Free-radical generating implantable devices

Abstract

The present disclosure provides implantable devices and methods of using the implantable devices in a subject. The implantable devices include a permanent or semi-permanent capsule (108) detectable by an imaging modality; an oxygen generating component including a reactive oxygen species, wherein: the oxygen generating component releases the reactive oxygen species when triggered by an external stimulus.

Description

FREE-RADICAL GENERATING IMPLANTABLE DEVICESTECHNICAL FIELD

[0001] The present disclosure relates generally to the field of free radical generating implantable medical devices for use in conjunction with radiotherapy and methods for use.BACKGROUND

[0002] When performing external beam radiation procedures such as intensity modulated radiation therapy (IMRT) and conformal radiation therapy (CRT) it is important that a target for radiation be accurately identified. To accomplish this, radiopaque markers (sometime referred to as fiducial or fiduciary markers) are often implanted into the patient at or near the target, so that the radiation can be accurately focused.

[0003] Brachytherapy seeds have been delivered in combination with drugs and other agents to provide additional treatment methods to a tumor or cells directly, or to surrounding environment. Additional agents that have been used in brachytherapy along with radioactive seeds include diagnostic markers such as imaging agents and contrast agents, therapeutic agents such as medication, immunological adjuvants, and cytotoxic agents, and chemical reactive agents.

[0004] The effectiveness of traditional radiation treatment, including both brachytherapy and external beam radiation, can be limited by the tissue environment, which may then require a combination therapy or multiple treatment protocols. For example, the intracellular microenvironment of most solid tumors can be significantly hypoxic, and tumor hypoxia has been found to result in radiotherapy resistance. Addition of an oxygen generating agent or a catalyst for forming a reactive oxygen species, for example, have been employed in various forms of radiotherapy to enhance the oxygen concentration in and around a tumor cells in an attempt to improve the radiosensitivity to radiotherapy. Issues arise with delivering or generating the reactive oxygen species to treat the tumor, particularly to treat the tumor cells directly.

[0005] It would be advantageous to provide a source of oxygen within target tumors to deliver reactive oxygen species along with radiation therapy through both external beam radiation and brachytherapy procedures to enhance radiosensitivity of the tumor and expand tumor cell death. The disclosed devices and methods enhance internal radiation treatment of a brachytherapy procedure by increasing the effectiveness of traditional brachytherapy on target tumor tissue, and decreasing the need for additional treatmentSUMMARY

[0006] The implantable device and methods of use described herein combine implantable medical devices used in conjunction with radiation therapy with a reactive oxygen species component to enhance the effect of radiation treatment.

[0007] Example embodiments disclosed herein are directed to implantable devices having a permanent or semi-permanent capsule detectable by an imaging modality; an oxygen generating component including a reactive oxygen species. The oxygen generating component releases the reactive oxygen species when triggered by an external stimulus. The capsule optionally encapsulates one or more radioactive isotopes selected from the group consisting of iodine-125 (1125), palladium-103 (Pdl 03), iridium-192 (Irl 92), cesium-131 (Csl 31), gold-198 (Aul98), yttrium-90 (Y90), and phosphorus-32 (P32). The reactive oxygen species is optionally selected from the group consisting of peroxides, superoxides, hydroxyl radicals, singlet oxygen, alpha-oxygen, and combinations thereof. The reactive oxygen species is optionally a peroxide selected from the group consisting of peroxy acids, metal peroxides, main group peroxides, and organic peroxides, such as formamide peroxide, dicumyl peroxide, dibenzoyl peroxide, diacyl peroxide, Caro’s acid, peroxynitric acid, peroxy disulfates, hydrogen peroxide, peroxynitrite, alkyl peroxide, tert-butyl peroxide, and combinations thereof. Optionally, the implantable includes an external housing, wherein at least a portion of the capsule is disposed within the external housing. Additionally, at least a portion of the oxygen generating component may be incorporated within the external housing. The oxygen-generating component is optionally a microsphere, optionally encapsulating the reactive oxygen species. The implantable device optionally includes an outer coating. The outer coating may include the oxygen-generating component.

[0008] Other embodiments of the present disclosure include methods of treating a tumor in a subject in need thereof, by administering to the subject the implantable devices of the present disclosure. Optionally, the tumor is a prostate or breast tumor. The implantable device may be implanted intratumorally. Optionally, the oxygen-generating component releases the reactive oxygen species in the tumor, generating an oxygen rich environment.

[0009] Still another embodiment of the present disclosure includes a method of generating free radicals in a tumor, by administering the implantable device to a subject having the tumor. Optionally, the tumor is a prostate or breast tumor. The implantable device may be implanted intratumorally. Optionally, the oxygen- generating component releases the reactive oxygen species in the tumor, generating an oxygen rich environment.

[0010] These and other features, aspects, and advantages will become better understood with reference to the following description and the appended claims.

[0011] Additional features and advantages of the embodiments described herein will be set forth in the detailed description that follows, and in part will be readily apparent to those skilled in the art from that description or recognized by practicing the embodiments described herein, including the detailed description that follows, the claims, as well as the appended drawings.

[0012] It is to be understood that both the foregoing general description and the following detailed description describe various embodiments and are intended to provide an overview or framework for understanding the nature and character of the claimed subject matter. The accompanying drawings are included to provide a further understanding of the various embodiments, and are incorporated into and constitute a part of this specification. The drawings illustrate the various embodiments described herein, and together with the description serve to explain the principles and operations of the claimed subject matter.BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG. 1 A schematically depicts an illustrative implantable device according to one or more embodiments of the present disclosure;

[0014] FIG. 1 B schematically depicts a partial cut-away perspective view of an illustrative implantable device according to one or more embodiments of the present disclosure;

[0015] FIG. 2A schematically depicts an illustrative implantable device according to one or more embodiments of the present disclosure;

[0016] FIG. 2B schematically depicts an illustrative implantable device with an alternating arrangement of components according to one or more embodiments of the present disclosure;

[0017] FIG. 3 shows a flow chart depicting a method of treating a tumor according to one or more embodiments of the present disclosure; and

[0018] FIG. 4 is a schematic of a treatment site with an implantable device generating an oxygen-rich environment according to one or more embodiments of the present disclosure.DETAILED DESCRIPTION

[0019] Embodiments described herein are generally directed to implantable medical devices, and methods of introducing the implantable medical devices of the present disclosure into a subject at a target site. For example, implantable medical devices according to the present disclosure generally include a capsule and a reactive oxygen component. In some embodiments, the implantable device includes a radioactive component. In further embodiments, the implantable device includes a coating layer. The implantable devices as set forth herein provide biocompatibility with the subject, such that no adverse reaction to the presence of the tissue marker can be expected.Implantable Devices

[0020] Embodiments of the present disclosure relate to implantable devices for use in treatments such as brachytherapy. In some embodiments, the implantable device includes one or more reactive oxygen species. In some embodiments, the implantable device includes a capsule. In some embodiments, the implantable device may be a tissue marker, a brachytherapy seed, or a combination thereof.Brachytherapy Seeds

[0021] Brachytherapy seeds have been delivered in combination with drugs and other agents to provide additional treatment methods to a tumor or cells directly, or to surrounding environment. Additional agents that have been used in brachytherapy along with radioactive seeds include diagnostic markers such as imaging agents and contrast agents, therapeutic agents such as medication, immunological adjuvants, and cytotoxic agents, and chemical reactive agents.

[0022] A brachytherapy seed is a small radioactive source that is used in brachytherapy, a type of radiation therapy for the treatment of various cancer. The seed is typically a tiny capsule or pellet made of a biocompatible material, such as titanium or stainless steel, that contains a radioactive material, discussed in further detail herein. Brachytherapy seeds are implanted directly into or near the tumor site, either temporarily or permanently. The seeds can be placed using various techniques, such as needles, catheters, or applicators, depending on the specific treatment plan and the location of the tumor. Once implanted, the brachytherapy seeds deliver a controlled dose of radiation to the surrounding tissues. The radiation emitted by the seeds has a short range, allowing for precise targeting of the tumor while minimizing damage to healthy surrounding tissues. Over time, the radiation from the seeds decays, becoming less radioactive until it eventually dissipates.

[0023] The use of brachytherapy seeds offers several advantages in cancer treatment, including targeted radiation delivery, reduced treatment time, and the ability to spare nearby healthy tissues from unnecessary radiation exposure. However, the effectiveness of traditional radioactive brachytherapy seed treatment can be limited by the tissue environment, which may then require a combination therapy or multiple treatment protocols. For example, the intracellular microenvironment of most solid tumors can be significantly hypoxic, and tumor hypoxia has been found to result in radiotherapy resistance. Addition of an oxygen generating agent or a catalyst for forming a reactive oxygen species, for example, have been employed in various forms of radiotherapy to enhance the oxygen concentration in and around a tumor cells in an attempt to improve the radiosensitivity to radiotherapy. Issues arise with delivering or generating the reactive oxygen species to treat the tumor, particularly to treat the tumor cells directly.

[0024] Thus, the present disclosure addresses the need for brachytherapy seeds, and methods of enhancing radiation treatments using a reactive oxygen species with the brachytherapy at a target site.Tissue Markers

[0025] The removal of or excision of tissue from a subject leaves a void. Even in instances where sealing or suturing the incision points to access the tissue is barely visible, the removal of underlying tissue leaves a void. Surrounding tissue may be able to sense the space and eventually refill the void, but such takes time and in the interim, the surrounding tissue is unsupported and risks repercussive events such as collapse. Furthermore, tissue is often removed to assess or resect tissue of concern. In such instances, it can be better to overestimate the amount of tissue that needs removal in order to reduce of chances of incomplete removal. For example, with cancerous or pre-cancerous tissue, the proliferative and / or anti-apoptotic nature of the cells can lead to a large volume of diseased tissue from only a small number of cells.

[0026] Obtaining a tissue sample, such as by biopsy or lumpectomy, and the subsequent examination are conventionally steps for varying processes such as assessment for the presence of cancerous or pre-cancerous cells.. The information obtained from tissue diagnostic tests and / or examinations is frequently used to plan for the appropriate surgical procedure and / or other course(s) of treatment. For example, breast biopsies may be performed where a suspicious lump or swelling is noticed in a breast. After a tissue sample is taken, it may take several days or weeks before the results of the examination of the sample are obtained, and still longer before a treatment plan is determined. Similarly, if surgery is utilized to remove malignant or suspected malignant tissue, the surrounding tissue requires monitoring over significant amounts of time to ensure complete resection of all malignant or tumorigenic cells. With time allowing for healing of tissue, it is clear how tissue markers or an implanted marker within the tissue provide a means to rapidly and easily locate the original site of resected tissue.

[0027] These tissue markers serve as reference points or landmarks for subsequent medical procedures or imaging studies. In some embodiments, the tissue markers aid in radiation therapy planning. For example, the tissue markers provide a reference point for accuratelytargeting the tumor during radiation treatment, ensuring precise delivery of radiation while minimizing damage to healthy tissues. Addition of an oxygen generating agent or a catalyst for forming a reactive oxygen species, for example, have been employed in various forms of radiotherapy to enhance the oxygen concentration in and around a tumor cells in an attempt to improve the radiosensitivity to radiotherapy.

[0028] Thus, the present disclosure addresses the need for tissue markers, and methods of enhancing radiation treatments using a reactive oxygen species with the tissue marker in a tissue at a target site.Reactive Oxygen Species

[0029] In some embodiments, the implantable devices of the present disclosure include an oxygen generating component. In embodiments, the oxygen generating component includes a reactive oxygen species. As used herein, a reactive oxygen species is a compound or molecule that renders cells sensitive to radiation by creating an oxygen rich environments, such that when the targeted tissue receives a dose of radiation, free radicals are produced. Examples of suitable reactive oxygen species include, but are not limited to peroxides, superoxides, hydroxyl radicals, singlet oxygen, and / or alpha-oxygen, and combinations thereof.

[0030] In some embodiments, the reactive oxygen species is a peroxide. Suitable peroxides include, but are not limited to, peroxy acids, metal peroxides, main group peroxides, and / or organic peroxides, and combinations thereof. For example, in some embodiments, the peroxide is formamide peroxide, dicumyl peroxide, dibenzoyl peroxide, diacyl peroxide, Caro’s acid, peroxynitric acid, peroxy disulfates, hydrogen peroxide, peroxynitrite, alkyl peroxide, tert-butyl peroxide, combinations thereof, and / or the like. In some embodiments, the reactive oxygen species comprises formamide. In some embodiments, the reactive oxygen species is formamide peroxide.

[0031] In some embodiments, the reactive oxygen species is released in a controlled manner. For example, the release of the reactive oxygen species is triggered through internal stimulation at the implantation site or external stimuli. Further, the responsiveness of the release of ROS to one or more of the triggers may be affected by the local pH of the device,the local temperature of the device, and / or an amount of time since the device was first introduced into the body. In some embodiments, the release of the reactive oxygen species is triggered by ultrasonic stimulation, radiofrequency, or magnetic pulse. In some embodiments, the release of the reactive oxygen species is triggered by radiation. In other embodiments, the release of the reactive oxygen species is triggered by ultrasonic stimulation.

[0032] For example, release of the reactive oxygen species is triggered by an energy source, such as radiofrequency, either from the radioactive compounds of the implantable device or external beam radiation. Thus, upon the application of radiation therapy, the reactive oxygen species is released and generates oxygen within the implanted site. The oxygen reacts with the radiation to generate free radicals in the tumor. The free radicals may cause or accelerate tumor cell death in combination with the radiation. Ultimately, after radiation has been applied, the reactive oxygen species generates free radical oxygen, causing cytotoxic effects to the targeted tissue of the subject.

[0033] In some embodiments, the reactive oxygen species component is a hydrogel containing one or more reactive oxygen species. Reactive oxygen species can be embedded within the hydrogel during formation and gradually released in response to various stimuli. For example, the reactive oxygen species may be incorporated into the gel in layers to prevent mixing and early release of the reactive oxygen species. In other embodiments, the hydrogels can be engineered to generate reactive oxygen species within the gel matrix through chemical reaction. For example, precursor molecules can be incorporated to generate reactive oxygen species upon exposure to the external stimuli.

[0034] In some embodiments, the reactive oxygen species component is a microsphere containing one or more reactive oxygen species. The microspheres are made from biocompatible materials, such as polymers. Illustrative polymers include, but are not limited to, homopolymers of lactide and glycolide, polylactic acid, polyglycolic acid, caprolactone, polydioxanone, poly (trimethylene carbonate), polyacrylic acid, and copolymers and polymer blends of these bioabsorbable polymers. In embodiments, the microspheres are engineered to release and / or generate reactive oxygen species under specific conditions. In some embodiments, the microspheres are engineered to release the reactive oxygen species on exposure to radiation. In some embodiments, the reactive oxygen species in encapsulated inthe microsphere. In other embodiments, the reactive oxygen species is embedded on the surface of the microsphere. In some embodiments, the microspheres may be covered in a biodegradable coating layer, discussed in greater detail herein.Permanent / Semi-Permanent Capsule

[0035] In some embodiments, the implantable device 100 may include a permanent or semipermanent capsule 102, as shown in FIG. 1A. In embodiments, the permanent or semipermanent capsule is formed of a metal and / or metallic compound. In some embodiments, the capsule remains in place over a prolonged period of time, including at least 6 months, at least one year, at least 5 years, and at least 10 or more years. Such materials may include metals or metallic materials, metal compounds, metal amalgams, metal alloys, or the like. In some embodiments, the capsule includes titanium, nitinol (nickel-titanium), stainless steel, cobaltchromium alloys, titanium alloys, magnesium alloys, and / or other biocompatible metals or metal alloys.

[0036] In some embodiments, as shown in FIG. IB the capsule 102 includes a metal or metallic compound 103 enclosing a radioactive component 106 discussed in greater detail herein. In embodiments, the capsule 102 prevents the unintended release or leakage of the radioactive component. The capsule provides a barrier that isolates the radioactive material from the surrounding environment and reduces the risk of radiation exposure to healthcare providers and patients.

[0037] In some embodiments, the capsule is easily or readily detected through the subject’s skin and / or muscle and / or tissue, such that detection is achieved without incision to the subject. Such techniques can include X-ray, ultrasound, magnetic resonance imaging (MRI), computerized tomography (CT) and / or computerized axial tomography (CAT) scans, fluoroscopy, and / or positron emission tomography (PET) scans. In some embodiments, the material should be selected with respect to the imaging system to be used so as to avoid conflicts, such as between ferromagnetic materials and magnetic-based imaging.

[0038] In some embodiments, the capsule is designed to enhance radiation sensitivity. In some embodiments, the capsule includes a reactive oxygen species component, discussed ingreater detail herein. For example, the capsule can be formed of materials including the one or more reactive oxygen species. In other embodiments, the reactive oxygen species can be disposed on an exterior surface of the capsule in one or more features such as grooves, ravines, or cavities that are formed on the permanent / semi -permanent material. In other embodiments, the reactive oxygen species is chemically etched into the capsule.

[0039] The implantable device may be any shape appropriate for implantation into a tumor in a subject, such as cylindrical, rectangular, or oval in shape. In some embodiments, described in greater detail herein, the implantable device is a strand or array of individual capsules. In embodiments, the implantable device and / or individual capsules are from about 3 mm to about 5 mm in length. The implantable devices and / or individual capsules may have a diameter from about 0.5 mm to about 5 mm, preferably from about 0.5 mm to about 0.8 mm, including about 0.6 mm, about 0.7 mm and about 0.8 mm. The reactive oxygen species component may be from 3 mm to 1 cm in length, preferably from 3 mm to 5 mm in length. In embodiments where the implantable device is a strand or array, the implantable device may be from 1 cm in length to 10 cm in length.Strands

[0040] Strands of radioactive brachytherapy seeds linked or connected together, often with connectors or spacers to separate the radioactive seeds, are commonly used in brachytherapy procedures. In embodiments of the present disclosure, the implantable device includes a plurality of individual capsules, such as seeds or markers, connected together in a strand, forming a flexible and elongated structure. In embodiments, the capsules are linked in a linear strand. In embodiment, the capsules are connected in a two or three-dimensional array. In embodiments, the array is planar. In embodiments, the capsules may be arranged in multiple planar arrays.

[0041] In embodiments, the capsules in a particular strand may be spaced apart by a predetermined interval to vary the spacing to create a desired radiation dosing level, depending on patient needs. The implantable devices disclosed herein may be a strand or an array of capsules connected by a linker and forming a flexible and elongated structure. In embodiments,the individual capsules are separated by components having a reactive oxygen- generating species.

[0042] In embodiments, the capsules contain one or more radioactive components, discussed in greater detail herein. In embodiments, the capsules are linked by a linker formed from a biocompatible material, such as a flexible polymer or stainless steel wire, though any suitable material is contemplated and possible.

[0043] In other embodiments, the linker is formed from material including a reactive oxygen species, separating the individual capsules. In such configurations, the reactive oxygen species component may also serve to space the radioactive brachytherapy seeds in a desired arrangement. For example, and as shown in FIG. 2A, an exemplary implantable device is illustrated. FIG. 2A depicts an implantable device 100 in which the components are arranged in a strand with capsules 102a, 102b connected via a linker formed from a material including a reactive oxygen species 104a, 104b.

[0044] In embodiments, the capsules are alternated with microspheres containing one or more reactive oxygen species. FIG. 2B depicts an implantable device 100 in which the components are arranged in a strand with capsules 102a, 102b, 102c alternating with reactive oxygen species components 106a, 106b, 106c. It should be understood that the radiotherapy device with the capsules and reactive oxygen species components as configured in FIGS. 2A- 2B is only exemplary, and that the device may have other configurations, provided the device retains the functional characteristics of the illustrative devices.

[0045] The strand or array disclosed herein may contain any number and combination of individual capsules and oxygen- generating species components. For example, the capsules and oxygen-generating species components may be arranged in a 1 :1 configuration in the strand or array, or in a 2:1 configuration, etc. Any N:1 ratio, where in N is any integer greater than 1, is contemplated and possible.Housing

[0046] In some embodiments of the present disclosure, as shown in FIG. 1 A the implantable device includes a housing 108.

[0047] In some embodiments, the capsule is housed within a protective material, such as fibroin, chitosan, carboxylmethyl cellulose (CMC), polyglycerol sebacate, and / or hyaluronic acid (HA). In some embodiments, the capsule is housed within a protective polymer to form a housing compartment. In some embodiments, the housing compartment includes a protective polymer surrounding or encasing the capsule within a single layer. In other aspects, the housing compartment includes two or more separated spaces therein, with one space surrounding the capsule and a second space surrounding a reloadable material, such as a hydrogel. In some embodiments, the second compartment can be loaded and / or re-loaded with solutions, such as with solutions containing one or more reactive oxygen species as described in greater detail herein. In further embodiments of the present disclosure the housing compartment(s) can be loaded and / or reloaded with reactive oxygen species in situ. Such techniques can be achieve by injection directly into the reloadable material portion within the housing compartment.

[0048] In some embodiments, the housing may be formed of a biodegradable material, such that the size of the implantable device decreases in situ over time within the subject, ultimately to leave the capsule portions embedded within the subject. In some embodiments, the capsule may be covered with a polymer protective material to promote biocompatibility, such as a coating with fibroin, chitosan, carboxylmethyl cellulose (CMC), polyglycerol sebacate, and / or hyaluronic acid (HA).

[0049] In some embodiments such as shown in FIGS. 1A-1B, the housing serves as a protective covering or enclosure used for radioactive components employed in the treatment and discussed in greater detail herein. In some embodiments, the housing is designed to contain and shield the radioactive material used in brachytherapy, ensuring safety during handling, transport, and implantation into a subject. In embodiments, the housing is designed with features that enhance the ease of handling and loading of the implantable device. For example, the housing may include tabs, grooves, or textured surfaces to facilitate gripping andmanipulation during the implantation procedure. These features ensure precise placement of the implantable device and reduce the risk of slippage or misalignment.

[0050] In embodiments, the housing is made of a biocompatible and / or radiation-resistant material, such as titanium or stainless steel. The housing may be formed of any suitable material, particularly of a material exhibiting features such as compatibility, durability lasting from introduction into the body of a subject and over the course of a treatment, radiation properties amenable to a treatment being performed, and ease of manufacturing. In some embodiments, the housing is titanium or stainless steel. In other embodiments, the housing is formed from one or more polymers, such as high-density polyethylene (HDPE), polytetrafluoroethylene (PTFE or Teflon), or polyurethane. Polymers are may be particularly appropriate when radiolucency (transparency to X-rays) is desired, allowing for better visualization during imaging procedures. In some embodiments, the housing includes gold. Gold may enhance X-ray visibility as compared to other materials, as well as increased photon scattering and improved dose distribution of radiation.

[0051] In some embodiments, the housing is constructed to ensure the stability and durability of the radioactive material. The housing helps maintain the integrity of the source during implantation and treatment, preventing damage or degradation that could affect its radiation characteristics.

[0052] In some embodiments, the housing is designed to facilitate accurate positioning and visualization of the implantable device during implantation. For example, the housing may have unique shapes, colors, or radiographic markers that aid in their identification and tracking under imaging techniques, such as X-rays or ultrasound.

[0053] In some embodiments, the housing is designed to attenuate the emission of radiation from the radioactive material. The housing helps minimize radiation exposure to healthy tissues surrounding the treatment area and protects individuals handling the implantable device. For example, the housing may be engineered to modify the radiation dose distribution around the implantable device. The housing may have varying thicknesses or composition to shape the radiation beam, allowing for tailored dose delivery to the target area and minimizing radiation exposure to surrounding healthy tissues.

[0054] In some embodiments, the housing is designed to enhance radiation sensitivity. In some embodiments, the housing includes one or more oxygen generating species to enhance radiotherapy. For example, the housing can be formed of materials including the one or more reactive oxygen species, the reactive oxygen species can be disposed on an exterior surface of the housing in one or more features such as grooves, ravines, or cavities that are formed on the housing.Coating Layer

[0055] In some embodiments, the implantable device includes a coating layer that at least partially covers the capsule and / or the housing. In some embodiments, the coating layer includes one or more reactive oxygen species, described in greater detail herein. As described above, in some embodiments, the capsule may be enclosed within a protective polymer or a housing compartment. It is accordingly to be understood that reference to coating of the capsule will also refer to coating of the housing compartment and / or protective polymer. In some embodiments, the capsule is entirely covered by the coating layer. In some embodiments, the coating layer is a porous matrix. In some embodiments, the coating layer may be disposed within features, such as grooves, ravines, or cavities that are formed on the housing. These features can be formed on the housing using any suitable method, such as etching.

[0056] In some embodiments, the coating layer is or includes a biocompatible polymer. The coating layer may be fabricated in any desired shape. In some embodiments, the coating layer is of a material that is inert to the subject and / or non-immunogenic, such that the subject’s immune system will not react to the material.

[0057] In some embodiments, the coating layer is designed to be of a material that dissolves and / or erodes following placement of the implantable device in situ within a subject. In some embodiments, the coating layer is of two or more materials that dissolve or naturally erode within a subject. In some embodiments, the coating layer is of a bioabsorbable or biodegradable polymer. As set forth herein, a biodegradable polymer may include a polymer that is well tolerated and / or non-reactive when contacted to a subject or immune-reactive cells thereof and is prone to erosion and / or enzymatic degradation and / or dissolution within the subject or the circulatory system thereof over a course of time. Examples of biodegradable polymers includepolylactic acid polymers (PLA, PLLA, PDLA, PDLLA), polycaprolactone (PCL), poly lactic- co-glycolic Acid (PLGA), poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide) (PLGA-b-mPEG), co-polymers thereof, combinations thereof, and other materials having similar or equivalent properties to the biodegradable polymers here exemplified.

[0058] In some embodiments, the coating layer is of a biodurable polymer. As set forth herein, a biodurable polymer may include a polymer that is well tolerated and / or non-reactive when contacted to a subject or immune-reactive cells thereof and is resistant to erosion and / or enzymatic degradation and / or dissolution within the subject or the circulatory system thereof. Biodurable polymers include polyethylene terephthalate (PET), nylon 6,6, polyurethane (PU), polytetrafluoroethylene (PTFE), polyethylene (PE, low density and high density and ultra-high molecular weight, UHMW), polysiloxanes (silicones) and poly(methylmethacrylate) (PMMA) and Poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP), co-polymers thereof, combinations thereof and other polymer materials fulfilling the functional requirements of biodurability in a specific application or treatment.

[0059] In some embodiments, the coating layer includes a material that provides resistance from water or water-based solutions. Such may include one or more of a purified starch, such as a plant starch (e.g. Arista™), chitosan, hyaluronic acid (HA), carboxymethyl cellulose (CMC), an HA-CMC co-polymer, beeswax, paraffin wax, glycerol, polyethylene glycol (PEG), sorbitol, polysorbates (such as TWEEN), dextran sulfate, pectin, pullulan, hydroxypropyl methyl cellulose (HPMC), sodium alginate, and polyvinyl alcohol (PVA).

[0060] The coating layer may be a material that is dissolved or released by pH dependent release, temperature dependent release, time dependent release, ultrasonic stimulation, radiofrequency, or magnetic pulse.

[0061] For example, degradation of the coating layer is triggered by an energy source, such as, radiofrequency, either from the radioactive compounds of the implantable device or external beam radiation. Thus, the coating layer is configured to open upon the application of external beam radiation therapy to release the reactive oxygen species. Ultimately, after radiation has been applied, the reactive oxygen species generates free radical oxygen, causing cytotoxic effects to the targeted tissue of the subject.Radioactive component

[0062] In some embodiments, the implantable device includes a radioactive component. In embodiments, the capsule encapsulates radioactive particles and / or microspheres. The radioactive component may be a radiotherapeutic agent having at least some efficacy for treating a disease such as cancer. In embodiments, the radioactive component comprises one or more radioactive isotopes or compounds. In some embodiments, the radioactive isotope or compound may have at least some efficacy for treating a cancer such as hepatocellular carcinoma, cancer that has metastasized to the liver, prostate cancer, or breast cancer. The radioactive isotope or compound may include a radioisotope such as a beta-gamma emitter that or a gamma emitter that emits sufficient gamma radiation to enable imaging. Examples of specific radioactive isotopes include, without limitation, bismuth-213, boron- 10, cesium-131, cesium-137, cobalt-60, dysprosium- 165, erbium-169, holmium-166, iodine-125, iodine-131, iridium-192, iron-59, lead-212, lutetium-177, molybdenum-99, palladium- 103, phosphorus- 32, potassium-42, radium-223, rhenium- 186, rhenium- 188, samarium- 153, selenium-75, sodium-24, strontium-89, technetium-99, thorium-227, xenon-133, ytterbium- 169, ytterbium- 177, and yttrium-90. Additional examples include actinium-225, astatine-211, bismuth-213, carbon-11, nitrogen-13, oxygen-15, fluorine-18, cobalt-57, copper-64, copper-67, fluorine-18, gallium-67, gallium-68, germanium-68, indium-i l l, iodine-123, iodine-124, krypton-81m, rubidium-82, strontium-82, thallium-201, or a combination of one or more of these. The microspheres according to embodiments herein may include a compound including any of the foregoing radioactive isotopes. In some specific embodiments, the microspheres may include yttrium-90 or a compound including a yttrium-90 atom such as yttrium phosphate (90YPO4), yttrium sulfate (90Y2(SO4)3) or (89Y90Y(SO4)3), or yttrium carbonate (90Y2(CO3)3) or(89Y90Y(CO3)3).

[0063] In embodiments, each implantable device and / or capsule contains between about 0.15 millicuries and 150 millicuries. In embodiments, each implantable device and / or capsule emits a radiation dose of between about 0.1 and 100 millicuries.

[0064] In some embodiments, the implantable device does not contain radioactive compounds or isotopes. In some embodiments, the radioactive compounds or isotopes may have decayed and can no longer emit a therapeutic level of radiation. In such embodiments,external beam radiation is used to trigger release of the reactive oxygen species from the implantable device.Methods

[0065] The implantable devices as described herein may be used in various methods of radiation therapy, such as brachytherapy. One embodiment provides a method of generating free radicals in a tumor comprising administering to the tumor of a subject implantable device described above. Further provided is a method of treating a tumor comprising administering the implantable device described herein within the tumor. A brachytherapy implantation needle or catheter may be used to implant the device in the tumor. In embodiments of the disclosed methods, the tumor is a prostate tumor. In other embodiments, the tumor is a breast tumor. Other types of tumors are contemplated, including, but not limited to, head and neck tumors, liver tumors, cervical tumors, and / or eye tumors.

[0066] FIG. 3 is a flowchart depicting a specific method 300 of generating free radicals in a tumor. The method includes introducing the reactive oxygen species into a tissue at a target site. The method may include a greater or fewer number of steps in any order without departing from the scope of the present disclosure. For example, in embodiments, the method may include providing an implantable device to a target site (e.g., a tumor or biopsy site).

[0067] The method of FIG. 3 generates free radicals in a targeted tissue. The method at step 302 includes introducing the implantable device into the tissue at the target site. In embodiments, the implantable device may be introduced by syringe, microcatheter, or any suitable introducer. In embodiments, the targeted tissue is a tumor. In some embodiments, the targeted tissue is a prostate tumor. In other embodiments, the targeted tissue is a breast tumor. In other embodiments, the targeted tissue is a biopsy site.

[0068] Since the reactive oxygen species is prevented from being released until triggered, the method of FIG. 3 may include step 304, inducing release of the reactive oxygen species. In some embodiments, the release is triggered by radiation, either from the radioactive isotopes in the implantable device or external beam radiation. In other embodiments, the release is triggered via focused ultrasound stimulation. In other embodiments, the release is triggered bychanges in pH or temperature. Step 304 releases the reactive oxygen species from the implantable device.

[0069] For example, and as shown in FIG. 4, when the implantable device 100 is triggered 401 to release the reactive oxygen species 402, the reactive oxygen species creates an oxygen rich environment 403 within the tissue at the target site 404 over a period of time. In embodiments, the oxygen in the oxygen rich environment 403 reacts with radiation 405 to produce free radicals 406 in the tissue.

[0070] The method of FIG. 3 may be performed as part of a biopsy procedure, for example, after a tissue sample has been taken, the implantable device may be introduced into the subject tissue at the target site. Alternatively, the method of FIG. 3 may be performed on its own or in conjunction with other invasive procedures.

[0071] In the methods provided, the reactive oxygen species component after implantation in the tumor releases the reactive oxygen species into the tumor. The reactive oxygen species dissolves in water, blood or other fluid in the tumor, releasing oxygen into the tumor. The oxygen released into the tumor saturates the tumor, generating an oxygen rich environment. In embodiments, the saturated oxygen in the oxygen rich environment reacts with the radiation from the radioactive brachytherapy seed to produce free radicals. In embodiments, the free radicals generated may be peroxide free radicals, for example. In embodiments of the disclosed methods, the free radicals generated in the tumor impact the tumor cells and cause tumor cell death. For example, the free radicals generated in the tumor react with the deoxyribonucleic acid (DNA) in the tumor cells and disrupt the DNA that leads to tumor cell death.

[0072] A further method provided is treating a tumor in a subject comprising administering the radiotherapy device described herein to the tumor. As described above, the radiation emitted from the radioactive brachytherapy seed and the free radicals generated by the oxygen released by the water-soluble oxygen- generating species in the tumor attack the tumor cells and cause cell death. Additional methods include methods of treating a subject with a tumor, or methods of performing brachytherapy comprising administering to a subject having a tumor the radiotherapy device described herein.

[0073] In the described methods, the implantable device confines the effects of the reactive oxygen species and / or the radiation to the tumor tissue and cells, and limits or eliminates adverse effects on the surrounding healthy tissue.Aspects Listing

[0074] A first aspect of the present disclosure, alone or in combination with any other aspect provided herein, concerns an implantable device comprising: a permanent or semi -permanent capsule detectable by an imaging modality; an oxygen generating component comprising a reactive oxygen species, wherein: the oxygen generating component releases the reactive oxygen species when triggered by an external stimulus.

[0075] A second aspect of the present disclosure, alone or in combination with any other aspect provided herein, concerns an implantable device of the first aspect, wherein the capsule encapsulates one or more radioactive isotopes selected from the group consisting of iodine- 125 (1125), palladium-103 (Pdl03), iridium-192 (Irl92), cesium-131 (Csl31), gold-198 (Aul98), yttrium-90 (Y90), and phosphorus-32 (P32).

[0076] A third aspect of the present disclosure, alone or in combination with any other aspect provided herein, concerns an implantable device of any of the previous aspects, wherein the reactive oxygen species is selected from the group consisting of peroxides, superoxides, hydroxyl radicals, singlet oxygen, alpha-oxygen, and combinations thereof.

[0077] A fourth aspect of the present disclosure, alone or in combination with any other aspect provided herein, concerns an implantable device of any of the previous aspects, wherein the reactive oxygen species is a peroxide selected from the group consisting of peroxy acids, metal peroxides, main group peroxides, and organic peroxides.

[0078] A fifth aspect of the present disclosure, alone or in combination with any other aspect provided herein, concerns an implantable device of any of the previous aspects, wherein the reactive oxygen species is selected from the group consisting of formamide peroxide, dicumyl peroxide, dibenzoyl peroxide, diacyl peroxide, Caro’s acid, peroxynitric acid,peroxydisulfates, hydrogen peroxide, peroxynitrite, alkyl peroxide, tert-butyl peroxide, and combinations thereof.

[0079] A sixth aspect of the present disclosure, alone or in combination with any other aspect provided herein, concerns an implantable device of any of the previous aspects, wherein the reactive oxygen species is formamide peroxide or methanamide.

[0080] A seventh aspect of the present disclosure, alone or in combination with any other aspect provided herein, concerns an implantable device of any of the previous aspects, further comprising an external housing, wherein at least a portion of the capsule is disposed within the external housing.

[0081] An eighth aspect of the present disclosure, alone or in combination with any other aspect provided herein, concerns an implantable device of any of the previous aspects, wherein at least a portion of the oxygen generating component is incorporated within the external housing.

[0082] A ninth aspect of the present disclosure, alone or in combination with any other aspect provided herein, concerns an implantable device of any of the previous aspects, wherein the oxygen- generating component is loaded on or disposed within the radiation device.

[0083] A tenth aspect of the present disclosure, alone or in combination with any other aspect provided herein, concerns an implantable device of any of the previous aspects, wherein the oxygen- generating component comprises a microsphere.

[0084] An eleventh aspect of the present disclosure, alone or in combination with any other aspect provided herein, concerns an implantable device of any of the previous aspects, wherein the reactive oxygen species is encapsulated within the microsphere.

[0085] A twelfth aspect of the present disclosure, alone or in combination with any other aspect provided herein, concerns an implantable device of any of the previous aspects, further comprising an outer coating.

[0086] A thirteenth aspect of the present disclosure, alone or in combination with any other aspect provided herein, concerns an implantable device of any of the previous aspects, wherein the outer coating comprises the oxygen- generating component.

[0087] A fourteenth aspect of the present disclosure, alone or in combination with any other aspect provided herein, concerns an implantable device of any of the previous aspects, wherein the reactive oxygen species is released by degradation of the outer coating.

[0088] A fifteenth aspect of the present disclosure, alone or in combination with any other aspect provided herein, concerns an implantable device of any of the previous aspects, wherein the external stimulus is selected from the group consisting of an ultrasonic stimulus, a radiofrequency stimulus, or a magnetic pulse.

[0089] A sixteenth aspect of the present disclosure, alone or in combination with any other aspect provided herein, concerns an implantable device of any of the previous aspects, wherein the external stimulus is a radiofrequency stimulus from an external beam radiation device.

[0090] A seventeenth aspect of the present disclosure, alone or in combination with any other aspect provided herein, concerns an implantable device of any of the previous aspects, wherein the oxygen generating component comprises a gel.

[0091] An eighteenth aspect of the present disclosure, alone or in combination with any other aspect provided herein, concerns an implantable device of any of the previous aspects, wherein the oxygen generating component is loaded or disposed on the capsule by coating, chemical etching, or within a hollow or porous material.

[0092] A nineteenth aspect of the present disclosure, alone or in combination with any other aspect provided herein, concerns a method of treating a tumor in a subject in need thereof, the method comprising: administering to the subject an implantable device of any of the previous aspects.

[0093] A twentieth aspect of the present disclosure, alone or in combination with any other aspect provided herein, concerns a method of generating free radicals in a tumor, the methodcomprising administering an implantable device of any of the previous aspects to a subject having the tumor.

[0094] A twenty-first aspect of the present disclosure, alone or in combination with any other aspect provided herein, concerns a method of the nineteenth or twentieth aspects wherein the tumor is in the prostate or breast.

[0095] A twenty-second aspect of the present disclosure, alone or in combination with any other aspect provided herein, concerns a method of any of the previous aspects wherein administering the implantable device comprises implanting the implantable device intratumorally.

[0096] A twenty-third aspect of the present disclosure, alone or in combination with any other aspect provided herein, concerns a method of any of the previous aspects wherein the oxygen generating component releases the reactive oxygen species in the tumor, generating an oxygen rich environment.

[0097] A twenty-fourth aspect of the present disclosure, alone or in combination with any other aspect provided herein, concerns a method of any of the previous aspects wherein irradiation of the oxygen-rich environment generates free-radicals in the tumor.

[0098] Although the foregoing devices and methods have, for the purposes of clarity and understanding, been described in some detail by way of illustration, it will be apparent that certain changes and modifications may be practiced, and are intended to fall within the scope of the appended claims. Additionally, it should be understood that the components and characteristics of the devices described herein may be combined and interchanged as appropriate, the steps of the methods described herein may be combined and interchanged as appropriate, and any of the devices described herein may be used in the methods described herein as appropriate. The description of certain elements, characteristics, or steps with respect to a specific figure are not intended to be limiting or nor should they be interpreted to suggest that the element cannot be used in combination with any of the other described elements. It is therefore intended that the appended claims cover all such changes and modifications that are within the scope of the claimed subject matter. Various patents and other publications arereferred to throughout the specification, and each of these publications is incorporated by reference herein, in its entirety.

[0099] It is noted that the terms “substantially” and “about” may be utilized herein to represent the inherent degree of uncertainty that may be attributed to any quantitative comparison, value, measurement, or other representation. These terms are also utilized herein to represent the degree by which a quantitative representation may vary from a stated reference without resulting in a change in the basic function of the subject matter at issue. The term “substantially” is used herein also to represent the degree by which a quantitative representation may vary from a stated reference without resulting in a change in the basic function of the subject matter at issue. Thus, it is used to represent the inherent degree of uncertainty that may be attributed to any quantitative comparison, value, measurement, or other representation, referring to an arrangement of elements or features that, while in theory would be expected to exhibit exact correspondence or behavior, may in practice embody something less than exact.

[0100] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. The terminology used in the description herein is for describing particular embodiments only and is not intended to be limiting. As used in the specification and appended claims, the singular forms “a,” “an,” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0101] It is noted that one or more of the following claims utilize the term “wherein” as a transitional phrase. For the purposes of defining the present technology, it is noted that this term is introduced in the claims as an open-ended transitional phrase that is used to introduce a recitation of a series of characteristics of the structure and should be interpreted in like manner as the more commonly used open-ended preamble term “comprising.”

[0102] It should be understood that where a first component is described as “comprising” or “including” a second component, it is contemplated that, in some embodiments, the first component “consists” or “consists essentially of’ the second component. Additionally, the term “consisting essentially of’ is used in this disclosure to refer to quantitative values that do not materially affect the basic and novel characteristic(s) of the disclosure.

[0103] It should be understood that any two quantitative values assigned to a property or measurement may constitute a range of that property or measurement, and all combinations of ranges formed from all stated quantitative values of a given property or measurement are contemplated in this disclosure.

[0104] While particular embodiments have been illustrated and described herein, it should be understood that various other changes and modifications may be made without departing from scope of the claimed subject matter. Moreover, although various aspects of the claimed subject matter have been described herein, such aspects need not be utilized in combination. It is therefore intended that the appended claims cover all such changes and modifications that are within the scope of the claimed subject matter.

Claims

CLAIMS1. An implantable device comprising: a permanent or semi-permanent capsule detectable by an imaging modality; an oxygen generating component comprising a reactive oxygen species, wherein: the oxygen generating component releases the reactive oxygen species when triggered by an external stimulus.

2. The implantable device of claim 1, wherein the capsule encapsulates one or more radioactive isotopes selected from the group consisting of iodine- 125 (1125), palladium- 103 (Pdl03), iridium-192 (Irl 92), cesium-131 (Csl31), gold-198 (Aul98), yttrium-90 (Y90), and phosphorus-32 (P32).

3. The implantable device of claim 1, wherein the reactive oxygen species is selected from the group consisting of peroxides, superoxides, hydroxyl radicals, singlet oxygen, alphaoxygen, and combinations thereof.

4. The implantable device of claims 1 or 3, wherein the reactive oxygen species is a peroxide selected from the group consisting of peroxy acids, metal peroxides, main group peroxides, and organic peroxides.

5. The implantable device of claims 1, 3, or 4, wherein the reactive oxygen species is selected from the group consisting of formamide peroxide, dicumyl peroxide, dibenzoyl peroxide, diacyl peroxide, Caro’s acid, peroxynitric acid, peroxy disulfates, hydrogen peroxide, peroxynitrite, alkyl peroxide, tert-butyl peroxide, and combinations thereof.

6. The implantable device of claim 1, wherein the reactive oxygen species is formamide peroxide or methanamide.

7. The implantable device of claim 1, further comprising an external housing, wherein at least a portion of the capsule is disposed within the external housing.

8. The implantable device of claim 7, wherein at least a portion of the oxygen generating component is incorporated within the external housing.

9. The implantable device of claim 1, wherein the oxygen-generating component is loaded on or disposed within the radiation device.

10. The implantable device of claim 1, wherein the oxygen-generating component comprises a microsphere.

11. The implantable device of claim 10, wherein the reactive oxygen species is encapsulated within the microsphere.12 The implantable device of claim 1, further comprising an outer coating.

13. The implantable device of claim 12, wherein the outer coating comprises the oxygengenerating component.

14. The implantable device of claim 13, wherein the reactive oxygen species is released by degradation of the outer coating.

15. The implantable device of claim 1, wherein the external stimulus is selected from the group consisting of an ultrasonic stimulus, a radiofrequency stimulus, or a magnetic pulse.

16. The implantable device of claim 15, wherein the external stimulus is a radiofrequency stimulus from an external beam radiation device.

17. The implantable device of claim 1, wherein the oxygen generating component comprises a gel.

18. The implantable device of claim 1, wherein the oxygen generating component is loaded or disposed on the capsule by coating, chemical etching, or within a hollow or porous material.

19. A method of treating a tumor in a subject in need thereof, the method comprising:administering to the subject the implantable device of any of claims 1 to 18 to the tumor.

20. A method of generating free radicals in a tumor, the method comprising: administering the implantable device of any of claims 1 to 18 to a subject having the tumor.

21. The method of claim 19 or 20, wherein the tumor is in the prostate or breast.

22. The method of claims 19 or 20 wherein administering the implantable device comprise implanting the implantable device intratumorally.

23. The method of claims 19 or 20 wherein the oxygen generating component releases the reactive oxygen species in the tumor, generating an oxygen rich environment.

24. The method of claim 23, wherein irradiation of the oxygen- rich environment generates free-radicals in the tumor.

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