Method for pressure mediated selective delivery of therapeutic substances and cannula

Abstract

Methods and devices are disclosed for selective delivery of therapeutic substances to specific histologic or microanatomic areas of organs. Introduction of the therapeutic substance into a hollow organ space (such as an hepatobiliary duct or the gallbladder lumen) at a controlled pressure, volume or rate allows the substance to reach a predetermined cellular layer (such as the ephithelium or sub-epithelial space). The volume or flow rate of the substance can be controlled so that the intralumenal pressure reaches a predetermined threshold level beyond which subsequent subepithelial delivery of the substance occurs. Alternatively, a lower pressure is selected that does not exceed the threshold level, so that delivery occurs substantially only to the epithelial layer. Such site specific delivery of therapeutic agents permits localized delivery of substances (for example to the interstitial tissue of an organ) in concentrations that may otherwise produce systemic toxicity. Occlusion of venous or lymphatic drainage from the organ can also help prevent systemic administration of therapeutic substances, and increase selective delivery to superficial epithelial cellular layers. Delivery of genetic vectors can also be better targeted to cells where gene expression is desired. The access device comprises a cannula with a wall piercing tracar within the lumen. Two axially spaced inflatable balloons engage the wall securing the cannula and sealing the puncture site. A catheter equipped with an occlusion balloon is guided through the cannula to the location where the therapeutic substance is to be delivered.

1 . A method for delivery of a therapeutic or diagnostic agent, the method comprising:
 administering a fluid comprising a therapeutic or diagnostic agent to a preselected region within an organ, by forming a substantially closed chamber within or adjacent the organ, and delivering the fluid at a preselected pressure, flow rate or volume of administration to direct delivery of the fluid to the preselected region.   
     
     
         2 . The method of  claim 1 , wherein the preselected region is a histological layer of the organ. 
     
     
         3 . The method of  claim 2 , wherein the histological layer is selected from the group consisting of (a) an epithelial or subepithelial layer; (b) an endothelial or subendothelial layer; (c) a serosa or subserosal layer; and (d) an adventitial or subadventitial layer. 
     
     
         4 . The method of  claim 1 , wherein the organ comprises a blood vessel or a hollow viscus, and an interior volume of the blood vessel or hollow viscus is isolated to control the predetermined pressure, flow rate or volume of administration. 
     
     
         5 . The method of  claim 1 , wherein an external area of the organ is isolated to control the preselected pressure, flow rate, or volume of administration. 
     
     
         6 . The method of  claim 1  further comprising:
 forming a closed chamber within the organ by forming a closed chamber within a hollow organ space within the organ or forming a closed chamber around the organ or a portion of the organ; and   administering the fluid into the hollow organ space or the chamber around the organ; and   controlling at least one of a pressure, a flow rate, and a volume of the administration of the fluid in the closed chamber such that the agent is selectively delivered either to a region deep to a superficial layer, or substantially only to a superficial layer surrounding the hollow organ space, or is selectively delivered to the external surface of the organ, or substantially only to a layer deep to the external surface of the organ.   
     
     
         7 . The method of  claim 1  wherein controlling at least one of the pressure, the flow rate, and the volume comprises determining a threshold pressure for disruption of microanatomic barriers that inhibit subepithelial delivery of the agent, and (a) administering the fluid at a pressure below the threshold pressure when delivery only to the superficial layer is desired, or (b) administering the fluid at a pressure at or above the threshold pressure when delivery to the region deep to the superficial layer is desired. 
     
     
         8 . The method of  claim 1 , wherein controlling at least one of the pressure, the flow rate, and the volume comprises controlling a liquid pressure. 
     
     
         9 . The method of  claim 8 , wherein controlling the liquid pressure comprises controlling a pressure gradient within or across the organ. 
     
     
         10 . The method of  claim 8 , wherein controlling the liquid pressure comprises administering the liquid at a constant pressure. 
     
     
         11 . The method of  claim 1 , wherein forming a closed chamber within a hollow organ space comprises accessing the hollow organ space, substantially occluding an outlet therefrom, and draining the hollow organ space to remove bodily fluids that may interfere with the action of the therapeutic or diagnostic agent. 
     
     
         12 . The method of  claim 11  further comprising, after draining the hollow organ space, rinsing the hollow organ space so as to remove traces of bodily fluids that may interfere with the action of the therapeutic or diagnostic agent. 
     
     
         13 . The method of  claim 6 , further comprising, after administering the fluid comprising the therapeutic or diagnostic agent, draining the hollow organ space to remove the agent. 
     
     
         14 . The method of  claim 13 , further comprising, after draining the hollow organ space to remove the therapeutic or diagnostic agent, rinsing the hollow organ space to remove traces of the agent. 
     
     
         15 . The method of  claim 6  wherein the superficial layer consists of epithelial cells surrounding the hollow organ space and the area deep to the superficial layer consists of areas deep to said epithelial cells. 
     
     
         16 . The method of  claim 1  wherein controlling at least one of the pressure, the flow rate, and the volume comprises substantially occluding an outlet from a hollow organ space, and varying the flow rate or volume so as to obtain a desired pressure. 
     
     
         17 . The method of  claim 1  wherein controlling at least one of the pressure, the flow rate, and the volume comprising administering a specified volume in a closed chamber. 
     
     
         18 . The method of  claim 1 , further comprising predetermining a threshold pressure, flow rate or volume for delivery to a selected anatomic or microanatomic site, and controlling at least one of a pressure, flow rate or volume to direct delivery of the agent to the selected site. 
     
     
         19 . The method of  claim 18  wherein predetermining a threshold further comprises administering a test fluid into the closed chamber at a given flow rate and measuring a peak pressure at which delivery to a region deep to the superficial layer commences, and wherein controlling at least one of the pressure, the flow rate or the volume comprises administering the fluid (1) as part of a fluid flow into the closed chamber during which the peak pressure is not exceeded, when selective delivery only to a superficial layer is desired, or (2) as part of a fluid flow into the closed chamber during which the peak pressure is equaled or exceeded, when selective delivery to a region deep to the superficial layer is desired. 
     
     
         20 . The method of  claim 1  further comprising administering a test fluid into the hollow organ space multiple times, at a given flow rate, and measuring respective multiple peak pressures at which delivery to a region deep to the superficial layer commences, and wherein controlling at least one of the pressure, the flow rate, and the volume comprises administering the fluid comprising the therapeutic or diagnostic agent (1) as part of a fluid flow during which the last-measured peak is not exceeded, when selective delivery only to a superficial layer is desired, or (2) as part of a fluid flow during which the last-measured peak pressure is equaled or exceeded, when selective delivery to a region deep to the superficial layer is desired. 
     
     
         21 . The method of  claim 1  wherein the closed chamber comprises a hollow organ space, and controlling at least one of the pressure, the flow rate, and the volume comprises administering the fluid comprising the therapeutic or diagnostic agent at a pressure only slightly above a normal physiologic intralumenal pressure in the hollow organ space, at a pressure sufficient to achieve selective delivery substantially only to the superficial layer. 
     
     
         22 . The method of  claim 21  wherein the fluid administered slightly above a normal physiologic intralumenal pressure is administered at a pressure no more than about 2-5 mg Hg above the normal physiologic intralumenal pressure in the hollow organ space. 
     
     
         23 . The method of  claim 6  wherein the hollow organ space comprises a non-vascular interior of a hollow viscus. 
     
     
         24 . The method of  claim 6  wherein the hollow organ space comprises the lumen of a duct. 
     
     
         25 . The method of  claim 1  wherein the closed chamber comprises a hollow organ space, and the method further comprises isolating a portion of the hollow organ space within the body to form the substantially closed chamber. 
     
     
         26 . The method of  claim 25  wherein isolating the portion of the hollow organ space comprises occluding a duct draining the organ. 
     
     
         27 . The method of  claim 26  wherein the isolated portion of the hollow organ space comprises the hepatobiliary tract. 
     
     
         28 . The method of  claim 25  wherein the isolated portion of the hollow organ space comprises the gall bladder and/or ducts of the hepatobiliary tract. 
     
     
         29 . The method of  claim 25  wherein the isolated portion of the hollow organ space comprises hepatic bile ducts or at least a portion of intestine. 
     
     
         30 . The method of  claim 7  wherein controlling at least one of the pressure, the flow rate and the volume comprises administering the fluid above the threshold pressure to the region deep to the superficial layer. 
     
     
         31 . The method of  claim 20  wherein the fluid is administered above the threshold pressure, at a sufficient pressure to drive the therapeutic or diagnostic agent into a parenchyma of the organ. 
     
     
         32 . The method of  claim 25  wherein the pressure drives the therapeutic or diagnostic agent into the parenchyma of the liver. 
     
     
         33 . The method of  claim 1  wherein the therapeutic or diagnostic agent comprises at least one of a chemotherapy agent, a pro-inflammatory agent, an anti-inflammatory agent, and a genetic vector. 
     
     
         34 . The method of  claim 6  wherein the therapeutic or diagnostic agent comprises a genetic vector, and at least one of a pressure, a flow rate, and a volume of the administration of the fluid is controlled such that selective delivery of the genetic vector is made substantially only to superficial cells adjoining the hollow organ space. 
     
     
         35 . The method of  claim 6  wherein the hollow organ space comprises at least a portion of the hepatobiliary tract, the therapeutic or diagnostic agent comprises a genetic vector, and at least one of a pressure, a flow rate, and a volume of the administration of the fluid is controlled such that selective delivery is made to hepatocytes near the hollow organ space. 
     
     
         36 . The method of  claim 6  wherein the hollow organ space is in an organ that includes a neoplasm, and the agent comprises an anti-neoplastic agent or a pro-inflammatory cytokine. 
     
     
         37 . The method of  claim 6  wherein the hollow organ space comprises:
 (a) a portion of the hepatobiliary system adjacent to or involved with hepatic fibrosis, primary biliary cirrhosis or sclerosing cholangitis, and the therapeutic or diagnostic agent comprises an anti-inflammatory agent; or   (b) a portion of intestine affected with Crohn's disease, and the therapeutic or diagnostic agent comprises an anti-inflammatory agent for delivery at a sufficient pressure to introduce the therapeutic or diagnostic agent to a subepithelial lamina propria of the intestinal wall; or   (c) a portion of hepatobiliary tract, the superficial layer comprises epithelial cells lining the hepatobiliary tract, and the region deep to the superficial layer comprises at least one of sinusoids of the liver, Space of Disse, lamina propria, and smooth muscle cells of the gall bladder; or   (d) a portion of the pancreas affected by pancreatic adenocarcinoma and the therapeutic agent comprises an anti-neoplastic agent or a pro-inflammatory agent or an agent that promotes the formation of blood vessels; and the agent is delivered to either the epithelial cells or subepithelial cells or both; or   (e) a portion of the esophagus affected by esophageal carcinoma and the therapeutic agent comprises an anti-neoplastic agent or a pro-inflammatory agent; or   (f) a portion of the prostate gland affected by prostatic carcinoma and the therapeutic agent comprises an anti-neoplastic agent or a pro-inflammatory agent; or   (g) a portion of the urinary bladder affected by carcinoma and the therapeutic agent comprises an anti-neoplastic agent or a pro-inflammatory agent delivered to either the superficial epithelial cells, the lamina propria, any or all of the circular and longitudinal muscle layers, and/or the serosa.   
     
     
         38 . The method of  claim 1 , wherein the agent comprises spherical particles having a diameter of no more than about 500 nm. 
     
     
         39 . The method of  claim 1 , wherein the agent is a nonparticulate agent. 
     
     
         40 . The method of  claim 1 , wherein the fluid is administered at a flow rate of 0.066-960 μl/sec. 
     
     
         41 . The method of  claim 1 , wherein the fluid is administered at a flow rate of less than 1000 μl/sec. 
     
     
         42 . The method of  claim 41 , wherein the fluid is administered at a pressure of no more than about 500 mm Hg. 
     
     
         43 . The method of  claim 42 , wherein the fluid is administered at substantially constant pressure. 
     
     
         44 . The method of  claim 43 , wherein the organ is non-vascular, and the fluid is administered at a substantially constant pressure of about 5-100 mm Hg. 
     
     
         45 . The method of  claim 43 , wherein the organ is vascular, and the fluid is administered at a substantially constant pressure of about 5-400 mm Hg. 
     
     
         46 . The method of  claim 1 , wherein pressure is controlled, and the method further comprises substantially constant monitoring of the pressure during administration of the fluid. 
     
     
         47 . The method of  claim 1 , further comprising administering a pharmacological substance that improves opening of tight junctions. 
     
     
         48 . The method of  claim 1 , wherein the organ is a hollow viscus, and the method further comprises partially filling the hollow viscus with an inflatable space occupier before administering the fluid. 
     
     
         49 . The method of  claim 1 , wherein the pressure is controlled by creating a pressure gradient in a solid portion of the organ, wherein the pressure gradient is preselected to deliver the agent to the predetermined region. 
     
     
         50 . The method of  claim 49 , wherein the pressure gradient is highest inside the organ. 
     
     
         51 . The method of  claim 49 , wherein the pressure gradient is highest outside the organ. 
     
     
         52 . A method of determining a threshold pressure for selective administration of a therapeutic or diagnostic substance, the method comprising:
 isolating a hollow organ space;   one or more times, introducing a test fluid into the hollow organ space at a preselected flow rate; and   one or more times, administering a test solution to determine a pressure at which leakage across epithelial or endothelial tight junctions occurs; and   administering a liquid including the therapeutic or diagnostic substance by introducing the liquid into the isolated hollow organ space, during which the pressure is not exceeded with the purpose of preferentially delivering the substance to an epithelial layer of the hollow organ space, or during which the peak pressure is exceeded with the purpose of preferentially delivering the substance to a subepithelial layer of the hollow organ space.   
     
     
         53 . The method of  claim 52  wherein administering the liquid comprises administering the liquid at a pressure that at least temporarily exceeds the peak pressure, with the purpose of preferentially delivering the substance to the subepithelial or subendothelial layer. 
     
     
         54 . A method of determining the delivery pressure for selective administration of a therapeutic or diagnostic substance, the method comprising:
 isolating a hollow organ space;   one or more times, introducing a test fluid into the hollow organ space at a preselected approximately constant pressure;   one or more times, measuring the infusion rate of the administered fluid as the test fluid is introduced; and   administering a liquid including a test solution into the hollow organ space and determining a flow rate at which paracellular leakage across endothelial or epithelial tight junctions occurs.   
     
     
         55 . The method of  claim 52  wherein the test fluid has a viscosity substantially similar to that of the liquid containing the therapeutic or diagnostic substance. 
     
     
         56 . The method of  claim 52  wherein isolating the hollow organ space comprises introducing a catheter into the hollow organ space, and substantially sealing one or more outlets from the hollow organ space. 
     
     
         57 . A method of delivering a therapeutic or diagnostic substance, the method comprising:
 introducing a flexible catheter into an organ lumen lined with polar epithelial cells; and   infusing a therapeutic or diagnostic substance through the catheter into the organ lumen under preselected, controlled pressure conditions at which the therapeutic or diagnostic substance is delivered substantially only to apical surfaces of the epithelial cells and substantially not to any subepithelial regions.   
     
     
         58 . The method of  claim 57  wherein the organ lumen is an hepatic or biliary duct and the therapeutic or diagnostic substance is infused at a pressure sufficient to deliver the agent substantially only to cholangiocytes lining the hepatic or biliary duct. 
     
     
         59 . The method of  claim 57 , further comprising infusing the therapeutic or diagnostic substance into the organ lumen under pre-selected, controlled pressure conditions at which the therapeutic or diagnostic substance is delivered not only to apical surfaces of the epithelial cells but also to subepithelial regions including basal surfaces of the epithelial cells. 
     
     
         60 . The method of  claim 59  wherein the body lumen is an hepatic or biliary duct, and the therapeutic or diagnostic substance is infused at a sufficient pressure to deliver the agent to cholangiocytes, hepatocytes, or both. 
     
     
         61 - 69 . (canceled) 
     
     
         70 . A method of accessing an interior of a gall bladder, the method comprising:
 inserting a trochar into a cannula having first and second peripheral inflatable cuffs;   introducing the trochar, together with the cannula, at an insertion site through the wall of the gall bladder and advancing the cannula into the gall bladder such that the first inflatable cuff enters the gall bladder but the second inflatable cuff does not;   inflating the first cuff so that it abuts an inner face of the gall bladder around the insertion site; and   inflating the second cuff so that it abuts an outer face of the gall bladder around the insertion site.   
     
     
         71 . A method of delivering a therapeutic or diagnostic agent to a selected portion of the liver, the method comprising:
 introducing a catheter into a hepatic duct draining the selected portion of the liver;   occluding the duct normograde from a distal tip of the catheter; and   infusing the therapeutic or diagnostic agent through the catheter into at least a portion of the selected portion of the liver at a preselected pressure that has been determined to move the agent out of the duct and into the periductular tissue.   
     
     
         72 . The method of  claim 71 , wherein the hollow gastrointestinal viscus is an hepatobiliary duct, and the periductular tissue is hepatic tissue. 
     
     
         73 . The method of  claim 71  wherein the viscus has a vascular flow exiting therefrom, and the method further comprises at least partially occluding the vascular flow exiting from the viscus such that uptake of the agent in the viscus is enhanced. 
     
     
         74 . The method of  claim 73 , wherein the vascular flow is venous or lymphatic flow. 
     
     
         75 . The method of  claim 71 , wherein the viscus is at least a portion of at least one of a gallbladder, a pancreas, a liver, a bile duct, an intestine, a stomach, an esophagus, a trachea, a bronchus, a fallopian tube, a uterus, a cervix, a vagina, a duct of a parotid gland, a duct of a salivary gland, a prostate gland, a ureter, a urinary bladder, and a kidney of the patient. 
     
     
         76 . The method of  claim 71 , further comprising introducing into the viscus a pharmacological substance that tends to open tight junctions between epithelial cells. 
     
     
         77 . A method of introducing a therapeutic or diagnostic agent into a biological structure within the body, comprising introducing the agent into the biological structure in a liquid at a constant pressure. 
     
     
         78 . A method of increasing a size of a body duct or viscus, comprising forming an isolated chamber within the body duct or viscus, and introducing fluid under pressure into the isolated chamber to increase the size.