Controlling cancer metastases with magnesium alloy

Abstract

Methods for localized treatment of cancer by implantation of a biodegradable magnesium alloy which releases anti-cancer eluents into or near a malignant tumor or tumors, within a diseased tissue, or a diseased organ, are described. The localized treatment may include a chemotherapy agent applied to a Mg-Zn-Ca-Mn alloy in wire form, or a chemotherapy agent in powder form co-implanted with a Mg-Zn-Ca-Mn alloy in powder form. The localized treatment may also include a biodegradable coating. Methods for the determination of appropriate placement and orientation of the magnesium alloy and chemotherapy agent with respect to the tumor, as well as ex vivo cancer cell testing systems are described.

Description

Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATIONCONTROLLING CANCER METASTASES WITH MAGNESIUM ALLOYCROSS REFERENCE TO RELATED APPLICATION

[0001] Priority is claimed to U.S. Provisional Application No. 63 / 747,756 (filed January 21 , 2025) and U.S. Provisional Application No. 63 / 804,295 (filed May 12, 2025), each of which is incorporated herein by reference in its entirety.STATEMENT OF GOVERNMENT INTEREST

[0002] None.BACKGROUND OF THE DISCLOSUREField of the Disclosure

[0003] The disclosure relates to techniques for localized treatment of cancer by implantation of biodegradable magnesium alloys and in combination with a chemotherapy agent into or near a malignant tumor or tumors, a diseased tissue, or a diseased organ.Background

[0004] Estimates for the worldwide occurrence of cancer in 2018 were at 18,000,000 new cancer cases / year and estimates for the worldwide occurrence of cancer deaths were at 10,000,000 cancer deaths / year. It has also been forecasted by The John Stoddard Cancer Institute that two in five adults will develop cancer by age 75. Despite many advances in the treatment of cancer, problems with state-of-the-art cancer treatments remain. These include, among others, painful and costly major surgery that may leave the patient disfigured; chemotherapy treatment and the debilitative effects thereof; radiotherapy and damage to surrounding tissue thereby; high death rates, of up to 50%, in some types of cancer; and new cases growing at greater than 9% per year.

[0005] Lung cancer is the leading cause of cancer-related deaths in the world, with 2,206,771 cases in 2020, 50% mortality and greater than 9% growth rate. The main types of lung cancer are small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLG). NSCLC is the most common type of lung cancer, which includes the sub-types of adenocarcinoma, squamous cell carcinoma and large cell carcinoma. Approximately 75 to 80% of individuals with lung cancer have NSCLC. Early NSCLC refers to cancer that has not spread widely outside of its site of origin. The earlier lung cancer is detected and treated, the better the outcome.Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATION

[0006] Patients with non-small cell lung cancer may be treated by surgery, chemotherapy, radiation therapy, targeted immunotherapy, or a combination of these treatments. The current standard treatment for early lung cancer consists of the surgical removal of as much of the cancer as possible followed by chemotherapy and / or radiation therapy. Surgical removal of a lung or lobe is the gold standard treatment for addressing stage 1 or 2 NSCLC. Unfortunately, only about 15% to 30% of patients diagnosed with lung carcinoma each year are surgical candidates. Particularly, many patients with concurrent Chronic Obstructive Pulmonary Disease (COPD) are not considered suitable for surgery. Anti-cancer chemotherapy such as cisplatin is effective; but can cost more than $20,000 / month and can lead to renal failure.Surgery imposes significant tissue damage and requires extensive hospital stays and slow recovery time. Clearly, another less costly, less damaging, and more effective approach to lung cancer control which increases life expectancy is a critical societal challenge.SUMMARY

[0007] Methods for localized treatment of cancer by implantation of a biodegradable magnesium alloy which releases anti-cancer eluents into or near a malignant tumor or tumors, within a diseased tissue or a diseased organ are described. A chemotherapy agent may be applied to a Mg-Zn-Ca-Mn alloy in wire form, or a chemotherapy agent in powder form may be implanted with a Mg-Zn-Ca-Mn alloy in powder form. Methods for the determination of appropriate placement and orientation of the magnesium alloy and chemotherapy agent with respect to the tumor, as well as ex vivo cancer cell testing systems are described.

[0008] In an aspect, the disclosure relates to a method of localized treatment of cancer in a patient. In some embodiments, the method includes providing (or preparing, selecting, etc.) a combination comprising at least one magnesium alloy wire, where the at least one magnesium alloy wire comprises magnesium, calcium, manganese and zinc, and a chemotherapy agent, and where the at least one magnesium alloy wire releases at least one anti-cancer eluent upon implantation into or near a diseased tissue or a malignant tumor of the patient; determining a rate of release and distance of diffusion of the at least one anti-cancer eluent; and then determining a selected number of magnesium alloy wires and a selected distance between magnesium alloy wires based upon i) size of malignant tumor or diseased tissue to be treated, ii) the rate of release of the at least one anti-cancer eluent, and iii) distance of diffusion of the at least one anti-cancer eluent; and implanting the selected number of magnesium alloy wires at the selected distance between magnesium alloy wires into or near the diseased tissue or the malignant tumor of the patient.Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATION

[0009] In some embodiments, the combination can be in the form on an implantable pharmaceutical dosage form. For example, the combination can further comprise a carrier comprising a hydrogel or a polymer; the chemotherapy agent and the carrier can together form a coating on the at least one magnesium alloy wire; and the chemotherapy agent can be present in the coating in an amount in a range of 10 wt.% to 60 wt.% chemotherapy agent relative to the coating. In some alternative or additional embodiments of the implantable pharmaceutical dosage form, the at least one magnesium alloy wire is present in an amount of 60 wt.% to 99.9 wt.% magnesium alloy wire relative to a combined amount of the at least one magnesium alloy wire and the coating; the coating is present in an amount of 0.1 wt.% to 40 wt.% coating relative to a combined amount of the at least one magnesium alloy wire and the coating; a combined amount of the chemotherapy agent and the carrier relative to the at least one magnesium alloy wire surface area is in a range of 0.5 pg / mm2to 5 pg / mm2; the chemotherapy agent comprises cisplatin; the carrier comprises the hydrogel; and / or the at least one magnesium alloy wire contains about 0.3 to about 2.0 weight percent zinc, about 0.1 to about 1.0 weight percent calcium, and about 0.1 to about 1 .0 percent manganese.

[0010] In some embodiments, determining the selected number of magnesium alloy wires includes determining a length and a diameter of the at least one magnesium alloy wire.

[0011] In some embodiments, the at least one anti-cancer eluent is hydrogen, magnesium, zinc, calcium or manganese.

[0012] In some embodiments, the chemotherapy agent is platinum, a platinum alloy, cisplatin, carboplatin, oxaliplatin or satraplatin.

[0013] In some embodiments, the cancer is lung cancer.

[0014] In some embodiments, the method also includes guiding the implantation of the magnesium alloy wires by x-ray or ultrasound imaging.

[0015] In some embodiments, the patient undergoes surgical removal of malignant tumors, chemotherapy, radiation therapy or a combination thereof before, after or at a same time as treatment with the combination of at least one magnesium alloy wire and a chemotherapy agent.

[0016] In some embodiments, the at least one magnesium alloy wire has (i) a diameter in a range of 0.1 mm to 3 mm and (ii) a length in a range of 5 mm to 7 cm (e.g., where different wires in a plurality of wires can have the same or different dimensions).Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATION

[0017] In some embodiments, the selected number of magnesium alloy wires is in a range of 2 to 30 wires (e.g., per tumor); and the selected distance between magnesium alloy wires is in a range of 1 mm to 5 mm (e.g., where spacing can be uniform or non-uniform in plurality of wires, such as at least and / or up to 1 , 2, 3, 4, or 5 mm).

[0018] In some embodiments, each magnesium alloy wire can be characterized by at least one of (I) a magnesium metabolic zone (MgMZ) diameter relative wire diameter in a range of 4 to 10 (e.g., at least and / or up to 4, 5, 6, 7, 8, 9, or 10 and ranges therebetween), and (II) an MgMZ volume relative to wire volume in a range of 10 to 100 (e.g., at least and / or up to 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 and ranges therebetween). One or both of the MgMZ diameter and MgMZ volume properties can be satisfied. Each wire can have an independently selected MgMZ value, although the collective wires would typically have the same values / ranges for each wire in the collection of wires. The selected number of magnesium alloy wires and the selected distance between magnesium alloy wires can provide a collective MgMZ that substantially (or completely) encompasses (or contains / envelops) the diseased tissue or the malignant tumor of the patient. The collective MgMZ for the collective wires can represent a volume that is the union or overlap of the MgMZ volumes and / or the MgMZ diameters for the multiple wire5s in their selected spatial relationship relative to each other. The number and positioning of the wires can be selected such that collective MgMZ encompasses at least and / or up to 80, 90, 95, 98, 99, or 100% of the diseased tissue or malignant tumor (e.g., volume thereof) that is targeted for treatment by the wires.

[0019] In some embodiments, the selected number of magnesium alloy wires is selected to provide at least one of the following properties (I), (II), and (III): (I) a hydrogen (H2) evolution of 0.5 ml / cm3to 2 ml / cm3H2per unit tumor volume (e.g., at least and / or up to 0.5, 0.7, 1 , 1 .2, 1.5, 1.7, or 2 ml / cm3); (II) a magnesium loading of 0.5 mg / cm3to 2 mg / cm3Mg per unit tumor volume (e.g., at least and / or up to 0.5, 0.7, 1 , 1.2, 1.5, 1.7, or 2 mg / cm3); and (III) a daily dosage (or release rate) of 1 mg / day to 20 mg / day Mg (e.g., at least and / or up to 1, 2, 3, 5, 7, 10, 12, 15, 17, or 20 mg / day, such as a maximum or average daily release over a 5, 10, 20, or 30-day period).

[0020] In a second aspect, the disclosure relates to a method of localized treatment of cancer in a patient. In some embodiments, the method includes providing (or preparing, selecting, etc.) a plurality of magnesium alloy wires, where each magnesium alloy wire (i) comprises magnesium, calcium, manganese and zinc, and a chemotherapy agent, and (ii) releases at least one anti-cancer eluent upon implantation into or near a diseased tissue or a malignant tumor ofAtty. Docket No. 30275 / 70816 / PC PATENT APPLICATIONthe patient; and implanting the plurality of magnesium alloy wires at a selected distance between adjacent magnesium alloy wires into or near the diseased tissue or the malignant tumor of the patient; where a concentration gradient of the at least one anti-cancer eluent between adjacent magnesium alloy wires is characterized by a percentage of greater than 30% of an amount of the at least one anti-cancer eluent in the magnesium alloy wire for a minimum concentration of the at least one anti-cancer eluent between adjacent magnesium alloy wires (e.g., at the centerline between adjacent wires) relative to a maximum concentration of the at least one eluent between adjacent magnesium alloy wires (e.g., at the wire surfaces).

[0021] In a third aspect, the disclosure relates to an implantable pharmaceutical dosage form including an anti-cancer eluent-releasing magnesium alloy in a wire form or in a powder form, a chemotherapy agent, and a carrier including a polymer and / or a hydrogel. In some embodiments, the implantable pharmaceutical dosage form includes from about 60 weight percent to about 99.9 weight percent of an anti-cancer eluent-releasing magnesium alloy in a wire form or in a powder form (e.g., at least and / or up to 60, 70, 80, 90, 95, 98, 99, or 99.9 wt.% magnesium alloy); and from about 0.1 weight percent to about 40 weight percent of a chemotherapy agent, and a carrier including a polymer or a hydrogel (at least and / or up to 0.1 , 1 , 2, 5, 10, 20, 30, or 40 wt.% chemotherapy agent and carrier combined). In some embodiments, the implantable pharmaceutical dosage form includes an anti-cancer eluentreleasing magnesium alloy in a wire form or in a powder form; and a coating on the anti-cancer eluent-releasing magnesium alloy (e.g., on one or more external surfaces of the powder or wire), wherein i) the coating comprises a chemotherapy agent, and a carrier comprising a polymer or a hydrogel, and ii) the chemotherapy agent is present in the coating in an amount in a range of 10 wt.% to 60 wt.% (e.g., at least and / or up to 10, 20, 30, 40, 50, or 60 wt.% and ranges therebetween) chemotherapy agent relative to the coating. In embodiments, the carrier is present in the coating in an amount in a range of 40 wt.% to 90 wt.% (e.g., at least and / or up to 40, 50, 60, 70, 80, or 90 wt.% and ranges therebetween) relative to the coating. In embodiments, a combined amount of the chemotherapy agent and the carrier is at least and / or up to 90, 95, 98, 99, or 100 wt.% relative to the coating.

[0022] In some embodiments, a combined amount of the chemotherapy agent and the carrier (e.g., a total coating amount) relative to the anti-cancer eluent-releasing magnesium alloy surface area (e.g., external alloy surface area on which the chemotherapy agent and the carrier are coated) is in a range of 0.5 pg / mm2to 5 pg / mm2(e.g., at least and / or up to 0.5, 1 , 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 pg / mm2).Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATION

[0023] In some embodiments, the chemotherapy agent includes platinum, a platinum alloy, cisplatin, carboplatin, oxaliplatin or satraplatin.

[0024] In some embodiments, the anti-cancer eluent-releasing magnesium alloy includes magnesium, about 0.3 to about 2.0 weight percent zinc, about 0.1 to about 1.0 weight percent calcium, and about 0.1 to about 1 .0 percent manganese.

[0025] In some embodiments, the anti-cancer eluent-releasing magnesium alloy is a magnesium alloy powder, and the chemotherapy agent is a chemotherapy agent powder.

[0026] In some embodiments, the magnesium alloy powder has a particle size in a range of 50 nm to 2000 nm; and the chemotherapy agent powder has a particle size in a range of 50 nm to 2000 nm (e.g., where the two powders can have the same or different size characteristics; particle size can represent a weight-, number-, volume-average size or size distribution).

[0027] In some embodiments, the anti-cancer eluent-releasing magnesium alloy releases hydrogen, magnesium, zinc, calcium, manganese or a combination thereof.

[0028] In some embodiments, the carrier is a polymer, and the polymer is poly(lactic acid), poly(lactic acid-co-glycolic acid), poly(lactic acid-co-polyethylene glycol), poly(lactic acid-co-glycidol) or a combination thereof.

[0029] In some embodiments, the carrier is a hydrogel, and the hydrogel is hyaluronic acid, cellulose, chitosan, collagen, alginate, agarose, gelatin, fibrin or a combination thereof.

[0030] In some embodiments, the anti-cancer eluent-releasing magnesium alloy is a magnesium alloy wire, and the magnesium alloy wire is a bundle of two or more magnesium alloy wires.

[0031] In some embodiments, at least one of the two or more magnesium alloy wires are coated with the chemotherapy agent to form coated wires.

[0032] In some embodiments, the percentage of chemotherapy agent on the coated wires is from about 1 weight percent to about 30 weight percent.

[0033] In some embodiments, the coated wires are fully coated or partially coated with chemotherapy agent.

[0034] In some embodiments, the bundle includes coated wires and uncoated wires.

[0035] In some embodiments, the bundle includes layered wires or wires twisted together.Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATION

[0036] In some embodiments, the anti-cancer eluent-releasing magnesium alloy also includes (surface) MgO, Mg(OH)2or a combination thereof.

[0037] In a fourth aspect, the disclosure relates to a method of making a medicament for lung cancer treatment. In some embodiments, the method includes cleaning a magnesium alloy with an acid to form a cleaned magnesium alloy; and then coating the cleaned magnesium alloy with a coating including a chemotherapy agent.

[0038] In some embodiments, the acid is citric acid or nitric acid.

[0039] In some embodiments, the coating also includes a polymer or a hydrogel.

[0040] In some embodiments, the coating includes a hydrogel, and where the hydrogel is hyaluronic acid.

[0041] In some embodiments, the hyaluronic acid is cross-linked.

[0042] In some embodiments, the coating is a polymer, and the polymer is poly(lactic acid) or poly(lactic acid-co-glycolic acid).

[0043] In some embodiments, the coating is dip coated, spray coated or vapor deposited onto the magnesium alloy.

[0044] In some embodiments, the coating fully coats or partially coats the cleaned magnesium alloy.

[0045] In some embodiments, the chemotherapy agent is platinum, a platinum alloy, cisplatin, carboplatin, oxaliplatin or satraplatin.

[0046] In a fifth aspect, the disclosure relates to a system for ex vivo testing a medicament. In some embodiments, the system includes human cancer cells; a first precision cut tissue slice having a top surface; and a second precision cut tissue slice; where the human cancer cells are seeded onto the top surface of the first precision cut tissue slice to form a seeded first precision cut tissue slice; and where the second precision cut tissue slice is layered above the seeded first precision cut tissue slice.

[0047] In some embodiments, the first precision cut tissue slice and second precision cut tissue slice are mouse precision cut lung slices.

[0048] In some embodiments, the system also includes a medicament disposed above the seeded first precision cut tissue slice and disposed below the second precision cut tissue slice.Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATION

[0049] In some embodiments, the medicament is an anti-cancer eluent-releasing magnesium alloy.

[0050] In a sixth aspect, the disclosure relates to a method of localized treatment of cancer in a patient. In some embodiments, the method includes preparing a combination comprising at least one magnesium alloy wire, where the at least one magnesium alloy wire comprises magnesium, calcium, manganese and zinc, and a chemotherapy agent, and where the at least one magnesium alloy wire releases at least one anti-cancer eluent upon implantation into or near a diseased tissue or a malignant tumor of the patient; determining a rate of release and distance of diffusion of the at least one anti-cancer eluent; and then determining a selected number of magnesium alloy wires and a selected distance between magnesium alloy wires based upon i) size of malignant tumor or diseased tissue to be treated, ii) the rate of release of the at least one anti-cancer eluent, and ill) distance of diffusion of the at least one anti-cancer eluent; and implanting the selected number of magnesium alloy wires at the selected distance between magnesium alloy wires into or near the diseased tissue or the malignant tumor of the patient.

[0051] In some embodiments, determining the selected number of magnesium alloy wires includes determining a length and a diameter of the at least one magnesium alloy wire.

[0052] In some embodiments, the at least one anti-cancer eluent is hydrogen, magnesium, zinc, calcium or manganese.

[0053] In some embodiments, the chemotherapy agent is platinum, a platinum alloy, cisplatin, carboplatin, oxaliplatin or satraplatin.

[0054] In some embodiments, the cancer is lung cancer.

[0055] In some embodiments, the method also includes guiding the implantation of the magnesium alloy wires by x-ray or ultrasound imaging.

[0056] In some embodiments, the patient undergoes surgical removal of malignant tumors, chemotherapy, radiation therapy or a combination thereof before, after or at a same time as treatment with the combination of at least one magnesium alloy wire and a chemotherapy agent.

[0057] In some embodiments, the at least one magnesium alloy wire has (i) a diameter in a range of 0.1 mm to 3 mm and (ii) a length in a range of 5 mm to 7 cm (e.g., where different wires in a plurality of wires can have the same or different dimensions).Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATION

[0058] In some embodiments, the selected number of magnesium alloy wires is in a range of 2 to 30 wires (e.g., per tumor); and the selected distance between magnesium alloy wires is in a range of 1 mm to 5 mm (e.g., where spacing can be uniform or non-uniform in plurality of wires).

[0059] In some embodiments, the selected number of magnesium alloy wires is selected to provide at least one of the following properties (I), (II), and (III): (I) a hydrogen (H2) evolution of 0.5 ml / cm3to 2 ml / cm3H2per unit tumor volume; (II) a magnesium loading of 0.5 mg / cm3to 2 mg / cm3Mg per unit tumor volume; and (III) a daily dosage (or release rate) of 1 mg / day to 20 mg / day Mg (e.g., as a maximum or average daily release over a 5, 10, 20, or 30-day period).

[0060] In any embodiment, the terms “preparing,” “providing,” and / or “selecting” can refer to obtaining and / or putting together the suitable magnesium alloy wire and chemotherapy agent for treatment of a malignant tumor or tumors, diseased tissue or diseased organ. The magnesium alloy wire(s), with or without a chemotherapy agent, can be already manufactured article(s) when the actions are performed. In some embodiments, these actions may be performed by the surgical team in the operating room, hospital or clinic.

[0061] While the disclosed apparatus, methods, and compositions are susceptible of embodiments in various forms, specific embodiments of the disclosure are illustrated (and will hereafter be described) with the understanding that the disclosure is intended to be illustrative, and is not intended to limit the claims to the specific embodiments described and illustrated herein.BRIEF DESCRIPTION OF THE FIGURES

[0062] FIG. 1 A is a cross-sectional view 100 of a coated magnesium alloy wire in accordance with certain disclosed embodiments.

[0063] FIG. 1 B is a top view 102 of a partially coated magnesium alloy wire in accordance with certain disclosed embodiments.

[0064] FIG. 1 C is a top view 104 of an alternate configuration for a partially coated magnesium alloy wire in accordance with certain disclosed embodiments.

[0065] FIG. 2A is a cross-sectional view 200 of a lung including a tumor, illustrating various options for the orientation of magnesium alloy wires with respect to a tumor, utilized in methods for tumor treatment in accordance with certain disclosed embodiments.Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATION

[0066] FIG. 2B is a cross-sectional view 220 of a tumor, illustrating various options for placement of magnesium alloy wires with respect to a tumor in accordance with certain disclosed embodiments.

[0067] FIG. 3A is a representative image of lung tissue precision cut lung slices (PCLS) 5 days after culture (AT2 cells in yellow, scale bar 1 mm) in accordance with certain disclosed embodiments.

[0068] FIG. 3B is a graph illustrating the viability of normal cells in PCLS over 5 days in accordance with certain disclosed embodiments.

[0069] FIG. 4 is a cross-sectional view 400 of an ex vivo single layer cell test model in accordance with certain disclosed embodiments.

[0070] FIG. 5 is a representative image of A549 cells (cyan) 3 days after seeding atop lung tissue lineage traced for lung progenitors, yellow). Nuclei of both human and mouse cells are stained with Hoechst (grey) in accordance with certain disclosed embodiments.

[0071] FIG. 6 is a cross-sectional view 600 of an ex vivo double layer cell test model (tissue sandwich) as utilized for testing magnesium alloy wires on cancer cells in accordance with certain disclosed embodiments.

[0072] FIG. 7A is a representative image of the PCLS - BioMg® 250 sandwich in accordance with certain disclosed embodiments.

[0073] FIG. 7B is a graph illustrating the viability of PCLS with BioMg® 250 wires placed between PCLS segments versus wires placed into the culture media (where n = 4 mice and n.s. = no significant) in accordance with certain disclosed embodiments.

[0074] FIG. 8A is an image of a PCLS tissue sandwich with BioMg® 250 wire (red arrows) at day 3 of culture with A549 cells (green, stained with human nuclear marker (hu NuMa), (scale bar 500 pm) in accordance with certain disclosed embodiments.

[0075] FIG. 8B is a graph of the average width of BioMg® 250 in the tissue sandwich model (*p < 0.05, **p<0.001) over time to illustrate the degradation rate in accordance with certain disclosed embodiments.

[0076] FIG. 8C provides images of A549 cells and the DNA damage marker y-H2AX next to a BioMg® 250 wire and in control area after 6 days (scale bars 100 pm).Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATION

[0077] FIG. 9A is a graph showing the reduction of A549 Cancer Cells after 4 days culture in MATRIGEL for a control sample (no wires), a sample with 1 bare BioMg® 250 wire, and a sample with 2 BioMg® 250 wires. * P < 0.05 ; ** P < 0.01.

[0078] FIG. 9B is a graph showing the reduction of A549 Cancer Cells after 4 days culture in MATRIGEL for a control (no wires), a sample with 1 bare BioMg® 250 wire, a sample with 1 cisplatin-coated BioMg® 250 wire at a loading of 10 pg cisplatin (20 wt.% of coating), and a sample with 1 cisplatin-coated BioMg® 250 wire at a loading of 25 pg cisplatin (50 wt.% of coating). * P < 0.05 ; “ P < 0.01 ; *** P < 0.001.Detailed DescriptionThe Magnesium Alloys

[0079] Magnesium (Mg) is a metal element that degrades in physiological environments to yield magnesium hydroxide, magnesium oxide, and / or hydrogen. This process is referred to in the art as corrosion. Magnesium is also known as a non-toxic element. The recommended dose of magnesium for the human body is 400 mg per day. In view of these characteristics, magnesium is considered as an attractive element for forming biodegradable metallic implants. Magnesium and its alloys are biocompatible, bioabsorbable and easy to mechanically manipulate. Radiological advantages of magnesium include compatibility with magnetic resonance imaging and computed tomography. The biocompatibility of magnesium and its alloys stems from its relative non-toxicity to cells. Magnesium is abundant in tissues of animals and plants; specifically, magnesium is the fourth most abundant metal ion in cells, the most abundant free divalent ion and therefore is deeply and intrinsically woven into cellular metabolism. Magnesium-dependent enzymes also appear in virtually every metabolic pathway.

[0080] The alloy can be a microalloyed magnesium (Mg) material consisting of 0.3 to 2.0 percent by weight of zinc (Zn), 0.2 to 1.0 percent by weight of calcium (Ca), 0.2 to 1.0 percent by weight of manganese (Mn) with the remainder being Mg and inevitable impurities. A suitable magnesium alloy is commercially available under the name BioMg® 250 (NanoOnco Inc.; Ann Arbor, Ml). In one variant, the alloy of the BioMg® 250 alloy is a microalloyed Mg material consisting of 0.85 to 1.5 percent by weight of Zn, 0.2 to 0.6 percent by weight of Ca, 0.2 to 0.6 percent by weight of Mn with the remainder being Mg and inevitable impurities.

[0081] Furthermore, by microalloying with multiple elements, nanometer-sized zones (mini prisms of 1-3 atom layers) of about 10 x 0.5 nanometers (nm) can be generated from a Mg-Zn-Ca-Mn solid solution by thermomechanical processing (TMP) and / or heat treatment. TheseAtty. Docket No. 30275 / 70816 / PC PATENT APPLICATIONordered zones contain enriched contents of Zn and Ca in an ordered atomic array in the hep Mg matrix. These elements report to the ordered zones in order to reduce misfits resulting from their difference in atomic size and electro-negativity from the Mg atom. Thus, the energy state of the alloy is lowered and the stability state of the alloy is increased. It was discovered that enhanced results can be engineered by combining additions of a large atom (Ga) with a small atom (Zn). The mixture of two small atoms assures short time access and supply of those species to the zone.

[0082] In some embodiments, the combined percent of Zn, Ca and Mn microalloyed with Mg is in the range of 1.4 to 2.4 percent. In some embodiments, the combined percent of Zn, Ca and Mn microalloyed with Mg is in the range of 1.5 to 2.4 percent. In some embodiments, the Zn content is in the range of 0.9 to 1.3 percent by weight. In some embodiments, the Ca content is in the range of 0.2 to 0.4 percent by weight. In some embodiments, the Mn content is in the range of 0.2 to 0.35 percent by weight. In some embodiments, nano-meter-sized ordered zones (mini prisms of 1-3 atom layers) of about 10 x 0.5 nm are included.

[0083] In some embodiments, the alloy is at least 96% weight percent magnesium. In some embodiments, the alloy is at least 97%, at least 98% or at least 99% magnesium. The alloy suitably does not include rare earth elements or aluminum. In some embodiments, the alloy contains not more than 0.01 , 0.1 , or 1 wt.% of materials or elements other than Mg, Mn, Zn, and Ca. For example, the alloy can contain up to 0.01 , 0.1 , or 1 wt.% of materials or elements other than Mg, Mn, Zn, and Ca. The alloy may have MgO or Mg(OH)2 on the surface of the material. Suitable alloys are described in U.S. Patent No. 10,022,470; U.S. Patent Pub. No.2020 / 0384160 and in WO 2024 / 073130, the disclosures of which are all hereby incorporated by reference.

[0084] A Mg-Zn-Ca-Mn alloy, such as BioMg® 250, can be produced in wire, tube, bar, cable, plate, foil, mesh, and particulate / powder forms that afford the alloy medicament applications for cancer or malignant tumor treatment employing minimally invasive implantation procedures using the above and other technologies.

[0085] Implantable medical devices may be made from the compositions disclosed herein. The implants have advantageous mechanical properties, including high yield strength, high ultimate tensile strength and elongation at break. In some embodiments, the alloy has a yield strength of at least 180 MPa. In some embodiments, the alloy has a yield strength of at least 200 MPa. In some embodiments, the alloy may have a yield strength of greater than 220 MPa, or between 300 MPa and 400 MPa. In some embodiments, the alloy has an ultimate tensileAtty. Docket No. 30275 / 70816 / PC PATENT APPLICATIONstrength of at least 240 MPa. In other embodiments, the alloy has an ultimate tensile strength of at least 260 MPa, at least 280 MPa, at least 300 MPa, at least 320 MPa, at least 340 MPa, at least 360 MPa, or at least 420 MPa. In some embodiments, the alloy has at least 5% elongation at break. In other embodiments, the alloy has elongation at break values of at least 10%, at least 12%, at least 14%, at least 16%, at least 18%, at least 20% or at least 25%.

[0086] When the alloy is in wire form, the wire may be of any suitable diameter. In some embodiments, the wire has a diameter in the range of about 0.05 mm to about 3 mm, about 0.05 mm to about 0.6 mm. In some embodiments, the wire has a diameter in the range of about 0.1 mm to about 0.4 mm. In some embodiments, the wire has a diameter of 0.1 mm or 0.3 mm. For example, the wire can have a diameter of at least and / or up to 0.05, 0.1 , 0.15, 0.2, 0.3, 0.4, 0.5, or 0.6 mm. Different wires inserted into the same tumor can have the same or different diameters.

[0087] Magnesium alloy wires may have any suitable length, depending upon size, number and location of tumors to be treated as well as the diameter of the wire. In some embodiments, a wire may have a length in the range of from about 1 mm to 10 cm; about 2 mm to 8 cm or about 5 mm to 7 cm. For example, the wire can have a length of at least and / or up to 0.1 , 0.2, 0.3, 0.5, 0.7, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 cm. In some embodiments, more than one magnesium alloy wire may be utilized. In some embodiments, the number of wires may 2, 3, 4, 5, 6, , 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 per tumor or tumor site. For example, two or more wires may be placed at specified distances apart to enhance therapeutic effects by placement at more than one site of a tumor or tumors; or two or more wires may be twisted together into a bundle, or otherwise joined together for insertion at a single tumor site. Different wires inserted into the same tumor can have the same or different lengths. Depending upon the treatment regimen desired, when there is more than one wire (two or more wires in a bundle or individually placed) the set of wires may include bare (uncoated) wire, fully coated wire, partially coated wire or a combination thereof.

[0088] In some embodiments, a wire may be coiled, or alternatively multiple wires may be woven together into a mesh.Methods of Localized Treatment of Cancer

[0089] It has been reported that, generally, a higher intake of Mg appears to be associated with a reduced risk of colorectal cancer, particularly colon cancer. Benefits have also been claimed in gall bladder and ovarian cases, the latter being greater than with titanium (Ti). It has alsoAtty. Docket No. 30275 / 70816 / PC PATENT APPLICATIONbeen reported that Mg2+ inhibits the ovarian SKOV3 cells, and that Mg promotes degradation of Snail 1 protein into the cell nucleus.

[0090] A number of reported studies have demonstrated the anti-tumor capabilities of Mg. These studies have been performed in vitro, on cells such as U2OS, SKOV3, LNCaP, MDA-MB-231, MG63, MRMT-1 and MC3T3-E1 cells. But perhaps more importantly, the anti-tumor action of Mg has been performed in vivo. Anti-tumor action of Mg has been recorded in vivo against osteosarcoma (OS), subcutaneous hemangiomas, epithelial ovarian carcinoma (EOC), breast carcinoma, bladder cancer and oral epidermoid cancer.

[0091] The benefits of Mg have been related to the byproducts of Mg's bioabsorption, i.e. the release of H2and Mg+2ions. There is evidence that H2gas that is generated by Mg bioabsorption operates as a control on cancer. Additional findings relating to Mg included: in addition to inhibiting inflammation and promoting bone formation, Mg may in combination reduce chemo-drug requirements; tumor cells have an acidic extracellular environment (pH being less than 7.0), while the release of (OH)-1from Mg alloy implants raises the extracellular pH above 7.0 (while the role of (OH)1ions and pH are not fully understood, the benefits of H2on humans has been touted); Mg inhibits gall bladder SGC996 cancer cells; H2induces tumor cell apoptosis at certain critical concentrations; H2decreases reactive oxygen species (ROS) in tumor cells; and tumor growth is inhibited in mice upon release of Zn from biodegrading Mg implanted wires.

[0092] Hydrogen generated by the bio-absorption of magnesium alloy in the body is directly correlated with the Mg corrosion due to the following reaction (I):

[0093] (gas) (I)

[0094] Thus, the evolution of 1 mole of H2gas (22.4 liters) directly corresponds to the dissolution of 1 mole of Mg (24.31 grams). The rate of hydrogen evolution is completely dependent upon the magnesium dissolution rate. Hence, the kinetics of the magnesium corrosion is the determining factor for the hydrogen evolution rate. While the capability of a human body to absorb, or release, the evolved hydrogen, and thus to avoid the accumulation of large hydrogen subcutaneous bubbles is limited, it is undesirable to use magnesium-based implants that lead to abnormal formation of hydrogen subcutaneous bubbles. Since the corrosion of magnesium in a physiological environment is spontaneous, reducing the hydrogen evolution rate can be effected solely by reducing the corrosion rate such as via alloying elements.Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATION

[0095] Thin Mg wire is a common shape for in vivo applications. However, one disadvantage of Mg implanted wire is that the Mg wire has insufficient strength to allow a simple needle-like injection of the wire into a tumor. Because of its insufficient strength, the unalloyed Mg wire will bend away from the tumor during insertion. Additionally, in one study, it was determined that unalloyed Mg wire is absorbed too fast in vivo and, therefore, unsuitable to provide long term treatment and care. Furthermore, unalloyed Mg is notoriously brittle because of its hep crystal structure.

[0096] However, a magnesium alloy such as a Mg-Zn-Ca-Mn alloy, and BioMg® 250 in particular, can be processed to afford simple hypodermic needle-like injection to a tumor and / or around tumors, when necessary. Whereas unalloyed Mg wire would have a yield strength less than 100 MPa, the Mg-Zn-Ca-Mn alloy can be processed to levels of up to 400 MPa, the BioMg® 250 alloy is microalloyed and processed to activate multiple slip systems to enhance ductility and bendability, thus avoiding fracture during insertion.

[0097] Magnesium based alloy implants may completely dissolve in the body with no detrimental effect either locally or generally to the human body. Hydrogen evolution resulting from magnesium degradation can be controlled to fit the body’s absorption capacity, such that for example up to 4.5 cm3of hydrogen for each square centimeter of surface metal are absorbed during 48 hours of exposure.

[0098] In some embodiments, the magnesium-based alloy may have an in vitro degradation rate of less than 10 mm / yr. In other embodiments, the alloy has an in vitro degradation rate of less than 5 mm / yr as measured in simulated body fluid (ASTM Standard Test F3268). In other embodiments, the alloy has an in vitro degradation rate of less than 6 mm / yr, less than 5 mm / yr, less than 2 mm / yr, less than 1 mm / yr, less than 0.5 mm / yr, less than 0.2 mm / yr, or less than 0.1 mm / yr, as measured in simulated body fluid.

[0099] Depending upon the composition of the alloy, the magnesium-based implant may fully degrade within about six months.

[0100] While magnesium alloys such as BioMg® 250 may be utilized alone (as bare wire), in some embodiments a coated alloy wire may be used either instead of bare wire, or in conjunction with bare wires. FIG. 1A is a cross-sectional view 100 of a coated magnesium alloy wire 10. The coated wire 10 includes a wire layer 101, a chemotherapy agent layer 103 and an optional coating layer 105 over the chemotherapy agent layer 103. The wire layer 101 is a magnesium alloy such as BioMg® 250, described above. The coated wire of FIG. 1A is not drawnAtty. Docket No. 30275 / 70816 / PC PATENT APPLICATIONto scale, as 101, 103, and 105 may be of differing thicknesses, depending upon the desired rate of diffusion of anti-cancer eluents and chemotherapy agent. Moreover, although 103 and 105 are shown as layers above and on top of the wire in FIG. 1A, the layers may instead completely coat the entire circumference of the wire.

[0101] Prior to coating the wire with any of 103 and 105, the wire may be cleaned with an acid such as citric acid or nitric acid. In some cases, the cleaning process includes 1) dipping the magnesium alloy wire in acid for 5 to 30 seconds, 2) dipping the magnesium alloy wire in distilled water, 3) dipping the magnesium alloy wire in alcohol, and 4) drying the magnesium alloy wire. In some cases, the concentration of acid is from about 0.5% to about 10%, about 1% to about 10%, or about 2% to about 5%. The wire may also advantageously be cleaned prior to implantation even if it is to be utilized without 103 or 105. Without wishing to be bound by theory, it is hypothesized that cleaning the wire facilitates more consistent bio-absorption behavior of the anti-cancer eluents.

[0102] Localized delivery of drugs such as chemotherapy agents within a patient’s body permits the establishment of a high local concentration of drug with concomitant low levels of systematic exposure and toxicity. In this manner, the pervasive toxicity of antineoplastics to all living cells can be focused on malignant cells by delivery of the drug only at, into or near a tumor. As used herein, the term “near” refers to a distance of no more than 0.5 mm between the tumor and the drug. Localized delivery also permits use of drugs that, for one reason or another, are not particularly amenable to delivery by other means. This includes drugs that are susceptible to degradation under physiological conditions of temperature, pH or enzymatic activity. For such drugs, biodegradation before reaching the treatment site occurs if administered systematically. Other drugs may be so insoluble in the physiological conditions (aqueous solution) that they would precipitate out and be immobilized almost immediately upon systematic administration. Of course, the ability to use less of a drug using localized delivery can also constitute a substantial economic advantage.

[0103] Examples of chemotherapy agents for chemotherapy agent layer 103 include, but are not limited to, aldesleukin, alendronic acid, alfaferone, alitretinoin, allopurinol, palonosetron, altretamine, aminoglutethimide, L-asparaginase, amifostine, amrubicin, amsacrine, anastrozole, anzmet, aranesp, arglabin, arsenic trioxide, aromasin, 5-azacytidine, azathioprine, BCG ortice-BCG, bestatin, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulphate, broxuridine, bortezomib, bleomycin, busulfan, calcitonin, campath,Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATIONcapecitabine, carboplatin, carmustine, casodex, cefesone, celmoleukin, cerubidin, chlorambucil, cisplatin, colaspase, cladribin, clodronic acid, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunoxome, decadron, decadron phosphate, delestrogen, denileukin diftitox, depomedrol, deslorelin, dexrazoxane, daunorubicin, diethylstilbestrol, 2’, 2’-difluorodeoxycytidine, diflucan, docetaxel, doxifluridine, doxorubicin, dronabinol, DW-166HC, eligard, elitek, ellence, emend, epirubicin, epoetin-alfa, epogen, eptaplatin, ergamisol, estrace, estradiol, estramustine sodium phosphate, ethinylestradiol, ethyol, etidronic acid, etopophos, etoposide, fadrozole, farstone, filgrastim, finasteride, fligrastim, floxuridine, fluconazole, fludarabin, fludarabin phosphate, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-Fll), fluoxymesterone, flutamide, hexamethylmelamine, formestane, fosteabine, fotemustine, fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel, goserelin, granisetron hydrochloride, histrelin, hycamtin, hydrocortone, erythro-hydroxynonyladenine, hydroxyurea, hydroxyprogesterone caproate, ibritumomab tiuxetan, idarubicin, ifosfamide, interferon-alpha, interferon-alpha-2, interferon-alpha-2a, interferon-alpha-2[3, interferon-alpha-n1, interferon-alpha-n3, interferon-beta, interferon-gamma-1a, interleukin-2, intron A, iressa, irinotecan, kytril, lentinan sulphate, letrozole, leucovorin, leuprolide, leuprolide acetate, levamisole, levofolic acid calcium salt, levothroid, levoxyl, lomustine, lonidamine, marinol, mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, menest, 6-mercaptopurine, mesna, methotrexate, metvix, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, modrenal, myocet, nedaplatin, neulasta, neumega, neupogen, nilutamide, nolvadex, NSC-631570, OCT-43, octreotide, ondansetron hydrochloride, orapred, oxaliplatin, paclitaxel, pediapred, pegaspargase, pegasys, pentostatin, N-phosphonoacetyl L-aspartate (PALA), picibanil, pilocarpine hydrochloride, pirarubicin, platinum, platinum alloys (including, but not limited to alloys with ruthenium, iridium, cobalt and / or copper), plicamycin, porfimer sodium, prednimustine, prednisolone, prednisone, premarin, procarbazine, procrit, raltitrexed, rebif, rhenium-186 etidronate, rituximab, roferon-A, romurtide, salagen, sandostatin, sargramostim, semustine, sizofiran, sobuzoxane, solu-medrol, streptozocin, strontium-89 chloride, Synthroid, tamoxifen, tamsulosin, tasonermin, tastolactone, taxoter, teceleukin, temozolomide, teniposide, testosterone propionate, testred, thioguanine, thiotepa, thyrotropin, tiludronic acid, topotecan, toremifen, tositumomab, tastuzumab, teosulfan, tretinoin, trexall, trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, virulizin, zinecard, zinostatin-stimalamer, zofran; ABI-007, acolbifen, actimmune, affinitak, aminopterin, arzoxifen, asoprisnil, atamestane, atrasentan, avastin, BAY 43-9006 (sorafenib), CCI-779, CDC-501, celebrex,Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATIONcetuximab, crisnatol, cyproterone acetate, decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, edotecarin, eflornithine, exatecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implant, holmium-166 DOTMP, ibandronic acid, interferon-gamma, intron-PEG, ixabepilone, keyhole limpet hemocyanine, L-651582, lanreotide, lasofoxifen, libra, lonafarnib, miproxifen, minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin, neovastat, nolatrexed, oblimersen, onko-TCS, osidem, paclitaxel polyglutamate, pamidronate disodium, PN-401, QS-21, quazepam, R-1549, raloxifen, ranpirnas, 13-cis-retic acid, satraplatin, seocalcitol, T-138067, tarceva, taxoprexin, thymosin-alpha-1 , tiazofurin, tipifarnib, tirapazamine, TLK-286, toremifen, transMID-107R, valspodar, vapreotide, vatalanib, verteporfin, vinflunin, Z-100, zoledronic acid and combinations of the foregoing.

[0104] The chemotherapy agents may be co-administered in conjunction with other bioactive agents including, but not limited to non-steroidal anti-inflammatory agents, steroidal antiinflammatory agents, antioxidants, vitamins, or hormones.

[0105] Exemplary non-steroidal anti-inflammatory agents which can be beneficially used include, but are not limited to, oxicams such as piroxicam, isoxicam, tenoxicam, and sudoxicam; salicylates such as aspirin, disalcid, benorilate, trilisate, safapryin, solprin, diflunisal and fendosal; acetic acid derivatives such as diclofenac, fenclofinac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acemetacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac and ketorolac; fenamates such as mefenamic, meclofenamic, flufenamic, niflumic and tolfenamic acids; propionic acid derivatives, such as ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, indopropfen, pirprofen, carprofen, oxprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, and tiaprofenic; pyrazoles such as phenylbutazone, oxyphenbutazone, feprazone, azapropazone, and trimethazone.

[0106] Exemplary steroidal anti-inflammatory drugs which can be beneficially used in this context of the present embodiments include, without limitation, corticosteroids such as hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethasone dipropionates, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylesters, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide,Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATIONfludrocortisone, difluorosone diacetate, fluradrenolone, fludrocortisone, difluorosone diacetate, fluradre-nolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and the balance of its esters, chloropred-nisone, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, diflurprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocor-tamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, triamcinolone, and mixtures thereof.

[0107] Exemplary anti-oxidants which can be beneficially used in this context of the present embodiments include, without limitation, ascorbic acid (vitamin C) and its salts, ascorbyl esters of fatty acids, ascorbic acid derivatives (e.g., magnesium ascorbyl phosphate, sodium ascorbyl phosphate, ascorbyl sorbate), tocopherol (vitamin E), tocopherol sorbate, tocopherol acetate, other esters of tocopherol, butylated hydroxy benzoic acids and their salts, 6- hydroxy-2, 5,7,8-tetramethylchroman-2-carboxylic acid (commercially available under the trade name Trolox®), gallic acid and its alkyl esters, especially propyl gallate, uric acid and its salts and alkyl esters, sorbic acid and its salts, lipoic acid, amines (e.g., N,N-diethylhydroxylamine, aminoguanidine), sulfhydryl compounds (e.g., glutathione), dihydroxy fumaric acid and its salts, lycine pidolate, arginine pilolate, nordihydroguaiaretic acid, bioflavonoids, curcumin, lysine, methionine, pro-line, superoxide dismutase, silymarin, tea extracts, grape skin / seed extracts, melanin, and rosemary extracts.

[0108] Exemplary vitamins which can be beneficially used in this context of the present embodiments include, without limitation, vitamin A and its analogs and derivatives: retinol, retinal, retinyl palmitate, retinoic acid, tretinoin, isotretinoin (known collectively as retinoids), vitamin E (tocopherol and its derivatives), vitamin C (L-ascorbic acid and its esters and other derivatives), vitamin B3(niacinamide and its derivatives), alpha hydroxy acids (such as glycolic acid, lactic acid, tartaric acid, malic acid, citric acid, etc.) and beta hydroxy acids (such as salicylic acid and the like).

[0109] Exemplary hormones which can be beneficially used in this context of the present embodiments include, without limitation, androgenic compounds and progestin compounds such as methyltestosterone, androsterone, androsterone acetate, androsterone propionate, androsterone benzoate, androstenediol, androstenediol-13 -acetate, androstenediol-17-acetate, androstenediol-3,17-diacetate, androstenediol-17-benzoate, androstenedione, androstenediol, dehydroepiandrosterone, sodium dehydroepiandrosterone sulfate, dromostanolone, dromostanolone propionate, ethylestrenol, fluoxymesterone, nandrolone phenpropionate, nandrolone decanoate, nandrolone furylpropionate, nandrolone cyclohexane propionate,Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATIONnandrolone benzoate, nandrolone cyclohexanecarboxylate, androsteronediol -3-acetate-1 -7-benzoate, oxandrolone, oxymethoIone, stanozolol, testosterone, testosterone decanoate, 4-dihydrotestosterone, 5a-dihydrotestosterone, testolactone, 17a-methyl-19-nortestosterone and pharmaceutically acceptable esters and salts thereof, and combinations of any of the foregoing, desogestrel, dydrogesterone, ethynodiodiacetate, medroxyprogesterone, levonorgestrel, medroxyprogesterone acetate, hydroxyprogesterone caproate, norethindrone, norethindrone acetate, norethynodrel, allylestrenol, 19-nortestosterone, lynoestrenol, quingestanol acetate, medrogestone, norg-estrienone, dimethisterone, ethisterone, cyproterone acetate, chlormadinone acetate, megestrol acetate, norgestimate, norgestrel, desogrestrel, trimegestone, gestodene, nomegestrol acetate, progesterone, acetoxypregnenolone, anagestone acetate, cyproterone, dihydrogesterone, fluorogestone acetate, gestadene, hydroxyprogesterone acetate, hydroxymethylprogesterone, hydroxymethyl progesterone acetate, 3 -ketodesogestrel, megestrol, melengestrol acetate, norethisterone and mixtures thereof.

[0110] The amount of the drug that is present, and that is required to achieve a therapeutic effect, depends on many factors, such as the minimum necessary dosage of the particular drug, the condition to be treated, the chosen location of the inserted device, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0111] The appropriate dosage level of the therapeutic agent, for more traditional routes of administration, are known to one skilled in the art. These conventional dosage levels correspond to the upper range of dosage levels for compositions, including a physiologically active substance and traditional penetration enhancer. However, because the delivery of the active substance occurs at the site where the drug is required, dosage levels significantly lower than a conventional dosage level may be used with success. Ultimately, the percentage of therapeutic agent in the composition is determined by the required effective dosage, the therapeutic activity of the formulation, and the desired release profile. In general, the active substance will be present in the composition in an amount from about 0.0001% to about 99%, more preferably about 0.01% to about 80% by weight of the total composition depending upon the particular substance employed. However, generally the amount will range from about 0.01% to about 75% by weight of the total composition, with levels of from about 25% to about 75% being preferred.Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATION

[0112] The active substance can further include, in addition to the bioactive agent, additional agents that may improve the performance of the bioactive agent. These include, for example, penetration enhancers, humectants, chelating agents, preservatives, occlusive agents, emollients, permeation enhancers, and anti-irritants. These agents can be encapsulated within the pores of a porous coat or can be doped within the polymer forming the coat.

[0113] Representative examples of humectants include, without limitation, guanidine, glycolic acid and glycolate salts (e.g. ammonium slat and quaternary alkyl ammonium salt), aloe vera in any of its variety of forms (e.g., aloe vera gel), allantoin, urazole, polyhydroxy alcohols such as sorbitol, glycerol, hexanetriol, propylene glycol, butylene glycol, hexylene glycol and the like, polyethylene glycols, sugars and starches, sugar and starch derivatives (e.g, alkoxylated glucose), hyaluronic acid, lactamide monoethanolamine, acetamide monoethanolamine and any combination thereof.

[0114] Non-limiting examples of chelating agents include ethylenediaminetetraacetic acid (EDTA), EDTA derivatives, or any combination thereof.

[0115] Non-limiting examples of occlusive agents include petrolatum, mineral oil, beeswax, silicone oil, lanolin and oil-soluble lanolin derivatives, saturated and unsaturated fatty alcohols such as behenyl alcohol, hydrocarbons such as squalane, and various animal and vegetable oils such as almond oil, peanut oil, wheat germ oil, linseed oil, jojoba oil, oil of apricot pits, walnuts, palm nuts, pistachio nuts, sesame seeds, rapeseed, cade oil, corn oil, peach pit oil, poppyseed oil, pine oil, castor oil, soybean oil, avocado oil, safflower oil, coconut oil, hazelnut oil, olive oil, grape seed oil and sunflower seed oil.

[0116] Non-limiting examples of emollients include dodecane, squalane, cholesterol, isohexadecane, isononyl isononanoate, PPG ethers, petrolatum, lanolin, safflower oil, castor oil, coconut oil, cottonseed oil, palm kernel oil, palm oil, peanut oil, soybean oil, polyol carboxylic acid esters, derivatives thereof and mixtures thereof

[0117] Non-limiting examples of penetration enhancers include dimethylsulfoxide (DMSO), dimethyl formamide (DMF), allantoin, urazole, N,N-dimethylacetamide (DMA), decylmethylsulfoxide (Gw MSO), polyethylene glycol monolaurate (PEGML), propylene glycol (PG), propylene glycol monolaurate (PGML), glycerol monolaurate (GML), lecithin, the I-substituted azacycloheptan-2-ones, particularly 1-n-dodecylcyclazacycloheptan-2-one (available under the trademark Azone® from Whitby Research Incorporated, Richmond, Va.), alcohols, and the like. The permeation enhancer may also be a vegetable oil. Such oils include, for example, safflower oil, cottonseed oil and corn oil.Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATION

[0118] Non-limiting examples of anti-irritants include steroidal and non-steroidal antiinflammatory agents or other materials such as aloe vera, chamomile, alpha-bisabolol, cola nitida extract, green tea extract, tea tree oil, licoric extract, allantoin, caffeine or other xanthin Nonlimiting examples of preservatives include one or more alkanols, disodium EDTA (ethylenediamine tetraacetate), EDTA salts, EDTA fatty acid conjugates, isothiazolinone, parabens such as methylparaben and propylparaben, propylene glycols, sorbates, urea derivatives such as diazolindinyl urea, or any combinations thereof. The composite structures according to the present embodiments are particularly beneficial when it is desired to encapsulate bioactive agents which require delicate treatment and handling, and which cannot retain their biological and / or therapeutic activity if exposed to conditions such as heat, damaging substances and solvents and / or other damaging conditions. Such bioactive agents include, for example, peptides, polypeptides, proteins, amino acids, polysaccharides, growth factors, hormones, antiangiogenesis factors, interferons or cytokines, cells and pro-drugs.es, glycyrrhizic acid and its derivatives.

[0119] Diagnostic agents can be utilized as active substances in the context of the present embodiments either perse or in combination with a bioactive agent, for monitoring / labeling purposes.

[0120] Diagnostic agents are also referred to herein interchangeably as "labeling compounds or moieties" and include a detectable moiety or a probe which can be identified and traced by a detector using known techniques such as spectral measurements (e.g., fluorescence, phosphorescence), electron microscopy, X-ray diffraction and imaging, positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), computed tomography (CT) and the like.

[0121] Representative examples of labeling compounds or moieties include, without limitation, chromophores, fluorescent compounds or moieties, phosphorescent compounds or moieties, contrast agents, radioactive agents, magnetic compounds or moieties (e.g., diamagnetic, paramagnetic and ferromagnetic materials), platinum, and heavy metal clusters.

[0122] Other active substances that can be beneficially utilized in this context of the present disclosure include agents that can impart desired properties to the surface of the composition, article or medical device, in terms of, for example, smoothness, hydrophobicity, biocompatibility and the like.Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATION

[0123] Chemotherapy agent layer 103 optionally is covered by coating layer 105. One function of the coating layer (when present) is to protect one or more therapeutic agents from deactivating or degrading conditions. The protection may come from the properties of the material when, for example, a hydrophobic coating layer would protect a water sensitive agent from water by resisting the influx of moisture. The coating layer may also act as a physical barrier. For example, a coating layer comprised of a hydrogel may allow water to be absorbed by the gel, and allow any agents contained within the gel to diffuse out of the gel into the reaction environment. Suitable hydrogels include cellulose, chitosan, collagen, alginate, agarose, gelatin, fibrin, hyaluronic acid which is optionally cross-linked, and combinations thereof. The hydrogel, however, would prevent enzymes from penetrating the layer, thereby protecting any agents contained within from the enzyme. In some embodiments, the coating layer is a degradable polymer which provides sustained release of an active agent such as the anti-cancer eluents and / or chemotherapy agents described herein. Finally, the coating layer does not have to act as a barrier. The coating layer may protect a therapeutic agent by releasing an agent, such as an activating agent or a deactivating agent, into the reaction environment prior to the release of the therapeutic agent. In some embodiments, the coating is a biodegradable coating.

[0124] The coating layer may be dip coated, spray coated, or applied by vapor deposition onto the magnesium alloy wire.

[0125] Although FIG. 1A illustrates that chemotherapy agent layer 103 and optional coating layer 105 are two separate layers, in some embodiments the chemotherapy agent and coating may be admixed for combination into a single layer (not shown). For instance, a chemotherapeutic agent may be incorporated directly in the coating layer. The therapeutic agent can be heterogeneously or homogeneously dispersed in the coating layer. The therapeutic agent can be a drug, or a drug formulated into a microcapsule, niosome, liposome, microbubble, microsphere, or the like. In addition, the coating layer may contain more than one therapeutic agent. For example, a water sensitive drugs, such as a limus, or any other drug that must be administered through intravenous, intramuscular, or subcutaneously, could be incorporated in a hydrophobic matrix such as SAIB, or fatty acid ester.

[0126] A chemotherapeutic agent may also be disposed in a therapeutic agent layer, separate from the coating layer. In this case the coating layer may be adjacent to the therapeutic agent layer and may serve to prevent or retard processes that would degrade or deactivate the therapeutic agent until the coating layer has substantially eroded. In this instance the coatingAtty. Docket No. 30275 / 70816 / PC PATENT APPLICATIONlayer is a barrier between a therapeutic layer and the reaction environment. This barrier may be a hydrophobic barrier that resists water absorption. The hydrophobic barrier would be used in conjunction with water-sensitive drugs as described above. Alternatively, the coating layer may be a hydrogel that resists the absorbance of enzymes. An enzyme resistant barrier may be used to protect a drug such as a DNA, RNA, peptide or protein based therapeutic agent.

[0127] Suitable components of coating layer 105 are polymers, including but not limited to poly-alpha-hydroxy acid esters such as, poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid), poly(lactic-co-polyethylene glycol), poly(lactic-co-glycidol), poly(lactic acid-co-caprolactone); polyethylene glycol and polyethylene oxide; polyvinyl pyrrolidone; polyorthoesters; polysaccharides and polysaccharide derivatives such as polyhyaluronic acid, polyalginic acid, chitin, chitosan, cellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose; polypeptides, and proteins such as polylysine, polyglutamic acid, albumin; polyanhydrides; polyhydroxy alkanoates such as polyhydroxy valerate, polyhydroxy butyrate, and the like, and copolymers thereof, and combinations thereof.

[0128] In some embodiments, the polymers are copolymers such as poly(lactide-co-glycolide) (PLGA) polymers. The rate at which the polymer erodes is determined by the selection of the ratio of lactide to glycolide within the copolymer, the molecular weight of each polymer used, and the crystallinity of the polymers used.

[0129] Bioerodible polymers may also be used to form barrier layers that erode at a rate that can be predetermined based on the composition and that contain no therapeutic agent.

[0130] Typical additives which may also be components of coating layer 105 include but are not limited to pharmaceutically acceptable excipients, adjuvants, carriers, antioxidants, preservatives, buffers, antacids, emulsifiers, inert fillers, fragrances, thickeners, tackifiers, opacifiers, gelling agents, stabilizers, surfactants, emollients, coloring agents, and the like.

[0131] The coating layers of the present invention are beneficial agents comprised of a bioerodible matrix and optionally contain additional additives, therapeutic agents, activating agents, deactivating agents, and the like. Either a property of the chosen material of the coating layer, or a chemical embedded in the coating layer provides protection from deactivating processes or conditions for at least one therapeutic agent. In addition to the polymer materials described above, the coating layer may also be comprised of pharmaceutically acceptable lipids or lipid derivatives, which are well known in the art and include but are not limited to fatty acids, fatty acid esters, lysolipids, phosphocholines, (Avanti Polar Lipids, Alabaster, Ala.), including 1-Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATIONalkyl-2-acetoyl-sn-glycero 3-phosphocholines, and 1-alkyl-2-hydroxy-sn-glycero 3-phosphocholines; phosphatidylcholine with both saturated and unsaturated lipids, including dioleoylphosphatidylcholine; dimyristoyl phosphatidylcholine; dipentadecanoylphosphatidylcholine; dilauroylphosphatidylcholine; dipalmitoyl phosphatidyl choline (DPPC); distearoylphosphatidylcholine (DSPG); and diarachidonylphosphatidylcholine (DAPC); phosphatidylethanolamines, such as dioleoylphosphatidylethanolamine, and distearoylphosphatidylethanolamine (DSPE); phosphatidylserine; phosphatidylglycerols, including distearoylphosphatidylglycerol (DSPG); phosphatidylinositol; sphingolipids such as sphingomyelin; glucolipids; sulfatides; glycosphingolipids; phosphatidic acids, such as distearoylphosphatidic acid (DSPA); palmitic acid; stearic acid; arachidonic acid; oleic acid; lipids bearing polymers, such as chitin, hyaluronic acid, polyvinylpyrrolidone or polyethyleneglycol (PEG), also referred to herein as "pegylated lipids", with preferred lipids bearing polymers including DPPE-PEG (DPPE-PEG), which refers to the lipid DPPE having a PEG polymer attached thereto, including, for example, DPPE-PEG5000, which refers to DPPE having attached thereto a is PEG polymer having a mean average molecular weight of about 5000; lipids bearing sulfonated mono-, di-, oligo- or polysaccharides; cholesterol, cholesterol sulfate and cholesterol hemisuccinate; tocopherol hemisuccinate; lipids with ether and ester-linked fatty acids; polymerized lipids (a wide variety of which are well known in the art); diacetyl phosphate; dicetyl phosphate; stearylamine; cardiolipin; phospholipids with short chain fatty acids of about 6 to about 8 carbons in length; synthetic phospholipids with asymmetric acyl chains, such as, for example, one acyl chain of about 6-25 carbons and another acyl chain of about 12 carbons; ceramides; non-ionic liposomes including niosomes such as polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohols, polyoxyethylene fatty alcohol ethers, polyoxyethylated sorbitan fatty acid esters, glycerol polyethylene glycoloxystearate, glycerol polyethylene glycol ricinoleate, ethoxylated soybean sterols, ethoxylated castor oil, polyoxyethylenepolyoxypropylene polymers, and polyoxyethylene fatty acid stearates; sterol aliphatic acid esters including cholesterol sulfate, cholesterol butyrate, cholesterol isobutyrate, cholesterol palmitate, cholesterol stearate, lanosterol acetate, ergosterol palmitate, and phytosterol n-butyrate; sterol esters of sugar acids including cholesterol glucuronide, lanosterol glucuronide, 7-dehydrocholesterol glucuronide, ergosterol glucuronide, cholesterol gluconate,lanosterol gluconate, and ergosterol gluconate; esters of sugar acids and alcohols including lauryl glucuronide, stearoyl glucuronide, myristoyl glucuronide, lauryl gluconate, myristoyl gluconate, and stearoyl gluconate; esters of sugars and aliphatic acids including sucrose acetate isobutyrate (SAIB), sucrose laurate, fructose laurate, sucrose palritate, sucroseAtty. Docket No. 30275 / 70816 / PC PATENT APPLICATIONstearate, glucuronic acid, gluconic acid and polyuronic acid; saponins including sarsasapogenin, smilagenin, hederagenin, oleanolic acid, and digitoxigenin; glycerol dilaurate, glycerol trilaurate, glycerol monolaurate, glycerol dipalmitate, glycerol and glycerol esters including glycerol tripalmitate, glycerol monopalmitate, glycerol distearate, glycerol tristearate, glycerol monostearate, glycerol monomyristate, glycerol dimyristate, glycerol trimyristate; long chain alcohols including n-decyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, and n-octadecyl alcohol; and / or combinations thereof

[0132] If desired, a cationic lipid may be used, such as, for example, N-[1 -(2,3-dioleoyloxy)propyl]-N, N ,N-trimethylammonium chloride (DOTMA), or N-[1 ,2-dioleoyloxy-3-(trimethylammonio)propane (DOTAP). If a cationic lipid is employed in the lipid compositions, the molar ratio of cationic lipid to non-cationic lipid may be, for example, from about 1:1000 to about 1 : 100.

[0133] The coating layer may optionally include activating and deactivating agents for the purpose of preparing the reaction environment for the subsequent release of a therapeutic agent. These activating and deactivating agents are well known to those skilled in the art and include but are not limited to antacids, buffers, enzyme inhibitors, hydrophobic additives, and adjuvants. For example, Mg(OH)2in particles of about 0.5 pm to about 5 pm more preferably, about 1 pm incorporated in a PLGA polymer layer could be used in conjunction with any acid sensitive drug. An example of an activating agent is chymotrypsin, which may be incorporated in polyvinyl pyrrolidone layer. The chymotrypsin could be used to convert a pro-drug to an active drug.

[0134] In another embodiment, chemotherapy agents may be delivered to a tumor site on a magnesium alloy wire. Alternatively, instead of fully coating the magnesium alloy wire as shown in FIG. 1A, one or more of the layers 103 and 105 may only partially coat the magnesium alloy wire. FIGS. 1 B and 1C show two possible alternative configurations for partially coated wires in cross-sectional views 102 and 104 respectively. In FIG. 1B, chemotherapy agent layer 103 coats only one end of the wire layer 101. In some embodiments, the FIG. 1 B coating configuration may be useful when the coated end of the wire is positioned nearer to or touching the tumor.

[0135] In FIG. 1C, chemotherapy agent layer 103 is striated, with wire layer 101 (bare wire) between sections of chemotherapy agent layer 103. The chemotherapy agent striations may be uniform, or of varying lengths along the bare wire. The ratio of coated wire to bare wire may be from about 10:90 to about 90:10. In some embodiments, the wire is 10% coated, 20% coated,Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATION30% coated, 40% coated, 50% coated, 60% coated, 70% coated, 80% coated, or 90% coated with chemotherapy agent. The percentage of coating is guided by the selected therapeutic treatment plan as determined by the doctor, recognizing that as the amount of coating increases, more chemotherapy agent will be initially dispersed at the tumor site than anti-cancer eluent. In some embodiments, it may be more advantageous to predominantly and initially release anti-cancer eluent. In such situations, the percentage of coating of the chemotherapy agent on the wire may be lower.

[0136] In some embodiments, chemotherapy agents may be delivered in a powder form, where the powder is admixed with a magnesium alloy powder for contemporaneous administration. In some embodiments, when the magnesium alloy powder and chemotherapy agent powder are mixed together, the magnesium alloy powder, the chemotherapy agent powder or both may be coated with a coating as described above. Alternatively, the magnesium alloy powder and the chemotherapy agent powder may be sequentially and separately administered. The mixture of powders may be delivered in a targeted fashion to a tumor site.Methods of Treating Cancer with Magnesium Alloys

[0137] The bare magnesium alloy wires, coated magnesium alloy wires or magnesium alloy powders may be used to treat tumors, such as lung cancer tumors. Cross-sectional view 200 of FIG. 2A shows some embodiments of treatment of tumor 203 within lung 201 by insertion of one or more magnesium alloy wires. Examples of suitable placement of wires are illustrated by wire 205 (positioned near, but not touching a tumor), wire 207 (which may touch the tumor surface, may be partially embedded, or may be fully embedded into a tumor) or wire 209 (which may be wrapped around at least a portion of a tumor). A single tumor may be treated by one or more magnesium alloy wires; or a group of tumors may be treated by one or more magnesium alloy wires.

[0138] The placement of the wires may be effected by implanting them as guided by either x-rays or ultrasound imaging. In some embodiments, wires may be inserted within the lung in a cavity or space left after a tumor has been surgically removed. A patient may be undergoing chemotherapy, radiation therapy or a combination of the two therapies before, after or at the same time as treatment with coated magnesium alloy wires. In some cases, the implanted magnesium alloy wire may serve as a target to identify the locus of treatment for procedures including, but not limited to, photothermal therapy or electroporation therapy.Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATION

[0139] FIG. 2B is a cross-sectional view 220 of a tumor, illustrating various options for placement of magnesium alloy wires. Tumor 223 has a width 235. Magnesium alloy wires 225, 227 and 229 may be located at various positions surrounding the tumor as described above with reference to FIG. 2A. Returning to FIG. 2B, wires 225 and 227 may be positioned with distance 231 between them. Wires may be touching the surface of the tumor 223 (as wires 225 and 227) or may be near but not touching the tumor 223 (as wires 229) at a distance 233 between the wire and the tumor. Optimal distances 231 and 233 can be selected based upon the width 235 of the tumor, the width and length of the wires, the number of wires, as well as the rate of diffusion and / or concentration gradient of anti-cancer eluents as described further below. In some embodiments, the method involves finding an optimum (e.g., a local optimum possibly among several optima) or preferred selection that balances release rate and / or concentration gradient of the active agents (chemotherapy agents and anti-cancer eluents). In some embodiments, the selection of wires may be determined based upon the number and size of tumors to be treated. The distances between wires may be uniform (equal) or non-uniform (unequal).

[0140] Other forms of cancer may be controlled by the medicaments described herein, including pancreatic, ovarian, breast, prostate, esophageal, liver, brain, colon, bone and melanoma cancer.ExamplesExample 1 - Anti-Cancer Eluent Diffusion Rates

[0141] The rates of evolution of the various anti-cancer eluents released from the magnesium alloy was calculated with respect to tumor size and number of wires per tumor. For experimental purposes, measurements are made on the current bench test system normally in units of milliliters of hydrogen, 1.0 ml of H2 is equivalent to 1.085 mg of magnesium that is dissolved. Data on the loading of tumors from magnesium alloy wires are shown in Table 1 below.Table 1 -Hydrogen Evolution from Magnesium AlloyAtty. Docket No. 30275 / 70816 / PC PATENT APPLICATION

[0142] The length and number of wires of the anti-cancer eluent-releasing magnesium alloy may be varied and / or adjusted in accordance with the stage of lung cancer to be treated. This variation affects the loading of the active anti-cancer elements (Mg, Zn, Ca and Mn) and the volume of generated anti-cancer hydrogen. When normalized for tumor volume, the volume of anti-cancer hydrogen per tumor is 0.84 to 1.5 ml; likewise, the weight of anti-cancer Mg loading is 2 to 200 mg.

[0143] In certain embodiments, a magnesium alloy wire may treat a malignant tumor or diseased tissue area about three times the diameter of the magnesium alloy wire. For instance, a 0.3 mm magnesium alloy wire may be suitable for treating a tumor section of about 1 mm in diameter. In some cases, a cable of three 0.3 mm magnesium alloy wires may be suitable for treating a tumor section of more than 2 mm in diameter.

[0144] As the anti-cancer elements and anti-cancer H2 (the anti-cancer eluents) are released, a greater amount of each will be found in the area closest to the wire which they originate from than farther away from the wire. The amount of the anti-cancer eluents will thus be varied over time within the lung or other tissue to be treated. This variation provides a concentration gradient which may be different for each of the anti-cancer eluents.

[0145] The loading of anti-cancer agents described herein is far below the daily limits for normal cells of the human body as shown in Table 2 below. The diameter of the wire tested was 0.3 mm, and the length the wire tested was 1.5 cm, 4 cm and 6 cm as provided in Table 1 above.Table 2 - Diffusion of Metals from Magnesium AlloyAtty. Docket No. 30275 / 70816 / PC PATENT APPLICATIONExample 2 - Ex Vivo Test Model Single Layer Evaluation

[0146] In order to develop the ex vivo double layer cell test model (also referred to as a tissue sandwich) for testing the biological effect of agents on ex vivo lung tissue; a single layer of test tissue was initially prepared and evaluated.

[0147] To form the single layer, agarose-infiltrated lungs of euthanized mice were sectioned into 300 pm sections using a compresstome. Preliminary data showed that PCLS from wildtype mice remains viable over at least 5 days of culture (FIGS. 3A and 3B).Example 3 - Ex Vivo Test Model Single Layer Evaluation with Cancer Cells

[0148] The single layer model of Example 2 was then modified to include cancer cells. A cross-sectional view 400 of the modified single layer model is illustrated in FIG. 4. The model includes a PCLS layer 401 and cancer cell layer 403 above it. When seeding human cancer cells (A549) atop ex vivo mouse PCLS, these cells integrated into existing lung structure over 3 days (FIG. 5). A549 cells form relatively distinct cell pockets which size depends on the initial seeding density atop mouse PCLS (0.5-3.0x106 / cm2mouse tissue. The A549 cells are an epithelial cell line derived from lung adenocarcinoma and have been widely used as a model for studying lung cancer. This cell line has been approved by the FDA; and the A549 CDX mouse model (cell line derived xenograft) is the most commonly used xenograft lung cancer model. Thus, co-culture of human A549 cells and mouse PCLS presents an ideal ex vivo model to test various effects of agents, such as BioMg® 250 wire bioabsorption as described further in Example 4 below. The ex vivo test is cost effective, as in vivo large animal testing may cost approximately $22,000 / animal over a one-to-three-year time period.Example 4 - Ex Vivo Test Model Double Layer Evaluation of Effects of Magnesium Alloy Wires on Cancer Cells

[0149] The single layer test model described in Example 3 was then incorporated into a double layer tissue sandwich model as illustrated in FIG. 6. Cross-sectional view 600 illustrates theAtty. Docket No. 30275 / 70816 / PC PATENT APPLICATIONupper half of the sandwich 617 which includes a PCLS layer 625; and the lower half of the sandwich 619 which includes lower PCLS layer 621 and associated cancer cell layer 623.

[0150] The upper and lower halves of the sandwich are prepared as in Example 3, and then active agent to be tested (shown in FIG. 6 as magnesium alloy wire 627) is placed on the lower half of the sandwich in contact with cancer cell layer 623. The upper half of the sandwich is then placed on top of the magnesium alloy wire to form the tissue sandwich including an active agent to be tested.

[0151] To confirm viability of the model, preliminary experiments were performed with magnesium alloy wires and PCLS. The BioMg® 250 wires (300 pm diameter, 5 mm length) were placed between two PCLS from wild-type mice and formed a tissue sandwich (FIG. 7A).In this configuration, there was no significant reduction in normal cell viability, comparable to PCLS tissue with BioMg® 250 wires added to a Dulbecco’s Modified Eagle Medium Mixture F-12 culture media (FIG. 7B). In addition, analysis of type 2 alveolar epithelial cells showed no significant reduction in cell numbers, indicating the compatibility of BioMg® 250 wires.

[0152] Following proof of viability, tissue sandwiches of A549 / mouse PCLS and BioMg 250 wires were prepared (FIG. 8A). Using this tissue sandwich model, it was determined that BioMg® 250 wires degrade at a rate of 5 pm / day (FIG. 8B). Increased expression of y-H2AX30 in A549 cells adjacent to the wire indicates increased local cell stress and DNA damage due to BioMg® 250 absorption (FIG. 8C). These preliminary data support the hypothesis that BioMg® 250 wires induce local cancer cell cytotoxicity and illustrate the localized gradient effect whereby cells closest to the wires are more affected.

[0153] A powder form of an active agent, such as magnesium alloy powder, may also be tested in a similar manner by sprinkling it over the cancer cell layer 623.Example 5 - In Vitro Culture Test Evaluation of Effects of Coated and Uncoated Magnesium Alloy Wires on Cancer Cells

[0154] This example provides in vitro cell testing results for coated and uncoated BioMg® wires in a MATRIGEL medium loaded with A549 cancer cells. Briefly, uncoated (or bare) wires exhibited a reduction in cancer cell count, and the inclusion of a cisplatin-containing hydrogel coating on the wires further reduced the cancer cell count, even at very low cisplatin loadings relative to convention chemotherapy treatments. Procedures and results are described in more detail below.Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATION

[0155] Control Samples: Control samples without any BioMg® wires were prepared by culturing A549 cancer cells in a MATRIGEL medium (solubilized basement membrane matrix secreted by Engelbreth-Holm-Swarm (EHS) mouse sarcoma cells; available from Corning) for a period of up to four days and using a starting seeding density of 5 x 104. A cell counter was used to analyze the sample to provide an estimated cell count and to assess cell proliferation without any BioMg® wires present.

[0156] Treated Samples: Treated samples including coated and uncoated BioMg® wires were prepared by culturing A549 cancer cells in a MATRIGEL medium with added wire(s) for a period of up to four days and using a starting seeding density of 5 x 104. A cell counter was used to analyze the sample to provide an estimated cell count and to assess cell proliferation with BioMg® wires present.

[0157] Media Preparation: Advanced DMEM (Dulbecco's Modified Eagle's Medium), 1% Pen Strep (penicillin-streptomycin), 1% GLUTAMAX (L-alanyl-L-glutamine) and 1% FBS (fetal bovine serum) was used. The following procedure was used:• Thaw A549 cells and culture.• Passage when cells are about 70 - 90% confluent (have not formed little cobblestones yet).• Aspirate and Wash 1x with PBS then add 0.05% trypsin and Incubate for 5 minutes. • Add media (same volume as trypsin) to stop the trypsin.• Collect all in a 50 mL tube and spin it down in centrifuge (300 G for 3 mins @ room temperature).• Aspirate supernatant and resuspend pellet in 1 mL media.• Count using the cell counter - take 20 pl of cell suspension and add 20 pl of trypan blue (1 : 1 ratio) - place 10 pl of mix in the cell counter slide, insert and read.• Once determined, calculate 250000 cells in suspension for 250 pl MATRIGEL for 5 samples (there will be 50000 cells in 50 pl MATRIGEL for each sample).• Take cell suspension with 250000 cells, spin down and remove supernatant - then place 250 pl MATRIGEL and gently mix together on ice.• Matrigel stays on ice when in use.Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATIONTake out 50 pl of cell Matrigel mix and place in 24 wells.Leave in 37°C incubator for gelation for 30 mins.

[0158] Wire Preparation: The BioMg® wires used had a 0.3 mm diameter, yield strength of 450 MPa, and an elongation of 4%. A total of five A549 cultire samples were prepared: 1 control sample (no wire), a sample with 1 bare wire, a sample with 2 bare wires, a sample with 1 wire including 10 pl cisplatin coated gel, and a sample with 1 wire including 25 pl cisplatin coated gel. The wires were prepared by the following procedure:• Cut wires to about 10 mm length and leave in the hood under UV Light for 30 mins to 1 hour.• Place wires in 0.5% citric acid for 15 seconds , rinse in distilled water for 5 seconds in ethanol, and allow to air dry.• Optionally, coat the wires with a fibrin hydrogel containing cisplatin (see below).• Once wires are prepared, place them in MATRIGEL using forceps.• Add 500 pl media. Do not change media until counting on day 4 of culture• 5 MATRIGEL A549 samples included; 1 control (no wire), 1 bare wire, 2 bare wires, a 10 pL cisplatin coated gel on 1 wire and a 25 pL cisplatin coated gel on 1 wire.

[0159] Hydrogel Preparation and Coating: A commercial fibrin hydrogel was formed according to manufacturer’s instructions using 30 pL fibrinogen solution and 20 pL thrombin solution to form a gel having a 50 pL total volume. Cisplatin powder was solubilized by dissolving 1 mg cisplatin powder in 1 mL PBS by vortexing and then filtering using a 0.22 pm syringe filter. The solubilized cisplatin was mixed in fibrinogen by mixing 10 pL or 25 pL of solubilized cisplatin solution in 30 pL the fibrinogen solution. A wire was placed in the mixture, and then the 20 pL thrombin solution was added for gelation at 37°C for 30 minutes. The wires were removed after gelation. The coated wires had loading levels of cisplatin in the hydrogel of 20 wt.% (10 pL solubilized cisplatin added to gel) or 50 wt.% (25 pL solubilized cisplatin added to gel).

[0160] Sample Analysis: After four days of culture in MATRIGEL with A549 cancer cells and with or without coated or uncoated BioMg® wires, the samples were analyzed using the following procedure:• Remove media and wires, then gently rinse with PBS twice.Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATIONAdd 500 pL of 0.25% trypsin in 24 well, disrupt MATRIGEL by pipetting up and down and incubate for 10 minutes,• Monitor cell separation under microscope to get a near single cell suspension.• Quench trypsin with 500 pL media and count using cell counter.• Run experiment 3 times for technical replicate.

[0161] Results - Hydrogen Evolution: After four days of culture, the samples were visibly inspected for the hydrogen (H2) evolution. Hydrogen evolution from the wires was visible in bubbles of varying diameter of up to about 1.5 mm. The number and size of bubbles increased as the number of wires increased. In location, the bubbles were closely related to the wires and had not penetrated widely into the plane of the gel. The initiation of a magnesium metabolic zone (MgMZ) was observed in the 2-wire sample. The MgMZ can represent the gross volume of metabolic action that surrounds a magnesium wire implant, which can be characterized as having an MgMZ diameter that is about 5 to 8 times the wire diameter and / or as having an MgMZ volume that is at least about 20 times the wire volume.

[0162] Results - Cancer Cell Reduction: FIG. 9A is a graph showing the reduction of A549 cancer cells after four days of culture for a control sample (no wires), a sample with 1 bare BioMg® 250 wire, and a sample with 2 BioMg® 250 wires. FIG. 9B is a graph showing the reduction of A549 cancer cells after four days of culture for a control (no wires), a sample with 1 bare BioMg® 250 wire, a sample with 1 cisplatin-coated BioMg® 250 wire at a loading of 10 pg cisplatin (20 wt.% of coating), and a sample with 1 cisplatin-coated BioMg® 250 wire at a loading of 25 pg cisplatin (50 wt.% of coating). The graphs show statistically significant decrease in A549 cancer cells in four different conditions when compared to the control (no wire) samples. The bare wires demonstrated benefits which increased as the number of wires was increased from 1 to 2 (FIG. 9A). With 1 wire, a cisplatin coating increased the cell death equally at 2 levels of cisplatin loading (FIG. 9B). More specifically for the coated wires, the cell count was reduced 66 % from the wire-free control sample, with p = 0.001 % (FIG. 9B); this level of body loading of cisplatin is only 0.001 % of the usual chemotherapy loading, providing a potential reduction damaging side effects. Two bare wires had almost the same influence as cisplatin coating of one wire (FIG. 9A and FIG. 9B). Scatter in data and p number were lower in the case of cisplatin coated wires.

[0163] Discussion: This example demonstrates that bare BioMg® 250 alloy effectively kills cancer cells in vitro, and the effectiveness increases with wire loading. The benefits of cisplatinAtty. Docket No. 30275 / 70816 / PC PATENT APPLICATIONloading were also demonstrated and appeared to be consistent across a wide range of cisplatin loading in the hydrogel coating. For both bare and coated wires, there is the potential of increased cancer cell death by increasing of number of wires (or wire density compared to a given tumor size). The evolution of hydrogen (H2) in all three dimensions relative to an implanted wire suggests that more influential in killing cancer cells in bulk 3-dimensional tumors. Furthermore, hydrogen is soluble in certain constituents of tissue and is a fast diffuser. Thus, the MgMZ for hydrogen could be even larger in some cases.

[0164] The examples collectively illustrate that the disclosed magnesium-containing alloys in combination with a chemotherapy agent (e.g., cisplatin or otherwise) provide multiple anticancer attacks that are effective across different cancer cell attack mechanism and across different time scales, providing both short- and long-time scale treatment efficacy (i.e., relative to implantation time) against a wide tumor types. For example, independent of activity provided by the chemotherapy agent, the elements of the magnesium-containing alloys provide several mechanisms of cancer cell attack, including pH increase (Mg), reactive oxygen species (ROS) (H2, Mn), cGAS STING (Zn, Mn), NK cell (Mg, Ca) and T cell (Mg, Ca) pathways, sometimes synergistically. Similarly, and without being bound by a particular theory, the sequence of tumor attack is expected to be as follows (e.g., in a generally increasing order of short-to-long time scales for different anti-cancer agents): (1) cisplatin (or other chemotherapy agent), because it sits on the alloy surface (e.g., wire surface); (2) H2, because it diffuses rapidly upon evolution; (3) Mg, due to its relatively high concentration in the alloy; (4) Ca, Zn and Mn, due to their relatively low concentration in the alloy; and (5) over longer times after full bioabsorption of the wires and H2exhaustion, continued cell death arising from the residual Pt, Mg, Zn, Ca and Mn still resident in the tumor site. These can collectively increase the efficacy of a single implantation or other treatment event (e.g., in terms of fraction of cancer cells killed and / or time of effective anti-cancer activity), and it can reduce or eliminate the need for subsequent implantation or other treatment events.

[0165] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0166] While the present teachings have been described in conjunction with various embodiments and examples, it is not intended that the present teachings be limited to suchAtty. Docket No. 30275 / 70816 / PC PATENT APPLICATIONembodiments or examples. On the contrary, the present teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art.

[0167] While various inventive embodiments have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and / or structures for performing the function and / or obtaining the results and / or one or more of the advantages described herein, and each of such variations and / or modifications is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and / or configurations will depend upon the specific application or applications for which the inventive teachings is / are used. Those skilled in the art will recognize many equivalents to the specific inventive embodiments described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, inventive embodiments may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and / or methods, if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent, is included within the inventive scope of the present disclosure.

[0168] The claims should not be read as limited to the described order or elements unless stated to that effect. It should be understood that various changes in form and detail may be made by one of ordinary skill in the art without departing from the spirit and scope of the appended claims. All embodiments that come within the spirit and scope of the following claims and equivalents thereto are claimed.

[0169] Because other modifications and changes varied to fit particular operating requirements and environments will be apparent to those skilled in the art, the disclosure is not considered limited to the example chosen for purposes of illustration, and covers all changes and modifications which do not constitute departures from the true spirit and scope of this disclosure.

[0170] Accordingly, the foregoing description is given for clearness of understanding only, and no unnecessary limitations should be understood therefrom, as modifications within the scope of the disclosure may be apparent to those having ordinary skill in the art.Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATION

[0171] All patents, patent applications, government publications, government regulations, and literature references cited in this specification are hereby incorporated herein by reference in their entirety. In case of conflict, the present description, including definitions, will control.

[0172] Throughout the specification, where the apparatus, compounds, compositions, methods, and processes are described as including components, steps, or materials, it is contemplated that the apparatus, compounds, compositions, methods, and processes can also comprise, consist essentially of, or consist of, any combination of the recited components or materials, unless described otherwise. Component concentrations can be expressed in terms of weight concentrations, unless specifically indicated otherwise. Combinations of components are contemplated to include homogeneous and / or heterogeneous mixtures, as would be understood by a person of ordinary skill in the art in view of the foregoing disclosure.

Claims

Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATIONWhat is claimed is:

1. A method of localized treatment of cancer in a patient, the method comprising:providing a combination comprising at least one magnesium alloy wire, wherein the at least one magnesium alloy wire comprises magnesium, calcium, manganese and zinc, and a chemotherapy agent, and wherein the at least one magnesium alloy wire releases at least one anti-cancer eluent upon implantation into or near a diseased tissue or a malignant tumor of the patient;determining a rate of release and distance of diffusion of the at least one anti-cancer eluent; and thendetermining a selected number of magnesium alloy wires and a selected distance between magnesium alloy wires based upon i) size of malignant tumor or diseased tissue to be treated, ii) the rate of release of the at least one anti-cancer eluent, and iii) distance of diffusion of the at least one anti-cancer eluent; andimplanting the selected number of magnesium alloy wires at the selected distance between magnesium alloy wires into or near the diseased tissue or the malignant tumor of the patient.

2. The method of claim 1 , wherein:the combination further comprises a carrier comprising a hydrogel or a polymer; the chemotherapy agent and the carrier together form a coating on the at least one magnesium alloy wire; andthe chemotherapy agent is present in the coating in an amount in a range of 10 wt.% to 60 wt.% chemotherapy agent relative to the coating.

3. The method of claim 2, wherein:the at least one magnesium alloy wire is present in an amount of 60 wt.% to 99.9 wt.% magnesium alloy wire relative to a combined amount of the at least one magnesium alloy wire and the coating;the coating is present in an amount of 0.1 wt.% to 40 wt.% coating relative to a combined amount of the at least one magnesium alloy wire and the coating;a combined amount of the chemotherapy agent and the carrier relative to the at least one magnesium alloy wire surface area is in a range of 0.5 pg / mm2to 5 pg / mm2;the chemotherapy agent comprises cisplatin;the carrier comprises the hydrogel; andAtty. Docket No. 30275 / 70816 / PC PATENT APPLICATIONthe at least one magnesium alloy wire contains about 0.3 to about 2.0 weight percent zinc, about 0.1 to about 1 .0 weight percent calcium, and about 0.1 to about 1.0 percent manganese.

4. The method of claim 1 , wherein determining the selected number of magnesium alloy wires comprises determining a length and a diameter of the at least one magnesium alloy wire.

5. The method of claim 1 , wherein the at least one anti-cancer eluent comprises hydrogen, magnesium, zinc, calcium or manganese.

6. The method of claim 1 , wherein the chemotherapy agent comprises platinum, a platinum alloy, cisplatin, carboplatin, oxaliplatin or satraplatin.

7. The method of claim 1 , wherein the cancer is lung cancer.

8. The method of claim 1 , further comprising guiding the implantation of the magnesium alloy wires by x-ray or ultrasound imaging.

9. The method of claim 1 , wherein the patient undergoes surgical removal of malignant tumors, chemotherapy, radiation therapy or a combination thereof before, after or at a same time as treatment with the combination comprising at least one magnesium alloy wire and a chemotherapy agent.

10. The method of claim 1 , wherein the at least one magnesium alloy wire has (i) a diameter in a range of 0.1 mm to 3 mm and (ii) a length in a range of 5 mm to 7 cm.

11. The method of claim 1 , wherein:the selected number of magnesium alloy wires is in a range of 2 to 30 wires; and the selected distance between magnesium alloy wires is in a range of 1 mm to 5 mm.

12. The method of claim 1 , wherein:each magnesium alloy wire is characterized by at least one of (I) a magnesium metabolic zone (MgMZ) diameter relative wire diameter in a range of 4 to 10, and (II) an MgMZ volume relative to wire volume in a range of 10 to 100; andthe selected number of magnesium alloy wires and the selected distance between magnesium alloy wires provide a collective MgMZ that substantially (or completely) encompasses (or contains / envelops) the diseased tissue or the malignant tumor of the patient.Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATION13. The method of claim 1 , wherein the selected number of magnesium alloy wires is selected to provide at least one of the following properties (I), (II), and (III):(I) a hydrogen (H2) evolution of 0.5 ml / cm3to 2 ml / cm3H2per unit tumor volume;(II) a magnesium loading of 0.5 mg / cm3to 2 mg / cm3Mg per unit tumor volume; and (III) a daily dosage of 1 mg / day to 20 mg / day Mg.

14. A method of localized treatment of cancer in a patient, the method comprising:providing a plurality of magnesium alloy wires, wherein each magnesium alloy wire (i) comprises magnesium, calcium, manganese and zinc, and a chemotherapy agent, and (ii) releases at least one anti-cancer eluent upon implantation into or near a diseased tissue or a malignant tumor of the patient; andimplanting the plurality of magnesium alloy wires at a selected distance between adjacent magnesium alloy wires into or near the diseased tissue or the malignant tumor of the patient;wherein a concentration gradient of the at least one anti-cancer eluent between adjacent magnesium alloy wires is characterized by a percentage of greater than 30% of an amount of the at least one anti-cancer eluent in the magnesium alloy wire for a minimum concentration of the at least one anti-cancer eluent between adjacent magnesium alloy wires relative to a maximum concentration of the at least one eluent between adjacent magnesium alloy wires.

15. An implantable pharmaceutical dosage form comprising:from about 60 weight percent to about 99.9 weight percent of an anti-cancer eluentreleasing magnesium alloy in a wire form or in a powder form; andfrom about 0.1 weight percent to about 40 weight percent of a chemotherapy agent, and a carrier comprising a polymer or a hydrogel.

16. An implantable pharmaceutical dosage form comprising:an anti-cancer eluent-releasing magnesium alloy in a wire form or in a powder form; and a coating on the anti-cancer eluent-releasing magnesium alloy, wherein i) the coating comprises a chemotherapy agent, and a carrier comprising a polymer or a hydrogel, and ii) the chemotherapy agent is present in the coating in an amount in a range of 10 wt.% to 60 wt.% chemotherapy agent relative to the coating.Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATION17. The implantable pharmaceutical dosage form of claim 15 or 16, wherein a combined amount of the chemotherapy agent and the carrier relative to the anti-cancer eluent-releasing magnesium alloy surface area is in a range of 0.5 pg / mm2to 5 pg / mm2.

18. The implantable pharmaceutical dosage form of claim 15 or 16, wherein the chemotherapy agent comprises platinum, a platinum alloy, cisplatin, carboplatin, oxaliplatin or satraplatin.

19. The implantable pharmaceutical dosage form of claim 15 or 16, wherein the anti-cancer eluent-releasing magnesium alloy comprises magnesium, about 0.3 to about 2.0 weight percent zinc, about 0.1 to about 1 .0 weight percent calcium, and about 0.1 to about 1.0 percent manganese.

20. The implantable pharmaceutical dosage form of claim 15 or 16, wherein the anti-cancer eluent-releasing magnesium alloy is a magnesium alloy powder, and wherein the chemotherapy agent is a chemotherapy agent powder.

21. The implantable pharmaceutical dosage form of claim 20, wherein:the magnesium alloy powder has a particle size in a range of 50 nm to 2000 nm; and the chemotherapy agent powder has a particle size in a range of 50 nm to 2000 nm.

22. The implantable pharmaceutical dosage form of claim 15 or 16, wherein the anti-cancer eluent-releasing magnesium alloy releases hydrogen, magnesium, zinc, calcium, manganese or a combination thereof.

23. The implantable pharmaceutical dosage form of claim 15 or 16, wherein the carrier is a polymer, and wherein the polymer comprises poly(lactic acid), poly (lactic acid-co-glycolic acid), poly(lactic acid-co-polyethylene glycol), poly(lactic acid-co-glycidol) or a combination thereof.

24. The implantable pharmaceutical dosage form of claim 15 or 16, wherein the carrier is a hydrogel, and wherein the hydrogel comprises hyaluronic acid, cellulose, chitosan, collagen, alginate, agarose, gelatin, fibrin or a combination thereof.

25. The implantable pharmaceutical dosage form of claim 15 or 16, wherein the anti-cancer eluent-releasing magnesium alloy is a magnesium alloy wire, and wherein the magnesium alloy wire comprises a bundle of two or more magnesium alloy wires.Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATION26. The implantable pharmaceutical dosage form of claim 25, wherein at least one of the two or more magnesium alloy wires are coated with the chemotherapy agent to form coated wires.

27. The implantable pharmaceutical dosage form of claim 26, wherein the percentage of chemotherapy agent on the coated wires is from about 1 weight percent to about 30 weight percent.

28. The implantable pharmaceutical dosage form of claim 26, wherein the coated wires are fully coated or partially coated with chemotherapy agent.

29. The implantable pharmaceutical dosage form of claim 25, wherein the bundle comprises coated wires and uncoated wires.

30. The implantable pharmaceutical dosage form of claim 29, wherein the bundle comprises layered wires or wires twisted together.

31. The implantable pharmaceutical dosage form of claim 15 or 16, wherein the anti-cancer eluent-releasing magnesium alloy further comprises MgO, Mg(OH)2or a combination thereof.

32. A method of making a medicament for lung cancer treatment, the method comprising:cleaning a magnesium alloy with an acid to form a cleaned magnesium alloy; and then coating the cleaned magnesium alloy with a coating comprising a chemotherapy agent.

33. The method of claim 32, wherein the acid comprises citric acid or nitric acid.

34. The method of claim 32, wherein the coating further comprises a polymer or a hydrogel.

35. The method of claim 34, wherein the coating comprises a hydrogel, and wherein the hydrogel comprises hyaluronic acid.

36. The method of claim 35, wherein the hyaluronic acid is cross-linked.

37. The method of claim 34, wherein the coating comprises a polymer, and wherein the polymer comprises poly(lactic acid) or poly(lactic acid-co-glycolic acid).

38. The method of claim 37, wherein the coating is dip coated, spray coated or vapor deposited onto the magnesium alloy.Atty. Docket No. 30275 / 70816 / PC PATENT APPLICATION39. The method of claim 32, wherein the coating fully coats or partially coats the cleaned magnesium alloy.

40. The method of claim 32, wherein the chemotherapy agent comprises platinum, a platinum alloy, cisplatin, carboplatin, oxaliplatin or satraplatin.

41. A system for ex vivo testing a medicament, the system comprising:human cancer cells;a first precision cut tissue slice having a top surface;and a second precision cut tissue slice;wherein the human cancer cells are seeded onto the top surface of the first precision cut tissue slice to form a seeded first precision cut tissue slice; andwherein the second precision cut tissue slice is layered above the seeded first precision cut tissue slice.

42. The system of claim 41 , wherein the first precision cut tissue slice and second precision cut tissue slice are mouse precision cut lung slices.

43. The system of claim 41 , further comprising a medicament disposed above the seeded first precision cut tissue slice and disposed below the second precision cut tissue slice.

44. The system of claim 43, wherein the medicament is an anti-cancer eluent-releasing magnesium alloy.

45. A method of localized treatment of cancer in a patient, the method comprising:preparing a combination comprising at least one magnesium alloy wire, wherein the at least one magnesium alloy wire comprises magnesium, calcium, manganese and zinc, and a chemotherapy agent, and wherein the at least one magnesium alloy wire releases at least one anti-cancer eluent upon implantation into or near a diseased tissue or a malignant tumor of the patient;determining a rate of release and distance of diffusion of the at least one anti-cancer eluent; and thendetermining a selected number of magnesium alloy wires and a selected distance between magnesium alloy wires based upon i) size of malignant tumor or diseased tissue to be treated, ii) the rate of release of the at least one anti-cancer eluent, and iii) distance of diffusion of the at least one anti-cancer eluent; andAtty. Docket No. 30275 / 70816 / PC PATENT APPLICATIONimplanting the selected number of magnesium alloy wires at the selected distance between magnesium alloy wires into or near the diseased tissue or the malignant tumor of the patient.

46. The method of claim 45, wherein determining the selected number of magnesium alloy wires comprises determining a length and a diameter of the at least one magnesium alloy wire.

47. The method of claim 45, wherein the at least one anti-cancer eluent comprises hydrogen, magnesium, zinc, calcium or manganese.

48. The method of claim 45, wherein the chemotherapy agent comprises platinum, a platinum alloy, cisplatin, carboplatin, oxaliplatin or satraplatin.

49. The method of claim 45, wherein the cancer is lung cancer.

50. The method of claim 45, further comprising guiding the implantation of the magnesium alloy wires by x-ray or ultrasound imaging.

51. The method of claim 45, wherein the patient undergoes surgical removal of malignant tumors, chemotherapy, radiation therapy or a combination thereof before, after or at a same time as treatment with the combination comprising at least one magnesium alloy wire and a chemotherapy agent.

52. The method of claim 45, wherein the at least one magnesium alloy wire has (i) a diameter in a range of 0.1 mm to 3 mm and (ii) a length in a range of 5 mm to 7 cm.

53. The method of claim 45, wherein:the selected number of magnesium alloy wires is in a range of 2 to 30 wires; and the selected distance between magnesium alloy wires is in a range of 1 mm to 5 mm.

54. The method of claim 45, wherein the selected number of magnesium alloy wires is selected to provide at least one of the following properties (I), (II), and (III):(I) a hydrogen (H2) evolution of 0.5 ml / cm3to 2 ml / cm3H2per unit tumor volume;(II) a magnesium loading of 0.5 mg / cm3to 2 mg / cm3Mg per unit tumor volume; and (III) a daily dosage of 1 mg / day to 20 mg / day Mg.

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