Electro-and chemical combination treatment of cancer

Abstract

Embodiments herein relate to a method for treating a cancerous tumor in a subject. The method may include applying one or more electric fields at or near a site of a cancerous tumor, wherein the cancerous tumor may comprise a population of cancerous cells. The applied one or more electric fields are effective to delay mitotic division and induce mitotic synchronization within a proportion of cancerous cell populations. The method may include removing the one or more electric fields to allow mitosis within the cancerous cell population. The method may include administering a chemotherapeutic agent to the subject after the one or more electric fields have been removed. Other embodiments are also included herein.

Description

[0001] This application is a divisional of a Chinese application filed on April 16, 2020, with application number 202080030769.1 and titled “Combined Electrical and Chemical Therapy for Cancer”.

[0002] This application is filed as a PCT International Patent Application on April 16, 2020 in the name of Boston Scientific Scimed, Inc. (a U.S. government corporation, as applicant for all designated countries) and Brian L. Schmidt, U.S. citizen, Benjamin Keith Stein, U.S. citizen, Keith R. Maile, U.S. citizen, Ron A. Balczewski, U.S. citizen, and Aleksandra Kharam, U.S. citizen (inventors for all designated countries). This application claims priority to U.S. Provisional Application No. 62 / 837,130 filed on April 22, 2019, the entire contents of which are incorporated herein by reference. Technical Field

[0003] Embodiments herein relate to methods, devices, and systems for treating cancerous tumors using one or more electrotherapy and / or chemotherapy modalities. Background Art

[0004] According to the American Cancer Society, cancer accounts for nearly 25% of deaths in the United States each year. The current standard of care for cancerous tumors can include first-line treatments such as surgery, radiation therapy, and chemotherapy. Additional second-line treatments can include radiation seeding, cryotherapy, hormone or biological therapy, ablation, etc. If a specific treatment is ineffective on its own, a combination of first-line and second-line treatments may also benefit the patient.

[0005] A cancerous tumor may form if a normal cell in any part of the body mutates and then begins to grow and multiply too much and too quickly. Cancerous tumors may be the result of genetic mutations in the cell's DNA or RNA during cell division, external stimuli such as ionizing or non-ionizing radiation, exposure to carcinogens, or inherited genetic mutations. Regardless of the cause, many cancerous tumors are the result of unchecked, rapid cell division.

[0006] All actively dividing somatic cells, including many types of cancerous cells, undergo cell division through the cell cycle. Actively dividing cells go through two major phases of the cell cycle: interphase and M phase. During interphase, the longest phase of the cell cycle, individual cells begin to double in size and replicate their DNA in preparation for cell division. Interphase can be broken down into three discrete phases in the following order: Gap 1, or G1 phase; Synthesis, or S phase; and Gap 2, or G2 phase. During the G1 phase, all of the cell's contents except the chromosomes are replicated, and the cell begins to double in size. During the S phase, DNA synthesis replicates the chromosomes, forming two sister chromatids for each chromosome in the cell. During the G2 phase, the cell continues to grow and prepares the cell and chromosomes for the M phase.

[0007] During the M phase, the cell exits interphase and begins mitosis or the nuclear division process, which includes the separation of sister chromatids. The M phase ends with cytokinesis or cytoplasmic division. Mitosis includes four basic stages: prophase, metaphase, anaphase, and telophase. During the prophase, the chromosomes begin to condense and the nuclear membrane surrounding the nucleus disappears. The mitotic spindle also begins to form during the prophase. The mitotic spindle includes a self-organized bipolar array of microtubules and centrosomes. Microtubules are usually formed by the polymerization of highly polar α-tubulin and β-tubulin. Centrosomes are similarly protein-based organelles, two of which migrate to opposite sides of the dividing cell at this stage. The negatively charged ends of the microtubules are attached to the centrosomes. The positively charged ends of the microtubules radiate toward the equator of the dividing cell, and they eventually attach to the kinetochores of each sister chromatid. Metaphase can be defined as the alignment of all chromosomes at the equator of the dividing cell and combined in the mitotic spindle. Then during the anaphase, equal numbers of sister chromatids are pulled toward the opposite ends of the cell. Once all chromosomes have separated, the process of telophase begins, in which the cell membrane begins to form a cleavage furrow between the two newly formed sister cells, and cell division is complete once the cells have physically separated from each other in a process known as cytokinesis. Summary of the invention

[0008] In a first aspect, a method for treating a cancerous tumor in a subject is included. The method may include applying one or more electric fields at or near the site of the cancerous tumor, wherein the cancerous tumor may include a cancerous cell population. The applied one or more electric fields are effective to delay mitosis and cause mitotic synchronization in a certain proportion of the cancerous cell population. The method may include removing the one or more electric fields to allow mitosis to occur in the cancerous cell population. The method may include administering a chemotherapeutic agent to the subject after the one or more electric fields have been removed.

[0009] In a second aspect, in addition to one or more of the foregoing or following aspects, or in an alternative to certain aspects, applying the one or more electric fields to the cancerous tumor comprises applying the one or more electric fields over a time period selected from a time period range from 1 minute to 24 hours.

[0010] In a third aspect, in addition to one or more of the foregoing or following aspects, or in an alternative to certain aspects, the method may include administering a chemotherapeutic agent to the subject when at least 5% of the cancerous cell population is synchronized in mitosis in response to the one or more electric fields.

[0011] In a fourth aspect, in addition to one or more of the above or following aspects, or in an alternative embodiment of certain aspects, the one or more electric fields are applied to the cancerous tumor at a frequency selected from the range between 100 kHz and 300 kHz.

[0012] In a fifth aspect, in addition to one or more of the foregoing or following aspects, or in an alternative to certain aspects, the electric field strength of the one or more electric fields is selected from the range of electric field strengths between 3V / cm and 5V / cm.

[0013] In a sixth aspect, in addition to, or in the alternative of, one or more of the foregoing or following aspects, wherein the chemotherapeutic agent is administered to the subject at a therapeutically effective dose.

[0014] In a seventh aspect, in addition to one or more of the foregoing or following aspects, or in an alternative embodiment of certain aspects, applying one or more electric fields to the subject comprises applying the one or more electric fields from outside the body of the subject to the site of or near the cancerous tumor.

[0015] In an eighth aspect, in addition to one or more of the preceding or following aspects, or in an alternative embodiment of certain aspects, applying one or more electric fields to a cancerous tumor comprises applying the one or more electric fields at least partially from within the subject's body to a site at or near the cancerous tumor.

[0016] In a ninth aspect, in addition to one or more of the foregoing or following aspects, or in an alternative embodiment of certain aspects, applying one or more electric fields to a cancerous tumor comprises applying the one or more electric fields at least partially from outside the body of the subject to a site at or near the cancerous tumor.

[0017] In a tenth aspect, in addition to or in the alternative of one or more of the preceding or following aspects, the medical device further comprises one or more electrical leads in electrical communication with the electric field generating circuit.

[0018] In an eleventh aspect, a method for treating a cancerous tumor is included. The method may include implanting one or more implantable electrodes into a subject having a cancerous tumor. The method may include placing one or more external electrodes on an external surface of the subject's body. The method may include: generating an electric field between at least one pair of electrodes according to a predefined schedule, wherein the frequency of the electric field is in the range of 10 kHz to 1 MHz. The method may include removing the one or more electric fields; and administering a chemotherapeutic agent at or near the site of the cancerous tumor after the one or more electric fields have been removed.

[0019] In a twelfth aspect, in addition to one or more of the foregoing or following aspects, or in an alternative to certain aspects, the applied one or more electric fields effectively delay mitosis and cause mitotic synchronization in a certain proportion of the cancerous cell population.

[0020] In a thirteenth aspect, in addition to or in the alternative of one or more of the preceding or following aspects, wherein one or more electric fields are removed to allow mitosis to occur within the cancerous cell population.

[0021] In a fourteenth aspect, a medical device for treating a cancerous tumor is included. The medical device may include an electric field generating circuit configured to generate one or more electric fields at or near the site of the cancerous tumor, wherein the cancerous tumor may contain a cancerous cell population. The medical device may include a control circuit in communication with the electric field generating circuit, wherein the control circuit may be configured to control the delivery of one or more electric fields from the electric field generating circuit to the site of the cancerous tumor or near the site. The control circuit may cause the electric field generating circuit to generate one or more electric fields at a frequency selected from a range between 10 kHz and 1 MHz at the site of the cancerous tumor located in body tissue, wherein the one or more electric fields effectively delay mitosis and cause mitosis synchronization in a certain proportion of the cancerous cell population.

[0022] In a fifteenth aspect, in addition to one or more of the foregoing or following aspects, or in the alternative of certain aspects, the medical device may further include one or more electrical leads in electrical communication with the electric field generating circuit.

[0023] In a sixteenth aspect, in addition to one or more of the foregoing or following aspects, or in an alternative to certain aspects, the medical device may further include one or more drug delivery cannulas for delivering one or more chemotherapeutic agents; optical leads which may include one or more light emitters for delivering photoactivated light energy; a biopsy device for obtaining a biopsy sample from a cancerous tumor; and an lavage cannula for flushing waste or body fluids.

[0024] In a seventeenth aspect, in addition to, or in the alternative of, one or more of the foregoing or following aspects, wherein the chemotherapeutic agent comprises an anti-mitotic agent.

[0025] In an eighteenth aspect, in addition to one or more of the foregoing or following aspects, or in the alternative of certain aspects, the chemotherapeutic agent comprises at least one of the following: vindesine, vincristine, vinblastine, paclitaxel, docetaxel, 2-methoxyestradiol, patupilone, trastuzumab, and derivatives thereof.

[0026] In a nineteenth aspect, in addition to, or in the alternative of, one or more of the foregoing or following aspects, wherein the chemotherapeutic agent comprises a photoactivated chemotherapeutic agent.

[0027] In a twentieth aspect, in addition to, or in the alternative of, one or more of the foregoing or following aspects, wherein the chemotherapeutic agent comprises nanoparticles.

[0028] The present invention is a summary of some teachings of the present application and is not intended to be an exclusive or exhaustive treatment of the subject matter of the present invention. Further details are present in the specific embodiments and the appended claims. Other aspects will be apparent to those skilled in the art by reading and understanding the following specific embodiments and viewing the accompanying drawings (each of which should not be considered to have a limiting meaning) that form a part of the specific embodiments. The scope of this article is limited by the appended claims and their legal equivalents. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Various aspects may be more fully understood in conjunction with the following drawings, in which:

[0030] Figure 1 is a schematic diagram of an exemplary cell cycle according to various embodiments herein.

[0031] Figure 2 is a schematic diagram of the M phase of a healthy eukaryotic cell according to various embodiments herein.

[0032] Figure 3is a schematic diagram of the M phase of a cancerous eukaryotic cell according to various embodiments herein.

[0033] Figure 4 is a schematic graph of the percentage of actively dividing cells versus time according to various embodiments herein.

[0034] Figure 5 is a schematic diagram of a method according to various embodiments herein.

[0035] Figure 6 is a schematic diagram of a method according to various embodiments herein.

[0036] Figure 7 is a schematic diagram of a method according to various embodiments herein.

[0037] Figure 8 is a schematic diagram of a method according to various embodiments herein.

[0038] Fig. 9 is a schematic diagram of a method according to various embodiments herein.

[0039] Fig.10 is a schematic diagram of a method according to various embodiments herein.

[0040] Fig.11 is a schematic diagram of a medical device according to various embodiments herein.

[0041] Fig.12 is a schematic diagram of a medical device according to various embodiments herein.

[0042] Fig.13 is a schematic diagram of a medical device according to various embodiments herein.

[0043] Fig.14 is a schematic diagram of a medical device according to various embodiments herein.

[0044] Fig.15 is a schematic cross-sectional view of a medical device according to various embodiments herein.

[0045] Fig.16 is a schematic diagram of components of a medical device according to various embodiments herein.

[0046] Fig.17 is a graph of exemplary electric fields according to various embodiments herein.

[0047] Fig.18 is a graph of exemplary electric fields according to various embodiments herein.

[0048] Although the embodiments are susceptible to various modifications and alternative forms, the details thereof have been shown by way of example and drawings and will be described in detail. However, it should be understood that the scope of this article is not limited to the specific embodiments described. On the contrary, the present invention will cover modifications, equivalents, and alternatives that fall within the spirit and scope of this article. DETAILED DESCRIPTION

[0049] As mentioned above, many cancerous tumors may be caused by unchecked rapid cell division. Some traditional first-line therapies for treating cancerous tumors may include surgery, radiation therapy, and chemotherapy. However, many first-line therapies are associated with adverse side effects, such as fatigue, hair loss, immunosuppression, and long surgical recovery times, to name a few.

[0050] Although not intended to be bound by theory, it is believed that the alternating electric field can disrupt the mitosis in cancerous tumors by interfering with the dipole arrangement of the key proteins (particularly tubulin and diaphragm proteins) involved in cell division. The polymerization of tubulin forming microtubule spindle fibers can be destroyed, thereby preventing the formation of the spindle fibers required for chromosome separation. This can stop cell division in the metaphase stage of mitosis. In some cases, the alternating electric field can stop the polymerization of the spindle fibers that have grown, thereby causing the spindle to be incomplete and causing unequal chromosome separation (if the cell survives for so long) in the later stage. In each case, in the later stage, due to the incomplete polymerization of microtubules, stopping the microtubule spindle formation and unequal chromosome separation may cause apoptosis (that is, programmed cell death). It should be further understood that in some embodiments, the alternating electric field can destroy mitosis by interfering with the protein involved in the formation of the contractile ring, and the contractile ring is responsible for generating contractile force when two daughter cells are separated. The various proteins involved in contractile ring formation may include, but are not limited to, F-actin, myosin-2, anillin, one or more septin proteins, Rho, arrestin, cofilin, and male germ cell Ras-related C3 botulinum toxin substrate GTPase activating protein (MgcRacGAP).

[0051] It is also believed that the alternating electric field can synchronize mitosis within a cell population, including cancerous cells. It is believed that synchronizing a cancerous cell population can make the cancerous cell population highly sensitive to one or more chemotherapeutic agents in a shorter period of time because chemotherapeutic agents more effectively target active cell populations that are synchronized in mitosis.

[0052] Additionally, in some embodiments, light-activated chemotherapeutic agents can be administered in conjunction with electrostimulation therapy. In some embodiments, nanoparticles can be administered with electrostimulation therapy.

[0053] See now Figure 1, a schematic diagram of an exemplary eukaryotic cell cycle 100 according to an embodiment of the present invention is shown. The eukaryotic cell cycle can be divided into two main phases, including interphase 102 and M phase 104. The interphase includes three key phases, namely: G1 phase 106 (i.e., interphase 1); S phase 108 (i.e., synthesis phase); and G2 phase 110 (i.e., interphase 2). During the G1 phase 106, the cell prepares for its own doubling by beginning the process of replicating all of its cell contents (excluding chromosomes). During the S phase 108, the cell synthesizes new DNA through the process of DNA replication to form two sister chromatids for each chromosome in the cell. During the G2 phase 110, the cell continues to grow and synthesizes the proteins required by the cell in the M phase.

[0054] The M phase of the cell cycle 100 consists of two key stages: mitosis 112 and cytokinesis 114. Mitosis 112 is the process of nuclear division, while cytokinesis 114 is the process of cytoplasmic division. Figure 2 , shows a schematic diagram of the M phase 104 in the exemplary eukaryotic cell cycle according to embodiments of this paper.For healthy exemplary cells 200, mitosis begins from the early stage 202 process, wherein chromosome 204 begins to condense to form a pair of identical sister chromatids (sister chromatids 215 will be discussed below), the nuclear envelope 206 around the nucleus disappears, and spindle (comprising spindle fibers 208) begins to form. Early stage 202 is followed by metaphase 210, wherein chromosome 204 is arranged on the equatorial plane of the splitting cell and is combined by spindle fibers 208 at the kinetochore of each chromosome.Then during late stage 212, by spindle fibers 208, each sister chromatid 215 is pulled to the effect of the opposite poles of each centrosome 214 and splitting cell, chromosome 204 is separated.During the telophase 216, nuclear membrane 218 is re-formed around each group of chromosome 204 at the opposite poles of splitting cell, and begins to form cleavage furrow 220 between the two halves of splitting cell. The final step of the cell cycle is the cytokinesis step 114, resulting in the formation of two genetically identical daughter cells 222, which can exit the cell cycle or re-enter a subsequent cell cycle process 224.

[0055] Many cancerous cells have high metabolic activity and have a high mitotic rate associated with cell division. The methods and medical devices described herein for treating cancerous tumors can target the mitosis of rapidly dividing cancerous cells. Without being bound by any particular theory, the application of chemotherapeutic agents and / or the anti-mitotic therapy applied can alter the mitotic phase within cancerous cells in a variety of ways.

[0056] See now Figure 3, shows a schematic diagram of the M phase 300 of an exemplary cancerous cell 301 according to embodiments herein, the cancerous cell having been damaged by a chemotherapeutic agent and / or an anti-mitotic therapy applied. Mitosis within the cancerous cell 301 is similar to that shown in FIG. Figure 2 The mitotic process in the cancerous cell 301 begins with prophase 302, in which the chromosomes 304 of the cancerous cell 301 begin to condense, the nuclear envelope 306 surrounding the nucleus disappears, and the spindle (including spindle fibers 308) begins to form. The anti-mitotic agent administered to the cancerous cell 301 and / or the anti-mitotic therapy applied may destabilize the formation of the spindle fibers 308, such that during metaphase 310, not all chromosomes are bound by the spindle fibers 308. In some embodiments, the chemotherapeutic agent is an anti-mitotic agent.

[0057] The consequence of unstable spindle fibers may include mitotic arrest or delay, which may lead to cell death (i.e., apoptosis) or mitotic slippage 311. The cancerous cell that divides may also undergo mitosis by abnormal cell division. If mitosis continues by abnormal cell division and chromosomes 304 cannot be evenly separated, sister chromatids 315 and / or replicated chromosomes 304 may be pulled toward the centrosome 314 to the opposite poles of the dividing cell and become unevenly distributed during the late stage 312. The cell can then proceed to the telophase 316, where the nuclear membrane 318 can be re-formed around each group of chromosomes 304 at the opposite poles of the dividing cell, and a cleavage furrow 320 can be formed between the two halves of the cell. The last step of the cell cycle of the cancerous cell 301 is the cytokinesis step 114, which leads to the formation of a first genetically different daughter cell 322 and a second genetically different daughter cell 324. In some embodiments, the genetically different daughter cells can die by apoptosis, re-enter the interphase of the subsequent cell cycle and die, or re-enter mitosis 326.

[0058] A given cell population can include a baseline percentage of actively dividing cells at any given moment. Figure 4, an exemplary graph 400 of percentage of actively dividing cells versus time according to various embodiments herein is shown. Curve 402 shows the average baseline percentage of actively dividing cells in a cancerous cell population of a cancerous tumor as a function of time. Curve 404 shows the percentage of actively dividing cells in an exemplary cancerous cell population of a cancerous tumor after undergoing a method for treating a cancerous tumor. The cancerous cell population exhibits a baseline percentage of actively dividing cells during time 406. When an electric field is applied to the cancerous cell population 408, this percentage of actively dividing cells stops and decreases during time 410. Without being bound by any particular theory, it is believed that the applied electric field can effectively delay mitosis within a given cell population and cause mitosis synchronization within at least a certain proportion of a given cell population. In some embodiments, the applied electric field can effectively delay mitosis within a healthy cell population and cause mitosis synchronization within at least a certain proportion of a healthy cell population. In some embodiments, the applied electric field can effectively delay mitosis within a cancerous cell population and cause mitosis synchronization within at least a certain proportion of a cancerous cell population.

[0059] After a predetermined amount of time, the applied electric field 412 is removed. The electric field is released to allow cells of the cancerous cell population to begin actively dividing and to proceed synchronously through mitosis. After releasing the electric field 412, a chemotherapeutic agent 414 may be administered to the cancerous cell population. The amount of time between releasing the electric field 412 and administering the chemotherapeutic agent 414 may vary, as described below. It should be noted that in some embodiments, the chemotherapeutic agent may be administered to the cancerous cell population prior to releasing the electric field.

[0060] Without being bound by any particular theory, when cells within the cancerous cell population are in a state of mitotic synchronization, it is believed that the administration of a chemotherapeutic agent can effectively reduce or destroy the number of viable cancerous cells present in the cancerous tumor. While releasing the electric field allows the cells to undergo mitosis, ultimately during time 414, the application of the electric field and / or the administration of the chemotherapeutic agent can reduce the number of actively dividing cells. Ultimately, during time 416, the combination treatment of the electric field and the chemotherapeutic agent can effectively reduce the number of viable cells in the cancerous tumor.

[0061] An exemplary method for treating a cancerous tumor may include applying one or more electric fields at or near the site of the cancerous tumor and then administering a chemotherapeutic agent. Figure 5, a schematic flow chart of an exemplary method 500 for treating a cancerous tumor 502 in a subject according to various embodiments herein is shown. The method 500 may include applying one or more electric fields 506 at or near the site of the cancerous tumor 502. The cancerous tumor 502 may include a cancerous cell population 504. The applied one or more electric fields may be effective to delay mitosis in the cancerous cell population 504 and cause mitotic synchronization 508 in at least a proportion of cells within the cancerous cell population. The method 500 may include removing the one or more electric fields to allow mitosis to proceed within the cancerous cell population 510. The method 500 may include administering a chemotherapeutic agent 512 at or near the site of the cancerous tumor after the one or more electric fields have been removed. In some embodiments, the chemotherapeutic agent may be delivered systemically through an intravenous port outside the body, or via an implantable device having an implantable catheter implanted within the systemic vasculature, such as in the chest cavity. Administration of the chemotherapeutic agent may interrupt mitosis 514 within the cancerous cell population and ultimately cause cell death 516 within the cancerous cell population. In some embodiments, the method 500 may include inserting a percutaneous access port at or near the site of a cancerous tumor.

[0062] The methods herein may include using one or more implantable electrodes to treat cancerous tumors. Figure 6 , a method 600 for treating a cancerous tumor according to various methods herein is shown. Method 600 includes implanting one or more implantable electrodes into the body of a subject having a cancerous tumor 602. Method 600 includes placing one or more external electrodes on the external surface of the subject's body 604. The method includes: generating an electric field 606 between at least one pair of electrodes according to a predefined schedule, the frequency of the electric field being in the range of 10kHz to 1MHz. Method 600 includes removing the one or more electric fields 608. The method includes administering a chemotherapeutic agent 610 at or near the site of the cancerous tumor, or systemically, after the one or more electric fields have been removed. In some embodiments, the applied one or more electric fields of method 600 are effective to delay mitosis and cause mitotic synchronization within a certain proportion of a cancerous cell population. In some embodiments, removing the one or more electric fields in method 600 allows mitosis to occur within a cancerous cell population.

[0063] To optimize mitotic delay within a given cell population and induce mitotic synchronization within a greater proportion of a given cell population, one or more electric fields may be applied multiple times prior to administration of a chemotherapeutic agent, as described in Figure 7 and Figure 8 Discussed. See now Figure 7, a method 700 for treating a cancerous tumor in a subject according to various embodiments herein is shown. The method 700 may include applying a first electric field having a first electric field strength at or near the site of the cancerous tumor 702, wherein the cancerous tumor comprises a population of cancerous cells. The first electric field may be effective to delay mitosis and induce synchronization of mitosis within a certain proportion of the population of cancerous cells. The method 700 may include removing the first electric field to allow mitosis within the population of cancerous cells 704. The method 700 may include administering a chemotherapeutic agent at or near the site of the cancerous tumor 706 after the first electric field has been removed.

[0064] See now Figure 8 , a method 800 for treating a cancerous tumor in a subject according to various embodiments herein is shown. The method 800 may include applying a first electric field having a first electric field strength at or near a site of the cancerous tumor 802, wherein the cancerous tumor comprises a population of cancerous cells. The first electric field may be effective to delay mitosis and cause synchronization of mitosis within a certain proportion of the population of cancerous cells. The method 800 may include removing the first electric field to allow mitosis within the population of cancerous cells 804. The method 800 may include applying a second electric field having a second electric field strength at or near a site of the cancerous tumor 806 after the first electric field has been removed and before a chemotherapeutic agent is applied. The second electric field may be effective to delay mitosis and cause synchronization of mitosis within a certain proportion of the population of cancerous cells. The method 800 may include applying a chemotherapeutic agent at or near a site of the cancerous tumor 808 after the first electric field has been removed. In some embodiments, the method 800 may include applying a third electric field having a third electric field strength at or near a site of the cancerous tumor. In some embodiments, method 800 may include applying a fourth electric field having a fourth electric field strength at or near the site of the cancerous tumor. In some embodiments, method 800 may include applying a fifth electric field, a sixth electric field, a seventh electric field, an eighth electric field, a ninth electric field, or a tenth electric field at or near the site of the cancerous tumor. In still other embodiments, method 800 may include applying an electric field greater than the tenth electric field at or near the site of the cancerous tumor.

[0065] The method of applying a second or greater electric field having a second or greater electric field strength may include waiting a predetermined amount of time between the application of successive electric fields. For example, method 800 may include waiting a predetermined amount of time after removing the first electric field and before applying the second electric field. Similarly, when applying a third electric field having a third electric field strength, the application of the third electric field may be delayed by waiting a predetermined amount of time after removing the second electric field and before applying the third electric field. However, in some embodiments, applying a second or greater electric field having a second or greater electric field strength may include applying the second or greater electric field immediately after applying the previous electric field.

[0066] In some embodiments, the second electric field strength is less than the first electric field strength. In some embodiments, the second electric field strength is greater than the first electric field strength. In other embodiments, the second electric field strength is the same as the first electric field strength. In some embodiments, each additional electric field having a unique electric field strength applied successively may include an additional electric field having an electric field strength less than, greater than, or equal to a previous electric field or a successive electric field.

[0067] In the methods herein, the application of one or more electric fields can be controlled in time. Fig. 9 , a method 900 for treating a cancerous tumor in a subject according to an embodiment of the present invention is shown. The method 900 may include applying one or more electric fields at or near the site of the cancerous tumor according to a predefined schedule 902. The cancerous tumor contains a population of cancerous cells. The predefined schedule may vary at least one of the electric field strength and frequency over a defined time period of at least six hours. The applied one or more electric fields of the method 900 are effective to delay mitosis and cause mitosis synchronization in a certain proportion of the cancerous cell population. In some embodiments, the method 900 may include removing the one or more electric fields to allow mitosis to occur in the cancerous cell population 904. In other embodiments, the method 900 may include applying a chemotherapeutic agent at or near the site of the cancerous tumor 906 after the one or more electric fields have been removed. In some embodiments, the method 900 may further include: receiving a pause command from the subject, wherein the pause command terminates the application of the electric field.

[0068] Temporal control of the application of the one or more electric fields may include causing at least one of the intensity and frequency of the one or more electric fields to vary over time according to a predefined schedule. In some embodiments, temporal control of the application of the one or more electric fields may include causing at least one of the intensity and frequency of the one or more electric fields to vary over time according to a predefined schedule compared to an initial intensity or frequency. In some embodiments, the predefined schedule includes one or more downtime periods in which the intensity or frequency of the applied one or more electric fields is reduced by at least 50% for at least 4 hours. In some embodiments, the predefined schedule includes one or more downtime periods in which the intensity or frequency of the applied one or more electric fields is reduced by at least 75% for at least 4 hours. In some embodiments, the predefined schedule includes one or more downtime periods in which the intensity or frequency of one or more applied electric fields is reduced by an amount greater than or equal to 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%, or an amount falling within any of the foregoing ranges.

[0069] Various methods herein may include receiving instructions from a subject and / or a care provider during treatment of a cancerous tumor. Fig.10 , a method 1000 for treating a cancerous tumor according to an embodiment of the present invention is shown. The method 1000 may include implanting one or more implantable electrodes into a subject having a cancerous tumor 1002. The method 1000 may include placing one or more external electrodes on an external surface of the subject's body 1004. The method 1000 may include: generating an electric field between at least one pair of electrodes according to a predefined schedule 1006, the frequency of the electric field being in a range between 10 kHz and 1 MHz. The method 1000 may include: receiving a pause command from the subject and / or a care provider, wherein the pause command suspends generating the electric field 1008. In some embodiments, the method 1000 may include: re-generating the electric field between at least one pair of electrodes according to a predefined schedule after a certain period of time has passed since the pause command was received from the subject and / or the care provider. In some embodiments, the method 1000 may include: receiving a start command from the subject and / or the care provider, wherein the start command re-generates the electric field. In other embodiments, the predefined schedule of the method 1000 may include a time-varying variation of at least one of the intensity and frequency of the electric field, as described elsewhere herein. In some embodiments, method 1000 may include administering a chemotherapeutic agent at or near the site of the cancerous tumor after the period of time during which the one or more electric fields have been suspended.

[0070] In the process of treating cancerous tumors with various methods herein, various commands can be received from the subject and / or the care provider. In some embodiments, the command received from the subject and / or the care provider may include a pause command. When the subject experiences one or more side effects, a pause command may be received from the subject and / or the care provider to pause the application of the first electric field, and the side effects include dizziness, nausea, fatigue, dizziness, headache or local pain. The pause command received from the subject and / or the care provider may include at least one of the following: a shutdown command, a command to shut down the set time, a shutdown button push command, or a shutdown status reminder command. The shutdown command can temporarily suspend the generation of an electric field. The command to shut down the set time can temporarily suspend the generation of an electric field for a predetermined time period. For example, the command to shut down the set time can temporarily suspend the generation of an electric field for at least 1 hour. In some embodiments, the command to shut down the set time can temporarily suspend the generation of an electric field for at least 6 hours. In some embodiments, the command to shut down the set time can temporarily suspend the generation of an electric field for at least 10 hours. In some embodiments, the command to shut down the set time can temporarily suspend the generation of the electric field for a certain period of time, which is greater than or equal to 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours, or can be an amount falling within any of the foregoing ranges.

[0071] In the various methods described herein, applying the one or more electric fields may include at least applying the electric field at various electric field strengths. For example, the one or more electric fields may be applied to the cancerous tumor at an electric field strength selected from the range of electric field strengths between 0.25V / cm and 500V / cm. In some embodiments, the one or more electric fields may be applied to the cancerous tumor at an electric field strength selected from the range of electric field strengths between 1V / cm and 10V / cm. In some embodiments, the one or more electric fields may be applied to the cancerous tumor at an electric field strength selected from the range of electric field strengths between 1V / cm and 5V / cm. In some embodiments, the one or more electric fields may be applied to the cancerous tumor at an electric field strength selected from the range of electric field strengths between 3V / cm and 5V / cm. In some embodiments, the electric field strength can be greater than or equal to 0.25V / cm, 0.50V / cm, 0.75V / cm, 1.00V / cm, 1.25V / cm, 1.50V / cm, 1.75V / cm, 2.00V / cm, 2.25V / cm, 2.50V / cm, 2.75V / cm, 3.00V / cm, 3.25V / cm, 3.50V / cm, 3.75V / cm, 4.00V / cm, 4.25V / cm, 4.50V / cm, 4.75V / cm, 5.00V / cm, 5.25V / cm, 5.50V / cm, 5.75V / cm, 6.00V / cm, 6.25V / cm, 6.50V / cm, 6.75V / cm , 7.00V / cm, 7.25V / cm, 7.50V / cm, 7.75V / cm, 8.00V / cm, 8.25V / cm, 8.50V / cm, 8.75V / cm, 9.00V / cm, 9.25V / cm, 9.50V / cm, 9.75V / cm, 10V / cm, 20V / cm, 30V / cm, 40V / cm, 50V / cm, 60V / cm, 70V / cm, 80V / cm, 90V / cm, 100V / cm, 150V / cm, 200V / cm, 250V / cm, 300V / cm, 350V / cm, 400V / cm, 450V / cm, or 500V / cm, or an amount falling within any of the foregoing ranges.

[0072] In the various methods described herein, applying the one or more electric fields may include at least applying the electric field at various frequencies. The one or more electric fields may be applied to the cancerous tumor at a frequency selected from the range of 10 kilohertz (kHz) to 1 megahertz (MHz). In some embodiments, the one or more electric fields may be applied to the cancerous tumor at a frequency selected from the range of 100kHz to 500kHz. In some embodiments, the one or more electric fields may be applied to the cancerous tumor at a frequency selected from the range of 100kHz to 300kHz. In some embodiments, the frequency of the applied electric field or fields may be greater than or equal to 10kHz, 20kHz, 30kHz, 40kHz, 50kHz, 60kHz, 70kHz, 80kHz, 90kHz, 100kHz, 125kHz, 150kHz, 175kHz, 200kHz, 225kHz, 250kHz, 275kHz, 300kHz, 325kHz, 350kHz, 375kHz, 400kHz, 425kHz, 450kHz, 475kHz, 500kHz, 525kHz, 550kHz, 575kHz, 600kHz, 625kHz, 650kHz, 675kHz, 700kHz, 725kHz, 750kHz, 775kHz, 800kHz, 825kHz, 850kHz, 875kHz, 900kHz, 925kHz, 950kHz, 975kHz, or 1MHz, or may be an amount falling within any of the foregoing ranges.

[0073] In various embodiments herein, the electric field can be released (stopped) and then the chemotherapeutic agent can be administered. In various embodiments, the amount of time between releasing the electric field and administering the chemotherapeutic agent can be about 0 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 90 minutes, 120 minutes, or 180 minutes, or an amount falling between any of the foregoing ranges.

[0074] In various methods described herein, applying the one or more electric fields may include at least applying the electric fields for a plurality of different predetermined time periods. The one or more electric fields may be applied to or near the site of the cancerous tumor for a predetermined time period selected from a predetermined time period range from 1 minute to 24 hours. In some embodiments, the one or more electric fields may be applied to or near the site of the cancerous tumor for a predetermined time period, and the predetermined time period may be greater than or equal to 1 minute, 10 minutes, 20 minutes, 30 minutes, 40 minutes, or 50 minutes, or 1.0 hour, 1.5 hours, 2.0 hours, 2.5 hours, 3.0 hours, 3.5 hours, 4.0 hours, 4.5 hours, 5.0 hours, 5.5 hours, 6.0 hours, 6.5 hours, 7.0 hours, 7.5 hours, 8.0 hours, 8.5 hours, 9.0 hours, 9.5 hours, 10.0 hours, 10.5 hours, 11 .0 hours, 11.5 hours, 12.0 hours, 12.5 hours, 13.0 hours, 13.5 hours, 14.0 hours, 14.5 hours, 15.0 hours, 15.5 hours, 16.0 hours, 16.5, 17.0 hours, 17.5 hours, 18.0 hours, 18.5 hours, 19.0 hours, 19.5 hours, 20.0 hours, 20.5 hours, 21.0 hours, 21.5 hours, 22.0 hours, 22.5 hours, 23.0 hours, 23.5 hours, 24.0 hours, or 48 hours, or an amount falling within any of the foregoing ranges.

[0075] In the various methods described herein, administering a chemotherapeutic agent may include administering the chemotherapeutic agent when at least a certain proportion of the cell population is synchronized in mitosis. In some embodiments, administering a chemotherapeutic agent to a cancerous tumor may include administering the chemotherapeutic agent when at least 5% of the cancerous cell population is synchronized in mitosis in response to the one or more electric fields. In some embodiments, administering a chemotherapeutic agent to a cancerous tumor may include administering the chemotherapeutic agent when at least 25% of the cancerous cell population is synchronized in mitosis in response to the one or more electric fields. In some embodiments, administering a chemotherapeutic agent to a cancerous tumor may include administering the chemotherapeutic agent when at least 50% of the cancerous cell population is synchronized in mitosis in response to the one or more electric fields. In some embodiments, administering a chemotherapeutic agent to a cancerous tumor may include administering the chemotherapeutic agent when at least 75% of the cancerous cell population is synchronized in mitosis in response to the one or more electric fields. In some embodiments, the percentage of cells in a state of delayed mitosis and synchronized mitosis can be greater than or equal to 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or can be an amount falling within any of the foregoing ranges.

[0076] In various methods described herein, applying chemotherapeutic agents can include applying chemotherapeutic agents in a plurality of different predetermined time periods. Chemotherapeutic agents can be applied to or near the position of cancerous tumors in a predetermined time period selected from the range of a predetermined time period of less than 1 minute to 600 minutes. In certain embodiments, chemotherapeutic agents can be applied to or near the position of cancerous tumors in a predetermined time period, and this predetermined time period can be greater than or equal to 1 second, 5 seconds, 10 seconds, 15 seconds, 20 seconds, 25 seconds, 30 seconds, 35 seconds, 40 seconds, 45 seconds, 50 seconds, 55 seconds or 60 seconds, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 120 minutes, 180 minutes, 240 minutes, 300 minutes, 360 minutes, 420 minutes, 480 minutes, 540 minutes or 600 minutes or can be the amount falling in any aforementioned range. It will be appreciated that chemotherapeutic agents may also be administered at sites throughout the body distant from the cancerous tumor.

[0077] In some embodiments, the chemotherapeutic agent is administered to the subject within a 12 hour period after the electric field is removed. In some embodiments, the chemotherapeutic agent is administered to the subject within a 6 hour period after the electric field is removed. In some embodiments, the chemotherapeutic agent is administered to the subject within a 3 hour period after the electric field is removed. In some embodiments, the chemotherapeutic agent is administered to the subject within a 1 hour period after the electric field is removed. The administration of chemotherapeutic agents is discussed in more detail below.

[0078] In various methods described herein, applying the one or more electric fields at or near the site of a cancerous tumor may include applying the one or more electric fields to the subject's body or body. In some embodiments, applying the one or more electric fields to a cancerous tumor may include applying the one or more electric fields entirely from outside the subject's body to the site of the cancerous tumor or near the site. In some embodiments, applying the one or more electric fields to a cancerous tumor may include applying the one or more electric fields entirely from inside the subject's body to the site of the cancerous tumor or near the site. In some embodiments, applying the one or more electric fields to a cancerous tumor may include applying the one or more electric fields at least partially from outside the subject's body to the site of the cancerous tumor or near the site. In some embodiments, applying the one or more electric fields to a cancerous tumor may include applying the one or more electric fields at least partially from inside the subject's body to the site of the cancerous tumor or near the site. In other embodiments, applying the one or more electric fields to a cancerous tumor may include applying the one or more electric fields partially from outside the subject's body and partially from inside the subject's body to the site of the cancerous tumor or near the site. It should be understood that applying an electric field from outside the subject's body may allow the electric field to propagate into the subject's body.

[0079] A variety of medical devices can be used to deliver the various methods herein to a subject having a cancerous tumor. Fig.11 and Fig.12 , shows a schematic diagram of a subject 1101 having a cancerous tumor 1110 according to embodiments herein. Fig.11 In , a subject 1101 has a medical device 1100 fully implanted within the subject 1101 at or near the site of a cancerous tumor located within body tissue. A variety of implantation sites may be used, including areas such as in a limb, upper torso, abdominal region, head, etc. In Fig.12 In the embodiment of the present invention, a subject 1101 has a medical device 1200 at least partially implanted in the body of the subject 1101 at or near the site of a cancerous tumor located within body tissue. In some embodiments, the medical device can be completely outside the body of the subject. In some embodiments, the medical device can be partially outside the body of the subject. In some embodiments, the medical device can be partially implanted in the body of the subject and partially outside the body of the subject. In other embodiments, the partially implanted medical device can include a percutaneous connection between components arranged inside the body and outside the body. The partially implanted medical device can wirelessly communicate with a partially external portion of the medical device via a wireless connection.

[0080] In some embodiments, a portion of the medical device may be completely implanted and a portion of the medical device may be completely external. For example, in some embodiments, one or more electrodes or leads may be completely implanted within the body, while the portion of the medical device that generates the electric field (such as an electric field generator) may be completely outside the body. It should be understood that in some embodiments described herein, the described electric field generator may include many of the same components as a pulse generator and may be configured to perform many of the same functions as a pulse generator. In embodiments where a portion of the medical device is completely implanted and a portion of the medical device is completely external to the body, the portion of the medical device that is completely external to the body may communicate wirelessly with the portion of the medical device that is completely internal to the body. However, in other embodiments, a wired connection may be used.

[0081] Medical device 1100 may include a housing 1102 and a head 1104 coupled to the housing 1102, and medical device 1200 may include the housing 1102. Various materials may be used. However, in some embodiments, the housing 1102 may be formed of materials such as metals, ceramics, polymers, composite materials, etc. In some embodiments, the housing 1102 or one or more portions thereof may be formed of titanium. The head 1104 may be formed of various materials, but in some embodiments, the head 1104 may be formed of a translucent polymer such as an epoxy material. In some embodiments, the head 1104 may be hollow. In other embodiments, the head 1104 may be filled with components and / or structural materials, such as epoxy or another material, so that it is not hollow.

[0082] In some embodiments where a portion of the medical device 1100 or 1200 is partially outside the body, the head 1104 and the housing 1102 may be surrounded by a protective casing made of a durable polymer material. In other embodiments, where a portion of the medical device 1100 or 1200 is partially outside the body, the head 1104 and the housing 1102 may be surrounded by a protective casing made of a combination of polymer materials, metal materials, and / or glass materials.

[0083] The head 1104 can be coupled to one or more leads 1106. The head 1104 can be used to provide fixation of the proximal end of one or more leads 1106, and electrically couple one or more leads 1106 to one or more components within the housing 1102. One or more leads 1106 can include one or more electrodes 1108 arranged along the length of the electrical lead 1106. In some embodiments, the electrode 1108 can include an electric field generating electrode, and in other embodiments, the electrode 1108 can include an electric field sensing electrode. In some embodiments, the lead 1106 can include both an electric field generating electrode and an electric field sensing electrode. In other embodiments, the lead 1106 can include any number of electrodes for both electric field sensing and electric field generation. It should be understood that although many embodiments of the medical device herein are designed to work with leads, a leadless medical device that generates an electric field is also contemplated herein. In some embodiments, the electrode 1108 can be a tip electrode on the farthest end of the lead 1106.

[0084] See now Fig.13 , a schematic diagram of a medical device 1300 according to an embodiment of the present invention is shown. The medical device 1300 may include a housing 1102 and a head 1104 and one or more leads 1106. The lead 1106 may include one or more electrodes, such as electrodes 1304, 1306, 1308, or 1310 arranged along the length of the lead 1106. In some embodiments, the electrodes 1304, 1306, 1308, or 1310 may include electric field generating electrodes, and in other embodiments, the electrodes 1304, 1306, 1308, or 1310 may include electric field sensing electrodes. In some embodiments, the lead 1106 may include both electric field generating electrodes and electric field sensing electrodes.

[0085] The proximal end of the lead 1106 is disposed within the head 1104. The distal end of the electrical lead 1106 can surround the cancerous tumor 1110 so that the electrode 1304, 1306, 1308, or 1310 is brought into proximity with the cancerous tumor 1110. In some embodiments, the lead 1106 can be positioned within the vasculature so that the electrode 1304, 1306, 1308, or 1310 is adjacent to or within the cancerous tumor 1110. However, it should be appreciated that the lead 1106 can be disposed in a variety of locations within or around the cancerous tumor 1110. In some embodiments, the lead 1106 can pass directly through the cancerous tumor 1110.

[0086] In some embodiments, the lead 1106 may include one or more tracking markers 1316 or 1318 along the length of the lead for determining the precise location of the electrode relative to the tumor. In some embodiments, the one or more tracking markers may be disposed directly distally or directly proximal to the one or more electrodes disposed on the lead. In some embodiments, the tracking markers may be formed of a magnetic material. In some embodiments, the tracking markers may be formed of a radiographic material. In some embodiments, the tracking markers may be formed of a fluorographic material.

[0087] In some embodiments, lead 1106 may include one or more light emitters 1320 for delivering light energy to the site of a cancerous tumor. The light emitter may be positioned along the length of lead 1106 or at the farthest end of lead 1106. In some embodiments herein, the chemotherapeutic agent may include a photoactivated chemotherapeutic agent, as discussed in more detail below. In some embodiments, lead 1106 may include one or more optical fibers to deliver light energy to the site of a cancerous tumor. The light emitter may include, but is not limited to, a light emitting diode (LED) or a laser diode. In some embodiments, lead 1106 may include one or more optical fibers to deliver light energy to the site of a cancerous tumor. The maximum emission wavelength of the light emitter suitable for activating a light-activated chemotherapeutic agent used herein may be greater than or equal to 350nm, 400nm, 450nm, 500nm, 550nm, 600nm, 650nm, 700nm, 750nm, 800nm, or 850nm, or may be those light emitters that fall within any of the aforementioned ranges. It will be appreciated that light emitters suitable for use herein may include those having an emission maximum of ±10 nm on either side of the emission maximum. It will be appreciated that light emitters suitable for use herein may include those having an emission maximum of ±20 nm on either side of the emission maximum.

[0088] It should be appreciated that multiple electric field vectors may be generated between various combinations of electrodes 1304, 1306, 1308, or 1310 arranged along lead 1106 to generate an electric field. For example, one or more electric field vectors may be generated between electrodes 1304 and 1308. Similarly, one or more electric field vectors may be generated between electrodes 1304 and 1310. It should also be appreciated that one or more electric field vectors may be generated between any combination of electrodes 1304, 1306, 1308, or 1310. In some embodiments, one or more electric field vectors may be generated between any combination of electrodes 1304, 1306, 1308, or 1310 and housing 1102 of the medical device. It should be appreciated that, according to embodiments herein, one or more monopolar or multipolar leads may be used. In some embodiments, a combination of monopolar and multipolar leads may be used. In other embodiments, round leads, clamp leads, cuff leads, paddle leads, or patch leads may be used.

[0089] See now Fig.14 , shows a schematic diagram of a medical device 1400 according to an embodiment of the present invention. The medical device 1400 may include an inner portion at the inner side 1450 of the subject's body and an outer portion at the outer side 1452 of the subject's body. The inner portion of the medical device 1400 may include an inner electrical lead 1401, and the outer portion may include a housing 1102 and an outer electrical lead 1402. The medical device 1400 may also include a percutaneous access port 1416 that spans across an outer surface 1418 of the subject's body at or near the site of the cancerous tumor, suitable for receiving one or more leads of a cannula. For example, the percutaneous access port 1416 may be configured to receive at least one of the following: the inner electrical lead 1401; a drug delivery cannula that delivers one or more chemotherapeutic agents; a light lead that includes one or more light emitters for delivering light energy; a biopsy device that is used to obtain a biopsy sample from a cancerous tumor; or an irrigation cannula for flushing the site of the cancerous tumor or waste or body fluids.

[0090] Inner electrical lead 1401 may include one or more electrodes, such as electrodes 1404, 1406, or 1408 arranged along the length of inner lead 1406. Outer electrical lead 1402 may include electrodes 1410, 1412, or 1414 arranged along the length of outer electrical lead 1402. In some embodiments, electrodes 1404, 1406, 1408, 1410, 1412, or 1414 may include electric field generating electrodes, and in other embodiments, electrodes 1404, 1406, 1408, 1410, 1412, or 1414 may include electric field sensing electrodes. In some embodiments, inner electrical lead 1401 or outer electrical lead 1402 may include electric field generating electrodes and electric field sensing electrodes.

[0091] The proximal end of the inner electrical lead 1401 or the outer electrical lead 1402 is disposed within the housing 1102. The distal end of the inner electrical lead 1401 can surround the cancerous tumor 1110 so that the electrodes 1404, 1406, or 1408 are brought into proximity with the cancerous tumor 1110. The outer electrical lead 1402 can be placed on the outside of the subject's body, near the cancerous tumor site, so that the electrodes 1410, 1412, and 1414 are in electrical communication with the electrodes 1404, 1406, and 1408 on the inner electrical lead 1106. In some embodiments, the inner electrical lead 1401 can be positioned within the vasculature so that the electrodes 1404, 1406, or 1408 are adjacent to or within the cancerous tumor 1110. However, it should be appreciated that the inner electrical lead 1401 can be positioned in a variety of locations within or around the cancerous tumor 1110. In some embodiments, internal electrical lead 1401 may be passed directly through cancerous tumor 1110 .

[0092] In some embodiments, the inner electrical lead 1401 can include one or more tracking markers 1316 along the length of the inner electrical lead 1401 for determining the precise location of the electrode relative to the tumor. In some embodiments, the one or more tracking markers can be disposed directly distally or directly proximal to the one or more electrodes disposed on the inner electrical lead 1401. In some embodiments, the tracking markers can be formed of a magnetic material. In some embodiments, the tracking markers can be formed of a radiographic material. In some embodiments, the tracking markers can be formed of a fluorographic material.

[0093] It should be understood that multiple electric field vectors can be generated between various combinations of electrodes 1404, 1406, 1408, 1410, 1412, or 1414 arranged along the inner electrical lead 1401 and the outer electrical lead 1402 to generate an electric field. For example, one or more electric field vectors can be generated between electrodes 1404 and 1410. Similarly, one or more electric field vectors can be generated between electrodes 1406 and 1412. It should also be understood that one or more electric field vectors can be generated between any combination of electrodes 1404, 1406, 1408, 1410, 1412, or 1414. In some embodiments, one or more electric field vectors can be generated between any combination of electrodes 1404, 1406, 1408, 1410, 1412, or 1414 and the housing 1102 of the medical device 1400. It should be understood that according to embodiments herein, one or more monopolar or multipolar leads can be used. In some embodiments, a combination of monopolar and multipolar leads can be used. In other embodiments, round leads, clip leads, cuff leads, paddle leads, or patch leads may be used.

[0094] See now Fig.15, showing various embodiments according to this document Fig.11 Schematic cross-sectional view of medical device 1100. It should be understood that any medical device described herein may include the features of medical device 1100. Housing 1102 may define an internal volume 1502, which may be hollow and, in some embodiments, hermetically sealed and separated from an area 1504 outside the medical device 1100. In other embodiments, housing 1102 may be filled with components and / or structural materials so that it is not hollow. Medical device 1100 may include control circuit 1506, which may include various components 1508, 1510, 1512, 1514, 1516, and 1518 arranged within housing 1102. In some embodiments, these components may be integrated, while in other embodiments, these components may be separate. In other other embodiments, there may be a combination of both integrated components and separate components. Medical device 1100 may also include antenna 1524 to allow one-way or two-way wireless data communication. In some embodiments, components of medical device 1100 may include an inductive energy receiver coil (not shown) communicatively coupled or attached thereto to facilitate transcutaneous recharging of the medical device via a recharging circuit.

[0095] The various components 1508, 1510, 1512, 1514, 1516, and 1518 of the control circuit 1506 may include, but are not limited to, a microprocessor, a memory circuit (such as a random access memory (RAM) and / or a read-only memory (ROM)), a recorder circuit, a controller circuit, a telemetry circuit, a power supply circuit (such as a battery), a timing circuit and an application-specific integrated circuit (ASIC), a recharging circuit, and the like. The control circuit 1506 may be in communication with an electric field generating circuit 1520, which may be configured to generate an electric current to form one or more fields. The electric field generating circuit 1520 may be integrated with the control circuit 1506, or may be a separate component from the control circuit 1506. The control circuit 1506 may be configured to control the delivery of an electric current from the electric field generating circuit 1520. In some embodiments, the electric field generating circuit 1520 may be present in a portion of the medical device that is external to the body.

[0096] In some embodiments, the control circuit 1506 may be configured to direct the electric field generating circuit 1520 to deliver the electric field using one or more frequencies selected from the range of 10kHz to 1MHz. In some embodiments, the control circuit 1506 may be configured to direct the electric field generating circuit 1520 to deliver the electric field at one or more frequencies selected from the range of 100kHz to 500kHz. In some embodiments, the control circuit 1506 may be configured to direct the electric field generating circuit 1520 to deliver the electric field at one or more frequencies selected from the range of 100kHz to 300kHz. In some embodiments, the control circuit 1506 may be configured to direct the electric field generating circuit 1520 to periodically deliver the electric field using one or more frequencies greater than 1MHz.

[0097] In some embodiments, the electric field can effectively disrupt cell mitosis in cancerous cells. The electric field can be delivered to the site of the cancerous tumor along more than one vector. In some instances, the electric field can be delivered along at least one vector (including at least one of the lead electrodes). In some embodiments, at least two vectors with spatial diversity between the two vectors can be used. The vectors can be spatially separated (e.g., the vectors can be arranged at an angle relative to each other) by at least about 10 degrees, 20 degrees, 30 degrees, 40 degrees, 50 degrees, 60 degrees, 70 degrees, 80 degrees, or 90 degrees.

[0098] The desired electric field strength can be achieved by delivering an electric current between the two electrodes. The specific current and voltage of the delivered electric field can vary and can be adjusted to achieve the desired electric field strength at the tissue site to be treated. In some embodiments, the control circuit 1506 can be configured to guide the electric field generating circuit 1520 to use a current in the range of 1 mAmp to 1000 mAmp to deliver the electric field to the site of the cancerous tumor. In some embodiments, the control circuit 1506 can be configured to guide the electric field generating circuit 1520 to use a current in the range of 20 mAmp to 500 mAmp to deliver the electric field to the site of the cancerous tumor. In some embodiments, the control circuit 1506 can be configured to guide the electric field generating circuit 1520 to use a current in the range of 30 mAmp to 300 mAmp to deliver the electric field to the site of the cancerous tumor.

[0099] In some embodiments, the control circuit 1506 can be configured to direct the electric field generating circuit 1520 to deliver an electric field using a current comprising: 1 mAmp, 2 mAmp, 3 mAmp, 4 mAmp, 5 mAmp, 6 mAmp, 7 mAmp, 8 mAmp, 9 mAmp, 10 mAmp, 15 mAmp, 20 mAmp, 25 mAmp, 30 mAmp, 35 mAmp, 40 mAmp, 45 mAmp, 50 mAmp, 60 mAmp, 70 mAmp, 80 mAmp, 90 mAmp, 100 mAmp, 125 mAmp, 150 mAmp, 175 mAmp, 200 mAmp, 225 mAmp, 25 0mAmp, 275mAmp, 300mAmp, 325mAmp, 350mAmp, 375mAmp, 400mAmp, 425mAmp, 450mAmp, 475mAmp, 500mAmp, 525mAmp, 550mAmp, 575mAmp, 600mAmp, 625mA mp, 650mAmp, 675mAmp, 700mAmp, 725mAmp, 750mAmp, 775mAmp, 800mAmp, 825mAmp, 850mAmp, 875mAmp, 900mAmp, 925mAmp, 950mAmp, 975mAmp or 1000mAmp. It should be understood that the control circuit can be configured to direct the electric field generating circuit 1520 to deliver the electric field with a current falling within a certain range, where any of the aforementioned currents can be used as the lower limit or upper limit of the range, provided that the lower limit of the range is a value less than the upper limit of the range.

[0100] In some embodiments, the control circuit 1506 can be configured to direct the electric field generating circuit 1520 to use a 1V rms Up to 50V rms In some embodiments, the control circuit 1506 can be configured to direct the electric field generating circuit 1520 to use a voltage within the range of 5V to deliver the electric field to the site of the cancerous tumor. rms Up to 30V rms In some embodiments, the control circuit 1506 can be configured to direct the electric field generating circuit 1520 to use a voltage within the range of 10V to deliver the electric field to the site of the cancerous tumor. rms Up to 20V rms Voltages within a range deliver the electric field to the site of the cancerous tumor.

[0101] In some embodiments, control circuit 1506 may be configured to direct electric field generating circuit 1520 to deliver an electric field using one or more voltages including: 1V rms , 2V rms , 3Vrms , 4V rms , 5V rms , 6V rms , 7V rms , 8V rms , 9V rms , 10V rms , 15V rms , 20V rms , 25V rms , 30V rms , 35V rms , 40V rms , 45V rms or 50V rms It will be appreciated that the control circuitry may be configured to direct the electric field generating circuitry 1520 to deliver the electric field using a voltage that falls within a range, wherein any of the aforementioned voltages may be used as the lower or upper limit of the range, provided that the lower limit of the range is a value less than the upper limit of the range.

[0102] In some embodiments, the control circuit 1506 can be configured to direct the electric field generating circuit 1520 to deliver the electric field using one or more frequencies including: 10 kHz, 20 kHz, 30 kHz, 40 kHz, 50 kHz, 60 kHz, 70 kHz, 80 kHz, 90 kHz, 100 kHz, 125 kHz, 150 kHz, 175 kHz, 200 kHz, 225 kHz, 250 kHz, 275 kHz, 300 kHz, 325 kHz, 350 kHz, kHz, 375kHz, 400kHz, 425kHz, 450kHz, 475kHz, 500kHz, 525kHz, 550kHz, 575kHz, 600kHz, 625kHz, 650kHz, 675kHz, 700kHz, 725kHz, 750kHz, 775kHz, 800kHz, 825kHz, 850kHz, 875kHz, 900kHz, 925kHz, 950kHz, 975kHz, 1MHz. It should be appreciated that the electric field generating circuit 1520 can deliver the electric field using frequencies that fall within a range, wherein any of the foregoing frequencies can be used as the upper or lower limit of the range, provided that the upper limit is greater than the lower limit.

[0103] In some embodiments, the control circuit 1506 may be configured to direct the electric field generating circuit 1520 to generate one or more applied electric field strengths selected from the range of 0.25 V / cm to 1000 V / cm. In some embodiments, the control circuit 1506 may be configured to direct the electric field generating circuit 1520 to generate one or more applied electric field strengths greater than 3 V / cm. In some embodiments, the control circuit 1506 may be configured to direct the electric field generating circuit 1520 to generate one or more applied electric field strengths selected from the range of 1 V / cm to 10 V / cm. In some embodiments, the control circuit 1506 may be configured to direct the electric field generating circuit 1520 to generate one or more applied electric field strengths selected from the range of 3 V / cm to 5 V / cm.

[0104] In other embodiments, the control circuit 1506 can be configured to direct the electric field generating circuit 1520 to generate one or more applied electric field strengths including: 0.25 V / cm, 0.5 V / cm, 0.75 V / cm, 1.0 V / cm, 2.0 V / cm, 3.0 V / cm, 5.0 V / cm, 6.0 V / cm, 7.0 V / cm, 8.0 V / cm, 9.0 V / cm, 10.0 V / cm, 20.0 V / cm, 30.0 V / cm, 40.0 V / cm, 50.0 V / cm, 60.0 V / cm, 70.0 V / cm, 80.0 V / cm, 90.0 V / cm / cm, 100.0V / cm, 125.0V / cm, 150.0V / cm, 175.0V / cm, 200.0V / cm, 225.0V / cm, 250.0V / cm, 275.0V / cm, 300.0V / cm, 325.0V / cm, 350.0V / cm, 375.0V / cm, 400.0V / cm, 425.0V / cm, 450.0V / cm, 475.0V / cm, 500.0V / cm, 600.0V / cm, 700.0V / cm, 800.0V / cm, 900.0V / cm, 1000.0V / cm. It should be understood that the electric field generating circuit 1520 can generate an electric field at the treatment site having an electric field strength falling within a certain range, where any of the aforementioned field strengths can be used as the upper or lower limit of the range, provided that the upper limit is greater than the lower limit.

[0105] In some embodiments, the control circuit 1506 can be configured to direct the electric field generating circuit 1520 to deliver the electric field to the site of the cancerous tumor located in the body tissue via the lead 1106. In other embodiments, the control circuit 1506 can be configured to direct the electric field generating circuit 1520 to deliver the electric field to the site of the cancerous tumor located in the body tissue via the housing 1102 of the medical device 1100. In other embodiments, the control circuit 1506 can be configured to direct the electric field generating circuit 1520 to deliver the electric field between the lead 1106 and the housing 1102 of the medical device 1100. In some embodiments, one or more leads 1106 can be in electrical communication with the electric field generating circuit 1520. In some embodiments, one or more leads 1106 can include one or more electrodes 1108 arranged along the length of the lead 1106, wherein the electrodes 1108 can be in electrical communication with the electric field generating circuit 1520.

[0106] In some embodiments, various components within medical device 1100 may include electric field sensing circuit 1522 configured to generate a signal corresponding to a sensed electric field. Electric field sensing circuit 1522 may be integrated with control circuit 1506, or it may be separate from control circuit 1506.

[0107] The sensing electrodes may be arranged on or near the housing of the medical device, on one or more leads connected to the housing, on a separate device implanted near or in a tumor, or any combination of these locations. In some embodiments, the electric field sensing circuit 1522 may include a first sensing electrode 1532 and a second sensing electrode 1534. In other embodiments, the housing 1102 itself may be used as a sensing electrode for the electric field sensing circuit 1522. The electrodes 1532 and 1534 may be in communication with the electric field sensing circuit 1522. The electric field sensing circuit 1522 may measure the potential difference (voltage) between the first electrode 1532 and the second electrode 1534. In some embodiments, the electric field sensing circuit 1522 may measure the potential difference (voltage) between the first electrode 1532 or the second electrode 1534 and an electrode arranged along the length of one or more leads 1106. In some embodiments, the electric field sensing circuit may be configured to measure the sensed electric field and record the electric field strength in V / cm.

[0108] It should be appreciated that the electric field sensing circuit 1522 can additionally measure the potential difference between the first electrode 1532 or the second electrode 1534 and the housing 1102 itself. In other embodiments, the medical device may include a third electrode 1536, which may be an electric field sensing electrode or an electric field generating electrode. In some embodiments, one or more sensing electrodes may be arranged along the lead 1106 and may be used as an additional location for sensing the electric field. According to embodiments herein, many combinations are conceivable for measuring the potential difference between electrodes arranged along the length of one or more leads 1106 and the housing 1102.

[0109] In some embodiments, one or more leads 1106 may be in electrical communication with electric field generating circuit 1520. One or more leads 1106 may include one or more electrodes 1108, such as Fig.11 In some embodiments, various electrical conductors (such as electrical conductors 1526 and 1528) can pass from the head 1104 through the feedthrough structure 1530 and into the interior volume 1502 of the medical device 1100. In this way, the electrical conductors 1526 and 1528 can be used to provide electrical communication between one or more leads 1106 and the control circuit 1506 disposed within the interior volume 1502 of the housing 1102.

[0110] In some embodiments, the recorder circuit can be configured to record data generated by the electric field sensing circuit 1522 and record a timestamp about the data. In some embodiments, the control circuit 1506 can be hardwired to perform various functions, while in other embodiments, the control circuit 1506 can be directed to implement instructions executed on a microprocessor or other external computing device. Telemetry circuitry can also be provided for communicating with an external computing device, such as a programmer, a unit installed in a room, and / or a mobile unit (e.g., a cellular phone, a personal computer, a smart phone, a tablet computer, etc.).

[0111] Elements of various embodiments of the medical devices described herein are Fig.16 However, it should be understood that some embodiments may include Fig.16 Additional elements beyond those shown. In addition, some embodiments may lack Fig.16Some elements shown. The medical device embodied herein can collect information through one or more sensing channels, and can output information through one or more field generation channels. Microprocessor 1602 can communicate with memory 1604 via a bidirectional data bus. Microprocessor 1602 can be electrically connected to power circuit 1620. Memory 1604 may include a read-only memory (ROM) or random access memory (RAM) for program storage and a RAM for data storage. Microprocessor 1602 can also be connected to telemetry interface 1618 to communicate with external devices such as programmers, units installed in rooms and / or mobile units (e.g., cellular phones, personal computers, smart phones, tablet computers, etc.), or directly connected to the cloud or another communication network such as promoted by a cellular or other data communication network. In some embodiments, the medical device may include an inductive energy receiver coil interface (not shown) communicatively coupled or attached thereto to facilitate transcutaneous recharging of the medical device.

[0112] The medical device may include one or more electric field sensing electrodes 1608 and one or more electric field sensor channel interfaces 1606 that can communicate with a port of the microprocessor 1602. The medical device may also include one or more electric field generating electrodes 1612, and one or more electric field generating channel interfaces 1610 that can communicate with a port of the microprocessor 1602 and one or more electric field generating circuits 1609. The medical device may also include one or more other sensors 1616, such as physiological sensors, respiratory sensors, or chemical sensors; and one or more other sensor channel interfaces 1614 that can communicate with a port of the microprocessor 1602. Channel interfaces 1606, 1610, and 1614 may include various components, such as analog-to-digital converters for digitizing signal inputs, sense amplifiers, registers that can be written by control circuits to adjust the gain and threshold of the sense amplifiers, source drivers, modulators, demodulators, multiplexers, and the like.

[0113] In some embodiments, physiological sensors may include sensors that monitor temperature, blood flow, blood pressure, etc. In some embodiments, respiratory sensors may include sensors that monitor respiratory rate, peak respiratory amplitude, etc. In some embodiments, chemical sensors may measure the amount of analytes present in the treatment area around the sensor, including but not limited to analytes such as blood urea nitrogen, creatinine, fibrin, fibrinogen, immunoglobulins, deoxyribonucleic acid, RNA, potassium, sodium, chloride, calcium, magnesium, lithium, hydrated hydrogen, hydrogen phosphate, bicarbonate, etc. However, many other analytes are also contemplated herein. Exemplary chemical / analyte sensors are disclosed in co-owned U.S. Patent No. 7,809,441 to Kane et al., and the entire contents of that application are incorporated herein by reference.

[0114] Although other sensors 1616 are shown as Fig.16 1618. However, it should be appreciated that in some embodiments, one or more of the other sensors may be physically separate from the medical device. In various embodiments, one or more of the other sensors may be within another implanted medical device that is communicatively coupled to the medical device via telemetry interface 1618. In still other embodiments, one or more of the other sensors may be external to the body and coupled to the medical device via telemetry interface 1618. In some embodiments, the other sensors may include drug delivery sensors, biopsy device sensors, optical sensors, or irrigation sensors.

[0115] In some embodiments, the medical device herein may include an electric field generating circuit configured to generate one or more electric fields at or near the site of a cancerous tumor. The medical device herein may include a control circuit in communication with the electric field generating circuit, the control circuit being configured to control the delivery of one or more electric fields from the electric field generating circuit to the site of the cancerous tumor or near the site. The control circuit may cause the electric field generating circuit to generate one or more electric fields at a site of a cancerous tumor located in body tissue at a frequency selected from a range between 10kHz and 1MHz, the one or more electric fields effectively delaying mitosis and causing mitosis synchronization in a certain proportion of a cancerous cell population. In some embodiments, the medical device may further include one or more electrical leads electrically connected to the electric field generating circuit.

[0116] In some embodiments, the medical device herein includes a medical device system for treating a cancerous tumor. The medical device housing may include an electric field generating circuit, which is configured to generate one or more electric fields at or near the site of the cancerous tumor, and the cancerous tumor contains a cancerous cell group. The medical device system may include a control circuit connected to the electric field generating circuit, wherein the control circuit is configured to control the delivery of one or more electric fields from the electric field generating circuit to the site of the cancerous tumor or near the site. The medical device system may include: a drug delivery cannula for delivering one or more chemotherapeutic agents to the site of the cancerous tumor or near the site. The control circuit of the medical device system can cause the electric field generating circuit to generate one or more electric fields at a frequency selected from a range between 10kHz and 1MHz at the site of the cancerous tumor located in the body tissue, and the one or more electric fields effectively delay mitosis and cause mitosis synchronization in a certain proportion of the cancerous cell group.

[0117] In some embodiments, the medical device herein may include a medical device for treating a cancerous tumor in a subject. The medical device may include an electric field generating circuit configured to generate one or more electric fields at or near the site of the cancerous tumor, the cancerous tumor comprising a cancerous cell population. The medical device may include a control circuit in communication with the electric field generating circuit. The control circuit of the medical device controls the delivery of one or more electric fields from the electric field generating circuit to or near the site of the cancerous tumor after a predefined schedule, the predefined schedule causing at least one of the intensity and frequency of the electric field to vary over a defined time period of at least six hours.

[0118] The medical device herein may include a medical device for treating a cancerous tumor, the medical device including one or more implantable electrodes configured to be placed in the body of a subject with a cancerous tumor. The medical device may include one or more external electrodes configured to be placed on the outer surface of the subject's body. The medical device may include an electric field generating circuit configured to generate an electric field between at least one pair of electrodes according to a predefined schedule, the frequency of the electric field being in a range between 10kHz and 1MHz. The medical device may include a control circuit configured to receive a pause command from the subject, wherein the pause command terminates the generation of the electric field.

[0119] Chemotherapeutic agents

[0120] One or more chemotherapeutic agents may be suitable for use in the methods and devices described herein. In certain embodiments, therapeutic agents suitable for use herein may include antimitotic agents. Antimitotic agents may include antimitotic agents acting on microtubules (i.e., spindle fibers) present during mitosis. Suitable antimitotic agents may include those with microtubule stabilizing properties or those with microtubule destabilizing properties. Without wishing to be bound by any particular theory, it is believed that including those antimitotic agents with microtubule stabilizing properties or those antimitotic agents with microtubule destabilizing properties will act on multiple different domains of alpha-tubulin or beta-tubulin constituting microtubule structures.

[0121] In some embodiments, the anti-mitotic agent herein may include an anti-mitotic agent acting on the contractile ring, which may include but is not limited to F-actin, myosin-2, aniline, one or more diaphragm proteins, Rho, arrestin, cofilin, and male germ cell Ras-related C3 botulinum toxin substrate GTPase activating protein (MgcRacGAP). In other embodiments, the anti-mitotic agent may include an anti-mitotic agent acting on nucleic acids, such as DNA and RNA. Suitable anti-mitotic agents may include those with contractile ring stabilizing properties or those with contractile ring destabilizing properties. Without wishing to be bound by any particular theory, it is believed that those anti-mitotic agents including those with contractile ring stabilizing properties or those with contractile ring destabilizing properties act on multiple different domains of the protein that forms the contractile ring.

[0122] Chemotherapeutic agents suitable for use herein may include, but are not limited to, at least one of the following: vindesine, vincristine, vinblastine, paclitaxel, docetaxel, 2-methoxyestradiol, patupilone, trastuzumab, and derivatives thereof. In some embodiments, the chemotherapeutic agents herein include agents with a treatment half-life of less than 24 hours. In some embodiments, the chemotherapeutic agents herein include agents with a treatment half-life of less than 48 hours. In some embodiments, the chemotherapeutic agents herein include agents with a treatment half-life of less than 60 hours.

[0123] The chemotherapeutic agents herein can be administered at or near the site of the cancerous tumor in a therapeutically effective dose. In some embodiments, the chemotherapeutic agents herein are administered into the systemic circulation at a therapeutically effective dose away from the site of the cancerous tumor. The chemotherapeutic agent can be administered through a percutaneous access port that is in fluid communication with the systemic venous system anywhere on the subject's body.

[0124] In some embodiments, the therapeutically effective dose of the chemotherapeutic agent comprises a concentrated dose delivered to the subject within a 6 hour period after removal of the electric field, wherein the concentrated dose is equivalent to a conventional non-concentrated dose delivered over a 24 hour period. In some embodiments, the concentrated dose of the chemotherapeutic agent may be delivered to the subject within one or two hours, and in some embodiments, the concentrated dose of the chemotherapeutic agent may be delivered to the subject within one or two hours, followed by administration of a diluted dose of the chemotherapeutic agent for a predetermined period of time, which may include 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, or longer, wherein the concentrated dose is equivalent to a conventional non-concentrated dose delivered within a 24 hour period to a 72 hour period.

[0125] The chemotherapeutic agents herein may include photoactivated chemotherapeutic agents. The photoactivated chemotherapeutic agents may include, but are not limited to, photoactivated platinum compounds or photoactivated photostatin compounds. In some embodiments, photoactivated photostatin compounds include photoactivated combretastatin A-4 and its analogs and derivatives. In some embodiments, the photoactivated chemotherapeutic agents may be photoactivated by visible light in the range of 350nm to 850nm emitted by a light emitter present on the various leads described herein. In some embodiments, the photoactivated chemotherapeutic agents may be photoactivated by visible light in the range of 450nm to 650nm. The photoactivated chemotherapeutic agents herein may include those photoactivated chemotherapeutic agents that are photoactivated by a certain wavelength, which wavelength may be greater than or equal to 350nm, 400nm, 450nm, 500nm, 550nm, 600nm, 650nm, 700nm, 750nm, 800nm, or 850nm, or may be an amount falling within any of the aforementioned ranges. In some embodiments, the photoactivated chemotherapeutic agents herein can be photoinactivated by visible light in the range of 350nm to 850nm. In some embodiments, the photoactivated chemotherapeutic agents herein can be photoinactivated by visible light in the range of 350nm to 850nm, can be further photoactivated by visible light in the range of 350nm to 850nm for multiple cycles.

[0126] Suitable photoactivated chemotherapeutic agents include, but are not limited to, photoactivated platinum compounds or photoactivated photostatin compounds. In some embodiments, photoactivated photostatin compounds include photoactivated combretastatin A-4 and its analogs and derivatives.

[0127] The methods herein may include a method for treating a cancerous tumor in a subject, the method comprising applying one or more electric fields at or near the site of the cancerous tumor, the cancerous tumor comprising a cancerous cell population. The method may include removing the one or more electric fields; and applying a photoactivated chemotherapeutic agent at or near the site of the cancerous tumor after the one or more electric fields have been removed. The method may include irradiating the photoactivated chemotherapeutic agent by delivering photoactivation light energy at or near the site of the cancerous tumor. In some embodiments, the photoactivated chemotherapeutic agent is administered at a therapeutically effective dose of the photoactivated chemotherapeutic agent to be released at or near the site of the cancerous tumor. In some embodiments, the therapeutically effective dose includes a concentrated dose delivered to the subject within a 6-hour period after the electric field is removed, wherein the concentrated dose is equal to a conventional non-concentrated dose delivered over a 24-hour period.

[0128] The medical device herein may include a method for treating a cancerous tumor in a subject, including an electric field generating circuit configured to generate one or more electric fields at or near the site of the cancerous tumor, the cancerous tumor comprising a cancerous cell population. The medical device may include a control circuit in communication with the electric field generating circuit, the control circuit being configured to control the delivery of one or more electric fields from the electric field generating circuit to the site of the cancerous tumor or near the site. The medical device may include a cannula configured to administer a photoactivated chemotherapeutic agent to or near the site of the cancerous tumor. The medical device may include one or more light emitters configured to irradiate the photoactivated chemotherapeutic agent by delivering photoactivated light energy to or near the site of the cancerous tumor.

[0129] The chemotherapeutic agent herein may include nanoparticles. In some embodiments, the nanoparticles are made of polymers, such as biodegradable polymers. In some embodiments, the nanoparticles may include an effective amount of chemotherapeutic agent released at or near the site of a cancerous tumor. In some embodiments, the nanoparticles include at least one of: vindesine, vincristine, vinblastine, paclitaxel, docetaxel, 2-methoxyestradiol, patupilone, trastuzumab, and derivatives thereof. The nanoparticles may be released at or near the site of a cancerous tumor to deliver a photoactivated chemotherapeutic agent of a therapeutically effective dose. In some embodiments, the therapeutically effective dose includes a concentrated dose delivered to a subject within a 6-hour period after the electric field is removed, wherein the concentrated dose is equal to a conventional non-concentrated dose delivered over a 24-hour period. In some embodiments, the nanoparticles may include an effective amount of photoactivated chemotherapeutic agent described elsewhere herein.

[0130] The methods herein may include a method for treating a cancerous tumor in a subject, the method comprising applying one or more electric fields at or near the site of the cancerous tumor, the cancerous tumor comprising a cancerous cell population. The method may include administering nanoparticles comprising a chemotherapeutic agent at or near the site of the cancerous tumor. In some embodiments, the method may include removing the one or more electric fields before administering nanoparticles at or near the site of the cancerous tumor.

[0131] The medical device herein may include a medical device for treating a cancerous tumor in a subject, the medical device including an electric field generating circuit configured to generate one or more electric fields at or near the site of the cancerous tumor, the cancerous tumor comprising a cancerous cell population. The medical device may include a control circuit in communication with the electric field generating circuit, the control circuit being configured to control the delivery of one or more electric fields from the electric field generating circuit to the site of the cancerous tumor or near the site. The medical device may include a cannula configured to administer nanoparticles to or near the site of the cancerous tumor.

[0132] Additional dosage forms and dosage forms

[0133] One or more additional agents or modalities may be suitable for use with the methods and devices described herein. For example, an immunological agent may be combined with an alternating electric field therapy. Suitable immunological agents may include, but are not limited to, immunostimulants and immunosuppressants. In some embodiments, an immunostimulant may include one or more agents that stimulate the immune system. In other embodiments, an immunosuppressant may include one or more agents that suppress the immune system. In some embodiments, a combination of an immunostimulant and an immunosuppressant may be used. In other embodiments, an immunostimulant and / or an immunosuppressant may be used in conjunction with a chemotherapeutic agent during a given therapy.

[0134] Exemplary immunostimulants can include bacterial vaccines, viral vaccines, therapeutic vaccines, interferons, interleukins, colony stimulating factors, male and female sex hormones, growth hormones, vitamin D, etc. In some embodiments, the immunostimulant can be specific, while in other embodiments, the immunostimulant can be non-specific. Exemplary immunosuppressants can include calcineurin inhibitors, interleukin inhibitors, TNFα inhibitors, antibodies, glucocorticoids, cytostatics, alkylating agents, antimetabolites such as nucleotide analogs, protein synthesis inhibitors, anti-rejection agents, etc.

[0135] One or more additional forms or agents may also be suitable for use with the methods and devices described herein. For example, it is also contemplated herein to combine radiation therapy with alternating electric field therapy. In some embodiments, targeted drug therapy, immunotherapy, or hormone therapy may be used in combination with the alternating electric field therapy described herein.

[0136] Applied electric field

[0137] The electric field applied to the cancerous tumor using the methods herein can be applied using a variety of forms. Exemplary treatment parameter sets may include those that implement the following concepts: sweeping through a range of frequencies; stacking one or more frequencies simultaneously; sequentially stepping through one or more frequencies; spatial or temporal delivery of one or more electric fields; sweeping through a range of electric field strengths; applying an effective rotating electric field; modulating a voltage control mode or a current control mode; implementing one or more duty cycles; pulse width modulation; manipulating the shape of the electrical waveform and / or the sequence of pulses; and occasionally using high frequency or high electric field strength pulses.

[0138] The treatment parameter set can be programmed into the medical device to operate autonomously, or can be queried and manipulated by the subject or clinician using an external computing device, such as a programmer, a unit installed in the room, and / or a mobile unit (e.g., a cellular phone, a personal computer, a smart phone, a tablet computer, etc.). In other embodiments, the treatment parameter set can be wirelessly transmitted to the medical device from the external computing device. The frequency and / or electric field strength applicable to any treatment parameter set herein are discussed above with respect to the electric field generating circuit. In some embodiments, one or more treatment parameter sets can be implemented simultaneously. In other embodiments, one or more treatment parameter sets can be implemented in an alternating manner.

[0139] For example, an electric field can be applied to the site of a cancerous tumor by sweeping through a range of frequencies. Fig.17 , exemplary graph 1702 shows an alternating electric field where the frequency increases over time. Similarly, Fig.18 The change in frequency over time during the programmed therapy parameters is shown in exemplary graph 1802. In some embodiments, the frequency sweep may include sweeping upward from a minimum frequency to a maximum frequency. In some embodiments, the frequency sweep may include sweeping downward from a maximum frequency to a minimum frequency. In other embodiments, sweeping upward from a minimum frequency to a maximum frequency and sweeping downward from a maximum frequency to a minimum frequency may be repeated as many times as desired throughout the duration of delivering the electric field from the electric field generating circuit.

[0140] As therapy is performed during the frequency sweep, it may be desirable to alternate between frequency ranges so that more cells can be targeted as the cells in the population change size and number in response to therapy. For example, in some embodiments, the frequency sweep may include alternating between a first frequency sweep covering a range of about 100kHz to 300kHz and a second frequency sweep covering a range of about 200kHz to 500kHz. It should be understood that sweeping through the first frequency range and the second frequency range as described above can be performed indefinitely throughout the course of therapy. In some embodiments, the second frequency sweep (range) may be at a higher frequency than the first frequency sweep (range). In some embodiments, the first frequency sweep (range) may be at a higher frequency than the second frequency sweep (range).

[0141] The frequency ranges used for the first frequency range and the second frequency range can be any range including the specific frequencies described above with respect to the electric field generating circuit 1609, provided that the lower end of each range is a value less than the upper end of each range. Sometimes, it may be beneficial to have a certain degree of overlap between the frequency ranges of the first frequency sweep and the second frequency sweep.

[0142] Leads and Electrodes

[0143] The leads described herein may be placed in the body at or near the site of a cancerous tumor using a variety of techniques. Placing one or more leads may include using techniques such as transvascular placement, penetration into the subcutaneous space, and / or surgical placement. In some embodiments, placing one or more leads may include placement via one or more natural body orifices. The leads may be placed near or within the cancerous tumor. In some embodiments, multiple leads may be used near or away from the cancerous tumor.

[0144] In some embodiments, one or more leads described herein may be placed in the subcutaneous space. The electrodes on the leads placed in the subcutaneous space may be used as the primary near-field generating electrodes or the far-field generating electrodes. In some embodiments, the electrodes on the leads placed in the subcutaneous space may be used as the primary near-field generating electrodes or the far-field generating electrodes in conjunction with the housing of the medical device. Similarly, one or more leads may be placed transvascularly to act as the far-field generating electrodes in conjunction with electrodes at or near the site of a cancerous tumor or in conjunction with the housing of a medical device.

[0145] The leads and electrodes described herein may include additional functional and structural features. In some embodiments, the leads may include leads compatible with imaging and therapeutic techniques, including but not limited to MRI (magnetic resonance imaging), X-ray imaging, deep brain stimulation techniques, and / or radiation therapy. In some embodiments, the leads may include one or more conductor cores made of a conductive material. The conductor cores may be formed of a conductive material including a metal and / or other conductive material. The metal may include but is not limited to palladium, platinum, silver, gold, copper, aluminum, various alloys (including stainless steel, such as In some embodiments, the conductor core may be a multi-winding coil, including but not limited to a double-winding coil, a triple-winding coil, and a quad-winding coil.

[0146] In some embodiments, as described herein, the electrode can be arranged along the length of one or more leads. The material suitable for the electrode described herein may include metals, such as palladium, to minimize the connection and artifact generation in the magnetic field. In some embodiments, the electrode can be made of other metals and / or other conductive materials. The metal may include but is not limited to palladium, platinum, platinum alloys (such as platinum-iridium alloys), gold, copper, tantalum, titanium, various alloys (including stainless steel), etc. In some embodiments, the electrode can be in the form of a winding coil, which can provide the additional benefit of increasing the surface area without compromising the flexibility of the electrode. In some embodiments, an implantable device housing can be used as an electrode.

[0147] The leads described herein may also include one or more electrodes arranged along the length of the lead. The lead may include two or more electrodes arranged along the length of the lead. In some embodiments, the electrode may be a tip electrode found at the distal end of the lead. In other embodiments, the electrode may be a ring electrode found along the lead but not at the tip of the lead.

[0148] In some embodiments, the electrode can be a coil electrode. In some embodiments, a ring or tip electrode can be positioned in or near a tumor or cancerous tissue, and the coil electrode can be positioned away from the tumor or cancerous tissue to help provide spatial diversity to the generated electric field. In some embodiments, the axis of one or more electrodes along the length direction (e.g., the axis from the proximal end to the distal end) can have the following lengths of about 0.5mm, 1mm, 1.5mm, 2mm, 3mm, 4mm, 5mm, 7.5mm, 10mm, 15mm, 20mm, 30mm, 40mm, 50mm, 75mm, 100mm or more. In some embodiments, the length of one or more electrodes can fall within the following range, wherein any of the aforementioned distances can be used as the upper or lower limit of the range, provided that the upper limit is greater than the lower limit.

[0149] The lead may be monopolar, bipolar, or multipolar. In some embodiments, a monopolar lead may include a lead that generates an electric field between one electrode and the housing of the medical device. In some embodiments, a bipolar lead may include a lead that generates an electric field between two electrodes arranged along the lead or between two electrodes and the housing of the medical device. In some embodiments, a multipolar lead may include a lead that generates an electric field between two or more electrodes arranged along the lead, between two or more electrodes and the housing of the medical device, or between any number of combinations of configurations of electrodes and the housing of the medical device.

[0150] The lead of this article may include one or more light emitters along the length of the lead. Light emitters suitable for use herein may include those light emitters whose emitted light falls anywhere along the visible spectrum from about 350nm to 950nm. Suitable light emitters may include light emitting diodes or laser diodes. Suitable LEDs may be made of one or more of the following: gallium arsenide (GaAs), gallium phosphide (GaP), gallium arsenide phosphide (GaAsP), silicon carbide (SiC), or indium telluride nitride (GaInN). In some embodiments, LEDs suitable for use herein may include LEDs capable of emitting only one color, or monochromatic LEDs; LEDs capable of emitting two colors, or bicolor LEDs; LEDs capable of emitting three colors, or tricolor LEDs; or LEDs capable of emitting more than three colors. The LED may be electrically connected to a control circuit in the housing of the medical device described herein. In some embodiments, one or more laser diodes may be included along the lead of this article, and the laser diode may be optically communicated with one or more optical fibers disposed in the lead and used to transmit light from a laser source to the laser diode.

[0151] Electrodes suitable for use herein can be made of conductive polymers, such as carbon-filled silicone, polyacetylene, polypyrrole, polyaniline, polythiophene, polyfuran, polyisoprene, polybutadiene, polyparaphenylene, and the like. In other embodiments, the electrodes can be insulating. In some embodiments, the insulation surrounding the electrodes can include microporous insulators to prevent cell attachment but still allow current to flow. The microporous insulators can be made of a variety of insulating materials described herein, including but not limited to polytetrafluoroethylene (ePTFE), polyethylene-tetrafluoroethylene copolymer (ETFE), polyurethane, silicone, polyparaxylene polymers (such as polyparaxylene polymers), polyether block amides (such as ), nylon or their derivatives. In some embodiments, the electrodes can be coated with various materials, including but not limited to hydrogels or fractal coatings, such as iridium oxide, titanium oxide, tantalum pentoxide, other metal oxides, polyparaxylene polymers (such as polyparaxylene), etc.

[0152] According to the embodiments of the present invention, a variety of lead fixation techniques and configurations can be used. Some non-limiting examples of lead fixation techniques can include biocompatible glue fixation, claw fixation, spiral coil fixation, passive centering of the lead in the vascular system, tooth fixation within the local vascular system, spiral offset fixation within the local vascular system, compression fixation, suture sleeve fixation, etc. In some examples, the lead embodied herein can be placed in the vascular system around or near the cancerous tumor site. In other embodiments, the lead embodied herein can be surgically placed at, within, or around the site of the cancerous tumor.

[0153] Leads suitable for use herein may also include one or more open cavities extending the entire longitudinal length of the lead or a selected portion of the longitudinal length. In some embodiments, the open cavity may include an integrated biopsy device adapted to periodically obtain biopsy samples from a cancerous tumor site to monitor the progression and / or regression of the disease. Leads with an open cavity may also be configured to include an integrated drug delivery cavity that may deliver one or more drugs (such as steroids or chemotherapy agents) to the tumor site in a single bolus or regularly via a metering pump. The lead may include one or more inlets arranged along the length of the lead to provide an outlet for delivering drugs at or near the site of a cancerous tumor.

[0154] In some embodiments, a portion or the entire lead may include a drug eluting coating. In some embodiments, the drug eluting coating may include an anti-inflammatory agent, such as a steroid. In some embodiments, the steroid may be dexamethasone. In other embodiments, the drug eluting coating may include a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent may include a taxane or a derivative thereof, including but not limited to paclitaxel, docetaxel, and the like. In other embodiments, the drug eluting coating may be configured to release other types of chemotherapeutic agents, including but not limited to alkylating agents, plant alkaloids (such as vinca alkaloids), cytotoxic antibiotics, topoisomerase inhibitors, and the like. In some embodiments, the drug eluting coating may be configured to release the drug from the coating in a delayed release manner.

[0155] The leads herein can take a variety of shapes or configurations. In some embodiments, the leads can be linear, while in other embodiments, the leads can be circular. A circular lead can be a fully enclosed ring or a semi-enclosed ring. In some embodiments, the leads can include a bendable core that can allow the leads to be formed into many configurations, including but not limited to U-shaped, S-shaped, spiral, semicircular, elliptical, etc.

[0156] In yet other examples, the leads suitable for use herein may include fluorescent or magnetic markers that can assist clinicians in accurately placing at or near a cancerous tumor site. The leads may also include an integrated pH sensor for detecting pH changes at or near a cancerous tumor, or other chemical sensors suitable for analyzing the concentration of a chemical analyte of interest.

[0157] Electric field generator

[0158] Medical devices embodied herein may include electric field generators that are particularly suitable for use in therapeutic and diagnostic techniques used in the treatment of cancerous tumors. In some embodiments, electric field generators suitable for use herein may include those that have been treated with radiation hardening to render the components resistant to the damaging effects of radiation therapy treatments that are often prescribed as the mainline treatment for cancerous tumors. Electric field generators may include, for example, those described above with reference to Figure 3 and Figure 5 Those parts described.

[0159] The electric field generators embodied herein can be programmed with any number of treatment parameter sets as described. The electric field generators can be programmed prior to implantation, or they can be programmed by a clinician using an external computing device, such as a programmer, a unit installed in a room, and / or a mobile unit (e.g., a cellular phone, a personal computer, a smart phone, a tablet computer, etc.). In some embodiments, the therapy parameters can be delivered to the electric field generator via a telemetry circuit. In some embodiments, the electric field generator may include a recharging circuit communicatively coupled to a receiver coil to facilitate transcutaneous recharging of the medical device. In some embodiments, the electric field generator may wirelessly communicate between the receiver coil and an external charging device.

[0160] Other embodiments

[0161] In an embodiment, a method for treating a cancerous tumor in a subject is included, the method comprising: applying one or more electric fields at or near the site of the cancerous tumor, the cancerous tumor comprising a population of cancerous cells; wherein the applied one or more electric fields are effective to delay mitosis and induce mitotic synchronization within a certain proportion of the cancerous cell population; removing the one or more electric fields to allow mitosis to proceed within the cancerous cell population; and administering a chemotherapeutic agent to the subject after the one or more electric fields have been removed.

[0162] In embodiments, applying one or more electric fields to the cancerous tumor comprises applying the one or more electric fields for a time period selected from the range of time periods from 1 minute to 24 hours.

[0163] In embodiments, the method may further comprise administering a chemotherapeutic agent to the subject when at least 5% of the cancerous cell population is synchronized in mitosis in response to the one or more electric fields.

[0164] In embodiments, the method may further comprise administering a chemotherapeutic agent to the subject when at least 25% of the cancerous cell population is synchronized in mitosis in response to the one or more electric fields.

[0165] In embodiments, the method may further comprise administering a chemotherapeutic agent to the subject when at least 50% of the cancerous cell population is synchronized in mitosis in response to the one or more electric fields.

[0166] In embodiments, the method may further comprise administering a chemotherapeutic agent to the subject when at least 75% of the population of cancerous cells are synchronized in mitosis in response to the one or more electric fields.

[0167] In an embodiment, the one or more electric fields are applied to the cancerous tumor at a frequency selected from within the range between 10 kHz and 1 MHz.

[0168] In an embodiment, the one or more electric fields are applied to the cancerous tumor at a frequency selected from within the range between 100 kHz to 500 kHz.

[0169] In an embodiment, the one or more electric fields are applied to the cancerous tumor at a frequency selected from within the range between 100 kHz to 300 kHz.

[0170] In an embodiment, the electric field strength of the one or more electric fields is selected from the range of electric field strengths from 0.25 V / cm to 1000 V / cm.

[0171] In an embodiment, the electric field strength of the one or more electric fields is selected from the range of electric field strengths from 1 V / cm to 10 V / cm.

[0172] In an embodiment, the electric field strength of the one or more electric fields is selected from the range of electric field strengths from 3 V / cm to 5 V / cm.

[0173] In embodiments, the chemotherapeutic agent is administered to the subject at a therapeutically effective dose.

[0174] In embodiments, the therapeutically effective dose comprises a concentrated dose delivered to the subject over a 6 hour period following removal of the electric field that is equivalent to a conventional non-concentrated dose delivered over a 24 hour period.

[0175] In embodiments, chemotherapeutic agents include agents with a therapeutic half-life of less than 48 hours.

[0176] In embodiments, the chemotherapeutic agent comprises an anti-mitotic agent.

[0177] In embodiments, the chemotherapeutic agent comprises at least one of vindesine, vincristine, vinblastine, paclitaxel, docetaxel, 2-methoxyestradiol, patupilone, trastuzumab, and derivatives thereof.

[0178] In embodiments, the chemotherapeutic agent comprises a photoactivated chemotherapeutic agent.

[0179] In embodiments, the photoactivated chemotherapeutic agent comprises a photoactivated platinum compound or a photoactivated photostatin compound.

[0180] In embodiments, the photoactivated photostatin compounds include photoactivated combretastatin A-4 and its analogs and derivatives.

[0181] In an embodiment, the activated chemotherapeutic agent can be photoactivated by visible light in the range of 350 nm to 850 nm.

[0182] In embodiments, the photoactivated chemotherapeutic agent can be photoinactivated by visible light in the range of 350 nm to 850 nm.

[0183] In embodiments, the chemotherapeutic agent comprises nanoparticles.

[0184] In embodiments, the nanoparticles comprise an effective amount of a chemotherapeutic agent for release at or near the site of a cancerous tumor.

[0185] In embodiments, the method further may include inserting a percutaneous access port at or near the site of the cancerous tumor.

[0186] In an embodiment, the percutaneous access port is configured to receive one or more guide wires.

[0187] In an embodiment, the one or more leads include: drug delivery cannulas having an open lumen for delivering one or more chemotherapeutic agents; optical leads which may include one or more light emitters for delivering photoactivated light energy; a biopsy device for obtaining a biopsy sample from a cancerous tumor; and an lavage cannula for flushing waste or body fluids.

[0188] In embodiments, applying the one or more electric fields to the subject may include applying the one or more electric fields from outside the body of the subject to at or near the site of the cancerous tumor.

[0189] In embodiments, applying one or more electric fields to a cancerous tumor may include applying the one or more electric fields at least partially from within the body of the subject to a site at or near the cancerous tumor.

[0190] In embodiments, applying one or more electric fields to a cancerous tumor may include applying the one or more electric fields at least partially from outside the body of the subject to at or near the site of the cancerous tumor.

[0191] In embodiments, applying one or more electric fields to a cancerous tumor may include implanting the one or more electric fields from within the subject at or near the site of the cancerous tumor using one or more implantable electrodes.

[0192] In an embodiment, a medical device that generates one or more electric fields may include: an electric field generating circuit; and a control circuit in communication with the electric field generating circuit, the control circuit being configured to control the delivery of the one or more electric fields from the electric field generating circuit to at or near the site of a cancerous tumor.

[0193] In embodiments, the medical device further comprises one or more electrical leads in electrical communication with the electric field generating circuit.

[0194] In an embodiment, the medical device is configured to be fully implanted within a subject.

[0195] In an embodiment, the medical device is configured to be entirely external to the subject.

[0196] In an embodiment, the medical device is configured to be partially implanted within a subject.

[0197] In an embodiment, the medical device is configured to be partially external to the subject.

[0198] In an embodiment, a method for treating a cancerous tumor is included, the method comprising: implanting one or more implantable electrodes into the body of a subject having a cancerous tumor; placing one or more external electrodes on the external surface of the subject's body; generating an electric field between at least one pair of electrodes according to a predefined schedule, the electric field having a frequency in a range between 10 kHz and 1 MHz; and removing the one or more electric fields; and administering a chemotherapeutic agent at or near the site of the cancerous tumor after the one or more electric fields have been removed.

[0199] In embodiments, the applied electric field(s) are effective to delay mitosis and induce mitotic synchronization in a proportion of the cancerous cell population.

[0200] In embodiments, the one or more electric fields are removed to allow mitosis to occur within the cancerous cell population.

[0201] In an embodiment, a method for treating a cancerous tumor in a subject is included, the method comprising: applying a first electric field having a first electric field strength at or near the site of the cancerous tumor, the cancerous tumor may include a population of cancerous cells; wherein the first electric field is effective to delay mitosis and induce mitotic synchronization within a certain proportion of the cancerous cell population; removing the first electric field to allow mitosis to occur within the cancerous cell population; and administering a chemotherapeutic agent at or near the site of the cancerous tumor after the first electric field has been removed.

[0202] In an embodiment, the method may further include applying a second electric field having a second electric field strength at or near the site of the cancerous tumor after the first electric field has been removed and before applying the chemotherapeutic agent, wherein the second electric field effectively delays mitosis and induces mitotic synchronization within a certain proportion of the cancerous cell population.

[0203] In an embodiment, the method may further include waiting a predetermined amount of time after removing the first electric field and before applying the second electric field.

[0204] In an embodiment, the second electric field strength is less than the first electric field strength.

[0205] In an embodiment, the second electric field strength is greater than the first electric field strength.

[0206] In an embodiment, the second electric field strength is the same as the first electric field strength.

[0207] In an embodiment, the method may further include receiving a pause command from the subject to pause application of the first electric field when the subject experiences one or more side effects, which may include dizziness, nausea, fatigue, lightheadedness, headache, or localized pain.

[0208] In an embodiment, the method may further include receiving an activation command from the subject, wherein the activation command regenerates the first electric field.

[0209] In an embodiment, a medical device for treating a cancerous tumor is provided, the medical device comprising: an electric field generating circuit, the electric field generating circuit being configured to generate one or more electric fields at or near the site of the cancerous tumor, which may contain a population of cancerous cells; a control circuit connected to the electric field generating circuit, the control circuit being configured to control the delivery of the one or more electric fields from the electric field generating circuit to the site of the cancerous tumor or near the site; wherein the control circuit causes the electric field generating circuit to generate the one or more electric fields at a frequency selected from a range between 10 kHz and 1 MHz at the site of the cancerous tumor located in body tissue, the one or more electric fields being effective in delaying mitosis and inducing mitosis synchronization in a certain proportion of the cancerous cell population.

[0210] In embodiments, the medical device may include one or more electrical leads in electrical communication with the electric field generating circuit.

[0211] In an embodiment, the medical device may include one or more of the following: a drug delivery cannula for delivering one or more chemotherapeutic agents; optical leads that may include one or more light emitters for delivering photoactivated light energy; a biopsy device for obtaining a biopsy sample from a cancerous tumor; and an lavage cannula for flushing waste or body fluids.

[0212] In an embodiment, the medical device is configured to be fully implanted within a subject.

[0213] In an embodiment, the medical device is configured to be partially implanted within a subject.

[0214] In an embodiment, the medical device is configured to be entirely external to the subject.

[0215] In an embodiment, a medical device system for treating a cancerous tumor is included, the medical device system having a medical device housing, the medical device including: an electric field generating circuit, the electric field generating circuit being configured to generate one or more electric fields at or near the site of the cancerous tumor, which may contain a population of cancerous cells; a control circuit connected to the electric field generating circuit, the control circuit being configured to control delivery of the one or more electric fields from the electric field generating circuit to at or near the site of the cancerous tumor; a drug delivery cannula for delivering one or more chemotherapeutic agents to at or near the site of the cancerous tumor; and wherein the control circuit causes the electric field generating circuit to generate the one or more electric fields at a frequency selected from a range between 10 kHz and 1 MHz at the site of the cancerous tumor located within body tissue.

[0216] In an embodiment, the medical device may include a delivery port configured to receive at least one of: a drug delivery cannula for delivering one or more chemotherapeutic agents; a light lead that may include one or more light emitters for delivering light energy; a biopsy device for obtaining a biopsy sample from a cancerous tumor; and an irrigation cannula for flushing the site of the cancerous tumor.

[0217] In an embodiment, a method for treating a cancerous tumor in a subject is included, the method comprising: applying one or more electric fields at or near the site of the cancerous tumor according to a predefined schedule, the cancerous tumor comprising a population of cancerous cells; wherein the predefined schedule varies at least one of the intensity and frequency of the electric field over the course of a defined period of at least six hours.

[0218] In embodiments, the applied electric field(s) are effective to delay mitosis and induce mitotic synchronization in a proportion of the cancerous cell population.

[0219] In embodiments, the method may further comprise removing the one or more electric fields to allow mitosis to occur within the cancerous cell population.

[0220] In embodiments, the method may further comprise administering a chemotherapeutic agent at or near the site of the cancerous tumor after the one or more electric fields have been removed.

[0221] In an embodiment, the method may further include receiving a pause command from the subject, wherein the pause command discontinues application of the electric field.

[0222] In an embodiment, the predefined schedule comprises a variation over time of at least one of an intensity and a frequency of the one or more electric fields.

[0223] In an embodiment, the predefined schedule comprises one or more off periods, wherein the intensity or frequency of the applied one or more electric fields is reduced by at least 50% for at least 4 hours.

[0224] In an embodiment, the predefined schedule includes one or more downtime periods, wherein the intensity or frequency of the applied one or more electric fields is reduced by at least 75% for at least 4 hours.

[0225] In an embodiment, a method for treating a cancerous tumor in a subject is included, the method comprising: applying one or more electric fields at or near the site of the cancerous tumor according to a predefined schedule, the cancerous tumor comprising a population of cancerous cells; wherein the applied one or more electric fields are effective to delay mitosis and induce mitotic synchronization in a certain proportion of the cancerous cell population; and removing the one or more electric fields to allow mitosis to occur within the cancerous cell population.

[0226] In an exemplary embodiment, a medical device for treating a cancerous tumor in a subject is included, the medical device having: an electric field generating circuit, the electric field generating circuit being configured to generate one or more electric fields at or near the site of the cancerous tumor, which may contain a population of cancerous cells; a control circuit connected to the electric field generating circuit; wherein the control circuit is configured to control the delivery of the one or more electric fields from the electric field generating circuit to the site of the cancerous tumor at or near the site after a predefined schedule, the predefined schedule causing at least one of the intensity and frequency of the electric field to vary over a defined period of time of at least six hours.

[0227] In an embodiment, a method for treating a cancerous tumor is included, the method comprising: implanting one or more implantable electrodes into the body of a subject having a cancerous tumor; placing one or more external electrodes on the external surface of the subject's body; generating an electric field between at least one pair of electrodes according to a predefined schedule, the frequency of the electric field being in a range between 10 kHz and 1 MHz; and receiving a pause command from the subject, wherein the pause command terminates generating the electric field.

[0228] In an embodiment, the method may further include regenerating the electric field between the at least one pair of electrodes according to a predefined schedule after a certain period of time has passed since a pause command was received from the subject.

[0229] In an embodiment, the predefined schedule comprises a variation over time of at least one of the intensity and the frequency of the electric field.

[0230] In an embodiment, the pause command received from the patient includes at least one of the following: a shut down command, a shut down command for a set time, a shut down button push command, or a shut down status reminder command.

[0231] In an embodiment, a method may include receiving an activation command from a subject, wherein the activation command regenerates the electric field.

[0232] In an embodiment, a medical device for treating a cancerous tumor is included, the medical device having: one or more implantable electrodes configured to be placed within the body of a subject having the cancerous tumor; one or more external electrodes configured to be placed on an external surface of the subject's body; an electric field generating circuit configured to generate an electric field between at least one pair of electrodes according to a predefined schedule, the frequency of the electric field being in a range between 10 kHz and 1 MHz; and a control circuit configured to receive a pause command from the subject, wherein the pause command terminates the generation of the electric field.

[0233] In an embodiment, a method for treating a cancerous tumor in a subject is included, the method comprising: applying one or more electric fields at or near the site of the cancerous tumor, the cancerous tumor comprising a population of cancerous cells; removing the one or more electric fields; administering a photoactivated chemotherapeutic agent at or near the site of the cancerous tumor after the one or more electric fields have been removed; and irradiating the photoactivated chemotherapeutic agent by delivering photoactivating light energy to the site of the cancerous tumor.

[0234] In embodiments, the photoactivated chemotherapeutic agent comprises releasing a therapeutically effective dose of the photoactivated chemotherapeutic agent at or near the site of the cancerous tumor.

[0235] In embodiments, the therapeutically effective dose comprises a concentrated dose delivered to the subject over a 6 hour period following removal of the electric field that is equivalent to a conventional non-concentrated dose delivered over a 24 hour period.

[0236] In embodiments, the photoactivated chemotherapeutic agent comprises a photoactivated platinum compound or a photoactivated photostatin compound.

[0237] In embodiments, the photoactivated photostatin compounds include photoactivated combretastatin A-4 and its analogs and derivatives.

[0238] In embodiments, the photoactivated chemotherapeutic agent can be photoactivated by visible light in the range of 350 nm to 850 nm.

[0239] In embodiments, the photoactivated chemotherapeutic agent can be photoinactivated by visible light in the range of 450 nm to 650 nm.

[0240] In an embodiment, a medical device for treating a cancerous tumor in a subject is included, the medical device having: an electric field generating circuit, the electric field generating circuit being configured to generate one or more electric fields at or near the site of the cancerous tumor, which may contain a population of cancerous cells; a control circuit connected to the electric field generating circuit, the control circuit being configured to control the delivery of the one or more electric fields from the electric field generating circuit to the site at or near the cancerous tumor; a cannula, the cannula being configured to administer a photoactivated chemotherapeutic agent to the site at or near the cancerous tumor; and one or more light emitters, the light emitters being configured to irradiate the photoactivated chemotherapeutic agent by delivering photoactivating light energy to the site at or near the cancerous tumor.

[0241] In an embodiment, a method for treating a cancerous tumor in a subject is included, the method comprising: applying one or more electric fields at or near the site of the cancerous tumor, the cancerous tumor comprising a population of cancerous cells; and administering nanoparticles at or near the site of the cancerous tumor, the nanoparticles may include a chemotherapeutic agent.

[0242] In embodiments, the method may further include removing the one or more electric fields prior to administering the nanoparticles at or near the site of the cancerous tumor.

[0243] In embodiments, the nanoparticles include a therapeutically effective dose of a chemotherapeutic agent that is released at or near the site of a cancerous tumor.

[0244] In embodiments, the therapeutically effective dose comprises a concentrated dose delivered to the subject over a 6 hour period following removal of the electric field that is equivalent to a conventional non-concentrated dose delivered over a 24 hour period.

[0245] In embodiments, the chemotherapeutic agent comprises at least one of vindesine, vincristine, vinblastine, paclitaxel, docetaxel, 2-methoxyestradiol, patupilone, trastuzumab, and derivatives thereof.

[0246] In an embodiment, the nanoparticles comprise a biodegradable polymer.

[0247] In an embodiment, a medical device for treating a cancerous tumor in a subject is provided, the medical device comprising: an electric field generating circuit configured to generate one or more electric fields at or near the site of the cancerous tumor, which may contain a population of cancerous cells; a control circuit connected to the electric field generating circuit, the control circuit configured to control delivery of the one or more electric fields from the electric field generating circuit to the site at or near the cancerous tumor; and a cannula configured to administer nanoparticles to the site at or near the cancerous tumor.

[0248] It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to a composition containing "a compound" includes a mixture of two or more compounds. It should also be noted that the term "or" is generally used in its sense including "and / or" unless the content clearly dictates otherwise.

[0249] It should also be noted that, as used in this specification and the appended claims, the phrase "configured" describes a system, device or other structure that is constructed or configured to perform a specific task or adopt a specific configuration. The phrase "configured" can be used interchangeably with other similar phrases (such as "arranged and configured", "constructed and arranged", "constructed", "manufactured and arranged"), etc.

[0250] All publications and patent applications in this specification are indicative of the levels of ordinary skill in the art to which the invention pertains. All publications and patent applications are herein incorporated by reference as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0251] The embodiments described herein are not intended to be exhaustive or to limit the invention to the precise forms disclosed in the following detailed description. Rather, these embodiments are selected and described so that those skilled in the art can understand and appreciate these principles and practices. Thus, various aspects have been described with reference to a number of different specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of this article.

Claims

1. A method for treating a cancerous tumor in a subject, comprising: applying one or more electric fields at or near the site of the cancerous tumor, the cancerous tumor comprising a population of cancerous cells; wherein the applied electric field(s) are effective to delay mitosis and induce synchronization of mitosis in a proportion of the cancerous cell population; removing the one or more electric fields to allow mitosis to occur within the cancerous cell population; and A chemotherapeutic agent is administered to the subject after the one or more electric fields have been removed.

2. The method according to any one of claims 1 and claims 3 to 10, wherein: Applying the one or more electric fields to the cancerous tumor comprises applying the one or more electric fields for a time period selected from the range of time periods from 1 minute to 24 hours.

3. The method of any one of claims 1 to 2 and 4 to 10, further comprising administering the chemotherapeutic agent to the subject when at least 5% of the cancerous cell population is synchronized in mitosis in response to the one or more electric fields.

4. The method according to any one of claims 1 to 3 and 5 to 10, wherein The one or more electric fields are applied to the cancerous tumor at a frequency selected from a range between 100 kHz to 300 kHz.

5. The method according to any one of claims 1 to 4 and 6 to 10, wherein The one or more electric fields include an electric field strength selected from a range of electric field strengths between 3 V / cm and 5 V / cm.

6. The method according to any one of claims 1 to 5 and 7 to 10, wherein The chemotherapeutic agent is administered to the subject at a therapeutically effective dose.

7. The method according to any one of claims 1 to 6 and 8 to 10, wherein Applying the one or more electric fields to the subject includes applying the one or more electric fields from outside the body of the subject to at or near the site of the cancerous tumor.

8. The method according to any one of claims 1 to 7 and 9 to 10, wherein Applying the one or more electric fields to the cancerous tumor includes applying the one or more electric fields at least partially from within the subject's body to at or near the site of the cancerous tumor.

9. The method according to any one of claims 1 to 8 and 10, wherein Applying the one or more electric fields to the cancerous tumor includes applying the one or more electric fields at least partially from outside the subject's body to at or near the site of the cancerous tumor.

10. The method according to any one of claims 1 to 9, wherein: The medical device further includes one or more electrical leads in electrical communication with the electric field generating circuit.

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