Tumor and cancer treatment devices, systems and methods

Abstract

A Mg-Zn-Ca-Mn alloy for use in the treatment of malignant tumors, use of the Mg-Zn-Ca-Mn alloy in the manufacture of a medicament for the treatment of malignant tumors, and a method of treating malignant tumors comprising administering to a patient a medicament containing the Mg-Zn-Ca-Mn alloy. The Mg-Zn-Ca-Mn alloy may consist of 0.3 to 2.0 percent Zn, 0.2 to 1.0 percent Ca, and 0.2 to 1.0 percent Mn, with the remainder being Mg and unavoidable impurities.

Description

[Technical Field]

[0001] The present invention relates to tumor and cancer treatment devices, systems and methods. [Background technology]

[0002] As recently as 2018, cancer incidence was estimated at 18 million new cases and 10 million cancer deaths per year worldwide, and The John Stoddard Cancer Institute predicts that two in five adults will develop cancer by age 75.

[0003] Despite many advances in cancer treatment, problems remain with prior art cancer treatments: major surgery is painful, expensive, and can be disfiguring; chemotherapy treatments are debilitating; radiation therapy damages surrounding tissue; mortality rates are as high as 50% for some types of cancer; and the number of new cases is increasing at a rate of more than 10% each year, among other problems.

[0004] Magnesium (Mg) is the lightest structural metal, with a density 60% that of aluminum (Al) implants, 38% that of Ti implants, and 20% that of stainless steel or cobalt (Co) implants. Furthermore, the fracture toughness of Mg alloys exceeds that of ceramic, hydroxyapatite, polymer, and ceramic implants. It is also important to note that Mg is biocompatible. It is naturally present in bone tissue and is essential for human metabolism. Furthermore, Mg cations are the fourth most abundant in the human body, are a cofactor for many enzymes, and stabilize both DNA and RNA.

[0005] A possible association between high intake of Mg in general and a reduced risk of colorectal cancer, especially colon cancer, has been reported. Its benefits have also been claimed in the cases of gallbladder cancer and ovarian cancer, with the benefits of Mg exceeding those of titanium (Ti) in the case of ovarian cancer. 2+ It has also been reported that Mg inhibits the nuclear translocation of Snail 1 protein in ovarian SKOV3 cells.

[0006] The antitumor potential of Mg has been demonstrated in numerous studies. These studies have been performed in vitro using cell lines such as U2OS, SKOV3, LNCaP, MDA-MB-231, MG63, MRMT-1, and MC3T3-E1 cells. However, perhaps more importantly, the antitumor effects of Mg have also been observed in vivo. Mg has been documented to have antitumor effects in vivo against osteosarcoma (OS), subcutaneous hemangioma, ovarian epithelial carcinoma (EOC), breast cancer, bladder cancer, and oral squamous cell carcinoma.

[0007] The benefits of Mg include the by-products of Mg bioabsorption, namely H2 and Mg +2 There is evidence that H2 gas produced by the bioabsorption of Mg has anti-cancer properties. Further findings regarding Mg include: in addition to suppressing inflammation and promoting bone formation, the required dose of chemotherapy drugs may be reduced when combined with Mg; tumor cells have an extracellular environment that is acidic (pH less than 7.0), but Mg alloy implants release (OH) -1 raises extracellular pH above 7.0 (although the beneficial effects of H2 on the human body have been widely cited, (OH) -1 The role of ions and pH is not fully understood); Mg inhibits gallbladder SGC996 cancer cells; H2 at critical concentrations induces apoptosis in tumor cells; H2 reduces reactive oxygen species (ROS) in tumor cells; and Zn released by biodegradation of implanted Mg wires inhibits tumor growth in mice.

[0008] The Mg-Zn-Ca-Mn microalloy, developed by nanoMAG, LLC in Livonia, Michigan, is formed using a proprietary process that creates specific nanostructures within the alloy. This alloy is bioresorbable and load-bearing, and is used in screw configurations for craniomaxillofacial surgery and other bone implant / fixation applications. This alloy is strong, malleable, biocompatible, and bioresorbable, meeting many of the requirements for orthopedic structural reinforcement during healing. At the same time, its strength is comparable to that of nonbiodegradable titanium (Ti) and exceeds that of biodegradable polymer implants. When synthesized for biomedical applications, this compositional microalloying provides additional important benefits: bone formation, bone growth, and scaffolding. The Mg-Zn-Ca-Mn alloy performed effectively in vertical bone augmentation tests on rabbit femurs, canine mandibles, canine dentin, ovine ACLs, and ovine vertebrae. The bioresorption rate of this alloy was measured at 1 mm / year. Summary of the Invention [Problem to be solved by the invention]

[0009] The present invention relates generally to cancer treatment, including therapeutic devices, systems, and methods using magnesium (Mg) alloys. More specifically, the present invention relates to therapeutic devices, such as implantable devices, that use bioabsorbable Mg alloys with anti-tumor activity to reduce tumor size and tumor growth (hereinafter simply referred to as "therapeutic devices"). Even more specifically, the present invention relates to Mg alloys and processes that provide localized and targeted tumor suppression, improved strength, improved ductility, and nutritional value for bone promotion, if needed, all without causing organ toxicity, inflammation, or residual particles after bioabsorption, thereby avoiding the harmful effects of chemotherapy and extensive surgery. The therapeutic devices incorporate Mg alloys, which are themselves anti-tumor substances. +2 It is a localized source of constant supply of Zn, Ca, Mn and H2. [Means for solving the problem]

[0010] Thus, in one aspect, the present invention provides a Mg alloy therapeutic device that has high strength and ductility and exhibits durability throughout the entire course of anti-tumor treatment.

[0011] In other aspects, the therapeutic device is non-irritating to body organs and is non-toxic.

[0012] In one aspect, the present invention provides an Mg alloy, more specifically an Mg-Zn-Ca-Mn alloy material, which is provided as a therapeutic device for treating tumors in a human or animal body, the Mg-Zn-Ca-Mn alloy material being used as a microalloy material and consisting of 0.3-2.0 weight percent zinc (Zn), 0.2-1.0 weight percent calcium (Ca), 0.2-1.0 weight percent manganese (Mn), the balance being magnesium (Mg) and unavoidable impurities.

[0013] In a further embodiment of the invention, the Zn content is in the range of 0.85 to 1.5 weight percent.

[0014] In yet another embodiment of the present invention, the Ca content is in the range of 0.2 to 0.6 weight percent.

[0015] In a further embodiment of the invention, the Mn content is in the range of 0.2 to 0.6 weight percent.

[0016] In a further embodiment of the invention, the Mg alloy contains ordered nanometer-sized domains of about 10×0.5 nanometers (small prisms of 1 to 3 atomic layers).

[0017] In other embodiments, the nanostructures include dislocations, stacking faults, subgrains, 6H-type layered crystal structures, αMn grains, and co-segregation of large and small atoms to these features on a scale of less than 20 nm.

[0018] In another aspect, the present invention provides a therapeutic device formed of a microalloyed Mg material for anti-tumor effects and absorption by the human or animal body, the therapeutic device comprising a microalloyed Mg material formed from Mg to which trace amounts of Zn, Ca, and Mn are added as microalloys, the microalloyed Mg material consisting essentially of 0.3-2.0 weight percent Zn, 0.2-1.0 weight percent Ca, 0.2-1.0 weight percent manganese Mn, and the balance being Mg and unavoidable impurities.

[0019] In a further embodiment of the present invention, the therapeutic device is an implantable device that is at least one of a wire-shaped body, a plate-shaped body, a mesh-shaped body, a tubular body, a coil-shaped body, a foil-shaped body, a powder-shaped body, a sphere-shaped body, and a cylinder-shaped body.

[0020] In other aspects of the invention, the microalloyed Mg material has a yield strength in the range of 200-400 MPa, and / or an elongation in the range of 3-35 percent, and / or a hardness in the range of 60-84 Hv, each of which facilitates the use and implantation of the thin wire form therapeutic devices or fragments or constructs thereof described herein.

[0021] In a further embodiment of the invention, the microalloyed magnesium Mg has a grain size of less than 5 μm and a subgrain size of less than 30 nm.

[0022] In another embodiment of the present invention, the microalloyed Mg material comprises Mn particles with diameters in the range of 5-100 nm.

[0023] In a further embodiment of the present invention, the microalloyed Mg material has an H2 generation rate of 5-30 ml per 21 days in simulated body fluid at 37°C, thereby enabling the treatment device to treat tumors for an extended / long-term period.

[0024] In another embodiment of the invention, the treatment device is inserted percutaneously using an introducer.

[0025] In another embodiment of the invention, the therapeutic device is placed within the cavity created by surgical removal of a tumor to treat any cancer cells that may remain.

[0026] In another aspect of the invention, the treatment device is placed adjacent to the tumor.

[0027] In another aspect of the invention, the therapeutic device is placed intratumorally.

[0028] In another embodiment of the invention, the treatment device has a cavity such that the outer surface of the device can displace a certain amount of tissue within the body, but the volume of microalloyed Mg material contained in the treatment device is smaller than a solid form having the same outer shape.

[0029] In another embodiment of the present invention, the therapeutic device is in the form of a pellet having a bioabsorbable membrane and comprising a microalloyed Mg material.

[0030] In another embodiment of the present invention, the therapeutic device is in the form of a sustained release pellet containing a microalloy loaded Mg material and having multiple bioabsorbable membranes that release the microalloy loaded Mg material at different times during the treatment period.

[0031] In another aspect, the present invention provides a method for manufacturing an implantable therapeutic device, the therapeutic device being formed at least in part from an anti-tumor therapeutic material and adapted for absorption into the human or animal body, the method comprising the steps of: providing a melt of an Mg material consisting essentially of 0.3-2.0 weight percent Zn, 0.2-1.0 weight percent Ca, 0.2-1.0 weight percent Mn, and the balance Mg, the melt forming a microalloyed Mg material; forming from the melt an article of manufacture as a casting, squeeze casting, semi-solid metal injection molding, or powder; deforming the article of manufacture by a thermo-mechanical deformation process to form a reduced thickness wrought article, thereby reducing the thickness of the article by more than 30 percent; and heat treating the reduced thickness wrought article to form a heat-treated wrought article, and forming the wrought article into the implantable therapeutic device.

[0032] In a further embodiment of the invention, the transforming step includes at least one of rolling the product, extruding the product, and reducing the thickness by more than 50 percent.

[0033] In yet another embodiment of the present invention, the heat treatment step includes an annealing step in the range of 200°C to 400°C.

[0034] In a further embodiment of the invention, the annealing step comprises annealing for up to 4 hours.

[0035] In another embodiment of the present invention, the hardening step comprises age hardening at 150°C to 225°C for 10 minutes to 3 hours.

[0036] In another embodiment, the processing F factor (F = time (min) x temperature (°K) x deformation rate (%)) is 0.05 to 1.0 x 10 6 is in the range.

[0037] In a further aspect of the invention, the molding step forms the product into one of a screw, plate, sheet, foil, wire, tube, coil, powder, or cylinder as an implantable therapeutic device.

[0038] In another aspect, the present invention provides a method for anti-tumor treatment of a patient, the method comprising the steps of implanting an anti-tumor treatment device into the patient's body; and attacking tumors in the patient's body over time through bioabsorption of the treatment device; wherein the implantation of the anti-tumor treatment device shrinks one or more tumors in the patient, the device being comprised of a microalloy-doped Mg material formed from an Mg material to which trace amounts of Zn, Ca, and Mn have been added as microalloys, the microalloy-doped Mg material consisting essentially of 0.3 to 2.0 weight percent Zn, 0.2 to 1.0 weight percent Ca, 0.2 to 1.0 weight percent Mn, and the balance Mg.

[0039] In another embodiment, the microalloyed Mg therapeutic device is non-toxic to the body and body organs and does not increase residual elements in the blood or urine to significant concentrations.

[0040] In another embodiment of the present invention, the Mg alloy therapeutic device is coupled to an external source of energy such as x-ray, eddy current, magnetic, microwave, etc. to enhance the anti-tumor effect.

[0041] In yet another embodiment, the treatment method using the microalloy loaded Mg therapeutic device is combined with reduced dose chemotherapy.

[0042] In another embodiment, the microalloyed Mg therapeutic device is bioabsorbed without leaving any intermetallic or radioactive particles behind.

[0043] In another embodiment, the Mn and Zn dissolved in the oxide and hydroxide layers of the microalloyed Mg therapeutic device are converted to Cl. -Mg, which controls the invasion of 2+ and H2 release is controlled, allowing the bioabsorption of the implant to match the rate of tumor shrinkage.

[0044] In another aspect, the wrought Mg—Zn—Ca—Mn alloy exhibits fine texture and fine grain size that contribute to high strength along with high ductility.

[0045] In another embodiment, a coating is applied to the therapeutic device to control the initial bioabsorption rate in order to enhance anti-tumor therapy.

[0046] In another embodiment, a platinum coating is applied to the treatment device to activate localized chemotherapy treatment.

[0047] In another embodiment, Mg 2+ To maximize the local availability of H2, tumor targeting is optimized by one or more of the following: targeting the spacing of the therapeutic device relative to the tumor; specifying the corrosion rate of the therapeutic device; providing a protective coating on the therapeutic device; providing a cathodic protection coating on the therapeutic device; pre-loading the therapeutic device with H2 in solid solution; specifying a specific geometric shape of the therapeutic device; and specifying a specific surface area of ​​the therapeutic device.

[0048] In another embodiment, the therapeutic device is coated with an x-ray marker such as platinum (Pt) to provide a monitoring device for the therapeutic device during and after surgery.

[0049] In another embodiment, chemotherapeutic agents can be targeted and coordinated with therapeutic devices to maximize the efficacy of the chemotherapeutic agent while minimizing side effects. An example is cisplatin, a chemotherapy agent that is an alkylating agent containing the metal platinum, which irreparably damages the DNA of dividing cells. Mg can reduce the kidney damage often associated with this chemotherapy agent. By localizing the chemotherapeutic agent-loaded therapeutic device to the tumor site, the therapeutic device may reduce the total dose of the agent and its associated harmful side effects.

[0050] In another aspect, a therapeutic device is provided for inhibiting angiogenesis and suppressing cancer tumor metastasis.

[0051] In other embodiments, the insertion device is designed to minimize surgical trauma, minimize surgical time and hospital stay, and minimize surgical costs. One insertion device design is a hypodermic needle, with one or more needles, or a single needle with multiple treatment devices, such as wires, connected in series. In the case of skin cancer, in one embodiment, the treatment device is a bandage-like plate-like body with multiple needle-like protrusions on the skin side that penetrate the skin.

[0052] In other aspects, the therapeutic device is implanted using a single or double-barreled laparoscope to image the tumor and surrounding tissue, combining imaging modalities to minimize the surgery required for a typical diagnostic biopsy.

[0053] In other embodiments, the therapeutic device is used to deliver tumor therapeutic agents, such as radioactive seeds.

[0054] In other embodiments, the therapeutic device is placed in vivo using a delivery device that houses the therapeutic device's reservoir to facilitate administration by a healthcare provider.

[0055] In other embodiments, the delivery device includes a reel of wire loaded with the microalloy as the therapeutic device, which is fed into the delivery device as the healthcare provider delivers the therapeutic device into and / or around the tumor.

[0056] In other embodiments, the delivery device is pre-loaded with a therapeutic device that can be easily delivered into the tumor.

[0057] In other embodiments, the therapeutic device is housed within one or more bioabsorbable membranes that contain the therapeutic device until such time as the therapeutic device can be placed within or near the tumor.

[0058] In other embodiments, the treatment device is a wire that is wrapped around the tumor.

[0059] Other objects, features, and advantages of the present invention will become readily apparent to those skilled in the art upon reading the following description, including the claims, in conjunction with the accompanying drawings, which form a part of this specification. [Brief explanation of the drawings]

[0060] [Figure 1] FIG. 1 is an enlarged view of a Mg—Zn—Ca—Mn alloy wire in which a knot has been made to illustrate some of the mechanical properties of the Mg—Zn—Ca—Mn alloy wire. [Figure 2] 1 is a graph illustrating BioMg 250™ alloy, a Mg—Zn—Ca—Mn alloy processed to achieve a moderate bioresorption rate in vivo in the human body. [Figure 3A] Scanning electron microscope (SEM) photograph of a microalloyed Mg implant 52 weeks after implantation, showing the transition zone and new bone formation around the implant, with no particles of the implant or microalloyed Mg material remaining in the new bone formation. [Figure 3B] This is an SEM photograph similar to that of Figure 3A, showing mapping of Ca in the surrounding layer. [Figure 4] μCT scan of a healed canine mandible 52 weeks after implantation of an Mg-Zn-Ca-Mn alloy device, showing the affected transitional layer thickness around the implanted device. [Figure 5A] FIG. 1 is an image of the microstructure of BioMg 250™ alloy, an Mg-Zn-Ca-Mn alloy, showing α-Mn grains within the microstructure. [Figure 5B] 1 is an image of the microstructure of BioMg 250™ alloy, an Mg-Zn-Ca-Mn alloy, showing GP zones of Zn and Ca atoms within the microstructure. [Figure 6] 1 shows the texture and grain size of BioMg 250™ alloy, an Mg-Zn-Ca-Mn alloy. [Figures 7A-7D] 1A-1C are schematic cross-sectional views of pellets incorporating various forms of cancer treatment devices. [Figures 8A-8D] 1 is a schematic cross-sectional view of a sustained release cancer treatment pellet having concentric layers with various forms of therapeutic devices incorporated therein. [Figures 9A-9D] 1 illustrates various forms of therapeutic devices introduced into a tumor or treatment site. [Figures 10A-10D] 1 illustrates various forms of treatment devices introduced around a tumor or treatment site. [Figure 11] 1 is a cross-sectional view of a delivery device for delivering a treatment device to a tumor or treatment site. [Figures 12A-12B] 2 is a further embodiment of a treatment device according to the basic concept of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0061] The therapeutic devices described below can be used in conjunction with a variety of surgical and visualization techniques. Noninvasive radiological imaging can be performed using two-dimensional x-ray imaging or multi-image computed tomography to construct a three-dimensional image. This can be further enhanced by elemental x-ray emission spectroscopy and histological analysis. Additionally, ultrasound imaging can be used to guide the placement of the therapeutic devices described below.

[0062] Furthermore, various diagnostic techniques are used to improve resolution down to the cellular level, including at least: nuclear magnetic resonance, which allows imaging of soft tissues that are radiolucent; single-photon radiation therapy; positron and electron emission sources for cell detection; and artificial intelligence software. It will be appreciated that such techniques can be used in the placement and positioning of the therapeutic devices described herein.

[0063] Laparoscopic imaging and detection devices are used in minimally invasive applications, minimizing incisions compared to open surgery. MediSCAPE allows for three-dimensional imaging of tumorous soft tissue and surrounding volumes, allowing for rapid diagnosis of the condition without surgery, avoiding tissue removal for pathological analysis. Accordingly, real-time images can be displayed during surgery to aid in the precise placement of therapeutic devices. Laparoscopic surgery is complemented by artificial intelligence software. Compared to open surgery, costs, hospital stays, and recovery times are reduced.

[0064] Thin Mg wires are a common form of wire used in in vivo applications. However, Mg wires lack sufficient strength to allow simple needle-like insertion of the wire into a tumor. Due to their insufficient strength, unalloyed Mg wires will bend away from the tumor when inserted into a tumor. Furthermore, one study determined that unalloyed Mg wires are absorbed too quickly in vivo and therefore are not suitable for long-term treatment and care.

[0065] BioMg 250 TM The alloy of the alloy, Mg-Zn-Ca-Mn alloy, can be manufactured in wire, tubular, rod, plate, foil, mesh and particulate / powder forms, which can be used in alloy medicament applications to treat cancer or malignant tumors using minimally invasive implantation procedures using the above-mentioned and other techniques. BioMg 250 TM The alloy is a magnesium (Mg) material with microalloys of 0.3-2.0 weight percent zinc (Zn), 0.2-1.0 weight percent calcium (Ca), 0.2-1.0 weight percent manganese (Mn), the balance being Mg and unavoidable impurities. TM The alloy of the alloy is an Mg material to which a microalloy containing 0.85 to 1.5 weight percent Zn, 0.2 to 0.6 weight percent Ca, 0.2 to 0.6 weight percent Mn, and the remainder being Mg and unavoidable impurities, has been added.

[0066] The following table and examples demonstrate the effectiveness of the above-mentioned Mg-Zn-Ca-Mn alloys:

[0067] [Table 1] [Example]

[0068] Example I. As mentioned above, unalloyed Mg wires do not have sufficient strength to allow simple needle-like insertion of the wire into a tumor. Due to the lack of strength, unalloyed Mg wires tend to bend away from the tumor when inserted into the tumor. On the other hand, Mg-Zn-Ca-Mn alloys, particularly BioMg 250 TMThe Mg-Zn-Ca-Mn alloy can be fabricated to allow for simple insertion into the tumor and / or surrounding area as needed, similar to a hypodermic needle. While unalloyed Mg wires have a yield strength of 200 MPa, Mg-Zn-Ca-Mn alloys can be fabricated to approximately 400 MPa. Furthermore, unalloyed Mg is well known to be brittle due to its hcp crystal structure, but BioMg 250 TM The alloy is micro-alloyed and processed to activate multiple slip systems for improved ductility and bendability, thereby avoiding fracture during insertion (see Table I above and Wire 10 in Figure 1). With the Mg-Zn-Ca-Mn alloy, a) the F factor (F = time x temperature x deformation rate (thickness reduction) (%)) is 0.5 x 10 6 A yield strength of about 300 MPa was achieved by using a hot working cycle such that the F factor was 0.5 × 10 6 Similar strengths were achieved with cold working cycles such that the wire or wire segment 10 exhibited sufficient strength to allow the wire or wire segment 10 to be inserted into the tumor itself or into the tissue surrounding the tumor site.

[0069] Example II. Figure 2 shows a graph of BioMg 250 processed to achieve an intermediate bioabsorption rate in the human body in vivo. TM Corrosion of alloys in simulated body fluid (SBF) is shown. BioMg 250 in SBF TM The corrosion of the alloy is compared to two common Mg alloys, ZK60 and AZ91D. The absorption / corrosion is plotted as H2 (in ml) versus number of weeks. As shown in Figure 2, the absorption / corrosion rate of ZK60 alloy was significantly higher than that of BioMg 250. TM The rate of resorption is twice as fast as that of the ZK60 alloy. The resorption profile makes the ZK60 alloy a non-viable long-term treatment option. The AZ91D alloy exhibits virtually no corrosion / resorption, and for the opposite reasons, it is not a viable long-term treatment option. Accordingly, the inventors have investigated the resorption profile of BioMg 250 TM They found that the alloy could be a potential option for long-term cancer treatment.

[0070] Example III. Toxicity and biocompatibility are major concerns when implanting metals into the human body. BioMg 250 TM Implants made from the alloy were placed in the mandibles of dogs, and a study of changes in each organ was conducted 26 weeks later. BioMg 250 was found to have a significant effect on the brain, heart, kidneys, liver, lungs including bronchi, mandibular lymph nodes, spleen, and thymus of the test dogs. TM No evidence of adverse pathological changes (e.g., necrosis and / or active inflammation) was found due to exposure to the alloy. The implant dimensions were 2 x 8 x 100 mm, and the implant bioresorption rate was 0.5 mm / year. Therefore, BioMg 250 TM The alloys can function in cancer treatment without significant concerns about adverse effects on other organs in the body.

[0071] Example IV. BioMg 250 TM The results of the toxicity tests on the alloy are shown in Table II below. As can be seen, BioMg 250 TM The alloy posed no risk, was not mutagenic and showed mild reactivity. Therefore, BioMg 250 TM The alloy poses no toxicity risk to patients during cancer treatment.

[0072] [Table 2]

[0073] Example V. Urinalysis was performed over 104 weeks in the dog mandible study described above. The results are shown in Tables III and IV below. Some changes in calcium (Ca) concentrations were observed, but these changes were not clinically significant, and Mg is excreted in the urine. Statistical differences were observed for Ca at 13 and 104 weeks, but these differences were not clinically significant. All other comparisons were not statistically significant.

[0074] [Table 3]

[0075] [Table 4]

[0076] Example VI. BioMg 250 as described above TM During the 104-week canine mandibular bone study of the implants, blood tests were conducted to evaluate the absorption of alloying elements. As shown in Tables V and VI, the blood test results showed that the concentrations of Mg, Zn, Ca, and Mn did not increase significantly. Therefore, it was concluded that there was no difference at the 95% confidence level.

[0077] [Table 5]

[0078] [Table 6]

[0079] Example VII. In another test, BioMg 250 TM The alloy device 12 was implanted in the femur of a New Zealand rabbit for 52 weeks. As shown in the SEM photograph in Figure 3A, no residual alloy particles were observed in the transition layer 14 or new bone layer 16 surrounding the bioabsorbed implant 12. Furthermore, as is clear from the SEM calcium mapping in Figure 3B, the implant 12 promoted bone formation. In the transition layer, 0.2-0.5% Mn and 1.0-1.7% Zn were detected. The corrosion rate and bioabsorption rate of the alloy can be adjusted by utilizing the presence or absence and ratio of Mn and Zn in the alloy. This allows the bioabsorption rate of the therapeutic device to be adjusted to the Mg content required for the therapeutic device to exert the desired antitumor effect. 2+ More specifically, Mn and Zn dissolved in the oxide and hydroxide layers of the therapeutic device can induce Cl release into the therapeutic device. - Therefore, by changing the amount of Mn and Zn, it is possible to suppress the invasion of Mg, which attacks tumors. 2+and H2 release can be controlled, thereby allowing the desired bioabsorption rate of the implant to be matched to the desired rate of tumor shrinkage.

[0080] Example VIII. In the long-term canine mandible study described above, implanted BioMg 250 TM A μCT scan of a healed canine mandible 18 containing the alloy device 12 after 52 weeks is shown in FIG. 4. The μCT scans showed that each BioMg 250 alloy device 12 implanted in the form of a screw TM The affected transition layer 14 around the alloy device was shown to be approximately 1 mm thick.

[0081] When separate Mg-Zn-Ca-Mn alloy wires are placed in an array on the tumor, the spacing between two adjacent wires should be approximately 2 mm, since each has an affected area of ​​1 mm.

[0082] Example IX. BioMg 250 TMThe alloy has a unique nanostructure resulting from its unique processing. One of the elements added as a microalloy is a large atomic element, with an atomic size larger than that of Mg atoms, and the other elements added as a microalloy are small atomic elements, with an atomic size smaller than that of Mg atoms. The large atomic element, i.e., Ca, has an atomic radius of 173 angstroms or more, and at least one of the small atomic elements, i.e., Zn and Mn, has an atomic radius of 145 angstroms or less. Therefore, the atomic diameter of the element added as a microalloy is 10% larger or smaller than that of the Mg atom of the alloy. The Ca atom also has an electronegativity of 1.1 or less, which is 10% lower than that of the Mg atom of the alloy, and the Zn and Mn atoms have an electronegativity of 1.4 or more, which is 10% higher than that of the Mg atom of the alloy. The novel processing technique results in the formation of clusters or short-range ordered regions (known as Guinier-Preston (GP) zones) on the basal {0001} planes of Mg, resulting in strength and ductility. Figures 5A and 5B show two features of this nanostructure, showing αMn particles 20 and GP zones 22 (which provide strength), respectively. The αMn particles have fine grain sizes ranging from 8 to 120 nm. The GP zones are decorated / co-segregated with Ca and Zn atoms, resulting in GP zones ranging from 0.5 to 15 nm. Furthermore, high-resolution electron microscopy reveals additional special features below 20 nm: stacking faults,<c+a> Dislocations, subgrains, and 6H-type layered crystal structures were identified, and Zn / Ca segregation was observed within each of these features. Intermetallic particles larger than 1 μm were minimized, while continuous films of these intermetallic compounds and the resulting denuded grain boundaries were avoided, resulting in high strength and ductility.

[0083] Example X. BioMg 250 TMThe fine texture of the alloy (shown in Figure 6) with an MRD of 2.4 to 2.8 provides high malleability, as opposed to brittle unalloyed Mg with an MRD of over 10. The fine grain size, also shown in Figure 6, enhances the strength and malleability of the therapeutic device.

[0084] Example XI. Mg-Zn-Ca-Mn alloy, specifically BioMg 250 TM The effectiveness of the alloy wire as a medicine or therapeutic device against lung cancer cells and normal cells was evaluated using an ex vivo "sandwich" test on mouse lung cells. Inside a sandwich consisting of mouse lung slices, a 0.3 mm diameter BioMg 250 TM The alloy wire was placed adjacent to both normal cells and A549 cancer cells. TM The alloy wire was bioabsorbed and its diameter decreased from 0.3 mm to 0.10 mm within 7 days. A high retention rate (>85%) of normal mouse cells was observed, while the A549 cancer cells showed a significant decrease with BioMg 250 TM It was observed that toxicity was induced near the alloy wire.

[0085] Example XII. BioMg 250 used in the lung cancer cell test described above TM The mechanical properties of the alloy wire were evaluated. The yield strength of the 0.1 mm diameter wire 10 was 402 MPa, the ultimate tensile strength was 467 MPa, and the elongation was 5%. BioMg 250 TM Alloy wire 10 was wrapped around a 0.7 mm diameter rod and tied into a tight knot as shown in Figure 1 without failure. The 0.3 mm diameter wire had a yield strength of 373 MPa, an ultimate tensile strength of 413 MPa, and an elongation of 4%. The latter wire was also wrapped around a 1.2 mm diameter rod without failure.

[0086] Example XIII. BioMg 250 TMThe processing of the alloy raw material was established to comply with Good Manufacturing Practice standards and nanoMAG's quality management system. These practices were audited and certified to comply with FDA standards. After heat treatment, 10 mm diameter rods obtained from this raw material had a yield strength of 287 MPa, an ultimate tensile strength of 308 MPa, an elongation of 12%, and a corrosion rate in SBF solution of 0.44-0.63 mm / year.

[0087] Example XIV. BioMAG 250 TM The corrosion rates of 1.1, 1.6, and 2.0 mm diameter Kirschner wires (also known as K-wires or K-pins) composed of the alloy in SBF were evaluated, and corrosion rates of 0.45 to 0.52 mm / year were determined.

[0088] 7A, 7B, 7C, and 7D, a pharmaceutical 24, also referred to herein as a therapeutic device 24, is shown in a schematic cross-sectional view, and includes a Mg-Zn-Ca-Mn alloy or BioMg 250 sol, provided in the form of a powder 26, spheres or particles 28, cut wires 30 (cylinders), coils 32, etc. TM It is shown as a single release pellet with the alloy material suspended within a solid bioabsorbable material 34 (such as a bioabsorbable polymer) or within a fluid or gel (such as a hydrogel) contained within a layer of membrane (formed of a bioabsorbable polymer).

[0089] As shown in the schematic cross-sectional views of Figures 8A, 8B, and 8C, the therapeutic device 24 can be provided as sustained release pellets arranged as concentric rings 36. Three concentric rings are shown in these figures. The concentric rings 36 are formed from a therapeutic Mg-Zn-Ca-Mn alloy or BioMg 250 in the form of powder 26, spheres or particles 28, cut wires 30 (cylinders), coils 32 (not shown), or the like. TMIt allows for a sustained release of the alloy material, with the outer ring or region 36 releasing first, followed by the adjacent inner region 36, followed by the adjacent inner region 36. The ring 36 can be formed from any of the suspending materials, fluids, gels and membranes 34 utilized in single release dosage forms.

[0090] Sustained-release or single-release pellets, or other therapeutic device formulations such as simple powders 26, spheres 28, cut wires 30 (cylinders), or coils 32, can be placed adjacent to or within a tumor to provide long-term treatment. Alternatively, the therapeutic device can be placed within the cavity created by surgical removal of a tumor. In this latter case, the pellets (or other therapeutic devices) provide a therapeutic agent to kill / inhibit cancer cells if any remain after surgical removal of the tumor.

[0091] 9A-9D show the results of the analysis of various forms of Mg-Zn-Ca-Mn alloy or BioMg 250 in tumor 38. TM The method and placement of the medical alloy / therapeutic device are shown in Figures 10A-10D. Various forms of Mg-Zn-Ca-Mn alloy or BioMg 250 are shown around the tumor. TM These drawings show the procedure and placement of the alloy treatment device. TM 9A-9D show various possibilities for alloy treatment devices other than the pellets shown in FIGS. 7A-D and 8A-8C. In FIGS. 9A-9D, Mg-Zn-Ca-Mn alloy or BioMg 250 TM The alloy treatment device is made of Mg-Zn-Ca-Mn alloy or BioMg 250 TM The devices are shown simplified as cylindrical (cut wire) pieces of alloy material, device 30 (Figs. 9B and 10C), spherical or powder devices 26, 28 (Figs. 9C and 10D), and wound wire-like device 32 (Figs. 9D and 10B). While the wound wire-like device is shown as a single wire bundle, it will be readily understood that multiple wires or wire bundles may be included within or around the tumor. Mg-Zn-Ca-Mn alloy or BioMg 250TM It will be appreciated that the alloy therapeutic device may be provided in other configurations and shapes apart from powder, sphere, cylinder, and wirewound. While the therapeutic device described above can be placed within or near a tumor for treatment, the device can also be placed in a cavity resulting from tumor removal or another cavity created by a physician. In such instances, the therapeutic device is used in case cancer or tumor cells remain after surgical resection.

[0092] Figure 11 shows the results of the Mg-Zn-Ca-Mn alloy or BioMg 250 TM 1 illustrates a cross section of an exemplary delivery device 40 that can be used to deliver a metal alloy treatment device. While a pistol-grip style delivery device 40 is shown, this configuration can be modified to many configurations, such as a syringe, an in-line handle, or other configurations. The delivery device 40 includes an introducer 42, which is a hollow awl having a distal end. The distal end is used to deliver the Mg-Zn-Ca-Mn alloy or BioMg 250 alloy through the introducer 42. TM The tip of the introducer 42 can be used to direct and place the Mg-Zn-Ca-Mn alloy or BioMg 250 alloy treatment device 24. This tip may be sharpened so that the introducer can easily penetrate skin or other soft tissue. The introducer 42 can then be positioned within or around the tumor 38, and the treatment device 24 can be delivered into the tumor 38 or surrounding tissue. The placement of the treatment device within or around the tumor 38 can be in a specific configuration, such as an array spaced 2 mm apart, or in a configuration defined herein, such as an unspaced configuration. The tip of the introducer 42 also serves to direct and place the Mg-Zn-Ca-Mn alloy or BioMg 250 alloy treatment device 24 delivered through its interior. TM The tip may have a feature for looping the alloy wire. Alternatively, the tip may have a directional feature for positioning the treatment device to the side of the tip or at an angle to the tip. The delivery device 40 may contain a bulk amount of Mg-Zn-Ca-Mn alloy or BioMg 250 TMThe reservoir 44 may contain a treatment device made of the alloy. The reservoir 44 may also contain a bulk amount of Mg-Zn-Ca-Mn alloy or BioMg 250 in wire form. TM It may consist of a reel that can house the alloy treatment device.

[0093] As shown, the delivery device 40 is made of a Mg-Zn-Ca-Mn alloy or BioMg 250 TM The delivery device 40 has a handle 46 and an operating mechanism (trigger) 48 for delivering the alloy treatment device to the treatment site through the hollow cone-shaped instrument. When the trigger 48 of the delivery device 40 is squeezed, a gear pair 50 connected to the trigger rotates at least one of a pair of drive wheels, and the Mg-Zn-Ca-Mn alloy or BioMg 250 alloy positioned between the drive wheels 52 rotates. TM The alloy treatment device advances within the hollow cone-shaped instrument and is pushed out the tip. As shown in Figure 11, trigger 48 is biased by spring 54, and a one-way clutch integrated with gear set 50 causes trigger 48 to release a predetermined additional amount of Mg-Zn-Ca-Mn alloy or BioMg 250 when trigger 48 is next squeezed. TM It can be returned to the initial position for delivery of the alloy treatment device.

[0094] The delivery device 40 may also be made of Mg-Zn-Ca-Mn alloy or BioMg 250 supplied in wire form. TM The delivery device may also include a cutting feature for cutting the alloy therapeutic device into separate pieces or cylinders. The delivery device may also include a wire form of Mg-Zn-Ca-Mn alloy or BioMg 250 TM The alloy can also be used to wrap therapeutic devices around tumors.

[0095] 12A and 12B show monolithic Mg-Zn-Ca-Mn alloy or BioMg 250 TM 1 shows an example of a metal alloy treatment device 60, 62. This monolithic body is made of Mg-Zn-Ca-Mn alloy or BioMg 250 TMThe therapeutic devices 60, 62 are comprised of one or more solid pieces of alloy material that can be delivered and exposed to the tumor or treatment site in one piece. The bodies that make up the therapeutic devices 60, 62 can be provided in many possible configurations, including spherical or cylindrical forms. In the example shown in Figures 12A and 12B, the therapeutic device body has holes 64 that penetrate into or through the body, and the body may be hollow or solid. This configuration allows the Mg-Zn-Ca-Mn alloy or BioMg 250 alloy that forms the therapeutic device to be able to deliver a desired amount of therapeutic material to the tumor and / or treatment site while maintaining a large external profile for the therapeutic devices 60, 62. TM The actual volume of the alloy can be individually adjusted. These treatment devices 60, 62 can utilize various methods, such as incorporating grooves, recesses, notches, etc., to reduce the bulk of the material used while maintaining a desired external envelope or shape.

[0096] For example, the therapeutic devices of Figures 12A and 12B can function to target and coordinate chemotherapeutic agents with the therapeutic device to maximize efficacy while minimizing damage from chemotherapy side effects. As an example, cisplatin (a chemotherapy drug containing the metal platinum) can be incorporated into the cavity of the therapeutic device in powder form or provided as a coating on the exterior and / or interior surfaces of the therapeutic device. Varying the available surface area can also vary the amount of chemotherapy agent used. In this way, the chemotherapy agent acts to irreparably damage the DNA of dividing cancer cells, causing the cells to stop further division and die. The resulting Mg uptake can help prevent kidney damage often associated with chemotherapy. By localizing the therapeutic device, which functions as a carrier for the chemotherapy agent, to the tumor site, the total dose of this agent and its associated harmful side effects can be reduced.

[0097] Similarly, the therapeutic device may be incorporated into and used in conjunction with other tumor treatments, for example, the therapeutic device may additionally function as a delivery vehicle for radioactive seeds to treat tumors.

[0098] In the manufacture of implantable therapeutic devices, a melt of an Mg-Zn-Ca-Mn alloy material forms a microalloyed Mg material. In one embodiment, the melt consists essentially of 0.3-2.0 weight percent Zn, 0.2-1.0 weight percent Ca, and 0.2-1.0 weight percent Mn, with the balance being Mg and unavoidable impurities. In another embodiment, the melt is an Mg-Zn-Ca alloy material forming a microalloyed Mg material. It should be noted that the absence of Mn may affect the ability to fine-tune the corrosion rate of the material to a desired rate. From this melt, an article is formed as a casting, squeeze casting, or semi-solid metal injection molding. The article is then transformed by a thermomechanical deformation process, whereby the thickness of the article is reduced by more than 30 percent, preferably more than 50%, resulting in a reduced-thickness wrought article. The wrought article is then heat treated to form the final wrought article, which is then molded into or incorporated into a therapeutic device. Alternatively, the product may be deformed by cold working by at least one of cold drawing, cold stamping, cold drawing, cold swaging, cold spinning, or cold rolling. The process for producing wrought Mg alloy products is disclosed in U.S. Patent Application No. 16 / 971,579, the entire contents of which are incorporated herein by reference.

[0099] Mg-Zn-Ca-Mn alloy or BioMg 250 used in the manufacture of pharmaceutical / therapeutic devices TMThe alloy may be provided in one of the following forms depending on its intended use: wire, cylinder, mesh, sheet, screw, plate, coil, foil, powder, or tube. Malignancies for which such medical / therapeutic devices are applicable include, but are not limited to, esophageal cancer, gallbladder cancer, osteosarcoma, bone metastasis, breast cancer, testicular cancer, ovarian cancer, inguinal hernia, obesity, sphincter, lung cancer, colorectal cancer, and prostate cancer.

[0100] The various disclosed medical / therapeutic devices may also be coated with oxides or other coatings to modify their initial bioabsorption rate.

[0101] Furthermore, various Mg-Zn-Ca-Mn alloys or BioMg 250 TM The alloy treatment device may also be provided with a cathodic protection coating on the treatment device for the purpose of regulating absorption.

[0102] Furthermore, various therapeutic devices are disclosed, including Mg-Zn-Ca-Mn alloys or BioMg 250 TM The alloy material can be preloaded with H2 in solid solution, thereby amplifying the amount of H2 present when the therapeutic device corrodes and is bioabsorbed.

[0103] External sources of energy such as x-rays, eddy currents, magnetism, microwaves, etc. can also be coupled to the treatment device to enhance the anti-tumor effect by heating the tumor via the applied energy and the implanted treatment device.

[0104] The implanted therapeutic device may also be monitored after implantation and during treatment by coating the device with an x-ray marker, such as a platinum coating.

[0105] Specific Mg-Zn-Ca-Mn alloy and / or BioMg 250 for preferred embodiments of the therapeutic device TMAlthough described with reference to alloys and their effectiveness, it should be understood that other variations of Mg alloys, including Mg-Zn-Ca alloys and other Mg alloys, or even pure Mg, can be provided in some forms of the disclosed therapeutic devices and function to inhibit and treat cancerous tumors with the devices, systems, and methods disclosed herein.

Claims

1. A Mg-Zn-Ca-Mn alloy for use in the treatment of malignant tumors.

2. 2. The Mg-Zn-Ca-Mn alloy according to claim 1, consisting of, by weight, 0.3 to 2.0% Zn, 0.2 to 1.0% Ca, 0.2 to 1.0% Mn, and the remainder being Mg and inevitable impurities.

3. 2. The Mg-Zn-Ca-Mn alloy of claim 1, wherein the Mg-Zn-Ca-Mn alloy comprises α-Mn grains with dimensions less than 20 nanometers.

4. 4. The Mg—Zn—Ca—Mn alloy according to claim 1, wherein the Mg—Zn—Ca—Mn alloy contains both a) alloying elements whose atomic radii are more than 10% larger or more than 10% smaller than Mg atoms, and b) alloying elements whose electronegativity is more than 10% higher or more than 10% lower than Mg.

5. 2. The Mg—Zn—Ca—Mn alloy of claim 1, wherein the Mg—Zn—Ca—Mn alloy comprises a nanostructure of less than 20 nanometers, and includes at least one of stacking faults, dislocations, <c+a> dislocations, subgrains, GP zones, and arrays of 6H-type layered crystals, and is populated with segregated elements.

6. The Mg—Zn—Ca—Mn alloy is 2 in a solid solution, and during the treatment of the malignant tumor, the Mg—Zn—Ca—Mn alloy corrodes and is bioabsorbed. 2 2. The Mg—Zn—Ca—Mn alloy of claim 1, wherein the amount of is amplified.

7. 2. The Mg—Zn—Ca—Mn alloy of claim 1, wherein the Mg—Zn—Ca—Mn alloy is a wrought alloy.

8. Use of an Mg—Zn—Ca—Mn alloy in the manufacture of a medicament for treating malignant tumors.

9. 9. Use of an Mg—Zn—Ca—Mn alloy in the manufacture of a medicine according to claim 8, wherein the Mg—Zn—Ca—Mn alloy consists, by weight, of 0.3 to 2.0% Zn, 0.2 to 1.0% Ca, and 0.2 to 1.0% Mn, with the remainder being Mg and unavoidable impurities.

10. 9. The use of an Mg—Zn—Ca—Mn alloy in the manufacture of a medicament according to claim 8, wherein the medicament is in any one of the forms of a wire, a cylinder, a mesh, a sheet, a screw, a plate, a coil, a foil, a powder, and a tube.

11. 9. Use of a Mg—Zn—Ca—Mn alloy in the manufacture of a medicament according to claim 8, wherein the medicament has the shape of a body having a defined volume by including one or more recesses or holes therein or therethrough.

12. 9. The use of an Mg—Zn—Ca—Mn alloy in the manufacture of a medicament according to claim 8, wherein one or more surfaces of the medicament are coated with an antitumor agent.

13. 13. The use of Mg—Zn—Ca—Mn alloy in the manufacture of a medicament according to claim 12, wherein the antitumor agent is one of cisplatin or platinum-containing alkylating agents.

14. 9. The use of an Mg—Zn—Ca—Mn alloy in the manufacture of a medicament according to claim 8, wherein one or more surfaces of the medicament are coated with a bioabsorption-modifying coating, and the bioabsorption-modifying coating modulates the initial absorption of the medicament.

15. 9. The use of an Mg—Zn—Ca—Mn alloy in the manufacture of a medicament according to claim 8, wherein the medicament comprises an antitumor agent.

16. 9. The use of an Mg—Zn—Ca—Mn alloy in the manufacture of a medicament according to claim 8, wherein one or more surfaces of the medicament are coated with a marker that is sensitive to X-rays, such as platinum (Pt).

17. 9. The use of an Mg—Zn—Ca—Mn alloy in the manufacture of a medicament according to claim 8, wherein the medicament is provided in the form of a pellet comprising at least one of a sphere, a cylinder, a powder, or a wire formed of the Mg—Zn—Ca—Mn alloy, and is contained within a bioabsorbable membrane.

18. 9. The use of an Mg—Zn—Ca—Mn alloy in the manufacture of a medicament according to claim 8, wherein the medicament is provided in a pellet form comprising at least one of a sphere, a cylinder, a powder, or a wire formed of the Mg—Zn—Ca—Mn alloy, and is contained within a plurality of layers of a bioabsorbable material forming a sustained release pellet.

19. The medicine is H 2 in a solid solution, and when the drug is eroded and bioabsorbed during the treatment of the malignant tumor, H 2 9. Use of an Mg—Zn—Ca—Mn alloy in the manufacture of a medicament according to claim 8, wherein the amount of is amplified.

20. The drug has an F factor of 0.05 x 10 6 ~1.0 x 10 6 9. The use of an Mg—Zn—Ca—Mn alloy in the manufacture of a pharmaceutical product according to claim 8, wherein the alloy is formed using cold working in the range of 0.5 to 1.0°C, where the F factor is defined as F=time (min) x temperature (°K) x deformation rate (reduction in thickness) (%).

21. The drug has an F factor of 0.05 x 10 6 ~1.0 x 10 6 9. The use of an Mg—Zn—Ca—Mn alloy in the manufacture of a pharmaceutical product according to claim 8, wherein the alloy is formed using hot working in the range of 0.5 to 1.0° C., and the F factor is defined as F=time (min)×temperature (° K)×deformation rate (reduction in thickness) (%).

22. 9. The use of an Mg-Zn-Ca-Mn alloy in the manufacture of a medicament according to claim 8, wherein the medicament comprises radioactive seeds.

23. 9. The use of an Mg—Zn—Ca—Mn alloy in the manufacture of a medicament according to claim 8, wherein the Mg—Zn—Ca—Mn alloy is a wrought alloy.

Images