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.

Description

FIELD OF THE INVENTION[0001]This invention concerns selective delivery of therapeutic agents, such as drugs or genetic vectors, to specific organs, tissue compartments or cell types.BACKGROUND OF THE INVENTION[0002]Local delivery of therapeutic agents to target organs or tissues is a very desirable technique for delivering drugs with minimal side effects. U.S. Pat. No. 5,087,244 is an example of such targeted drug delivery, in which an endovascular catheter has a flexible balloon that is inflated to contact the internal walls of the vessel. A drug is then delivered through minute holes in the balloon, which is in intimate contact with the walls of the vessel. U.S. Pat. No. 5,282,785 discloses another endovascular drug delivery catheter, in which an expandable balloon brings a perforated drug delivery portion of the catheter into intimate contact with a radially restricted portion of the vessel wall, for transmural delivery of drugs through the contiguous catheter and lumen wall. See...

AI Technical Summary

Benefits of technology

[0007]Improved regional-, organ-, tissue-, and cell-specific delivery of therapeutic agents is achieved via infusion of therapeutic agents into body lumens (such as the gallbladder or hepatobiliary ducts, gastrointestinal tract, genitourinary tract, trachea, arteries, veins, or other ductular sites) under controlled pressures. In particular, it has been found that delivery of liquid agents to specific histological depths in the walls of the lumen (for example walls of an organ space) can be achieved by controlling the conditions (such as pressure / flow rate / volume) under which the agent is delivered to the lumen. Administration of the agent into a closed region of the hollow organ that is capable of being pressurized, at relatively low pressures, permits specific delivery of the agent to superficial layers of the organ, such as the apical surface of epithelial cells. Administration of the agent at least initially above a threshold higher pressure / flow rate / volume can disrupt microanatomic barriers, and selectively deliver the agent to deeper layers, such as the subepithelial space. Delivery into the subepithelial space permits access of the agent to the basal surface of the cell and other anatomic structures (such as the vascular sinusoids in the liver). Local administration of the drug in accordance with this invention can therefore permit site (and even cell type) specific drug delivery.

[0010]Another aspect of the invention is a method of delivering agents to a hollow, pressurizable organ cavity, such as the interior of a hollow viscus or the lumen of a duct, at a controlled or preselected pressure, that selectively targets either superficial internal cells (such as the apical surface of a polarized epithelium), or deeper histological regions (such as the subepithelial space) substantially without damaging the cells or causing significant systemic delivery of the agent. In particular embodiments, the preselected pressure is only slightly above a normal, physiologic intralumenal pressure, and is below the first pressure peak threshold (or in more specific embodiments below the second pressure peak threshold). The delivery pressure may be, for example, no more than about 2-5 mm Hg above the normal physiologic intralumenal pressure to achieve specific epithelial delivery. In certain embodiments, for non-vascular delivery the constant pressure is 5-100 mm Hg (for example 25-75 or about 50 mm Hg, or at least 5, 25, 50 or 100 mm Hg), and for vascular delivery the constant pressure is 5400 mm Hg (for example 5-200 mm Hg, 5-100 mm Hg, or at least 5, 25, 50 or 100 mm Hg). In specific embodiments, the delivery pressure is below a threshold pressure for disruption of microanatomic structures such as tight junctions between the epithelial cells that inhibit access of the agent to the subepithelial space under normal physiological conditions.

[0012]In vascular surgery creating an anastomosis between two vessels is often complicated by a disparity in diameter between the donor and recipient vessels. Similarly, surgical reversal of a vasectomy or an ovarian tubal ligation is complicated by having to locate portions of the vas deferens or fallopian tubes that are sufficiently wide to permit effective rejoining. A mechanism for achieving expansion of tubular structures would therefore be clinically useful and helpful. Devices of the present invention can be used to expand a tubular structure (such as a blood vessel or duct) or viscus to a predetermined cross-sectional target diameter. Such expansion can be performed either in vivo or ex vivo, with subsequent anastomosis between donor and recipient structures. In another embodiment of the invention, this expansion is combined with continuous intralumenal infusion of drugs, genetic vectors, or other therapeutic agents to the donor and / or recipient structures.

[0017]There are also instances in which systemic delivery of drugs via high pressure infusion is desired. The method of the invention could be used as a substitute for invasive vascular procedures, such as direct intra-arterial delivery of chemotherapeutic substances. Instead of intravascular delivery (and the attendant problem of thrombosis), direct delivery to organs can be achieved by introduction of the agent into a hollow, pressurized viscus or duct (such as the hepatobiliary tree or parotid duct) at a pressure that is intended to provide subepithelial delivery. Avoidance of intravascular administration (as in hepatic artery infusion) for targeted delivery eliminates the problems of endothelial damage and attendant morbidity, while also avoiding the more widespread systemic delivery that is inherent when any drug is delivered directly into the cardiovascular system. It is also possible to combine intrabiliary delivery with temporary occlusion of venous or lymphatic drainage, to further isolate the organ and prevent widespread systemic administration of a drug, even when it is introduced at a sufficient pressure to provide subepithelial delivery of the drug.

[0024]The process of the present invention may include sealing, evacuating and rinsing the targeted body lumen, followed by infusion of the therapeutic substance under controlled conditions as above. After infusion, any remaining infusate may be aspirated, further reducing potential systemic effects.

[0025]Pressure itself may also facilitate cell transport processes and this may be utilized for improved delivery. For example, constant rate and constant pressure intralumenal infusion may be utilized to enhance uptake via the apical membrane surface of epithelial and / or endothelial cells. Alternatively, constant rate and constant pressure intralumenal infusion may also be utilized to enhance transcytosis of molecules from the apical to basal or basolateral cell surface.

Problems solved by technology

Administration of the agent at least initially above a threshold higher pressure / flow rate / volume can disrupt microanatomic barriers, and selectively deliver the agent to deeper layers, such as the subepithelial space.

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