BACKGROUND OF THE INVENTION Numerous diseases or disorders present in humans can be treated with presently available therapeutic agents, provided the agent can be delivered to tissue effected by the disease or disorder. Cancer is a prime example of such a disease. Traditionally, chemotherapeutics are delivered into the blood stream of a subject via subcutaneous injection. Once in the blood, the chemotherapeutic is distributed throughout the body. Upon encountering a cancer cell, the chemotherapeutic generally interferes with a vital function of the cell, such as respiration, or DNA replication, resulting in inhibition of uncontrolled replication and death of the cancer cell. However, a difficulty involved in treating cancer comprises the specificity of the chemotherapeutic for the tumor, i. e., the cytotoxicity of the chemotherapeutic. It has been determined that many chemotherapeutics used in the treatment of cancer have limited cytotoxicity, and consequently kill and damage healthy, normal cells. Efforts to increase the cytotoxicity of chemotherapeutics, such as coupling the chemotherapeutic to a ligand of a surface protein of a cancer cell, e. g., an antibody made against the surface protein, have met with only limited success.

An alternative means for treating cancer, and diseases or disorders related to a subjects genotype, such as diabetes mellitus, cystic fibrosis, sickle cell anemia, or Alzheimers Disease, to name only a few, involves the use of gene therapy.

Broadly, gene therapy involves the treatment of various genetic diseases or disorders by transferring or introducing genetic material into cells of the subject.

The genetic material is then transcribed and translate to produce a protein that can ameliorate the effects of the disease or disorder. In one type of gene therapy, the subjects genome is missing a particular gene. Hence, the absence of the protein encoded by the missing gene is largely responsible for the genetic disorder. In this form of gene therapy, the genetic material transferred into cells of the patient comprises an exogenous gene that encodes the missing protein.

When the exogenous gene is expressed, the resulting protein performs a function that previously was not being performed, and provides the subject with a substantially normal phenotype.

In another form of gene therapy, a normal gene is inserted into cells of the subject and expressed because the endogenous gene corresponding to the normal gene, although present in the genome of the subject, is damaged and unable to be expressed.

One of the most common methods of performing gene therapy is the ex vivo method. This method involves removing cells from the subject, inserting the genetic material of the gene therapy into the cells in vitro, and then reintroducing the transformed or transfected cells into the subject. However, this method comprises numerous limitations. For example, removal of the cells and in vitro transfection, and then subsequent reintroduction of the cells in the subject places the cells under enormous stress, which can kill or disrupt physiological functions of the cells, particularly the expression of the inserted genetic material.

Another limitation is related to the reintroduction of the transformed or transfected cells into the subject. More specifically, it is quite possible that many of the cells will diffuse from the target tissue, or enter the blood stream and be drawn away from the target tissue. Hence, the protein produced by the expression of the genetic material, which would provide the subject with the greatest benefit if produced in the target tissue, may not necessarily be produced in the target tissue in sufficient quantities to ameliorate the genetic disorder. Yet another limitation of this method involves the inconvenience to the subject. In particular, the subject must undergo an operation to remove cells from the target tissue, and a second operation to reintroduce the cells of the target tissue into in the body of the subject.

Accordingly, what is needed is a device that delivers a therapeutic agent, such as a chemotherapeutic agent, directly to a target tissue so that the cytotoxic effects of the therapeutic agent at the target tissue is maximized. What is also needed is a device that can deliver a therapeutic agent to a target tissue located within a body cavity, so that delivery of the chemotherapeutic agent is not dependent merely on the circuiatory system of the subject. Also, what is needed is a device that delivers genetic material to target tissue in which wh. ich does not require disturbance and removal of target tissue from the subject. As a result, the stress under which cells from the target tissue are placed is minimized, and the subject undergoes only one operation, e. g., delivery of the genetic material to the target tissue.

SUMMARY OF THE INVENTION There is provided, in accordance with the present invention a device and method for delivery of a therapeutic agent directly to a target tissue in vivo, so that the cytotoxic effects of the therapeutic agent at the target tissue is maximized.

Furthermore, in instances of gene therapy, the device and method of the invention permit delivery of genetic material directly to the target tissue for incorporation into cells of the target tissue where the genetic material is subsequently expressed.

This invention provides a device for delivering a therapeutic agent to a target tissue in vivo, comprising: a shaft comprising an outer surface, a proximal end and a distal end, wherein said distal end forms a sealed point, a bore running longitudinally through said shaft from said proximal end to said point, such that said bore forms an inner surface of said shaft; and a fenestrated area located near said point of said distal end, wherein said fenestrated area comprises a plurality of pores running radially from said inner surface to said outer surface such that said bore is in fluid communication with said outer surface.

Further, this invention provides a device for delivery of a therapeutic agent to a target tissue in vivo, said device comprising: a shaft comprising an outer surface, a proximal end and a distal end, wherein said distal end forms a sealed point, a bore running longitudinally through said shaft from said proximal end to said sealed point wherein said pore forms an inner surface of said shaft, and at least one pore running from said bore to said outer surface such that said bore and outer surface are in fluid communication; a container comprising a nozzle, wherein said container defines a reservoir for holding said therapeutic agent; a connector means connected to said proximal end of said shaft, wherein said connector means permits said container to be connected in a resealably sealable manner to said proximal end of said shaft such that said reservoir is in fluid communication with said bore; means for creating a flow of said therapeutic agent from said reservoir through said bore and said at least one pore; and an obturator which can be inserted into said shaft after said therapeutic agent has flowed from said reservoir and into said shaft, and said container has been disconnected from said proximal end of said shaft, such that said obturator forces residual therapeutic agent remaining in said bore through said at least one pore so that said residual therapeutic agent is delivered to said target tissue.

Further, this invention provides a method for delivery of a therapeutic agent to a target tissue in vivo in a subject, the method comprising the steps of: providing a shaft comprising an outer surface, a proximal end, a distal end which forms a sealed point, a bore running longitudinally through the shaft from the proximal end to the sealed point, such that the bore forms an inner surface of the shaft, and a fenestrated area located near the sealed point, wherein the fenestrated area comprises a plurality of pores running radially from the inner surface to the outer surface so that the bore is in fluid communication with the outer surface of the shaft; inserting the shaft into the subject such that the sealed point penetrates the target tissue and the pores of the fenestrated area are in contact with the target tissue; and flowing the therapeutic agent through the bore and through the pores of the fenestrated area so that the therapeutic agent is delivered to the target tissue in vivo Lastly, this invention provides a method for delivery of a therapeutic agent to a target tissue in vivo in a subject, the method comprising the steps of: providing a shaft comprising an outer surface, a proximal end, a distal end which forms a sealed point, a bore running longitudinally through the shaft from the proximal end to the sealed point, such that the bore forms an inner surface of the shaft, and at least one pore running radially from the inner surface to the outer surface so that the at least one bore is in fluid communication with the outer surface of the shaft; connecting a connector means to the proximal end of the shaft; providing a container comprising a nozzle, wherein the container defines a reservoir for holding the therapeutic agent; inserting an inflexible shaft into the bore of the shaft; inserting the shaft into the subject such that the distal end of the shaft penetrates the target tissue and the at least one pore is in contact with the target tissue; removing the inflexible shaft from the bore of the needle; connecting the nozzle of the container to the connector means in a resealably sealable nnanner such that the reservoir is in fluid communication with the bore; and flowing the therapeutic agent from the reservoir, through the bore and through the at least one pore of the shaft, such that the therapeutic agent is delivered to the target tissue.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematical view of a device of the invention, an inflexible shaft, and an obturator; P) G. 2 is a schematical view of device of the invention wherein an inflexible shaft is inserted into the bore of the shaft of the device of the invention.

F) G. 3 is a schematical view of the device of the invention wherein a container is a syringe, and is connected to the proximal end of the shaft of the device in a resealably sealable manner via a connector means.

FIG. 4 is a schematical view of a device of the obturator.

DETAILED DESCRIPTION OF THE) NVENT) ON The present invention relates to a device for delivery of a therapeutic agent to a target tissue in vivo, wherein the device comprises: a shaft comprising an outer surface, a proximal end and a distal end, wherein the distal end forms a sealed point, a bore running longitudinally through the shaft from the proximal end to the point, such that the bore forms an inner surface of the shaft; and a fenestrated area located near the seated point of the distal end, wherein the fenestrated area comprises a plurality of pores running radially from the inner surface to the outer surface such that the bore is in fluid communication with the outer surface.

In another embodiment, the present invention extends to a device for delivery of a therapeutic agent to a target tissue in vivo, the device comprising: a shaft comprising an outer surface, a proximal end and a distal end, wherein the distal end forms a sealed point, a bore running longitudinally through the shaft from the proximal end to the sealed point wherein the pore forms an inner surface of the shaft, and at least one pore running from the bore to the outer surface so that the bore and outer surface are in fluid communication; a container comprising a nozie, wherein the container defines a reservoir for holding the therapeutic agent; connector means connected to the proximal end of the shaft and the nozzle, wherein the connector means permits the container to be resealably connected to proximal end of the shaft so that the reservoir is in fluid communication with the bore; and means for creating a flow of the therapeutic agent from the reservoir through the bore and the at least one pore.

Moreover, the present invention comprises a method for delivery of a therapeutic agent to a target tissue in vivo in a subject, the method comprising the steps of: providing a shaft comprising an outer surface, a proximai end, a distal end which forms a sealed point, a bore running longitudinally through the shaft from the proximal end to the sealed point, wherein the bore forms an inner surface of the shaft, and a fenestrated area located near the sealed point, wherein the fenestrated area comprises a plurality of pores running radially from the inner surface to the outer surface so that the at least one bore is in fluid communication with the outer surface of the shaft; inserting the shaft into the subject such that the sealed point penetrates the target tissue and the pores of the fenestrated area are in contact with the target tissue; and flowing the therapeutic agent through the bore and the pores of the fenestrated area so that the therapeutic agent is delivered to the target tissue.

In another embodiment, the present invention extends to a method for delivering a therapeutic agent to a target tissue in vivo in a subject, comprising the steps of : providing a shaft comprising an outer surface, a proximal end, a distal end which forms a sealed point, a bore running longitudinally through the shaft from the proximal end to the sealed distal point, wherein the bore forms an inner surface of the shaft, and at least one pore running radially from the inner surface to the outer surface so that the bore is in fluid communication with the outer surface of the shaft; providing a connector means connected to the proximal end of the shaft; providing a container comprising a noale, wherein the container defines a reservoir for holding the therapeutic agent; inserting an inflexible shaft into the bore of the shaft; inserting the shaft into the subject such that the distal end of the shaft penetrates the target tissue and the at least one pore of the shaft is in contact with the target tissue; removing the inflexible shaft from the bore of the shaft; connecting the nozzle of the container to the connector means in a reseatably sealable manner such that the reservoir is in fluid communication with the bore of the shaft; and flowing the therapeutic agent from the reservoir and through the bore and the at least one pore of the shaft, such that the therapeutic agent is delivered to the target tissue.

In a particular embodiment of the invention, the at least one pore comprises a plurality of pores running radially from the inner surface of the shaft to the outer surface, and the plurality is located within a fenestrated area of the shaft located near the sealed point of the shaft.

Numerous terms are used throughout the Specification and Claims in order to describe the present invention. Accordingly, as used herein, the phrase resealably sealable as used herein refers to the connecting of a container forming a reservoir holding a therapeutic agent to the proximal end of the shaft of the invention in a manner such that the reservoir is in fluid communication with the bore of the shaft, and no therapeutic agent escapes from device of the invention as it flows from the reservoir and into the bore of the shaft. Hence, the connection is sealed. However, the device of the invention permits the disconnection of the container from the proximal end, and then reconnection of the container to the proximal end such that the reservoir of the container is in fluid communication with the bore of the shaft. As a result, the container is connected to the proximal end of the shaft in a resealably gealable manner.

Furthermore, the phrase a fenestrated area refers to a segment of the shaft comprising a plurality of pores running radially from the bore of the shaft to the outer surface of the shaft, such that the bore of the shaft is in fluid communication with the outer surface of the shaft.

Moreover, the phrase inflexible shaft as used herein refers to a shaft having sufficient rigidity such that when inserted into the shaft of the device of the invention, the inflexible shaft provides support and prevents collapse of the shaft of the invention when inserted into the tissue of a patient.

In addition, as used herein, the term obturator refers to an efongated rigid shaft which can be inserted into the bore of the shaft of the invention after therapeutic agent has flowed from the reservoir and into the bore of the shaft. Due to the length of the shaft, residual fluid may remain in the bore after the flow of therapeutic agent from the reservoir has ceased. Hence, the obturator is inserted into the bore and forces any residual therapeutic agent in the bore to the distal end of the shaft. There, the therapeutic agent is forced through the pores of the fenestrated area, and is delivered to the target tissue. As a result, no therapeutic agent is wasted.

Also, as used herein, the phrase sealed point in regards to the distal end of the shaft indicates the bore of the shaft does not pass through the point at the distal end of the shaft. Hence, the bore of the shaft is open only to the periphery of the shaft only at the proximal end, so that therapeutic agent can pass from the reservoir and into the bore of the shaft.

The shaft of the device can be composed of numerous materials, provided the shaft does not chemically react with the therapeutic agent or the target tissue.

Furthermore, the material must be able to withstand the stress placed on the shaft when inserted into the target tissue. Examples of materials having applications as the shaft of the invention include, but certain are not limited to polypropylene, polyethylene, polytrimethylpentene, polytetrafluoroethylene, potyvinytidene difluoride, polysulfone, polydimethylsifoxane (silicone rubber), nitrile rubber, neoprene rubber, silicone-polycarbonate copolymers, fluoroelastomers, polyurethane, polyvinyl chloride, polybutadiene, polyolefin elastomers, po (yesters, polyethers, stainless steal, or silica. In a preferred embodiment, the shaft is comprised of stainless steel.

Furthermore, the present invention extends to a device for delivery of a therapeutic agent to a target tissue in vivo, as described above, wherein the shaft comprises a needle having sufficient length to penetrate the target tissue from the periphery of the body of a patient. Hence, the location of the target tissue in vivo is a factor to be considered when determining an appropriate length for a shaft of the invention. For example, if the target tissue involves skeletal muscle, particularly of the extremities, the shaft requires a length of about 5 to about 10 centimeters. However, if the target tissue involves an internal organ, such as the prostate, pancreas or liver, to name on (y a few, then the length of the shaft may range from about 10 to about 20 cm. In a particular embodiment of the invention, wherein the target tissue is the prostate, the shaft comprises a length of about 16 cm.

In addition, numerous means are presently available for inserting the device of the invention into a subject without damaging the shaft. For example, a sturdy inflexible shaft can be initially inserted into the bore of shaft such that the outer surface of the inflexible shaft is in contact with the inner surface of the shaft of the device. An example of such an inflexible shaft is a prostate biopsy needle of a prostate biopsy needle gun. Generally, a prostate biopsy needle has a length of approximately 16 cm, and is 18 gauge in diameter. Hence, in a particular embodiment of the invention, the shaft of the invention comprises a length of approximately 16 cm, and a diameter of approximately 17 gauge. As a result, a typical prostate biopsy needle of a prostate biopsy needle gun can readily be inserted into the shaft of the invention, and then propelled into the target tissue in vivo. After the shaft of the invention penetrates the target tissue and the pores of the fenestrated area of the shaft are in contact with the target tissue, the prostate biopsy needle can be removed from the bore. A container forming a reservoir holding a therapeutic agent to be delivered to the target tissue can then be connected in a resealably sealable manner to the proximal end of the shaft via a connector means connected to the proximal end, such that the reservoir is in fluid communication with the bore of the shaft. The therapeutic agent is then flowed from the reservoir, through the bore of the shaft, and through the plurality of pores of the fenestrated area, so that the therapeutic agent is delivered to the target tissue in vivo.

As explained above, a device for delivering a therapeutic agent to a target tissue in vivo comprises in part a shaft as described above, and a fenestrated area located near the point of the distal end of the shaft, wherein the fenestrated area comprises a plurality of pores running radially from the inner surface of the shaft to the outer surface of the shaft, such that the bore within the shaft is in fluid communication with the outer surface of the shaft. Since the pores run radially from the bore to the outer surface, a therapeutic agent delivered with the device of the invention is evenly distributed around the distal end of the shaft, and into the target tissue. Generally, the longitudinal length of the fenestrated area is about 0.25 to 1.25 cm. Furthermore, the distance between the sealed point of the distal end of the shaft and the fenestrated area ranges from about 0.1 cm to approximately 1.25 cm. In a particular embodiment of the invention, the fenestrated area comprises a length of approximately 1 cm, and is located approximately 0.4 cm from the sealed point of the distal end. In addition, the diameter of the pores of the fenestrated area can vary in size. In particular, the diameters can range from about 5 mm to about 500 mm In a particular embodiment, the pores of the fenestrated area have a diameter of approximately 100 mm.

Numerous connector means have applications in the device of the invention.

For example, the connector means can comprise a valve connected to the proximal end of the shaft, which can be adapted for connection to a container forming the reservoir. In particular, the valve can comprise an externally threaded nozzle to which an intemally threaded adaptor connected to the reservoir and in fluid communication therewith is screwed onto the nozzle. In another example, the connector means can comprise a Luer-lock connector which permits the container to be connected to the proximal end of the shaft in a resealably sealable manner, such that the reservoir is in fluid communication with the bore of the shaft.

In another embodiment, the present invention extends to a device for delivery of a therapeutic agent to a target tissue in vivo, comprising a shaft comprising an outer surface, a proximal end and a distal end, wherein the distal end forms a sealed point. The shaft of the invention also comprises a bore running longitudinally through the shaft from the proximal end to the sealed point, wherein the bore forms an inner surface of the shaft. At least one pore runs radially from the inner surface of the shaft to the outer surface near the sealed point of the distal end such that the bore of the shaft is in fluid communication with the outer surface. The device also comprises a connector means connected to the proximal end of the shaft, and a container comprising a nozzie.

The container defines a reservoir for holding the therapeutic agent prior to its delivery. The connector means enables the container to be connected to the proximal end of the shaft in a resealably sealable manner, such that the reservoir of the container is in fluid communication with the bore of the shaft. This embodiment of the invention also comprises a means for creating a flow of therapeutic agent from the reservoir, through the bore of the shaft and the at least one pore such that the therapeutic agent is delivered to the target tissue in vivo. When the reservoir is empty, the container can be disconnected from the connector, Moreover, the present invention extends to a device for delivering a therapeutic agent to a target tissue in vivo as set forth above, wherein the shaft comprises a sufficient length to penetrate the target tissue from the periphery of the body of the subject. In situations where the target tissue is skeletal muscle or bone, and particularly when the target tissue is located in an extremity, the shaft of the device can have a length of about 5 cm to about 10 cm. However, when the target tissue is an internal organ, a longer shaft, generally ranging from about 10 cm to about 20 cm may be needed. In a particular embodiment of the invention wherein the target tissue comprises the prostate, the shaft comprises a length of about 16 cm and a diameter of about 17 gauge. With this diameter, it is possible to provide support for the shaft when it is inserted into a subject by inserting an inflexible shaft into the bore. A particular example of such an inflexible shaft comprises a prostate biopsy needle of a prostate biopsy needle gun. A standard prostate biopsy needle generally comprises a length of 16 cm and a diameter of 18 gauge. Hence, the prostate needle can be inserted into the bore of the shaft of the device. After the shaft has been inserted into the subject and the pores of the fenestrated area are in contact with the target tissue, the prostate biopsy needle is removed from the shaft, and a therapeutic agent is flowed through the shaft and the pores of the fenestrated area, directly to the target tissue.

Furthermore, numerous containers have applications in the device of the invention. For example, the container can be a syringe. Other examples include a glass vial, a plastic via or bag. These types of containers can be readily connected to the proximal end of the shaft in a resealably sealable manner via the connector means of the invention using methods known to those of ordinary skill in the art. Examples of connector means having applications in the present invention comprise a valve connected to the proximal end of the shaft, or a Luer Lock connector attached to the proximal end.

Whats more, numerous means for creating a flow of therapeutic agent from the reservoir and through the bore and at least one pore of the shaft have applications herein. For example, a pump can be connected to the noale of the container and the connector means connected to proximal end of the shaft in a resealably seatabte manner. The pump can then pump the therapeutic agent from the reservoir, through the bore the pores of the fenestrated area so that the therapeutic agent is delivered to the target tissue. Another example of a flow creating means involves the use of gravitational forces. In particular, the container forming the reservoir is connected in a resealably sealable manner to the connector means connected to the proximal end of the shaft so that the reservoir is in fluid communication with the bore of the shaft. The container is then located above the distal end of the shaft. Gravitational force pulls the therapeutic agent from the reservoir, through the bore of the shaft and the pores of the fenestrated area. As a result, the therapeutic agent is delivered to the target tissue in vivo.

Yet another means for creating a flow of the therapeutic agent involves the use of a syringe comprising a reservoir for holding a therapeutic agent, and naturally, a plunger and a nozzle, each be located on opposite sides of the reservoir. In particular, a syringe containing the therapeutic agent to be delivered, is connected to the connector means in a resealably sealable manner such that the reservoir is in fluid communication with the bore. The plunger of the syringe is then compressed, which forces the therapeutic agent from the reservoir, through the bore of the shaft and the pores of the fenestrated area resulting in delivery of the therapeutic agent to the target tissue.

The present invention further extends to a device for delivery of a therapeutic agent to a target tissue in vivo, as set forth above, wherein the therapeutic agent is a fluid comprising an anti-cancer agent, or a suitable gene for gene therapy.

Examples of anti-cancer agents which can be delivered to a target tissue in vivo with the present invention are described infra. Moreover, the therapeutic agent may comprise genetic material for insertion into celts of the target tissue for expression. Genetic material which can be delivered to target tissue in vivo is also described infra.

Moreover, the present invention extends to a device for delivery of a therapeutic agent to a target tissue in vivo, as set forth herein, wherein the target tissue comprises muscle tissue, bone, brain, prostate, pancrease, liver, colon, breast, cardiac, or an internal organ or a tumor. Examples of muscle tissue include skeletal and cardiac muscle.

The present invention further extends to a method for delivering a therapeutic agent to a target tissue in vivo, as explained herein, wherein the connector means connected to the proximal end of the shaft comprises a Luer-lock connector. This connector permits a container forming a reservoir for holding the therapeutic agent to be delivered to the target tissue to be connected in a resealably sealable manner to the connector means, such that the reservoir is in fluid communication with the bore of the shaft. Consequently, after the shaft has been inserted into the subject and positioned such that the fenestrated area of the shaft is in contact with the target tissue, a container comprising a reservoir holding the therapeutic agent can be readily connected to the shaft so that the agent can be delivered to the target tissue. Further, since the container is connected to the proximal end of the shaft in a resealably sealable manner, it can be easily disconnected from the shaft when the reservoir is empty in order to refill the container or substitute it for a new container.

Moreover, numerous means are available, and encompassed by the present invention to flow the therapeutic agent from the reservoir, through the bore of the shaft and the pores of the fenestrated area of the shaft such that the therapeutic agent is delivered to the target tissue in vivo. One such means comprises pumping the therapeutic agent from the reservoir and into the bore and the at least one pore of the shaft. The pumping of the therapeutic agent is accomplished by providing a pump that is in fluid communication with the reservoir and the bore of the shaft at the proximal end of the shaft. Numerous types of pumps have applications in this aspect of the invention. Examples include a peristaltic pump, a piston pump, a valveless pump, or a gear pump to name only a few.

Yet another means for flowing the therapeutic agent from the reservoir and into the bore of the shaft and through the pores of the fenestrated area involves using a syringe as the container, wherein the syringe comprises a nozzle. The therapeutic agent to be delivered is initially placed in the reservoir of the syringe.

Then, the nozzle of the syringe is connected to connector means in a resealably sealable manner such that the reservoir of the syringe is in fluid communication with the bore of the shaft. The plunger of the syringe is then compressed, which forces the therapeutic agent through the nozzle, through the connector means, through the bore of the shaft, and through the pores of the fenestrated area so that the therapeutic agent is delivered to the target tissue in vivo.

Yet another means for flowing the therapeutic agent from the reservoir and through the bore and the pores of the fenestrated area of the shaft involves the location of container forming the reservoir relative to the distal end of the shaft.

More specifically, locating the container above the distal end of the shaft after connection of the container to the connector means in a resealably sealable manner such that the reservoir is in fluid communication with the bore of the shaft, permits gravitational force to act upon the therapeutic agent in the reservoir. As a result, the therapeutic agent flows from the reservoir, into the bore of the shaft, and through the at least one pore of the fenestrated area of the shaft, such that the therapeutic agent is delivered to the target tissue in vivo.

The greater the height of the container above the distal end of the shaft, and greater the flow rate of the therapeutic agent.

As explained above, numerous therapeutic agents can be delivered to a target tissue with the device and method of the invention. Such agents include proteins, lipids, glycoproteins, amino acids, peptides, or nucleic acids.

Chemotherapeutics are a particular example of a therapeutic agent that can be delivered with a device and method of the invention. Particular examples of chemotherapeutics that can be delivered include, but certain are not limited to methotrexate, cisplatin, actinomycin, dichlorambucil, cyclophosphamide, daunomycin, mefphalan, streptozotocin, uracil mustard, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), 6-mercaptopurine. 5-fluorouracil (5FU), doxorubicin, adriamycin, mitomycin-C, bleomycin, vincristine and vinblastine.

Other therapeutic agents that can be delivered directly to target tissues in vivo include numerous types of antibiotics.

Furthermore, genetic material can be delivered directly to a target tissue in vivo using a device and method of the invention. The genetic material introduced into cells of target tissues using a device and method of the invention can be any native or non-native genetic molecule that can provide a desirable activity to target cells. The genetic material can encode any native or non-native protein or polypeptide having such a desirable activity in a target cell. Alternatively, the introduction of the genetic material itself can alter the target in a desirable way, such as by interference with the transcription or translation of an endogenous gene of the target tissue. Non-native as used herein indicates that neither the genetic material, nor any protein polypeptide encoded by the genetic material is detectable in the untreated target cells or tissue. The nature of the introduced genetic material itself forms no part of the present invention.

Furthermore, the agents include but are not limited to: proteins, nucleic acids, RNA, DNA, cDNA, or supercoiled plasmid DNA, genes, liposomes, lipids, sugars, glycofipids, prodrugs, or vectors. The agent can be prepared according to any standard preparation or purification method among the many known to the skilled artisan and is provided in an aqueous solution, buffered or unbuffered.

The amount of agent is not absolutely critical, although better results may be observed for DNA molecules tested when the amount of DNA is below 500 mg, and preferably below 200 mg. Suitable concentrations can readily be determined by routine experimentation. Delivery to the target tissue of approximately 100 ml of an aqueous solution containing the agent in the preferred concentration range is sufficient to function in the method. The agents can be attached to microparticles such as iron oxide particles in the range of 0.5 to 1 micron in size. Altematively, unsupported agent in solution is also suitable for delivery according to the method of the invention.

The agent typically inclues an expressible DNA sequence that encodes a native or non-native polypeptide. The DNA can be of any length and can include genomic DNA fragments, engineered DNA produced in a microbial host, or synthetic DNA produced according to known chemical synthetic methods, including, but not limited to, the Polymerase Chain Reaction. The art is cognizant of the various required and preferred elements (including promoters, terminators, transcription-and translation-regulating sequences, and the like) that one of ordinary skill in the art would provide on an expressible genetic construct. One of ordinary skill in art is also able to select appropriate elements from the many known elements to facilitate or optimize expression of the genetic material in a particular target animal. The native or non-native polypeptide produced from expression of the genetic material in the target tissue in vivo can be maintained intracellularfy or secreted to the extracellular space. One of ordinary skill in the art is familiar with the genetic elements necessary to direct a sequence to a particular cellular or extraceilular mir-roenvironment and with methods for constructing a genetic construct to facilitate such direction. For example, a polypeptide produced after gene transfer can be directed to cross a cell membrane by adding an appropriate signal peptide to the gene that encodes the polypeptide.

Desirable proteins that can be produced from expression of the genetic material after delivery of the agent to the target tissue in vivo include, without limitation, growth factors, hormones, and other therapeutic proteins. These therapeutic proteins can speed the healing of wounds and correct certain deficiencies such as parathyroid, growth hormone, and other hormone deficiencies, as well as deficiencies of certain clotting factors such as factor VIII, For instance, if the gene encoding the growth factor is introduced into the genome or cytoplasm of target skin cells in a wound, these cells can be made to produce a desirable growth factor. The growth factor produced from expression of the delivered genetic material will then not only speed the healing of the wound, but may also help to heal wounds that would not heaf otherwise.

Cells can also be engineered to not produce a particular protein, such as a protein involved in an immune response, e. g., human leukocyte antigen (HLA).

Such engineering can be accomplished in a variety of ways wel within the knowledge of the skilled artisan. A particular example of such engineering involves the introduction of antisense genetic material that hybridizes with mRNA present in a cell to prevent translation of the mRNA, and the production of the protein or peptide encoded by the mRNA.

Referring to FIG. 1, inflexible shaft (1) comprises a prostate biopsy needle having sealed sharpened tip (2) and proximal end (3). Furthermore, proximal end (3) is mounted into biopsy gun system (5). In a particular embodiment of the invention, the biopsy needle is an 18 gauge needle having a length of 16 cm.

Furthermore, as shown in Figure 2, an example of shaft (6) of the device of the invention is schematically shown wherein shaft (6) comprises distal end (7) which forms sealed point (9), proximal end (8), an open ended bore from proximal end (8) to the sealed point (9) of distal end (7). Moreover, shaft (6) comprises a fenestrated area (10) comprising a plurality of pores running radially from the inner surface to the outer surface of shaft (6). As a result, the bore and outer surface of shaft (6) are in fluid communication, e. g., fluid can flow from the bore, through the at least one pore to the outer surface of shaft (6). Since distal end (7) comprised sealed point (9), and proximal end (8) is open, the bore is open ended. As explained above, the length of shaft (6), the longitudinal length of fenestrated area (10), and the distance between fenestrated area (10) and sealed point (9) can vary. In a particular embodiment of the invention, shaft (6) is about 16 cm in length, and has a diameter of 17 gauge. Furthermore, fenestrated area (10) comprises a longitudinal length of about 1 cm, and is located about 0.4 cm from sealed point (9).

FIG. 3 is a schematical view showing a bore of shaft 6 is open ended in that it passes through base (11), but does not pass through sealed point (9) of distal end (7) of shaft (6). Bore (19) passing through shaft (6) forms inner surface (21).

Furthermore, fenestrated area (10) is comprised of a plurality of pores (20) that run radially from inner surface (21) of shaft (6) to outer surface (22) of shaft (6).

As a result, bore (19) is in fluid communication with outer surface (22) of shaft (6). The pores (20) run radially from inner surface (21) to outer surface (22) of shaft (6). Hence, bore (19) of shaft (6) is in fluid communication with outer surface (22) of shaft 6, and therapeutic agent flowing through bore (19) can be delivered to a target tissue in vivo when fenestrated area (10) is in contact with the target tissue.

In one embodiment, the proximal end of shaft (6) is connected to a container having a reservoir for holding a therapeutic agent to be delivered. In particular, Moreover, in a particular embodiment of the invention, a connector means (15) is connected to proximal end (8) of shaft (6) and to a the nozzle (16) container (17), which in this embodiment is syringe (17). Syringe (17) comprises a reservoir (18) for holding a therapeutic agent to be delivered, and a plunger (19) which is located opposite to nozzle (16). Other examples of containers having applications herein include a plastic bag or a glass container, to name only a few. The connector means (15) permits the reservoir (18) of the syringe (19) to be in fluid communication with the bore of shaft (6) in a resealably sealable manner. As a result, syringe (17) can be disconnected from proximal end (8) of shaft (6) when necessary, e. g., refilling of syringe (17) with therapeutic agent, if necessary. Furthermore, numerous connector means (15) can be used to connect proximal end (8) of shaft (6) to nozzle (16) of syringe (17) such that reservoir (18) is in fluid communication with the bore within shaft (6). In a particular embodiment of the invention, connector means (15) is a Luer Lock connector. In addition, although syringe (17) is used in this embodiment as a container for holding the therapeutic agent, any container known to the skilled artisan can be used in this manner, provided the container forms a reservoir for holding therapeutic agent to be delivered to a target tissue. Examples of such containers include a plastic bag similar to bags presently used to hold intravenous (I. V.) solutions delivered to the circulatory system of a subject by subcutaneous injection, or a glass vial with a nozzle, to name only a few examples. The reservoir (18) of syringe (17) is initially filled with the therapeutic agent. Syringe (17) is then connected in a resealably sealable manner to the proximal end (8) of the shaft (6) via Luer-lock connector (15) so that reservoir (18) within syringe (17) is in fluid communication with the bore of shaft (6). When plunger (19) is compressed, the therapeutic agent is forced from reservoir (18), through nodale (17), through Luer Lock connector (15), through the bore of shaft (6), and ultimate through the pores of fenestrated area (10), and is delivered to the target tissue in vivo.

As explained above, the present invention provides a means for creating a flow of the therapeutic agent from the reservoir and through the bore and at least one pore of the shaft, wherein the at least one pore is located near the sealed point so that the therapeutic agent is delivered to the target tissue. Numerous means of creating such a flow are presently available to one skilled in the art. For example, container (17) forming a reservoir (18) for holding therapeutic agent can be elevated to a position above distal end (7) of shaft (6) in the target tissue.

As a result, gravitational force acting on the therapeutic agent in reservoir (18) will cause the agent to flow from the reservoir, and the connector means connecting container (17) to proximal end (8) of shaft (6), and through the bore of shaft (6) and pores of fenestrated area (10), to be delivered to the target tissue. Another example of a flow creating means comprises providing a pump which is in fluid communication with reservoir (18) and the bore of shaft (6). The therapeutic agent is then pumped from reservoir (18) through the bore of shaft (6), and through the pores of fenestrated area (10), such that a flow of therapeutic agent is created. Examples of pumps having applications herein include, but are not limited to, a peristaltic pump, a piston pump, a valveless pump, or a gear pump.

Referring again to FIG. 2, proximal end (8) of shaft (6) is fixed to base (11). In the particular example set forth herein, base (11) is rectangular in shape, and comprises a rectangular receded rim which permits base (11) to sit stably against the surface of prostate biopsy gun system (5) from which inflexible shaft (1), e. g. a prostate biopsy needle in this embodiment, would protrude. The inflexible shaft (1) is inserted into the bore of shaft (6) in order to provide support for shaft (6) when inserted into the subject. Such cooperation between shaft (6) and inflexible shaft (1) can be seen in FIG. 3, which schematically shows the insertion of inflexible shaft (1) into the bore of shaft (6). However, as explained above, other articles can serve as inflexible shaft (1).

Again referring to FIG. 3, inflexible shaft (1) is inserted into the bore of shaft (6).

Proximal end (4) of inflexible shaft (1) can be seen passing through base (11) from biopsy gun system (5). In this particular embodiment of the invention, shaft (6) comprises a length of 16 cm and a diameter of 17 gauge, so that the inflexible shaft (1) can be readily inserted into the bore of shaft (6) such that tip (2) of the inflexible shaft (1) is flush with the closed end of the bore running longitudinally through shaft (6).

Referring again to FIG. 3, proximal end (8) of shaft (6) is attached to base (11), through which inflexible shaft (1) can pass through and enter the bore of shaft (6) in order to provide support and stability to shaft (6) when inserted into the body of a subject. Base (11) rests against biopsy gun system (5), and optionally can be mechanically held in place against gun system (5), such as, for example, with a finger attached to gun system (5). In a particular embodiment of the invention, wherein gun system (5) is rectangular in shape, base (11) is also rectangular in shape and comprises a receded rim so that base (9) rests against biopsy gun system (5).

After the device of the invention is configured as set forth in FIG. 3, shaft (6) can be inserted into the body of a subject so that fenestrated area (10) of shaft (6) contacts the target tissue. Inflexible shaft (1) can then be removed from the bore of shaft (6). The nozzle of a container forming a reservoir holding the therapeutic agent can then be connected to a connector means like a Luer Lock connector, such that the container is connected to the proximal end (8) of shaft (6) in a resealably sealable manner and the reservoir of the container is in fluid communication with the bore of shaft (6). The agent in the reservoir can then be flowed through the bore of shaft (6), and through the plurality of pores of fenestrated area (10), and is delivered to the target tissue. The flow of therapeutic agent from the reservoir is accomplished with a means for creating a flow, examples of which are set forth and explained above.

Since shaft (6) in this particular embodiment is large, i. e., 16 cm, some therapeutic agent may remain in the bore of shaft (6) after all the therapeutic agent has flowed out of the reservoir. In order to ensure delivery of all the therapeutic agent to the target tissue, the present invention further comprises obturator (12) schematically shown in FIG. 4. Obturator (12) comprises a base (13) and a shaft (14) which protrudes from base (13). After the reservoir holding the therapeutic agent is emptied, the container is disconnected from the connector means connected to the proximal end of shaft (6). Shaft (14) of obturator (12) is then inserted into the bore of shaft (6). This insertion forces any residual therapeutic agent in the bore of shaft (6) through the plurality of pores of fenestrated area (10). Obturator (12) may be comprised of any material that does not react with the therapeutic agent, provided the material is rigid. Examples of such materials include silicone, polypropylene, polyethylene, or polystyrene, to name only a few. Also, in order for obturator (12) to operate effectively, shaft (14) should have a diameter less than the diameter of the bore of shaft (6), and a length at least equal to the length of shaft (6).

Many other variations and modifications of the invention will be apparent to those skilled in the art without departing from the spirit and scope of the invention. The above-described embodiments, therefore, are intended to be merely exemplary, and all such variations and modifications are intended to be included within the scope of the invention as defined in the appended claims.