EP0984813A1 - Global medical treatment method and apparatus - Google Patents

Global medical treatment method and apparatus

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Publication number
EP0984813A1
EP0984813A1 EP19980922282 EP98922282A EP0984813A1 EP 0984813 A1 EP0984813 A1 EP 0984813A1 EP 19980922282 EP19980922282 EP 19980922282 EP 98922282 A EP98922282 A EP 98922282A EP 0984813 A1 EP0984813 A1 EP 0984813A1
Authority
EP
European Patent Office
Prior art keywords
medicament
device
kit
coupled
agent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19980922282
Other languages
German (de)
French (fr)
Inventor
Stuart D. Edwards
Original Assignee
Stuart D. Edwards
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US4635697P priority Critical
Priority to US46356 priority
Priority to US4672997P priority
Priority to US46729 priority
Application filed by Stuart D. Edwards filed Critical Stuart D. Edwards
Priority to PCT/US1998/009840 priority patent/WO1998051369A1/en
Publication of EP0984813A1 publication Critical patent/EP0984813A1/en
Application status is Withdrawn legal-status Critical

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142Pressure infusion, e.g. using pumps
    • A61M5/14244Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body
    • A61M5/14276Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body specially adapted for implantation
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M39/00Tubes, tube connectors, tube couplings, valves, access sites or the like, specially adapted for medical use
    • A61M39/02Access sites
    • A61M39/0208Subcutaneous access sites for injecting or removing fluids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00Radiation therapy
    • A61N5/06Radiation therapy using light
    • A61N5/0601Apparatus for use inside the body
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00Radiation therapy
    • A61N5/06Radiation therapy using light
    • A61N5/0613Apparatus adapted for a specific treatment
    • A61N5/062Photodynamic therapy, i.e. excitation of an agent

Abstract

A kit includes a medicament delivery device including a medicament housing with a drug delivery reservoir and a membrane coupled to the medicament housing. The kit further includes a medicament selected from the group of a chemotherapeutic agent, immunotherapeutic agent, cell, anti-angiogenic agent, vascular sealing agent, gene therapy agent, antibiotic, resistance modification agent and a photodynamic therapy agent.

Description

GLOBAL MEDICAL TREATMENT METHOD AND APPARATUS

BACKGROUND OF THE INVENTION

Cross-Related Applications

This application is a continuation- in-part of U.S. Provisional Patent Application Serial No. 60/046,356, filed May 13, 1997, and U.S. Provisional Patent Application Serial No. 60/046,729 filed May 16, 1997, with the named inventor Stuart D. Edwards, both applications of which are incorporated herein by reference.

Field of the Invention

The method and apparatus of the invention provides a total treatment regime for a variety of disease states including diseases such as cancer, and more particularly to a system that couples energy sources, drug delivery devices, diagnostics, medications, cell therapy, immunotherapy, gene therapy, hardware and software.

Description of Related Art

Great strides have been made in the treatment of cancer in the last 30 years in terms of reduced mortality and improved life expectancy through a variety of treatments including the use of chemotherapy, radiation treatments and more recently immunotherapy, cell therapy and gene therapy. Chemotherapy involves the infusion of cytotoxic agents (e.g. cell killing) to selectively kill cancer cells. Radiation therapy involved the irradiation of a tumor site with annexing radiation to kill cancer cells. Immunotherapy involves the in vitro or in vivo use of cell activating agents called cytokines that activate and mobilize the cells in the immune system to attack cancer cells. Cell therapy a related treatment to immunotherapy, involves the removal and reinfusion of immune cells which have been activated by cytokines to fight specific cancers. Finally, gene therapy involves the delivery and incorporation of genetic material into cancer or other cells that either kills cancer cells directly, or makes them more susceptible to other therapies. Such forms of treatment are disclosed in US Patent

Nos: 5,670,537 (Method for effecting tumor regression with a low dose, short infusion taxol regimen), 5,702,702 (Modified cytotoxic tall cell line and compositions and methods for manufacture and use thereof as therapeutic reagents for cancer), 5,192,537 (Method of treating renal cell carcinoma using activated mononuclear cells, renal tumor antigen and cimetidine), 5,728,388 (Method of cancer treatment), 5,693,522 (Anti-cancer immunotherapeutics), 5,652,130 (Retroviral vectors expressing tumor necrosis factor (TNF)), 5,641,484 (Methods for the suppression ofneu mediated tumors by adenoviral E1A andSV40 large T antigen), 5,662,896 (Compositions and methods or cancer immunotherapy) and 5,652,130 (Retroviral vectors expressing tumor necrosis factor (TNF)); all incorporated herein by reference. Despite the promise shown by the above therapies, they possess one or more medical limitations which can significantly reduce their ability to treat and cure cancer, a disease which in 1998 will have 1,228,600 new diagnosed cases in the US and will claim more than 580,000 Americans lives and an estimated 1.2 million lives by the year 2000 (1998 Estimates of the American Cancer Society and the Data Monitor Corporation). The major limitation for chemotherapy is the fact that the medications used are toxic and that their distribution throughout the body can often not be controlled. Consequently, the dosage of medicine necessary to kill cancer cells often proves harmful to other organs and or systems in the body resulting in a number of detrimental side affects. These include protracted nausea to the point of causing significant weight loss, severe anaphylactic-reactions (refer to patent # 566576), hair loss, fever, severe pain and general discomfort. Nausea is a particularly significant complication because it is well accepted that protein calorie malnutrition (due to nausea- induced weight loss) impairs the immune system with particular detrimental effects on the T-cell system (Daly, JM, et al: Effect of dietary protein and amino acids on immune function. Crit Care Med. 1990 Feb; 18(2 Suppl): S86-S93). Consequently, many forms of chemotherapy can not be tolerated for prolonged periods of time, necessitating a cycled treatment regimen with on and off periods. During the off periods, cancer cells can recover, grow and multiply. As a result, a cycled treatment regimen can significantly reduce the effectiveness of chemotherapy. Another related limitation with use of chemotherapy and also radiation therapy is the fact that the dosages of cytotoxic agents or radiation required to kill all of the cancer cells throughout the body, or in a large tumor can not be fully administered because the toxicity of such dosages would prove extremely harmful (e.g. liver damage, reduced immune function) if not fatal to the patient. Also in some instances, systemic chemotherapy can not adequately reach the tumor site, as is the case for solid tumors which are poorly vascularized and brain tumors where the blood-brain barrier impedes the crossing of large chain molecules. Also, there are a number of cancer cells lines that have, or develop (e.g. acquire) varying degrees of resistance to chemotherapy, radiation therapy and in some cases both. These resistances known, as intrinsic and acquired resistance are well described in scientific literature (Kern MA, et al.: Human melanoma cell lines selected in vitro displaying various levels of drug resistance against cisplatin, fotemustine, vindesine or etoposide: modulation of proto-oncogene expression. Anticancer Res 1997 Nov.

17(6D):4359-4370; St Croix B,et.al.: Cell adhesion and drug resistance in cancer. Curr Opin Oncol. 1997 Nov; 9(6): 549-556; Denecke, J, et. al.: Multiple drug-resistant C6 glioma cells cross-resistant to irradiation. Anticancer Res. 1997 Nov; 17(6D): 4531-4534; Nakagawa K, et. al.: High-dose conformal radiotherapy influenced the pattern of failure but did not improve survival in glioblastoma multiform. Int J Radiat

Oncol Biol Phys. 1998 Mar 15; 40(5): 1141-1149.). Substances known as resistance modification agents have been shown to reverse drug resistance of some types of cancer in vitro. However, many of these substances are toxic when given in the dosages required to produce their effect in vivo such as azide and verapamil. U.S. Patent No. 5,591,715 (Methods and compositions for reducing multidrug resistance) discloses a chemical formation for reducing chemical resistance of drug resistant cancers. However, this invention has several potential limitations. First, the chemical may not be able to penetrate into all tumors particularly nonvacularized tumors. Second, it may not be effective against all forms of chemoresistance since the inventors postulate only one key mechanism (blocking of P-glycoprotein substrate binding) that their compound uses for blocking chemoresistance, and others may exist. Moreover, it may not be able to prevent or reduce acquired chemoresistance and the inventors did not present data to determine effectiveness for acquired chemoresistance. This is particularly important since many cancers divide rapidly and express a great deal of genetic variation, which is the same mechanism utilized by bacteria in acquiring resistance to antibiotics.

As a result of one or more of the above conditions, a sufficient number of cancerous cells survive chemotherapy and/or radiation therapy to cause a recurrence of the disease. Another limitation of the aforementioned treatments is the fact that they can not readily contain metastatic cancer, nor take the energetic burden off the immune system in fighting cancer that has metastasized and spread to one or more locations throughout the body. During the course of metastatic cancer disease process, cancer cells spread and engulf the body such that the immune system becomes overwhelmed, functionally impaired and may even shut down. This happens because the immune system expends a great deal of energy in generating antibodies and immune cells, such as T4, T8, lymphocytes and macrophages to engulf and kill tumor cells. The more sites the cancer has spread to, the more cells and antibodies, and hence energy, the immune system must expend over a longer period of time. Because of the limitations of the current forms of cancer treatment described above, there is a need for new forms of cancer therapy. First, a need exists for a therapy that can kill all or most of the cells at tumor site that is nonvascularized or otherwise in accessible to chemotherapy. Another need exists for a means of treatment of chemotherapy and radiation therapy resistant cancer cell. Yet another need exists for a treatment that can contain cancer at a tumor site and prevent its spread to other parts of the body. Still another need exists for a treatment that kills cancers cells at the tumor site, and does reduces the energy burden on the immune system required by the production of antibodies and immune cells to fight the disease.

These and other needs are meet in an invention that includes a global treatment apparatus.

SUMMARY OF THE INVENTION An object of the invention is to provide a medicament delivery kit. Another object of the invention is to provide a medicament delivery kit used to create cell necrosis and deliver a medicament to a selected treatment site.

Yet another object of the invention is to provide a kit with a medicament delivery device, a medicament and an energy delivery device.

Still another object of the invention is to provide a medicament delivery device. Another object of the invention is to provide an implantable medicament delivery device.

Yet another object of the invention is to provide a medicament delivery device that creates cell necrosis and delivers a medicament to a selected treatment site.

These and other objects of the invention are achieved a kit. The kit includes a medicament delivery device including a medicament housing with a drug delivery reservoir and a membrane coupled to the medicament housing. The kit further includes a medicament selected from the group of a chemotherapeutic agent, immunotherapeutic agent, cell, anti-angiogenic agent, vascular sealing agent, gene therapy agent, antibiotic, resistance modification agent and a photodynamic therapy agent.

In another embodiment, the kit includes an energy delivery device. In yet another embodiment, a medicament delivery device includes a medicament housing with a drug delivery reservoir. A membrane is coupled to the medicament housing. A medicament is in the medicament housing. The medicament is selected from the group of a chemotherapeutic agent, immunotherapeutic agent, cell, anti-angiogenic agent, vascular sealing agent, gene therapy agent, antibiotic, resistance modification agent and a photodynamic therapy agent.

These and other features and advantages of the present invention will become more apparent to those skilled in the art from the following detailed description in conjunction with the appended drawings in which:

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic view of the total treatment system of the present in invention. FIG. 2 is a flow chart that illustrates a method for using the total treatment kit of the present in invention.

FIG. 3 is a block diagram that illustrates the different functions performed by the central control unit of the present invention.

FIG. 4 is a block diagram that illustrates the computer architecture and data communication used by the central control unit.

FIG. 5 is a block diagram that depicts one embodiment of a control system used to regulate the delivery of medication.

FIG. 6 is a lateral view of the cell necrosis system illustrating the energy delivery device, power supply, catheter, target tissue site and creation of a cell necrosis zone.

FIG. 7 is a lateral view illustrating the use of electrolytic solution with the cell necrosis apparatus to create an enhanced RF electrode.

FIG. 8 is a lateral illustrating a visualization device used with the cell necrosis apparatus.

FIG. 9 is a lateral view of a target tissue site illustrating the infiltration of tissue healing cells into a cell necrosis zone.

FIG. 10A is a graphical illustration of an RF waveform used to cut tissue. FIG. 1 OB is a graphical illustration of an RF waveform used to coagulate tissue.

FIG. 11A is a block diagram illustrating the use of a pump to delivery medication in one embodiment of the present invention.

FIG. 1 IB is a perspective view illustrating the use of an inhalation chamber to deliver aerosol medicine particles.

FIG. 11C is a perspective view illustrating the use of a skin patch and voltage source to deliver medication transdermally.

FIG. 12A is a cross sectional view illustrating the configuration of one embodiment of the docking device. FIG. 12B is a cross sectional view illustrating the use of a pump coupled to the docking device.

FIG. 12C is a cross sectional view illustrating the use of a cell necrosis zone as a docking device.

FIG. 12D is a cross sectional view illustrating the use of a biocompatible matrix material as a docking device.

FIG. 12E is a cross sectional view illustrating the use of the docking device as a cell activation chamber.

FIG. 13A is a cross sectional view of a liposome. FIG. 13B is a cross sectional view illustrating the use of liposomes and thrombogenic agents to seal the microvasculature supplying blood to a tumor site.

FIG. 14 is a perspective view illustrating the use of heating to increase blood flow and medicine delivery to a treatment site.

FIG. 15 is a diagram of the cell therapy system. FIG. 16 is a diagram of the gene therapy system. FIG. 17 depicts a block diagram of the feed back control system that can be used with the cell necrosis system.

FIG. 18 depicts a block diagram of an analog amplifier, analog multiplexer and microprocessor used with the feedback control system of FIG. 17.

FIG. 19 depicts a block diagram of the operations performed in the feedback control system depicted in FIG. 17.

FIG. 20 depicts a block diagram of the feed back control system that can be used with the drug delivery system.

FIG. 21 depicts a block diagram of an analog amplifier, analog multiplexer and microprocessor used with the feedback control system of FIG. 20.

FIG. 22 depicts a block diagram of the operations performed in the feedback control system depicted in FIG. 20.

DETAILED DESCRIPTION Although the following discussion is directed to the treatment of cancer and benign tumors, it will be appreciated that the present invention is equally useful for other disease states including autoimmune diseases such as diabetes, lupus, and arthritis and diseases of the immune suppression such as AIDS and ARC.

Referring now to FIG. 1, one embodiment of a total treatment kit 10 includes a combination of one or more of the following systems: (i) a cell necrosis system 12 , (ii) an electronic drug delivery system 14 (iii) a cell therapy system 16, (iv) a gene therapy system 18 and (v) an in vivo delivery site or port also called a docking device 20 and (vi) an imaging system 21. All or a portion of the components of the total treatment kit

10 may be housed on a single cart, and is capable from movement from room to room. Also one or more of these systems can be linked by a central control unit 22.

In various embodiments, treatment kit 10, along with delivery systems, provide for the treatment of tumors, reduction and/or remodeling of tissue, delivery of medications, immunotherapies, cellular therapy, gene therapy and the like to desired sites of the human anatomy. Treatment kit 10 permits the introduction of medicine 24 (also called medication 24, medicament 24, drug 24 and treatment 24) to one or more desired treatment sites 26 (also called target tissue sites 26) of the human anatomy. This provides for the full medication and hence more complete treatment of the human body. Not only does treatment kit 10 provide for delivery of medicine 24, including cell and gene therapies and energy to multiple sites, but also provides for the ongoing delivery of that treatment over a long term basis (e.g. months to years) to maximize treatment efficacy. Moreover, treatment kit 10 provides for the on going medical monitoring of that treatment, and the ability to update and modify treatment based on medical monitoring feedback to maximize the effectiveness of treatment in curing one or more diseases. Also treatment kit 10 provides for the ability to deliver multiple and varied treatment regimens (e.g. chemotherapy, immunotherapy and cell therapy) as dictated by each type of therapy and allows for the optimization of the treatment regimen based on feedback. For the case of a cycled chemotherapy treatment regimen using toxic medications 24, the monitoring ability of treatment kit 10 is used to determine the optimal intervals for when the delivery of toxic medication should be halted (e.g. based on maximum plasma concentration of the medication and/or white blood cell or bone marrow cell count) and then resumed so as to maximize the effectiveness of the treatment while minimizing the adverse side effects.

Treatment kit 10 also allows for disease diagnosis and the control of the delivery of multiple therapies in order to maximize efficacy. Accordingly, in one embodiment of the invention shown in FIG. 2., treatment kit 10 is used to perform one or more of the following tasks: i) imaging and/or biopsy to determine the location, characterize and diagnose tumor sites 26', ii) delivery of cell and gene therapies to kill cancer cells at treatment sites 26 and make them more susceptible to other treatments, iii) activation of immune cells by immunotherapy, iv) the delivery of energy to ablate and or necrose cancerous tissue at one or more selected tumor sites 26', v) the placement of docking device 20 adjacent to one or more treatment sites 26, vi) the delivery of medication 24 to treatment sites 26 from one or more docking sites 20, vii) monitoring of medication concentrations, and the response of the immune system (e.g quantification of immune cell concentrations), viii) reimaging to monitor tumor size, and ix) delivery of additional medication 24 as needed. Clinical indications and other medical applications for total treatment kit 10 include, but are not limited to, the following: benign hyperplasia of the prostrate (BHP), cancer of the breast, brain, colon, esophagus, lymph nodes, liver, lung, kidney, pancreas, prostrate, stomach and other oncological applications; orthopedics, enterology, neurology, OBGYN, cardiology, wound closure, dermatology, plastic surgery, radiology, immune system disorders (e.g. AIDS and ARC) and the like.

Referring now to FIG. 3, in various embodiments central control unit 22 can be configured to have the following capabilities: control and monitoring (using one or more control systems described herein); and data display, communication and storage. The control and monitoring capabilities of central control unit 22 include the following: drug concentration including in vivo concentrations and concentrations from in vitro testing of biological fluids (e.g. blood, urine, etc); energy delivery, including delivery rates and total delivered energy; temperature, including that of tissue, electrodes and fluids; pressure, including that of intravenous lines and catheters, blood and tissue; and flow rates including that of intravenous flows, electrolytic and cooling solutions and blood. For the case of drug concentrations, in vitro measurement can be done using a point of care chemical analyzer 23 incorporating an antibody or enzymatic calorimetric assay well known to those skilled in the art. Referring back to FIG. 1, chemical analyzer 23 can be electronically coupled to central control unit 22. Other preceding capabilities can be accomplished with sensor and biomedical instrumentation technology well known to those skilled in the art, portions of which are described herein.

Referring now to FIG. 4, control and monitoring operations of control unit 22 can be performed by one or more microprocessors 22' such as a Pentium® series microprocessor (available from the Intel Corporation, Santa Clara, CA.) However, it will be appreciated that any suitable microprocessor or general purpose digital or analog computer can be used. Data can be displayed on display device 22" which includes, but is not limited to, a CRT, an active or passive matrix flat screen or liquid crystal display. Central control unit 22 also includes a data interface 22'" (also called I/O port 22'" ) and a databus 22"" that electronically communicate between one or more microprocessors 22' and any or all of the subsystems of total treatment kit 10 including cell necrosis system 12, electronic drug delivery system 14 and docking device 20. Databus 22"" is employed to communicate between microprocessor 22', display device 22", I/O port 22'" and memory 22'"". Medications 24 include, but are not limited to, chemotherapeutic agents also called chemotherapy (e.g. cytotoxin), resistance modification agents (RMA's), antibiotics, anti-angiogenic agents, drug delivery agents (e.g. liposomes), energy (e.g. RF energy and radiation), immunotherapeutic agents, radiotherapeutic agents, cellular therapies, gene therapies, photodynamic therapy agents and the like, all well known to those skilled in the art. Medications 24 may be administered singularly or concurrently in a combination of one or more of the above. In one embodiment, chemotherapeutic agents are administered concurrently with resistance modification agents in order to reduce the chemoresistance of one or more cancer cell types as described herein. Formulations for medications 24 include but are not limited to intravenous solutions (both aqueous and non aqueous solutions), enteral solutions (both aqueous and non aqueous solutions) and aerosol particles in a size range optimized for inhalation and deep lung delivery (diameter 1-5 μm) or transdermal injection (diameter 20-70 μm) using granulation and glass stabilization techniques known to those skilled in the art.

Chemotherapeutic agents include but are not limited to actinomycin D, bleomycin, colchicine, cytorabine, doxyrubicin, fluorouracil, paclitaxel, vinblastine, vincristine and VP-16. Antiangiogenic agents include angiostatin as disclosed in US Patent No. 5,733,876, which is incorporated herein by reference, and endostatin. Resistance modification agents include verapamil, Solutol® HS 15 and fatty acid diesters designated CRL 1095 (available from the CytRx Corporation, Atlanta, Ga.) and CRL 1065 as disclosed in US Patent No. 5,591,715 and also described by Vasanthakumar G., et al. in an abstract entitled: Modulation of multi-drug resistance in MDR erythroleukemic cells. (Proc Annu Meet Am Assoc Cancer Res 1996;37:A2268.). The preferred resistance modification agent is CRL 1065. Antibiotics include ampicillin, cefamandole nafate and vancomycin HCL and others known to those skilled in the art.

Referring now to FIG. 5, the regulation of the delivery of medicine 24 to treatment site 26 by drug delivery system 14 can be controlled by a control algorithm 25 (also called feedback control system 25 discussed herein) such as a proportional integral, proportional derivative or proportional integral derivative based control algorithm (all well known to those skilled in the art), or an H-infinity theory based control algorithm ( as described by Kienitz, K.H., Yoneyama, T.: A robust controller for insulin pumps based on H-infinity theory. IEEE Trans Biomed Eng 40:1133-1 137, 1993). Algorithm 25 can be electronically stored in the memory 22'"" (which can be a read only memory or ROM ) coupled to microprocessor 22', or a microprocessor integral to drug delivery system 14 or docking device 20.

Imaging system 21 has imaging capability including but not limited to, fiber optic viewing and video imaging devices, ultrasound, fluoroscopy, CAT/CT scan, PET scan and MRI. Imaging system 21 can be used by the physician to do one or more of the following: (i) diagnose disease states including the detection of tumors, neoplasms, metastases and polyps, (ii) assist in the placement of energy delivery devices 34, docking devices 20, needles, infusion lines, catheters and other devices throughout the body, (iii) assist in the placement and formation of cell necrosis zones 28 (also called lesions 28), (iv) monitor the delivery of medication 24 to various locations in the body, (v) assess the effectiveness of treatment by determination of tumor size, blood flow and cellular activity at various treatment sites 26 throughout the body, and (vi) be used by the physician to provide feedback for the administration of medications 24 and the determination of disease remission, relapse and cure.

Referring now to FIG. 6, one embodiment of a tissue necrosis system 12 delivers energy to a target tissue site 26 to produce cell necrosis zones 28. Tissue site 26 can include the surface, wall or interior of an organ, a blood vessel, a layer of fascia, a layer dermis (skin), a bone or lymph duct or node. In this embodiment, tissue necrosis system 12 comprises a flexible elongate shaft 30, also called catheter 30, with a distal extremity 32, also called catheter end 32, in turn coupled with one or more energy delivery devices 34. Energy delivery devices 34 are coupled to a cable 36 and are also configured to be coupled to a power source 38 and feedback control system 25. Sensors 35 (discussed herein) can be coupled to energy delivery device 34 and can also be configured to be coupled to a feedback control system 25.

Catheter end 32 is configured to be position able in a variety of target tissue sites 26 within the body including, but not limited to, those in the following systems: the vascular system (both venous and arterial, both via a percutaneous approach), the digestive system (via a transoral or rectal approach), the respiratory system (via a transoral approach) the urinary system (via a transurethral approach), the lymphatic system (via a percutaneous approach) and the nervous system (via a percutaneous approach). Catheter 30 has sufficient length to position catheter end 32 in the desired tissue site 26 using various approaches including, percutaneous (including femoral and carotid approaches) and transoral. Typical lengths for catheter 30 include, but are not limited to, a range of 10-300 cms, more preferable for cardiac and gastro-enteral applications is the range 90-200 cms. Suitable materials for catheter 30 include, but are not limited to, polyethylenes, polyimides, polyurethanes, silicones and other biocompatible polymers known to those skilled in the art. Catheter 30 may have one or more lumens 30' that extend the full length of catheter 30, or only a portion thereof. Lumens 30' may be used as paths for cables, catheters, guide wires, pull wires, insulated wires, fluid and optical fibers.

Turning now to a discussion of energy delivery, suitable power sources 38 and energy delivery devices 34 that can be employed in one or more embodiments of the invention include: (i) a radio-frequency (RF) source coupled to an RF electrode, (ii) a coherent source of light coupled to an optical fiber, (iii) an incoherent light source coupled to an optical fiber, (iv) a heated fluid coupled to a catheter with a closed channel configured to receive the heated fluid, (v) a heated fluid coupled to a catheter with an open channel configured to receive the heated fluid, (vi) a cooled fluid coupled to a catheter with a closed channel configured to receive the cooled fluid, (vii) a cooled fluid coupled to a catheter with an open channel configured to receive the cooled fluid, (viii) a cryogenic fluid, (ix) a resistive heating source, (x) a microwave source providing energy from 915 MHz to 2.45 GHz and coupled to a microwave antenna, (xi) an ultrasound power source coupled to an ultrasound emitter, wherein the ultrasound power source produces energy in the range of 300 KHZ to 3 GHz, or (xii) a microwave source. For ease of discussion for the remainder of this application, the energy source utilized is an RF source and energy delivery device 34 is a single or a plurality of RF electrodes 34', also described as electrodes 34'. However, all of the other mentioned energy sources are equally applicable to treatment kit 10.

For the case of RF energy, electrode 34' may operated in either bipolar or monopolar mode with a ground pad electrode. In a monopolar mode of delivering RF energy, a single electrode 34' is used in combination with an indifferent electrode patch that is applied to the body to form the other contact and complete an electrical circuit. Bipolar operation is possible when two or more electrodes 34' are used. Multiple electrodes 34' may be used.

Also when the energy source is RF, power source 38, which will now be referred to as an RF energy source 38, may have multiple channels, delivering separately modulated power to each electrode 34'. This reduces preferential heating that occurs when more energy is delivered to a zone of greater conductivity and less heating occurs around electrodes 34' which are placed into less conductive tissue. If the tissue hydration or the blood infusion in the tissue is uniform, a single channel RF energy source may be used to provide power for generation of lesions 28 relatively uniform in size. Referring now to FIG. 7, electrodes 34' can be in the form of needle electrodes, both solid or hollow, as is well known to those skilled in the art. In other embodiments, electrodes 34' can be conical, cylindrical, rectangular or any polyhedron; each of said shapes having a flat, rounded, beveled, or pointed tip. In one embodiment shown in FIG. 7, electrode 34' includes a tissue piercing distal end 37 which is configured to penetrate a fixed depth into a tissue site 26 and deliver energy to a portion thereof. Suitable materials for electrodes 34' include a combination of one or more of the following: i) stainless and other steels suitable for electrode applications known to those skilled in the art, ii) alloys of gold, silver and platinum, iii) nickel-titanium alloys, or iv) other conductors known to those skilled in the art. Also, electrolytic solution 39 can serve as an enhanced RF electrode 34" when coupled with an RF electrode 34'. In other embodiments, absorbable electrodes 34' can also be utilized.

Turning now to discussion of sensors, one or more sensors 35 can be coupled to RF electrode 34' for sensing the temperature of tissue at target tissue site 26. More specifically, sensors 35 permit accurate determination of the surface temperature at treatment site 26 or at an electrode tissue interface 34". This information can feedback to control system 25 and be used to regulate both the delivery of energy and cooling medium to electrode tissue interface 34" as will be discussed herein. Sensors 35 can be positioned on or adjacent to RF electrode 34'. Suitable sensors that may be used for sensor 35 include: thermocouples, fiber optics, resistive wires, thermocouple IR detectors, and the like. Suitable thermocouples for sensor 35 include: T type with copper constantene, J type, E type and K types as are well known those skilled in the art. Referring now to FIG. 8, another embodiment of cell necrosis system 12 includes a visualization device 40 coupled to catheter 30. Visualization device 40 can include a combination of one or more of the following: a viewing scope, an expanded eyepiece, fiber optics (both imaging and illuminating fibers), video imaging devices and the like. Electric current flowing through targeted tissue causes heating due to resistance of the tissue resulting in injury to the tissue which can be sufficient to cause the death of affected cells, a phenomenon known as necrosis. For ease of discussion for the remainder of this application, cell injury will include all cellular effects resulting from the delivery of energy from the electrode 34' up to and including cell necrosis. Cell injury can be accomplished as a relatively simple medical procedure with local anesthesia. Once tissue has been sufficiently thermally injured to cause necrosis it is removed (e.g ablated) or otherwise displaced by immune cells 29 involved in the tissue healing process. As shown in FIG. 9., these cells infiltrate the necrosis zone 28 and ingest or otherwise absorb necrosed tissue. Cells involved in the tissue healing process include fibroblasts 29', myofibrob lasts 29" and macrophages 29'". Another benefit of energy delivery and the creation of cell necrosis zones 28 within treatment site 26, is to promote the infiltration and concentration of immune cells 29 to the treatment site to attack remaining cancerous and diseased cells as well as foreign organisms including bacteria and viruses. Additionally the delivery of energy can be selectable to enhance the preferential destruction of the microvasculature supplying blood to a tumor 26'. In another embodiment, the rate of energy delivered to tissue site 26 can be sufficient to vaporize and hence, ablate all or a portion of the tissue at tissue site 26. Referring now to FIGS 10A and 10B, in other embodiments the RF energy waveform

41 is selectable configured to cut, resect or coagulate tissue at tissue site 26. An RF waveform used for cutting is shown in FIG. 10A, while an RF waveform used for coagulation is shown in FIG. 10B. In yet another embodiment (described herein), RF energy is used to rupture liposomes 27' in or adjacent to a treatment site 26 or to initiate a polymer curing reaction or blood clotting reaction to a portion of treatment site 26 including a tumor site 26'.

Referring now to FIG. 11A, drug delivery system 14 can include one or more pumps 14' which include displacement, syringe and peristaltic pumps, well known to those skilled in the art. Pumps 14' can be microprocessor controlled and programmed to deliver one or more medicines 24 concurrently or sequentially. Pump 14' can also be programmed to deliver a specified total dose of medicine 24 at a specified flow rate, where flow rates can range from 10 μL to 200 ml per minute. Pumps 14' can be configured to be connected to intravenous, intra-arterial and enteral lines and/or catheters. Pumps 14' can also include electronics sensors and alarms systems to detect and alarm for line occlusions, air bubbles, over and under delivery of medication, fluid infiltration into interstitial tissue and other conditions. Medicine 24 can be aqueous solutions, non aqueous solutions or emulsions. Pump 14' can be configured to electronically communicate with central control unit 22. Pump 14' can also be configured to fluidically and electronically coupled to docking device 20 so as to deliver medicines 24 to docking device 20 and transfer data and software instructions to and from docking device 20. Pump 14' can also be battery powered and be of sufficient size and weight (e.g. < 1 lb) to ambulatory and even worn by the patient. In another embodiment shown in FIG. 1 IB, delivery system 14 can include an inhalation device 14" capable of mixing and delivering aerosol particles 24' of medicine 24 to a respiratory tissue site 26", including deep lung tissue. In a related embodiment (not shown), delivery system 14 can be an aerosol transdermal delivery using a shockwave chamber capable of accelerating aerosol particles 24' to sufficient speed to penetrate through one or more layers of the skin. In a preferred embodiment for both aerosol inhalation and aerosol transdermal delivery, aerosol particles 24' are made from an Antiangiogenic compounds such as angiostatin and a tumor suppressing compound such as endostatin. In still another embodiment shown in FIG. 11 C, delivery system 14 can be a transdermal system that includes drug impregnated transdermal patches 24" that are attached to a skin surface site 26" which may have an applied electric field (e.g. voltage) supplied by voltage source 15 to facilitate medication transport through the skin using a technique known as electroporation disclosed in US Patent Nos: 5,019,034 and 5,667,491 which are incorporated by reference herein. A preferred embodiment of transdermal system includes a skin patch 24" impregnated with an Antiangiogenic compounds such as angiostatin or endostatin.

One embodiment of the invention includes a docking device 20. Docking device 20 provides access, delivery, treatment and closure of a target tissue site 26. More specifically, docking device 20 provides for the localized delivery and/or storage of antibiotics, chemotherapeutic agents, cell therapy, drug delivery agents, immunotherapeutic agents, gene therapy, radiotherapeutic agents and energy to a target tissue site 26. The combination of one or more of these compounds delivered locally accomplishes the following: (i) continues the tumor necrosis process (ii) fights against local infection, and (iii) provides continual gene therapy to the target tissue to assure ongoing incorporation and expression of desired genetic material by cells at the treatment site. Another key benefit of the use docking devices 20 is the fact the immune system does not have to act upon all localized tumor sites 26', which may be numerous particularly for metastatic cancer. Consequently, the immune system is not worn down after a protracted disease episode and remains more viable and effective in fighting disease over a prolonged period of time (e.g. weeks to years). By providing localized delivery of medication 24, the use of docking device 20 substantially reduces the unwanted distribution and buildup of toxic levels of medicines 24 in various locations throughout the body (including the circulation system, liver, spleen and fat tissue) that may occur with systemic drug delivery. This permits higher, and hence more efficacious dosages of medicines 24 to be delivered to selected sites over a prolonged period of times without injurious side effects such as nausea that are typical of chemotherapy treatment. As a result, chemotherapy and other medicines 24 are better tolerated by patients, efficacy is enhanced and adverse side effects are reduced. In various other embodiments (not shown), further reductions in levels of toxic medicines 24 can be achieved by the use of stents and other implants that contain materials which selectively absorb or filter medication 24.

Docking device 20 can be positioned in one or more locations throughout the body in order to enhance treatment to target tissue sites 26. In one embodiment, docking devices 20 can be located on the surface of the skin or can be implanted subcutaneously in proximity to the skin to allow access by subcutaneous injection. Docking device 20 can also be positioned in or adjacent a blood vessel, duct or organ as will be described herein. In another embodiment docking device 20 can also be positioned in combination of one or more of the following locations, intramuscularly, in lymphatic tissue, adipose tissue, bone, cartilage or fascia.

Referring now to FIG. 12A, in one embodiment, docking device 20 comprises a hollow volume structure with an interior and exterior surface 20' and 20" repectively and may contain one or more internal compartments 20'" (also called docking device reservoirs 20'" ) which may contain one or more medicines 24 described herein. Docking device 20 is made of one or biocompatible polymeric materials (e.g. polyurethane) well known to those skilled in the art. Additionally, all, or a portion of docking device 20, may be made of semipermeable and/or porous membranes which allow the controlled diffusion of one or more medicines 24 from internal compartments 20'" to the exterior surface 20" and surrounding tissue 26. Suitable semipermeable materials include, but are not limited to, expanded polytetraflouroethylene, silicone, polyurethane, polystyrenes and polyamides; and hollow fibers (having a pore size < \μ ) made of cellulose acetates, cellulose nitrates, polysulfones and copolymers and derivatives thereof. Also, all, or a portion of docking device 20 may be made of self sealing materials which allows external access by hypodermic needle to internal compartments 20'" without compromising the fluidic integrity of docking device 20.

Suitable self sealing materials include silicone, polyurethanes and other elastomeric materials known to those skilled in the art. Docking device 20 may also be fluidically coupled to a catheter 31 which cannulates a vein, artery or other vessel or organ. This allows for the repetitive and controlled delivery of medicines 24 into the circulation system or selected organ via subcutaneous injection. Various medicines 24, including but not limited to chemotherapy, gene therapy, cell therapy, immunotherapy, radiotherapy and be can be can delivered to, disposed in and delivered by docking device 20 to one or more treatment sites 26. Docking device 20 may also be coupled to a visualization device 40 and sensors 35. In this embodiment, sensors 35 are used to sense flow, temperature and chemical concentrations and may be selected from a variety known to those skilled in the art including fiber optic sensors, thermocouples, thin film sensors and dark electrodes. In another embodiment shown in FIG. 12 B, docking device 20 can include an internal pump 42, which can be driven osmotically (a technique well known to those skilled in the art of drug delivery) or by electric motor and can include microprocessor control. Pump 42 serves allows the long term controlled delivery of medicine 24 to treatment site 26 or to other selected sites in the body including the circulation system. Pump 42 can also be configured to be reprogrammed by radio telemetry device 43 well known to those skilled in the art.

In another embodiment, shown in FIG. 12 C, docking device 20 can be a cell necrosis zone 28 (which may be partially at least partially hollow) that acts to at least partially contain an infused medication 24 and may be configure to allow for the subsequent controlled diffusion of medicine 24 to a localized tissue site 26.

Containment of medication 24 can be facilitated by the creation of a semipermeable barrier 28' along the border of cell necrosis zone 28 through introduction and in situ curing of a biopolymer such as collagen. In this embodiment, cell necrosis zone 28 acts as reservoir 28" for medication 24 such as antibiotics, chemotherapy agents, etc. Reservoirs 28" are positioned close enough to treatment site 26 to allow for a localized delivery of medicine 24 to the treatment site without the buildup of toxic levels of the solution in the circulation system and other biocompartments in the body. Additionally, one or more necrosis zones 28 may positioned around a treatment site 26 in such a manner as to provide a long term continuous dose of medicine 24 to treatment site without producing toxic concentrations of the medicine 24 in the circulation system. In one embodiment, flow through stents (not shown) can be employed to facilitate the delivery of medicine 24. Stents may also be used to maintain the long term patency of arteries, veins and other vessels receiving repeated IV injections that are prone to collapse.

In yet another embodiment, shown in FIG. 12D, docking device 20 can be a biocompatible matrix 44 that partially or completely surrounds a treatment site 26 which can include a tumor site 26', neoplasm or cell necrosis zone 28. Matrix 44 can be made of a biocompatible polymer membrane, a porous polymer membrane or a mesh material. Matrix 44 can also be impregnated with medications 24 including chemotherapy and Antiangiogenic agents that are controlled released (via diffusion or other means) to tumor site 26' over a period of time. Thus, matrix 24 serves as physical and physicochemical barrier to reduce and contain the spread of tumor sites 26'. Accordingly, matrix 26 is particularly effective against inoperable tumor sites 26'.

Material for matrix 26 include blends of collagen and other curable biocompatible polymers such as silicone which can be delivered by docking device 20 and cured in situ via the applications of RF energy as is described in U.S. Patent No. 5,669,934 which is incorporated herein by reference. Suitable material for meshes include woven and knitted Dacron® velour. In still other embodiments, docking device 20 can be a flow through device such as a stent or a catheter that include one or more inflatable balloons to dilate a treatment site, block an orifice (e.g.., a sphincter) or a blood vessel and deliver medicine 24.

There are several methods for controlling and enhancing delivery of medications 24 to a target tissue site 26 which can be employed with treatment kit 10.

One involves the use of delivery agents 27 which are able to carry potentially toxic medicines 24 (such as chemotherapeutic agents) in an inert or protected form until they reach treatment site 26. Referring now to FIG. 13 A, delivery agents 27 include liposomes 27', a microscopical spherical particle made of a lipid membrane 27" which surrounds medication 24 and protects it from entering the body under normal physiological conditions. One method for using liposomes disclosed in U.S. Patent No. 5,580,575, incorporated herein by reference, involves the application of ultrasound to a selected area of the body which is sufficient to cause the rupture the liposomal membrane 27" and release of medication 24 at that site. Thus, using an ultrasound power source and emitter described herein, this method can be used to control and limit the release of cytotoxic agents and other medication 24 to tumor site 26' or other treatment site 26. In a related embodiment, liposomes 27' are designed to rupture and release medication 24 upon exposure to localized heating which can be supplied by RF electrode 34'. Rupture temperatures include but are not limited to values greater than 41 ° C and more preferably greater than 50 ° C. In yet another embodiment, liposomes 27' are made of materials which degrade in response to the microchemical conditions surrounding a neoplasm or other developing tumor. Such conditions can include pH and the presence of angiogenic agents such as nitric oxide. The pH rupture value can be any value outside the normal physiologic range of 7.3-7.4. In one embodiment liposomes 27' are used to deliver medicines 24 that have adverse side effect. In a preferred embodiment, liposomes 27' are long circulating liposomes as described in US Patent No. 5,013,556 (which is incorporated herein by reference) and are used to deliver chemotherapeutic agents such as doxorubicin and vincristine to one or more tumor sites 26'.

In a related embodiment liposomes 27' can be used for sealing off the vasculature, the micro-vasculature in particular, to a tumor site 26'. Referring now to FIG. 13B, the sealing process is accomplished by the selected release into the vasculature of a thrombogenic agents 46 such as fibrin or thrombin or combination thereof (disclosed in US Patent Nos: 5,739,288 and 5,437,292 and incorporated by reference herein); or an in situ curable polymer 48 such as collagen or a hydrogel (disclosed in US Patent No. 5,669,934 and is included by reference herein). The quantity of thrombogenic agent 46 or curable polymer 48 is selectable in order to selectively occlude vessels of a given size. For the case of capillaries 50, liposomes 27' are sized to fit to be to flow through a capillary, which are preferably of diameters less than 1 μm. Furthermore, in this embodiment liposomes 27' contain a quantity of a thrombogenic agent 46 or a curable polymer 48 (such as collagen), such that when released, only vessels the size of capillaries will be occluded. In one embodiment the sealing method is as follows, (i) liposomes are injected to treatment site 26 and taken up by the microvasculature, (ii) RF energy is applied to treatment site 26, (iii) liposomes rupture and release thrombogenic agents 46 or curable polymer 48 (iv) the introduction of heat from RF energy cures polymer 48 and or accelerates the clotting reaction (iv) a clot 52 or polymer seal is formed and seals capillary 50 blocking off capillary flow, but not that of larger vessels .

Referring now to FIG. 14, another means for enhancing the delivery of medicines 24, including chemotherapeutic agents to tissue site 26 involves the pre heating of a selected volume of tissue 26'" (also called heated site 26'") in and around treatment site 26 prior to the delivery of the chemotherapy agents. Heating can be accomplished using any of the energy delivery devices 34 described herein including an RF electrode 34' or an ultrasound emitter. Temperature elevation may be in the range of 37° to 45° C. This causes capillary 50 to become a dilated capillary 50' increasing blood flow which increases the flow of medicine 24 to treatment site 26. The increase in blood flow to heated site 26'" is monitored using one or more imaging modalities 21' (such as Doppler ultrasound). Energy levels of power source 38 are adjusted accordingly in order to achieve the desired level of increased blood flow.

Referring now to FIG. 15, cell therapy is introduced using cell therapy system 16 Cell therapy system 16 comprises therapeutic cells 16', cell harvesting site 16" immunotherapeutic agents (also called activating agents) 24 and activation chamber 16'" which can be docking site 20. Cells therapy can be introduced into one or more of the following locations: treatment site 26, docking site 20, necrosis site 28 or the systemic system. Cells 16' can introduced via intravenous, or subcutaneous injection using a hypodermic needle, or intravenously or intra-arterially using iv and arterial catheters and methods well known to those skilled in the art. In an alternative embodiment, cells 16' can be proceeded in vitro into docking device 20 which is then implanted at the desired location. Cells 16' to be included in cell therapy system 16 include one or more of the following types : B- lymphocytes, neutrophils, macrophages, T/4 cells and T/8 cells and stem cells; antibodies can also be introduced as will be described herein. In a various embodiments, cells 16' can be autologous or foreign cells. In one embodiment autologous cells are removed from cell harvesting site 16" using a blood filter a catheter or cell collection device well known to those skilled in the art. Cells 16' can then be separated using one or more of the following devices/methods: filtration, centrifugation, affinity cell chromatography, electrophoresis, ELISA and antibody separation. Once separated and/or isolated the desired cells 16' can be activated for enhanced immune response with one or more of the following cytokines by methods known to those skilled in the art: interleukins (IL): including IL 1, IL 2, IL 6 and IL 10;, interferons (IF) including IFα & IFβ), tumor necrosis factors (TNF) including TNF-α and TNF-β; Transforming Growth Factors (TGF) including TGFβ and other cytokines known to those skilled in the art. In another embodiment, one or more of the cytokines described herein can be directly introduced into the body systemically or orally or at one more of the following locations in the body: treatment site 26 reservoir/necrosis site 28, docking site 20, or another site (such as an intramuscular site or adipose tissue by means described herein). By generating large numbers of activated cells 16' and or antibodies outside the body, cell therapy system 16 significantly reduces the energetic and physiological stress on the immune system and therefore improves the ability of the immune system to combat cancer and other diseases over the long term.

Another embodiment of cell therapy system 16 involves the use of antibodies 17 (shown in FIG. 15) to cancerous cells, other tumor cells, viruses and viral infected cells. Antibodies 17 can be produced outside the body through vitro or in vivo means (described herein) and subsequently introduced into the body at docking site 20, necrosis site 28 or systemically through intravenous injection. Antibodies 17 attach to cancer cells and target them for attack by various cells in the immune system (described herein) and or make them more susceptible to chemotherapeutic agents and other treatments 24 including radiation. Means of antibody production include the use of hybridomas and animals (e.g genetically engineered mice or rabbit), both known to those skilled in the art, by exposing animals or in vitro B cells cultures to one or more antigens taken from the tissue site including antigens taken from the tumor. Antibodies 17 are then harvested by methods known to those skilled in the art. These methods permit the production of a large number of monoclonal antibodies to a specific cancer cell. Antibodies 17 used are selected for their antitumor activity to specific tumors or cancers. Additionally, cell therapy can be combined with chemotherapy by using antibodies 17 to deliver chemotherapy to tumor cells. This combination approach has been used by researchers to treat breast cancer using the HER2 monoclonal antibody (Park J., et al.: Anti-HER2 immunoliposomes for targeted therapy of human tumors. Cancer Let 1997 Oct 14;118(2): 153- 160. Hudziak RM, et al.: P185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol. 1989 Mar; 9(3): 1165-1172.)

In one embodiment cell activation can be accomplished in vitro in a cell activation chamber 16'" as described in US Patent # 5627070 (Cell growing device for in vitro cell population expansion), which is incorporated by reference herein. After activation, cells 16' can reintroduced into the body at one or more sites including the systemic system or the treatment site 26 or cell necrosis site 28, or docking site 20. Referring now to FIG. 12 E, in one embodiment docking site 20 can also be an implanted artificial porous chamber 20"" where cells 16' are introduced and initially contained. Porous chamber 20"" permits nutrients to enter allowing cells 16' to stay viable for a prolong time period and produce one or more cytokines described herein which can diffuse out of the chamber into treatment site 26 or the systemic system. Entrapped cells 16' can also be reactivated by subsequent addition of cytokines into porous chamber 20"" by direct injection into the chamber or systemic introduction.

Chamber 20"" may also be configured to allow for the controlled release of cells 16' into the systemic system or treatment site 26. Controlled release means include absorbable membranes, osmotic pumps and programmable displacement pumps all know to those skilled in the art. Treatment kit 10 can also provide for the full body exchange of blood. The blood is then down loaded through an apparatus (not shown) such as an in-line centrifuge and separated into its components of plasma, white blood cells and red blood cells. The components are filtered to remove undesired components including but not limited to cancerous white blood cells, metastatic and malignant cells, infected cells, viruses, pyrogens and toxins. The neutralized blood can then be returned to the body.

Referring now to FIG. 16, gene therapy can introduced to localized target treatment sites 26 throughout the body using docking device 20 or in alternative embodiments via the circulatory system using catheter delivery systems such as that disclosed in US Patent No. 5,674,192 (which is incorporated herein by reference) well known to those skilled in the art. Gene therapy system 18 comprises a genetic sequence

18' (also called gene 18' or genetic material 18' and is made of one or more nucleotide base pairs), vector 18" and target cell 18'" (also called target tissue 18"'). Gene therapy is used to introduce one or more genes 18' into target cells 18'" to encode for the production of one or more proteins 18"", or alternatively to prevent the expression of undesired proteins 18"". Gene 18' size can include genetic sequences 18' ranging from 1 to 1 x 106 base pairs in length. Vectors 18" for genetic sequences 18' to be delivered to target cells 18'" include, but are not limited to, the following: cosmids, yeast artificial chromosomes, viruses and cells such as hematopoietic cells all are well known to genetic engineering scientist and technicians skilled in their art. Viral vectors 18" include but are not limited to retro viruses, adenoviruses, Aden-associated viruses and herpes simplex virus. Vectors 18" can introduced via injection into tissue or introduced onto the mucous membranes of the respiratory system via aerosols. Other means of introducing genetic material 18' into targeted tissue/cells 18'" include introduction of naked DNA (single or double stranded or in plasmid form) directly to the tissue (preferably into muscle tissue), injections of liposome enclosed DNA (a technique known as lipofection), injection of DNA protein complexes (e.g DNA ligand complexes) and calcium phosphate transfection, techniques all well known to those skilled in the art. Alternatively genetic material 18' can be introduced into target cells

18'" in vitro and then seeded onto/into an implant device (such as a vascular graft or docking device 20) which is then implanted in one or more target treatment sites 26 in the body. The uptake of vectors 18" and/or genetic material 18' to targeted cells 18'" can enhanced via the application of ultrasound or electromagnetic energy to target site using energy delivery device. This can include the technique of electroporation to increase the permeability of the target cell's membrane to genetic material through the applications of an electric charge as is well known to those skilled in the art.

One method for the use of treatment kit 10 involves one or more of the following steps: (i) Diagnosis and biopsy of the tumor site using one or more imaging modalities 21' described herein, (ii) removal and in vitro tumor specific activation of immune cells, (iii) treatment of one or more of tumor sites 26' using energy delivery devices 34 described herein to ablate, resect or necrose all or a portion of a tumor or other target tissue to be removed, (iv) creation of one or more necrosis sites 28 at or around tumor, (v) placement of docking device 20 at or around tumor site 26', (vi) use of docking device 20 to delivery medicines 24 including antibiotics, chemotherapy agents, cytokines, gene therapy vectors, (vii) systemic introduction of activated immune cells, and (viii) diagnosis of treatment efficacy using imaging modalities 21' and (ix) repeat of one or more of the preceding steps. Steps i-viii can then be repeated as desired for each selected treatment site 26. This procedure can be used to treat all selected treatments sites 26 concurrently or done so in a chronological fashion.

In one embodiment, cell necrosis system 12 is coupled to an open or closed loop feedback control system 25. Referring now to FIG. 17, an open or closed loop feedback system couples sensor 346 to energy source 392. In this embodiment, electrode 314 is one or more RF electrodes 314. The temperature of the tissue, or of RF electrode 314 is monitored, and the output power of energy source 392 adjusted accordingly. The physician can, if desired, override the closed or open loop system. A microprocessor 394 can be included and incorporated in the closed or open loop system to switch power on and off, as well as modulate the power. The closed loop system utilizes microprocessor 394 to serve as a controller, monitor the temperature, adjust the RF power, analyze the result, refeed the result, and then modulate the power.

With the use of sensor 346 and the feedback control system a tissue adjacent to RF electrode 314 can be maintained at a desired temperature for a selected period of time without causing a shut down of the power circuit to electrode 314 due to the development of excessive electrical impedance at electrode 314 or adjacent tissue as is discussed herein. Each RF electrode 314 is connected to resources which generate an independent output. The output maintains a selected energy at RF electrode 314 for a selected length of time.

Current delivered through RF electrode 314 is measured by current sensor 396. Voltage is measured by voltage sensor 398. Impedance and power are then calculated at power and impedance calculation device 400. These values can then be displayed at user interface and display 402. Signals representative of power and impedance values are received by a controller 404.

A control signal is generated by controller 404 that is proportional to the difference between an actual measured value, and a desired value. The control signal is used by power circuits 406 to adjust the power output in an appropriate amount in order to maintain the desired power delivered at respective RF electrodes 314. In a similar manner, temperatures detected at sensor 346 provide feedback for maintaining a selected power. Temperature at sensor 346 is used as a safety means to interrupt the delivery of energy when maximum pre-set temperatures are exceeded. The actual temperatures are measured at temperature measurement device 408, and the temperatures are displayed at user interface and display 402. A control signal is generated by controller 404 that is proportional to the difference between an actual measured temperature and a desired temperature. The control signal is used by power circuits 406 to adjust the power output in an appropriate amount in order to maintain the desired temperature delivered at the sensor 346. A multiplexer can be included to measure current, voltage and temperature, at the sensor 346, and energy can be delivered to RF electrode 314 in monopolar or bipolar fashion.

Controller 404 can be a digital or analog controller, or a computer with software. When controller 404 is a computer it can include a CPU coupled through a system bus. This system can include a keyboard, a disk drive, or other non-volatile memory systems, a display, and other peripherals, as are known in the art. Also coupled to the bus is a program memory and a data memory.

User interface and display 402 includes operator controls and a display. Controller 404 can be coupled to imaging systems including, but not limited to, ultrasound, CT scanners, X-ray, MRI, mammographic X-ray and the like. Further, direct visualization and tactile imaging can be utilized.

The output of current sensor 396 and voltage sensor 398 are used by controller 404 to maintain a selected power level at RF electrode 314. The amount of RF energy delivered controls the amount of power. A profile of the power delivered to electrode

314 can be incorporated in controller 404 and a preset amount of energy to be delivered may also be profiled.

Circuitry, software and feedback to controller 404 result in process control, the maintenance of the selected power setting which is independent of changes in voltage or current, and is used to change the following process variables: (i) the selected power setting, (ii) the duty cycle (e.g., on-off time), (iii) bipolar or monopolar energy delivery; and, (iv) fluid delivery, including flow rate and pressure. These process variables are controlled and varied, while maintaining the desired delivery of power independent of changes in voltage or current, based on temperatures monitored at sensor 346.

Referring now to FIG. 18, current sensor 396 and voltage sensor 398 are connected to the input of an analog amplifier 410. Analog amplifier 410 can be a conventional differential amplifier circuit for use with sensor 346. The output of analog amplifier 410 is sequentially connected by an analog multiplexer 412 to the input of A/D converter 414. The output of analog amplifier 410 is a voltage which represents the respective sensed temperatures. Digitized amplifier output voltages are supplied by A/D converter 414 to microprocessor 394. Microprocessor 394 may be a type 68HCII available from Motorola. However, it will be appreciated that any suitable microprocessor or general purpose digital or analog computer can be used to calculate impedance or temperature.

Microprocessor 394 sequentially receives and stores digital representations of impedance and temperature. Each digital value received by microprocessor 394 corresponds to different temperatures and impedances.

Calculated power and impedance values can be indicated on user interface and display 402. Alternatively, or in addition to the numerical indication of power or impedance, calculated impedance and power values can be compared by microprocessor 394 to power and impedance limits. When the values exceed predetermined power or impedance values, a warning can be given on user interface and display 402, and additionally, the delivery of RF energy can be reduced, modified or interrupted. A control signal from microprocessor 394 can modify the power level supplied by energy source 392. FIG. 19 illustrates a block diagram of a temperature and impedance feedback system that can be used to control the delivery of energy to tissue site 416 by energy source 392 and the delivery of a cooling solution 70 to electrode 314 and/or tissue site 416 by flow regulator 418. Energy is delivered to RF electrode 314 by energy source 392, and applied to tissue site 416. A monitor 420 ascertains tissue impedance, based on the energy delivered to tissue, and compares the measured impedance value to a set value. If the measured impedance exceeds the set value, a disabling signal 422 is transmitted to energy source 392, ceasing further delivery of energy to RF electrode 314. If measured impedance is within acceptable limits, energy continues to be applied to the tissue. The control of cooling solution 70 to electrode 314 and/or tissue site 416 is done in the following manner. During the application of energy, temperature measurement device 408 measures the temperature of tissue site 416 and/or RF electrode 314. A comparator 424 receives a signal representative of the measured temperature and compares this value to a pre-set signal representative of the desired temperature. If the tissue temperature is too high, comparator 424 sends a signal to a flow regulator 418 (connected to an electronically controlled micropump, not shown) representing a need for an increased cooling solution flow rate. If the measured temperature has not exceeded the desired temperature, comparator 424 sends a signal to flow regulator 418 to maintain the cooling solution flow rate at its existing level. The responses of flow regulator 418 can be based on proportional control, proportional intergral control, or proportional intergral derivative control, control methods all well known to those skilled in the art. In another embodiment, drug delivery device 14 or docking device 20 are coupled to an open or closed loop feedback control system 25'. Referring now to FIG. 20, an open or closed loop feedback system couples chemical sensor 546 (which can also be the also be the output of the chemical analyzer describe herein) to drug delivery device 592 which in this embodiment is a fluid pump, but can be any drug delivery device described herein.

The concentration of medication in the tissue site 514, or in bodily fluid 514' is monitored, and the output of pump 592 is adjusted accordingly. The physician can, if desired, override the closed or open loop system. A microprocessor 594 can be included and incorporated in the closed or open loop system to switch power on and off, as well as modulate the power. The closed loop system utilizes microprocessor 594 to serve as a controller, monitor the medication concentration, adjust the flow rate, analyze the result, refeed the result, and then modulate the power.

With the use of channel sensor 546 and the feedback control system 25' the medication concentration at tissue site 514 or bodily fluid 514' can be maintained at a desired level for a selected period of time. Each sensor 546 is connected to resources which generate an independent output.

A control signal is generated by controller 604 that is proportional to the difference between an actual measured value, and a desired value. The control signal is used by flow rate circuits 606 to adjust the medication flow rate output in an appropriate amount in order to maintain the desired medication concentration at tissue site 514 or bodily fluid 514'. The actual tissue medication concentrations are measured at medication measurement device 608, and the medication concentrations are displayed at user interface and display 602. Controller 604 can be a digital or analog controller, or a computer with software. When controller 604 is a computer it can include a CPU coupled through a system bus. This system can include a keyboard, a disk drive, or other non-volatile memory systems, a display, and other peripherals, as are known in the art. Also coupled to the bus is a program memory and a data memory. User interface and display 602 includes operator controls and a display.

Controller 604 can be coupled to imaging systems including, but not limited to, ultrasound, CT scanners, X-ray, MRI, mammographic X-ray and the like. Further, direct visualization and tactile imaging can be utilized.

Referring now to FIG. 21, chemical sensor 546 and flow sensor 598 are connected to the input of an analog amplifier 610. Analog amplifier 610 can be a conventional differential amplifier. The output of analog amplifier 610 is sequentially connected by an analog multiplexer 612 to the input of A/D converter 614. The output of analog amplifier 610 is a voltage which represents the respective sensed medication concentrations. Digitized amplifier output voltages are supplied by A/D converter 614 to microprocessor 594. Microprocessor 594 may be a type 68HCII available from Motorola. However, it will be appreciated that any suitable microprocessor or general purpose digital or analog computer can be used to calculate impedance or temperature.

Microprocessor 594 sequentially receives and stores digital representations of medication concentration and flow rate. Each digital value received by microprocessor 594 corresponds to different concentration and flow rates.

FIG. 22 illustrates a block diagram of a medication feedback system that can be used to control the delivery of medication to tissue site 616 by pump 592. As medication is delivered to tissue site 514 medication measurement device 608 measures the concentration of medication at tissue site 514 or bodily fluid 514'. A comparator 624 receives a signal representative of the measured medication concentration and compares this value to a pre-set signal representative of the desired concentration. If the medication concentration is too high, comparator 624 sends a signal to a flow regulator 618 which can be intergral to pump 592 representing a need for a decreased medication solution flow rate. If the measured medication concentration has not exceeded the desired concentration, comparator 624 sends a signal to flow regulator 618 to maintain the medium flow rate at its existing level. If the medication concentration is too low, comparator 624 sends a signal to a flow regulator 618 representing a need for an increased medication solution flow rate. In each case the responses of flow regulator 618 can be based on proportional control, proportional intergral control, or proportional intergral derivative control, control methods all well known to those skilled in the art. The following examples are offered by way of illustration and are not intended to limit the invention in any manner: Example 1 :

Dosage of paclitaxel administered at docking device for the treatment of ovarian or breast cancer: 175 mg/m2 of body surface area (BSA) of drug is directly delivered (by closed fluid path or direct injection) to docking device reservoir over 3 hours every 3 weeks. It should be diluted for injection USP in 0.9% Sodium Chloride Injection, or

5% Dextrose in Ringer's Injection to a final concentration of 0.3 to 1.2 mg/mL.

Example 2:

Dosage of doxorubicin administered at docking device for the treatment of breast or colon cancer: Between 60 to 75 mg/m2 BSA of drug is directly delivered (by closed fluid path or direct injection) to docking device reservoir at 21 -day intervals. An alternative dose schedule is weekly doses of 20 mg/m2. It should be diluted for injection USP with Sterile Water for Injection, 5% Dextrose Injection or 0.9% Sodium Chloride Injection to a final concentration of approximately 2 mg/mL.

Example 3:

Dosage of Vinblastine administered at docking device with a venous connection only: Initially 3.7 mg/m2 BSA of drug is directly delivered (by closed fluid path or direct injection) to docking device reservoir. Thereafter, for most adults 5.5 to 7.4 mg/m2 BSA. dosage may be gradually increased to between 5.5 to 7.4 mg/m2 BSA at no less than weekly intervals. It should be diluted for injection USP with Sterile Water for Injection and 0.9% Sodium Chloride Injection to a final concentration of approximately 1 mg/mL.

Example 4:

Dosage of Vincristine administered at docking device for the treatment of bladder cancer: 1.4 mg/m2 BSA of drug is directly delivered (by closed fluid path or direct injection) in about one minute to docking device reservoir at weekly intervals. It should be diluted for injection USP with Sterile Water for Injection to a final concentration of approximately 1 mg/mL. It may also be diluted with 5% Dextrose

Injection or 0.9% Sodium Chloride for Injection.

Example 5: Dosage of Flourouracil administered at docking device for treatment of breast or bladder cancer: Approximately 12 mg/kg (kg of body weight) of drug is directly delivered (by closed fluid path or direct injection) to docking device reservoir daily for five days and repeated every 28 days. An alternative dose schedule is 6 to 10 mg/kg (250 to 400 mg/m2 BSA) given daily for 5 days and repeated every 28 days. It should be diluted for i.v infusion with 5% Dextrose Injection to a final concentration of approximately 2 mg/mL.

Example 6: Dosage of angiostatin administered at docking device for the treatment of

Lewis Lung carcinoma and melanoma: Between 1.5 mg/kg to 100 mg/kg is directly delivered (by closed fluid path or direct injection) to docking device reservoir at 1-5 day intervals. It should be diluted for injection USP with Sterile Water for Injection, 5% Dextrose Injection or 0.9% Sodium Chloride for Injection to a final concentration of approximately 1-10 mg/mL.

Example 7:

Dosage of angiostatin impregnated into a skin patch for the treatment of Lewis Lung carcinoma: Between 1-20 grams of drug is impregnated into the patch. The patch thickness can vary between 0.1 to 10 mm. The surface area can vary between 1 to 10 cm2. The matrix material can be RTV silica free silicone.

Example 8:

Dosage of angiostatin impregnated into a porous implanted matrix for the treatment of Lewis Lung carcinoma: Between 1-20 grams is impregnated into the matrix. The matrix thickness can vary between 0.1 to 10 mm. The surface area can vary between 1 to 10 cm2. The matrix material can be knitted Dacron velour.

Example 9: Dosage of endostatin administered at the docking device for the treatment of

Lewis Lung carcinoma and melanoma: Between 1.5 mg/kg to 100 mg/kg of drug is directly delivered (by closed fluid path or direct injection) to docking device reservoir at 1-5 day intervals. It should be diluted for injection USP with Sterile Water for Injection, 5% Dextrose Injection or 0.9% Sodium Chloride for Injection to a final concentration of approximately 1-10 mg/mL.

Example 10: Dosage of endostatin impregnated into a skin patch for the treatment of Lewis

Lung carcinoma: Between 1-20 grams of drug is impregnated into the patch. The patch thickness can vary between 0.1 to 10 mm. The surface area can vary between 1 to 10 cm2. The matrix material can be RTV silica free silicone.

Example 1 1 :

Dosage of angiostatin impregnated into a porous implanted matrix for the treatment of Lewis Lung carcinoma: Between 1 -20 grams of drug is impregnated into the matrix. The matrix thickness can vary between 0.1 to 10 mm. The surface area can vary between 1 to 10 cm2. The matrix material can be knitted Dacron velour

Example 12:

Concentration of Solutol HS 15® administered with doxorubicin and/or vinblastin at docking device for the reduction of chemoresistance by erythroleukemia: An aqueous emulsion of Solutol HS 15® is administered intravenously one hour prior to the solutions of doxorubicin (described in Example 2) or vinblastin (described in example 3) and then continued to be administered during and 12 to 24 hours after the administration of doxorubicin or vinblastin in order to achieve and maintain a plasma concentration between 0.1 and 2 mg/ml. The Solutol HS 15® should be heated till it becomes fluid but yet remains stable (typically a temperature between 50-80° C) and then mixed with sterile water for injection (heated to the same temperature) to achieve a viscosity appropriate for injection.

Example 13:

Concentration of CRL 1065 administered with doxorubicin and/or vinblastin at docking device for the reduction of chemoresistance by erythroleukemia: An aqueous emulsion of is CRL 1065 administered intravenously one hour prior to the solutions of doxorubicin (described in Example 2) or vinblastin (described in example 3) and then continued to be administered during and 12 to 24 hours after the administration of doxorubicin or vinblastin in order to achieve and maintain a plasma concentration between 0.1 and 2 mg/ml. The CRL 1065 should be heated till it becomes fluid but yet remains stable (typically a temperature between 50-80° C) and then mixed with sterile water for injection (heated to the same temperature) to achieve a viscosity appropriate for injection.

Example 14:

Concentration of Verapamil administered with doxorubicin and/or vinblastin at docking device for the reduction of chemoresistance by erythroleukemia: Approximately 75 mg/kg of verapamil is added to the solutions of doxorubicin described in example 2 or vinblastin described in example 3. The solution is then administered as described in each example.

Example 15 : Dosage of Ampicillin administered at docking device: 250 to 500 mg every 6 hours is directly delivered (by closed fluid path or direct injection) to the docking device reservoir. It should be diluted for injection USP with Sterile Water for Injection to a final concentration of approximately 0.05 to 0.1 gr/mL.

Example 16 :

Dosage of Cefamandole Nafate administered at docking device: 500 mg to 1 g every 4 to 8 hours is directly delivered (by closed fluid path or direct injection) to the docking device reservoir for a two to three day duration. It should be diluted for injection USP with Sterile Water for Injection, 5% Dextrose Injection or 0.9% Sodium Chloride Injection to a final concentration of approximately 0.05 to 0.1 gr/mL.

Example: 17

Dosage of Vancomycin HCL administered at docking device: 500 mg to 1 g every 6 to 12 hours is directly delivered (by closed fluid path or direct injection) to the docking device reservoir. It should be diluted for injection USP with Sterile Water for

Injection to a final concentration of approximately no more than 5 mg/mL.

Example 18: Dosage of Interleukin II administered at docking device used for the treatment of leukemia or lung cancer: Between 15 to 80 mg/m2 bSA is directly delivered (by closed fluid path or direct injection) to the docking device reservoir daily. Alternatively, 15,000-18,000 units IL-2/kg is administered daily over a nine period, (as disclosed in US Patent No: 5,098,702). It should be diluted for injection USP with Sterile Water for

Injection to a final concentration of approximately 5 to 10 mg /mL

Example 19:

Dosage of gamma interferon administered at docking device used for the treatment of ovarian cancer (as disclosed in US Patent No: 5,268,169) : Between 10 to

50x106 U/m2 BSA is directly delivered (by closed fluid path or direct injection) to docking device reservoir on at least two non-consecutive days per week over a two month period. It should be diluted for injection USP with Sterile Water.

Example 20:

Dosage of Tumor Necrosis Factor to be administered at docking device used for the treatment of lung cancer (as disclosed in US Patent No: 5,098,702) : Between 230-260 μg /kg is directly delivered (by closed fluid path or direct injection) to docking device reservoir daily for three days. It should be diluted for injection USP with Sterile Water.

Example 21

Dosage of Colony Stimulating Factor- 1 (CSF-1) to be administered at docking device used for the treatment of cancer (as disclosed in US Patent No: 5,098,702) : Between 0.01 to 10 mg CSF-1 /kg is directly delivered (by closed fluid path or direct injection) to docking device reservoir daily. It should be diluted for injection USP with Sterile Water.

Example 22: Dosage of Liposomally-encapsulated doxorubicin to be administered at the docking device to treat one or more cancers including breast and colon cancer : Between 1 to 5 mg/kg or 60 to 75 mg/m2 bSA doxorubicin encrypted in a lipsomally encapsulated solution is directly delivered (by closed fluid path or direct injection) to docking device reservoir, The liposomes are sized between 0.05 and 0.5 μm and are composed of vesicle-forming lipids and between 1-20 mole percent of an amphipathic vesicle-forming lipid derivatizedwith a polyalkylether, as exemplified by phosphatidylethanolamine derivatized withpolyethyleneglycol (as disclosed in US Patent No:5,013, 556). The lipsomes contain between 1- 2.5 mole % doxorubicin (or a pharmacologically acceptable salt thereof) and have greater than 50 μg drug/ liposome lipid (as disclosed in US Patent No: 5,043,166 and 5,213,804 which are incorporated herein by reference ). The solutions is mixed to a final concentration of between 1.0 to 2.5 mg doxorubicin/ ml using sterile water.

Example 23:

Dosage of Liposomally-encapsulated vincristine to be administered at the docking device to treat one or more cancers including breast and colon cancer : Between 1 to 5 mg/m2 bSA vincristine contained in a lipsomally encapsulated solution is directly delivered (by closed fluid path or direct injection) to docking device reservoir.

The liposomes are sized between 0.05 and 0.5 μm and are composed of vesicle-forming lipids and between 1-20 mole percent of an amphipathic vesicle-forming lipid derivatizedwith a polyalkylether, as exemplified by phosphatidylethanolamine derivatized withpolyethyleneglycol (as disclosed in US Patent No:5,013,556). The lipsomes contain between 1- 2.5 mole % vincristine (or a pharmacologically acceptable salt thereof) and have greater than 50 μg drug/ liposome lipid (as disclosed in US Patent No: 5,043,166 and 5,213,804 which are incorporated herein by reference ). The solutions is mixed to a final concentration of between 0.1 to 0.15 mg vincristine/ml using sterile water and sodium phosphate for injection (Embree, L., et al.: Pharmacokinetic behavior of vincristine sulfate following administration of vincristine sulfate liposome injection. Cancer Chemotherapy Pharmacology. 1998;41(5):357- 352)).

Example 24: Dosage of Liposomally-encapsulated angiostatin to be administered at the docking device or intravenously to treat one or more cancers: Between 1.5 mg/kg to 100 mg/kg of angiostatin contained in a lipsomally encapsulated solution is directly delivered (by closed fluid path or direct injection) to docking device reservoir or intravenously. The liposomes are sized between 0.05 and 0.5 μm and are composed of vesicle-forming lipids and between 1-20 mole percent of an amphipathic vesicle-forming lipid derivatizedwith a polyalkylether, as exemplified by phosphatidylethanolamine derivatized withpolyethyleneglycol (as disclosed in US Patent No: 5,013,556). The lipsomes contain between 1- 2.5 mole % doxorubicin (or a pharmacologically acceptable salt thereof) and have greater than 50 μg drug/ liposome lipid (as disclosed in US Patent No: 5,043,166 and 5,213,804 which are incorporated herein by reference ). The solutions is mixed to a final concentration of between 1.0 to 2.5 mg aniostatin/ ml using sterile water for injection.

Example 25:

Dosage of Liposomally-encapsulated endostatin to be administered at the docking device or intravenously to treat one or more cancers: Between 1.5 mg/kg to 100 mg/kg of endostatin contained in a lipsomally encapsulated solution is directly delivered (by closed fluid path or direct injection) to docking device reservoir or intravenously. The liposomes are sized between 0.05 and 0.5 μm and are composed of vesicle- forming lipids and between 1-20 mole percent of an amphipathic vesicle-forming lipid derivatized with a polyalkylether, as exemplified by phosphatidylethanolamine derivatized withpolyethyleneglycol (as disclosed in US Patent No:5013556). The lipsomes contain between 1- 2.5 mole % doxorubicin (or a pharmacologically acceptable salt thereof) and have greater than 50 μg drug/ liposome lipid (as disclosed in US Patent No: 5,043,166 and 5,213,804 which are incorporated herein by reference ). The solutions is mixed to a final concentration of between 1.0 to 2.5 mg endostatin/ml using sterile water for injection.

Example 26:

Dosage of gas filled Liposomes containing fibrin to be administered intravenously or through a docking site and ruptured at selected site using ultrasound to occlude the vasculature of a tumor site: Between 1 to 10 ml of an aqueous solution containing between 25 and 50 mg/ml of fibrin (disclosed in US Patent No. 5,739,288) encapsulated in gas filled lipsomes is administered intravenously or is directly delivered (by closed fluid path or direct injection) to docking device reservoir. Liposomes are filled with 50-90% nitrogen, and have a lipid membrane composed of at least one dipalmitoyl lipid and polyethyleneglycol (disclosed in US Patent No. 5,580,575). Lipsosomes and have a diameter between 0.05 and 0.5 μm, a peak resonant frequency between 0.5 to 10 mHz and contain between 1-5 mole % fibrin and have greater than 50 μg drug/ liposome lipid (as disclosed in US Patent No: 5,043,166 and 5,213,804). The solution is prepared to a final concentration using sterile water for injection. Ultrasound energy with a frequency between 0.5 tolOmHz is delivered to the treatment using a piezoelectric ultrasound probe coupled to an ultrasound power source. The probe may be applied externally or internally.

Example 27:

Dosage of gas filled Liposomes containing collagen to be administered intravenously or through a docking site and ruptured using RF energy to occlude the vasculature of a tumor site: Between 1 to 10 ml of a an aqueous solution containing between 1 and 50 mg/ml of collagen composition (disclosed in US Patent No. 5,669,934) encapsulated in gas filled lipsomes is administered intravenously or is directly delivered (by closed fluid path or direct injection) to docking device reservoir. Liposomes are filled with 50-90% nitrogen, and have a membrane composed of at least one dipalmitoyl lipid and polyethyleneglycol (disclosed in US Patent No. 5,580,575). Lipsosomes and have a diameter between 0.05 and 1 μm and contain between 1-5 mole % collagen and have greater than 50 μg drug/ liposome lipid (as disclosed in US

Patent No: 5,043,166 and 5,213,804). The final solution is prepared to a final concentration using sterile water for injection. The liposomes are ruptured and the collagen fused in place to capillaries via the applications of between 100 to 1200 joules of RF energy delivered to the site using an RF electrode (as disclosed in US Patent No:5,669,934).

Example 28:

Dosage of an adenoviral vector administered at docking device for treating localized solid tumors of the brain, liver colon and skin and other organs using gene therapy: Approximately 1-5 ml of an aqueous solution containing 1 to 5 X lOVml adenoviral particles is directly delivered (by closed fluid path or direct injection) to docking device reservoir. The adenovioral vector is comprised of a DNA sequence encoding for HSV-tk (thymidine kinase of Herpes Simplex Virus) operatively linked to a promoter (as disclosed in US Patent No: 5,631,236, which is incorporated herein by reference). The vector infects the tumor resulting in the expression of the HSV-tk sequence which cause tumor cell death and promotes the activation of a prodrug, in this case ganciclovir to a compound that is also toxic to tumor cells. Adenoviral particles are suspended either in a solution of sterile water for injection or 14.2 mg/ml sodium phosphate for injection. Ganciclovir is administered in a dose of from about lmg/day/ kg to about 20 mg/ day/kg body weight.

Example 29: Dosage of T-cell therapy for the treatment of leukemia: Between 1-5 ml of an aqueous solution containing between 1 X 106 to X lOVml of TALL- 104 cells is directly delivered (by closed fluid path or direct injection) to docking device reservoir. These cells are T-cells that have been modified (in this case activated) by treatment in vitro with one or a combination of IL-2 and IL-12 to enhance its cytotoxicity and gamma-irradiated at a dose suitable to irreversibly arrest cell proliferation but retain its cytotoxic activity in vitro and in vivo as disclosed in US Patent No. 5,702,702 (which is incorporated herein by referece. Cells are suspended either in a solution of sterile water for injection, or 14.2 mg/ml sodium phosphate for injection, or 0.9% Sodium Chloride Injection.

Example 30:

Dosage of HER2 antibody therapy for the treatment of breast cancer: An initial loading dosage of 250 mg of recombinant humanized monoclonal (rhuMAb) HER2 is directly delivered (by closed fluid path or direct injection) to the docking device reservoir. Subsequently, a weekly dose 100 mg of rhuMAb HER2 is administered in the same manner for 10 weeks (refer to Baselga J, et al.: Phase II study of weekly intravenous recombinant humanized anti-pl85HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. Clin Oncol 1996 Mar;14(3):737-744). Antibodies are suspended either in 0.15M sodium phosphate for injection or 5% Dextrose Injection to a concentration of between 1 to 100 mg rhuMAb

HER2/ml.

The foregoing description of a preferred embodiment of the invention has been presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise forms disclosed. Obviously, many modifications and variations will be apparent to practitioners skilled in this art. It is intended that the scope of the invention be defined by the following claims and their equivalents. What is claimed is:

Claims

I CLAIM:
1. A kit, comprising: a medicament delivery device including a medicament housing with a drug delivery reservoir, a membrane coupled to the medicament housing; and a medicament positionable in the medicament housing, the medicament being selected from the group of a chemotherapeutic agent, immunotherapeutic agent, cell, anti-angiogenic agent, vascular sealing agent, gene therapy agent, antibiotic, resistance modification agent and a photodynamic therapy agent.
2. The kit of claim 1, further comprising: a pump device coupled to the medicament housing and to a source of medicament.
3. The kit of claim 2, wherein the pump device is an osmotic pump.
4. The kit of claim 2, wherein the pump device is electronically driven.
5. The kit of claim 1, further comprising: a catheter coupled to the medicament housing.
6. The kit of claim 5, wherein a proximal end of the catheter is coupled to a body lumen.
7. The kit of claim 2, further comprising: a control system coupled to the pump device.
8. The kit of claim 7, wherein the control system includes a controller and a microprocessor coupled to the controller.
9. The kit of claim 1, further comprising: an energy delivery device.
10. The kit of claim 1, wherein the medicament is doxorubicin.
11. The kit of claim 1 , wherein the medicament is vincristine.
12. The kit of claim 1, wherein the medicament is vinblastine.
13. The kit of claim 1 , wherein the medicament is paclitaxel.
14. The kit of claim 1, wherein the medicament is angiostatin.
15. The kit of claim 1 , wherein the medicament is endostatin.
16. The kit of claim 1, further comprising: a sensor coupled to the medicament housing.
17. The kit of claim 1, further comprising: an imaging device coupled to the medicament housing.
18. The kit of claim 1 , wherein the membrane is porous.
19. The kit of claim 1 , wherein the membrane is made of a hollow fiber.
20. The kit of claim 1, wherein the membrane is semiporous.
21. The kit of claim 2, wherein the pump device provides controlled diffusion of the medicament into a treatment site and systemic delivery of the medicament.
22. The kit of claim 9, wherein the energy delivery device is an RF electrode.
23. The kit of claim 9, wherein the energy delivery device is a microwave antenna.
24. The kit of claim 9, wherein the energy delivery device is a waveguide.
25. The kit of claim 9, wherein the waveguide is configured to be coupled to a laser.
26. The kit of claim 9, wherein the energy delivery device is an acoustical transducer.
27. The kit of claim 9, wherein the energy delivery device is a resistive heating device.
28. A medicament delivery device, comprising: a medicament housing including a drug delivery reservoir; a membrane coupled to the medicament housing; and a medicament in the medicament housing, the medicament being selected from the group of a chemotherapeutic agent, immunotherapeutic agent, cell, anti-angiogenic agent, vascular sealing agent, gene therapy agent, antibiotic, resistance modification agent and a photodynamic therapy agent.
29. The device of claim 28, further comprising: a pump device coupled to the medicament housing and to a source of medicament.
30. The device of claim 29, wherein the pump device is an osmotic pump.
31. The device of claim 29, wherein the pump device is electronically driven.
32. The device of claim 28, further comprising: a catheter coupled to the medicament housing.
33. The device of claim 32, wherein a proximal end of the catheter is coupled to a body lumen.
34. The device of claim 29, further comprising: a control system coupled to the pump device.
35. The device of claim 34, wherein the control system includes a controller and a microprocessor coupled to the controller.
36. The device of claim 28, further comprising: an energy delivery device coupled to the medicament housing.
37. The device of claim 28, wherein the medicament is doxorubicin.
38. The device of claim 28, wherein the medicament is vincristine.
39. The device of claim 28, wherein the medicament is vinblastine.
40. The device of claim 28, wherein the medicament is paclitaxel.
41. The device of claim 28, wherein the medicament is angiostatin.
42. The device of claim 28, wherein the medicament is endostatin.
43. The device of claim 28, further comprising: a sensor coupled to the medicament housing.
44. The device of claim 28, further comprising: an imaging device coupled to the medicament housing.
45. The device of claim 28, wherein the membrane is porous.
46. The device of claim 28, wherein the membrane is made of a hollow fiber.
47. The device of claim 28, wherein the membrane is semiporous.
48. The device of claim 29, wherein the pump device provides controlled diffusion of the medicament into a treatment site and systemic delivery of the medicament.
EP19980922282 1997-05-13 1998-05-13 Global medical treatment method and apparatus Withdrawn EP0984813A1 (en)

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