts of the body where such radiation is not desired. A colloid form of binding while not required is preferable.

This beta- or alpha-emitting material is then encapsulated by a fast-resorbable polymer that acts to give physical form and rigidity to the brachytherapy seed, enable surgical placement, and restrain the radioactive material in a desired position and location. In addition to these microspheres, the resorbable seeds of the present invention also contain an imaging material. Various examples of imaging materials may be utilized including but not limited to metallic, preferably gold, particles. Preferably, these microspheres and these imaging materials are mixed within a resorbable polymer matrix that holds the materials together but can respond, after surgical delivery, to various stimuli such as temperature, pH, ultrasonic energy, body fluid characteristics and other influences which increase polymer dissolution rates. This combination can then be pressed or extruded into a shape, preferably rods and then and cut into individual seeds of a particular preselected size. While in some applications the geometry of the particular seed is that of a cylinder having dimensions appropriate for the use of most typical implantation tools, it is to be distinctly understood that the invention not limited thereto but that a variety of other sizes, shapes and dimensions are also contemplated and may be utilized according to the needs and necessities of the user. In particular it is contemplated that generally flat or slightly convex seeds in any of a variety of geometries could be die cut from sheet a flat thin sheet of material may have various useful applications depending upon a particular embodiment. Individual seeds can then be coated with a preferably thin, outer coating so as to provide particular advantages consistent with the needs and necessities of the user.

Preferably, the resorbable therapy seed of the present invention provides a therapeutic index greater than 1.0, and has an effective therapy range that is limited by the range of beta- or alpha-particles in the seed or target tissue (approximately 1.1 cm for yttrium-90) to limit therapy doses to target tissues within this range and protect normal tissue outside of this range from undesirable radiation effects. With these seeds, the method of the present invention can then be performed. In one embodiment of the invention the method comprises the steps of implanting a resorbable therapy seed such as those described above within a preselected tumor or at a preselected location. Once surgically placed, if desired, imaging of the location of the seed can be accomplished. After the seed has been placed, it is rapidly dissolved through any of a variety of ways depending upon the particular material that the polymer matrix is composed of. Thus the dissolution of his material may take place through ultrasonic energy, reaction with the internal temperature of the body, reaction with a body fluid or any of a variety of other ways. Once the seed polymer encapsulation has been appropriately placed and dissolved, the radioactive microspheres are appropriately released within the target cancer. These microspheres generally remain in place and the beta- or alpha-particles from radioactive emissions from the microspheres are appropriately delivered to the target tissues.

The present invention provides a variety of additional advantages over the prior art. These include but are not limited to better radiation quality for tumor cell killing, a better therapeutic index by reducing the dose to nearby normal tissues, and therefore the ability to treat tumors at higher doses than is taught in the prior art, lower cost for materials and preparation, resorbable seed materials dissolve into the body rather than leaving metal pieces in the body, the provision of an outer thin coating that can be variously configured for alternative embodiments and modalities, the ability of the seed to be degraded by ultrasound, and the prevention of unintended migration of the beta emitting material throughout the body.

The purpose of the foregoing abstract is to enable the United States Patent and Trademark Office and the public generally, especially the scientists, engineers, and practitioners in the art who are not familiar with patent or legal terms or phraseology, to determine quickly from a cursory inspection the nature and essence of the technical disclosure of the application. The abstract is neither intended to define the invention of the application, which is measured by the claims, nor is it intended to be limiting as to the scope of the invention in any way. Various advantages and novel features of the present invention are described herein and will become further readily apparent to those skilled in this art from the following detailed description. In the preceding and following descriptions I have shown and described only the preferred embodiment of the invention, by way of illustration of the best mode contemplated for carrying out the invention. As will be realized, the invention is capable of modification in various respects without departing from the invention. Accordingly, the drawings and description of the embodiments set forth hereafter are to be regarded as illustrative in nature, and not as restrictive.

In most preferred embodiments of the present invention the beta- or alpha-emitting radiation source has a generally short half-life (less than 60 days, and preferably less than 9 days). More specifically, in certain cases the radioisotope is selected from the group of yttrium-90, phosphorus-32, copper-64, copper-67, iodine-131, lutetium-177, samarium-153, holmitim-166, rhenium-186, rhenium-188, and combinations thereof. Beta particles have short path length in tissue, which indicates minimal irradiation of surrounding normal tissue. In addition, these beta emitting radiation sources are generally confined to a specific target tissue. Alpha particle ranges are even shorter (typically 40 to 80 micrometers in tissue.

n one example of the present invention, seeds 10 as described above are implanted into a selected portion of tumor tissue. The tumor is preferably imaged to verify placement of the seeds in the desired location. After this imaging has taken place, the seeds are dissolved and microparticles that contain the beta- or alpha-emitting source are then released to provide therapeutic radiation to the tumor to destroy the unwanted tumor tissue. This method provides several advantages. First, this method provides a user the ability to use inexpensive materials as the seed matrix, radioisotope, and markers. Second, this less expensive seed has the ability to deliver higher localized radiation doses to radiation-insensitive solid tumors (which could include cancers of the liver, pancreas, brain, kidney, head and neck, prostate, colon, and others, or solid tumors that are not resectable and that must be treated effectively without surgical removal, such as those that may surround major blood vessels, the vocal chords or spinal column nerves. The present invention provides an ability to use radioisotopes other than the more common Auger-electron-emitters traditionally used in seed brachytherapy, such as iodine-125, paladium-103, and cesium-131, which are all relatively expensive to produce. The present invention also provides the ability to deliver more locally intense radiation doses to tumor tissues than achieved using the Auger-electron emitters mentioned above.

The brachytherapy seed of claim 2 wherein the radioisotope is a beta-particle-emitting radionuclide.

4. The brachytherapy seed of claim 1 wherein the radioisotope is one of yttrium-90, rhenium-186, rhenium-188, or lutetium-177.

5. The brachytherapy seed of claim 1 wherein the radioisotope is an alpha-particle-emitting radionuclide.

6. The brachytherapy seed of claim 1 wherein the radioisotope is one of actinium-225, bismuth-213, bismuth-212, thorium-227, radium-223, astatine-211, or terbium-149.