Methods, devices, and systems for treating neointimal growth

Abstract

The present invention generally relates to pharmaceutical compositions, methods, and devices / systems for treating vascular diseases. More particularly, the present invention relates to medical methods, devices, and kits for delivering drugs to peripheral vascular tissue to treat neointimal growth. More specifically, the present invention described herein is intended to overcome the drawbacks of existing treatments for peripheral artery disease (PAD). The devices and methods of the present invention are for reducing one or more pathological conditions; reducing treatment complications in the treated patient population, reducing the target lesion revascularization (TLR) rate; and reducing the patient population that requires any type of leg amputation, particularly for patients with PAD associated with infrapopliteal (tibial) arteries, such as patients with clinical indications for treatment below the knee (e.g., claudication and / or critical limb ischemia (CLI)) for treatment below the knee, and patients with complex pathologies are specifically contemplated.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 330,949, filed Apr. 14, 2022, which is incorporated herein by reference.

[0002] Field of the Invention The present invention generally relates to pharmaceutical compositions, methods, and devices / systems for treating vascular diseases. More particularly, the present invention relates to medical methods, devices, and kits for distributing drugs to peripheral vascular tissue to treat neointimal growth. More specifically, the described invention is intended to overcome the drawbacks of existing treatments for peripheral artery disease (PAD). The devices and methods of the present invention are for reducing one or more pathological conditions; for reducing treatment complications in treated patient populations, for reducing the target lesion revascularization (TLR) rate; and for reducing the patient population that requires any type of leg amputation, particularly for patients with PAD related to below - the - knee (tibial) arteries, e.g., patients having clinical indications (e.g., claudication and / or critical limb ischemia (CLI)) for below - the - knee treatment, and patients having complex pathologies.

Background Art

[0003] Occlusions can result from blood vessels under various pathological conditions. In atherosclerosis, the narrowing of arteries in the body, particularly in the heart, legs, carotid arteries, and renal anatomy, can lead to tissue ischemia from insufficient blood flow. Mechanical revascularization methods such as balloon angioplasty, atherectomy, stent placement, or surgical endarterectomy can be used on blood vessels to dilate the vessels and improve blood flow to downstream tissues. Unfortunately, mechanical revascularization can initiate a cascade of damage that hardens the blood vessels and thickens the vessel wall with scar - like tissue, which can reduce blood flow and may require another revascularization method. Furthermore, although some drug delivery devices have been shown to be effective in treating lesions above the knee, these devices, for example, were unable to effectively treat small blood vessels below the knee. Importantly, current devices have a fixed length and thus, without relying on using multiple types of devices or devices of different lengths, the same device cannot treat lesions of various lengths. Therefore, there is a need for treating blood vessels to reduce hardening and thickening of blood vessels after mechanical revascularization in order to maintain or improve blood vessel patency. SUMMARY OF THE INVENTION

[0004] The present invention generally relates to pharmaceutical compositions, methods, and devices / systems for treating vascular diseases. More particularly, the present invention relates to medical methods, devices, and kits for distributing drugs to peripheral vascular tissue to treat neointimal growth. More specifically, the described present invention is intended to overcome the drawbacks of existing treatments for peripheral artery disease (PAD). The devices and methods of the present invention are for reducing one or more pathological conditions; reducing treatment complications in the treated patient population, reducing the target lesion revascularization (TLR) rate; and reducing the patient population that requires any type of leg amputation, particularly for patients with PAD related to below-the-knee (tibial) arteries, for example, patients having clinical indications for below-the-knee treatments (e.g., claudication and / or critical limb ischemia (CLI)), and patients having complex pathological conditions.

[0005] Occlusions can result from blood vessels under various pathological conditions. Atherosclerosis, which causes narrowing or stenosis of arteries in the body, particularly in the heart, legs, carotid arteries, and renal anatomy, can lead to tissue ischemia from insufficient blood flow. Atherosclerosis in the coronary arteries can cause myocardial infarction, commonly known as a heart attack, which can be immediately fatal or, even if the patient survives, can cause damage to the heart that can incapacitate the patient. Other coronary artery diseases include congestive heart failure, vulnerable or unstable plaques, and cardiac arrhythmias that cause death and incapacitation. In addition, peripheral artery disease or PAD, where the arteries in the peripheral tissues narrow, most commonly affects the legs, kidneys, and carotid arteries. Blood clots and thrombi, such as debris, in the peripheral vasculature can flow to other parts of the body and cause tissue and organ necrosis. Some patients with PAD develop ulcers and, in the worst cases, experience severe lower limb ischemia where partial or complete leg amputation may be required. PAD in the renal arteries can cause renovascular hypertension, while clotting in the carotid arteries can form emboli that migrate to the brain and, in some cases, cause ischemic stroke.

[0006] Current methods of vascular treatment are such that they cause mechanical damage to tissue; require high doses of active ingredients to be effective and thus increase the risk of side effects; do not evenly distribute drugs on the surface of the target tissue; generate different types of debris due to the placement of the device, including but not limited to, peeling of the drug coating material from drug-coated devices, and debris release (use of non-water-soluble solid drug components pressed against the tissue wall to treat the target lesion, disrupted cellular components and / or basement membrane from the manipulated tissue); and they fail because they coat the device, which generally requires excipients to attach the drug to the device, and the drug coating is inconsistent and, for example, non-uniform on the device. Some drug delivery devices have been shown to be effective in treating some lesions, but such devices have been unable to effectively treat small blood vessels.

[0007] The present invention described herein is intended to address the above-mentioned drawbacks of existing treatments. Embodiments have clinical applications for patients with, for example, lower extremity peripheral artery disease (PAD), intermittent claudication, which literally means "dragging the feet," which is one of the symptoms of severe limb ischemia (CLI) that significantly reduces blood flow due to severe blockage of the arteries in the lower extremities, and patients with PAD associated with complex medical conditions such as coronary artery disease (CAD), PAD with diabetes, specifically intended to treat patients with PAD related to the infrapopliteal (tibial) artery. Advantages of using the devices, systems, and methods described herein include, but are not limited to, reduction of pathological conditions and complications in the patient population being treated, for example, excellent patency at six months with a reduction in the target lesion revascularization (TLR) rate; reduction of the patient population that requires some type of leg amputation, and the like. "Target lesion revascularization" refers to any method performed to restore vessel patency after late vascular loss due to in-stent restenosis (ISR).

[0008] The specific embodiments described below have a number of advantages, including a) removal of drug balloon decoration, b) easy formulation, c) no need for preparation or synthesis of a drug carrier, d) high output, or bioavailability, e) rapid delivery, and f) easy handling. In addition, the techniques described below minimize i) particle loss, ii) mechanical stress applied to the vessel during treatment, and iii) exposure to the drug and the total drug required, reducing side effects.

[0009] In some embodiments, the present invention contemplates stopping blood flow to treat a target tissue. Since the vasculature is a closed system, blood flow may be stopped by distal (downstream) or proximal (upstream) blood flow occlusion (or both). Thus, in one embodiment, the present invention is a method of treating a target tissue exhibiting neointimal growth in a blood vessel of a subject, comprising: a) occluding the blood vessel in the subject with a device, at least a portion of the device being disposed downstream of the target tissue exhibiting neointimal growth, the portion stopping blood flow at the distal end of the blood vessel; b) introducing a treatment solution containing a growth inhibitor or other drug to contact the target tissue for a period of time (e.g., 1 to 100 minutes, more typically 2 to 30 minutes), and c) removing the device from the blood vessel, thereby restoring blood flow at the distal end of the blood vessel. In one embodiment, the growth inhibitor is sirolimus. In one embodiment, sirolimus is introduced into or onto nanoparticles. In one embodiment, sirolimus is incorporated during nanoparticle generation. In one embodiment, sirolimus is encapsulated in a plurality of nanoparticles. In one embodiment, sirolimus is encapsulated in gelatin nanoparticles (GNPs).

[0010] In another embodiment, the present invention is a method for treating target tissue indicative of neointimal growth in a blood vessel of a subject, comprising: a) occluding the blood vessel in the subject with a device, at least a portion of the device being disposed upstream of the target tissue indicative of neointimal growth, and the portion stopping blood flow at the proximal end of the blood vessel; b) introducing a treatment solution containing a growth inhibitor to contact the target tissue for a certain period (e.g., 1 to 100 minutes, more typically 2 to 30 minutes), and c) removing the device from the blood vessel, thereby restoring blood flow at the distal end of the blood vessel. The present invention is not intended to be limited to specific growth inhibitors or treatment solutions for these embodiments. In one embodiment, the growth inhibitor is paclitaxel. In another embodiment, the growth inhibitor is sirolimus (also known as rapamycin). In one embodiment, rapamycin is present in a treatment solution containing dimethyl sulfoxide (DMSO). In one embodiment, rapamycin is introduced into or onto nanoparticles. In one embodiment, rapamycin is incorporated during nanoparticle generation. In one embodiment, rapamycin is made into a plurality of nanoparticles. In one embodiment, rapamycin is encapsulated in gelatin nanoparticles (GNP). In a preferred embodiment, the treatment solution in step b) immerses the target tissue such that the treatment solution (or a portion thereof) penetrates the tissue and allows the drug to enter the blood vessel, e.g., the vessel wall. In one embodiment, the device is a hypodermic tube containing a channel. In one embodiment, the hypodermic tube further includes one or more openings, e.g., holes such as pores. In a preferred embodiment, the treatment solution is introduced through the channel of the hypodermic tube and released to the target tissue through the opening, e.g., the pore. In one embodiment, the hypodermic tube is at least partially covered by a restraining catheter. In one embodiment, the present invention further contemplates moving the restraining catheter to limit or increase the amount and location of the therapeutic agent eluted by the hypodermic tube, thereby allowing for various lengths of blood vessels and lesions therein.In other words, in one embodiment, the present invention uses one device / system to provide treatment for different lesion lengths by expanding and contracting a hollow restriction catheter on a hypo tube containing holes, so that drug discharge of various lengths is possible from the opening holes not covered by the surrounding restriction catheter. In one embodiment, the device is a hypo tube having a filter. In one embodiment, the filter is deployed like an umbrella at the distal end and stops blood flow at the distal end. In one embodiment, the filter is deployed like an umbrella at the proximal end and stops blood flow at the proximal end.

[0011] Regardless of whether it is deployed at the distal end or the proximal end, the filter can also function to stop particles, such as potential emboli, from escaping from the target site. In one embodiment, the blood vessel includes a partial or complete occlusion in or near the target tissue. In one embodiment, the method further includes performing a procedure to remove or reduce the occlusion before step b) of any of the above embodiments. The present invention is not intended to be limited by the nature of the procedure for removing or reducing the occlusion. In one embodiment, the procedure is a chemical procedure that dissolves at least a part of the occlusion, for example, removal of calcification using a chemical procedure (further discussed below). In one embodiment, the chemical procedure includes delivering a chemical substance through the channel of the hypo tube for a certain period (e.g., 1 to 100 minutes, more typically 2 to 30 minutes), and the hypo tube further includes holes, such as pores, so that the occlusion is perfused by the chemical substance entering through the pores. Without intending to be limited to chemical substances, non-limiting examples include amines and alcohol-based solvents, chelating agents, papain enzymes, and the like. Non-limiting examples of amine-based compounds include, but are not limited to, urazole, glutamic acid, solvents such as ethanol containing octanol or octanediol, and the like. Non-limiting examples of chelating agents include, but are not limited to, disodium ethylenediaminetetraacetate (EDTRA), diethylenetriaminepentaacetic acid (DTPA), and sodium thiosulfate (STS), and the like.

[0012] In another embodiment, the procedure is a surgical procedure. In one embodiment, the surgical procedure is an angioplasty. In another embodiment, the surgical procedure is an atherectomy. In one embodiment, the atherectomy is selected from the group consisting of rotational atherectomy, transcatheter atherectomy, and directional coronary atherectomy. In one embodiment, the method (any of the methods of the above embodiments) further comprises, prior to step b), removing particles generated by the procedure after performing the procedure that removes or reduces the occlusion. The particles can be removed in various ways and by combinations of methods. In one embodiment, the particles are potential emboli and they are removed by a drainage catheter. In one embodiment, the particles are blocked by the filter (described above) and are removed when the filter is removed. In one embodiment, the particles are removed by both a drainage catheter and the filter. The present invention is not intended to be limited to the nature or size of the vessels treated in any of the above embodiments. The present invention contemplates treating vessels (arterial or venous) in the arms, legs and torso of animals and humans. However, in a preferred embodiment, the treatment is contemplated with respect to the vessels (arteries and veins) shown in FIG. 28, particularly the vessels below the knee region and below.

[0013] For example, in any of the above embodiments, the treatment can be performed on the popliteal artery or vein. Similarly, in any of the above embodiments, the treatment can be performed on the tibial artery or vein. Typically, for any of the above embodiments, the target tissue showing neointimal growth is in the vessels below the knee of the subject. In one embodiment, the portion of the device disposed downstream of the target tissue showing neointimal growth is a distal balloon that is inflated to stop blood flow at the distal end of the vessel. In one embodiment, the portion of the device disposed upstream of the target tissue showing neointimal growth is a proximal balloon that is inflated to stop blood flow at the proximal end of the vessel. In other embodiments including a distal balloon, the device also has a connected proximal balloon disposed upstream to block proximal blood flow.

[0014] As described above, in some embodiments, the present invention contemplates stopping blood flow to treat a target tissue. Since the vasculature is a closed system, blood flow may be stopped by distal (downstream) or proximal (upstream) blood flow occlusion. Thus, in one embodiment, the present invention is a method of treating a target tissue exhibiting neointimal growth in a blood vessel of a subject, comprising: a) occluding the blood vessel in the subject with a device, wherein at least a portion of the device is disposed upstream of the target tissue or downstream of the target tissue exhibiting neointimal growth, and the portion stops blood flow at either the proximal or distal end of the blood vessel; b) introducing a treatment solution comprising rapamycin and dimethyl sulfoxide (DMSO) to contact the target tissue for a period of time (e.g., 1 to 100 minutes, more typically 2 to 30 minutes), and c) removing the device from the blood vessel, thereby restoring blood flow at the distal end of the blood vessel. In a preferred embodiment, the treatment solution in step b) immerses the target tissue such that the treatment solution (or a portion thereof) penetrates the tissue and allows the drug to enter the blood vessel, e.g., the vessel wall. In one embodiment, rapamycin is introduced into or onto nanoparticles. In one embodiment, rapamycin is incorporated during nanoparticle generation. In one embodiment, rapamycin is encapsulated in a plurality of nanoparticles. In one embodiment, rapamycin is encapsulated in gelatin nanoparticles (GNPs). In one embodiment, the device is a hypodermic tube comprising a channel. In one embodiment, the hypodermic tube further comprises one or more openings, e.g., holes such as pores. In a preferred embodiment, the treatment solution is introduced through the channel of the hypodermic tube and released to the target tissue through the opening, e.g., the pore. In one embodiment, the hypodermic tube is at least partially covered by a restrictive catheter. In one embodiment, the present invention further contemplates moving the restrictive catheter to limit or increase the amount and location of the therapeutic agent eluted by the hypodermic tube, thereby allowing for various lengths of blood vessels and lesions therein.In other words, by using one device / system, in order to provide a therapeutic agent to different lesion lengths, by expanding and contracting a hollow restrictive catheter on a hypo-tube including holes, drug discharge of various lengths becomes possible from the opening holes not covered by the surrounding catheter. In one embodiment, the device is a hypo-tube having a filter. In one embodiment, the filter is deployed like an umbrella at the distal end and stops blood flow at the distal end. In one embodiment, the filter is deployed like an umbrella at the proximal end and stops blood flow at the proximal end. Regardless of whether it is deployed at the distal end or the proximal end, the filter can also function to stop particles, for example, potential emboli, from escaping from the target site. In one embodiment, the blood vessel includes a partial or complete occlusion in or near the target tissue. In one embodiment, the method further includes performing a procedure to remove or reduce the occlusion before step b) of any of the above embodiments. The present invention is not intended to be limited by the nature of the procedure for removing or reducing the occlusion. In one embodiment, the procedure is a chemical procedure that dissolves at least a part of the occlusion, for example, removal of calcification using a chemical method. In one embodiment, the chemical procedure includes delivering a chemical substance through the channel of the hypo-tube for a certain period (for example, 1 to 100 minutes, more typically 2 to 30 minutes), and the hypo-tube further includes holes, for example, pores, such that the occlusion is perfused by the chemical substance entering through the pores. In another embodiment, the procedure is a surgical operation. In one embodiment, the surgical operation is an angioplasty. In another embodiment, the surgical operation is an atherectomy. In one embodiment, the atherectomy is selected from the group consisting of rotational atherectomy, transcatheter atherectomy, and directional coronary atherectomy. In one embodiment, the method (any method of the above embodiments) further includes removing the particles generated by the procedure after performing the procedure to remove or reduce the occlusion before step b). The particles can be removed in various ways and by combinations of methods. In one embodiment, the particles are potential emboli and they are removed by a drainage catheter.In one embodiment, the particles are blocked by the filter (described above) and are removed when the filter is removed. In one embodiment, the particles are removed by both the drainage catheter and the filter. The present invention is not intended to be limited to the nature or size of the blood vessels treated in any of the above embodiments. The present invention contemplates treating blood vessels (arteries or veins) in the arms, legs, and torso of animals and humans. However, in a preferred embodiment, the treatment is contemplated with respect to the blood vessels (arteries and veins) shown in FIG. 28, particularly the blood vessels in and below the knee region.

[0015] For example, in any of the above embodiments, the treatment can be performed on the popliteal artery or vein. Similarly, in any of the above embodiments, the treatment can be performed on the tibial artery or vein. Typically, for any of the above embodiments, the target tissue exhibiting neointimal growth is in the blood vessels below the knee of the subject. In one embodiment, the portion of the device disposed downstream of the target tissue exhibiting neointimal growth is a distal balloon that is inflated to stop blood flow at the distal end of the blood vessel. In one embodiment, the portion of the device disposed upstream of the target tissue exhibiting neointimal growth is a proximal balloon that is inflated to stop blood flow at the proximal end of the blood vessel. In other embodiments including a distal balloon, the device also has a connected proximal balloon disposed upstream to block proximal blood flow.

[0016] Again, as described above, in some embodiments, the present invention contemplates stopping blood flow to treat a target tissue. Since the vasculature is a closed system, blood flow may be stopped with a distal (downstream) or proximal (upstream) blood flow occlusion, e.g., a distal or proximal balloon (or both) that expands to stop blood flow. Thus, in one embodiment, the present invention is a method of treating a target tissue exhibiting neointimal growth in a blood vessel of a subject, the method comprising: a) providing a device comprising a hypodermic tube including a channel and holes such as one or more openings or pores, the hypodermic tube having a connected distal (or proximal) balloon; b) introducing the device into the blood vessel of the subject, at least a portion of the device being disposed downstream of the target tissue exhibiting neointimal growth, the portion including the connected distal balloon (or, in another embodiment, disposing a proximal balloon upstream of the target tissue); c) inflating the connected distal (or proximal) balloon, thereby stopping blood flow at the distal end of the blood vessel; d) introducing a treatment solution containing a growth inhibitor into the hypodermic tube and through the pores such that the treatment solution contacts the target tissue for a period of time (e.g., 1 to 100 minutes, more typically 2 to 30 minutes); and e) deflating the connected distal (or proximal) balloon and removing the device from the blood vessel, thereby restoring blood flow in the blood vessel. The present invention is not intended to be limited to specific growth inhibitors or treatment solutions with respect to these embodiments. In one embodiment, the growth inhibitor is paclitaxel. In another embodiment, the growth inhibitor is rapamycin. In one embodiment, rapamycin is introduced into or onto nanoparticles. In one embodiment, rapamycin is incorporated during nanoparticle generation. In one embodiment, rapamycin is encapsulated in a plurality of nanoparticles. In one embodiment, rapamycin is encapsulated in gelatin nanoparticles (GNPs). In one embodiment, the rapamycin is present in a treatment solution containing dimethyl sulfoxide (DMSO).In a preferred embodiment, the treatment solution in step b) immerses the target tissue such that the treatment solution (or a portion thereof) penetrates the tissue and enables the drug to enter blood vessels, such as the vessel wall. In one embodiment, the hypo tube is at least partially covered by a limiting catheter. In one embodiment, the present invention further contemplates moving the limiting catheter to limit or increase the amount of therapeutic agent eluted by the hypo tube and the position of the therapeutic agent, thereby allowing for various lengths of blood vessels and lesions therein. In other words, by using one device / system, the telescoping of a hollow limiting catheter on a hypo tube containing holes allows for drug discharge of various lengths from the aperture openings not covered by the surrounding catheter to provide treatment agents for different lesion lengths. In one embodiment, the hypo tube further includes a filter. Regardless of deployment at the distal or proximal end, the filter can also function to prevent particles, such as potential emboli, from escaping the target site. In one embodiment, the blood vessel includes a partial or complete occlusion in or near the target tissue. In one embodiment, the blood vessel includes a partial or complete occlusion in or near the target tissue. In one embodiment, the method further includes performing a procedure to remove or reduce the occlusion prior to step d) of the above embodiments. The present invention is not intended to be limited by the nature of the procedure for removing or reducing the occlusion. In one embodiment, the method is a chemical procedure that dissolves at least a portion of the occlusion, such as the removal of calcification using a chemical method. In one embodiment, the chemical procedure includes delivering a chemical substance through the channel of the hypo tube and one or more of the openings in the hypo tube for a period of time (e.g., 1 to 100 minutes, more typically 2 to 30 minutes), and the openings further include holes, such as pores, such that the occlusion is perfused by the chemical substance entering through the pores. In another embodiment, the procedure is a surgical operation. In one embodiment, the surgical operation is an angioplasty. In another embodiment, the surgical operation is an atherectomy. In one embodiment, the atherectomy is selected from the group consisting of rotational atherectomy, transcatheter atherectomy, and directional coronary atherectomy.In one embodiment, the method (any method of the above embodiments) further comprises removing the particles generated by the procedure after performing the method of removing or reducing the occlusion and before step d). The particles can be removed in various ways and by combinations of methods. In one embodiment, the particles are potential emboli and they are removed by a drainage catheter. In one embodiment, the particles are blocked by the filter (described above) and are removed when the filter is removed. In one embodiment, the particles are removed by both a drainage catheter and the filter. The present invention is not intended to be limited to the nature or size of the blood vessels treated in any of the above embodiments. The present invention contemplates treating blood vessels (arteries or veins) in the arms, legs and torso of animals and humans. The present invention is not intended to be limited to the means by which the balloon is deflated. In one embodiment, deflation is performed by aspirating the saline present in the inflated balloon.

[0017] However, in a preferred embodiment, the treatment is contemplated with respect to the blood vessels (arteries and veins) shown in FIG. 28, particularly the blood vessels in the knee region and below. For example, in any of the above embodiments, the treatment can be performed on the popliteal artery or vein. Similarly, in any of the above embodiments, the treatment can be performed on the tibial artery or vein. Typically, for any of the above embodiments, the target tissue exhibiting neointimal growth is in the blood vessels below the knee of the subject. In one embodiment, the device disposed downstream of the target tissue exhibiting neointimal growth is a distal balloon that is inflated to stop blood flow at the distal end of the blood vessel. In one embodiment, the device disposed upstream of the target tissue exhibiting neointimal growth is a proximal balloon that is inflated to stop blood flow at the proximal end of the blood vessel. In other embodiments including a distal balloon, the device also has an associated proximal balloon disposed upstream to block proximal blood flow.

[0018] In one embodiment, the present invention contemplates a system or kit that includes: i) a hypodermic tube having a channel and one or more openings, such as pores, and having a connected distal balloon and / or a connected proximal balloon; ii) a drainage catheter having an opening cavity into an inner portion between the distal and proximal balloons; and iii) a limiting catheter that allows for various lengths to accommodate different lesion lengths. In one embodiment, the limiting catheter is configured like a cover or sheet over a smaller hypodermic tube that delivers a therapeutic agent. The limiting catheter can be moved substantially distally relative to the distal balloon to limit the amount and location of the therapeutic agent eluted by the hypodermic tube, thereby allowing for various lengths of blood vessels and the lesions therein. As an example, if the target lesion is only 20 mm in length, the limiting catheter can adjust the length of the hypodermic tube that releases the therapeutic agent. If the lesion is quite long, e.g., 150 mm, more pores in the hypodermic tube are exposed, and thereby the limiting catheter can be retracted to release the therapeutic agent (in the treatment solution) over a longer length.

[0019] In another embodiment, the present invention contemplates a device that includes a combination of a wire and a hypodermic tube with a balloon or other mechanical occlusion device attached to the distal end. The small hypodermic tube surrounding the wire is used to deliver a drug through a plurality of holes (pores), i.e., through the perforated hypodermic tube. As the drug flows through the hypodermic tube, the drug elutes into the vasculature including blood. An additional feature of this device is a means to vary the length or distance into the vasculature that the drug is introduced, and thus enable treatment of lesions of different lengths using the same device. In a further embodiment, an additional tube, e.g., a limiting catheter, is provided to block the flow of a treatment solution (e.g., DMSO + rapamycin) to avoid treatment of that portion of the blood vessel and then to surround a portion of the perforated hypodermic tube to cover some of the holes in the hypodermic tube that target treatment of a specific length of blood vessel. Figure 5 is an illustration of an example of this type of embodiment. In one embodiment, the balloon is moved proximally to prevent blood flow. In some embodiments, the filter is disposed distally from the balloon to prevent embolisms. FIG. 6 is an illustration of one embodiment of this type. In one embodiment, the balloon is disposed proximally to prevent blood flow and the distal hypo-tube having a perforated sidewall perfuses the drug into the blood vessel. FIG. 7 is an illustration of one embodiment of this type.

[0020] In one embodiment, the device and / or system further includes one or more hypo-tubes, wires, balloons, along with a micro-catheter as an occlusion mechanism at the distal end of the treatment region, and the balloon occludes the proximal end of the treatment region. In further embodiments, the catheter extrudes a treatment formulation into a targeted vascular region for treatment. In some embodiments, a radiopaque substance in a fluid, such as iodine, may be added to the DMSO + rapamycin formulation, and pieces of radiopaque substance adhering to the wire, catheter, inside of the balloon, etc., provide a means for the clinician to clearly identify the region of the blood vessel being treated during the procedure using an X-ray or other radiation emitting device. The radiopaque substance includes, but is not limited to, small molecular weight salts or compounds or nanoparticles containing iodine, barium, tantalum, bismuth, or gold. FIG. 8 is an illustration of one embodiment of this type.

[0021] Furthermore, embodiments of the device include a drainage catheter for the removal of thrombi or emboli after completion of the treatment procedure (irrespective of whether chemically or surgically related). The catheter may also be used in place of a hypo-tube to deploy a fluid, such as a drug solution, and to drain residual blood or treatment remnants within the treatment region, such as emboli, debris, etc. The distance of the catheter from the balloon is adjusted to accommodate treatment of lesions of different lengths. In one embodiment, the device further includes an additional mechanism of a balloon surrounding the hypodermic tube or catheter for a method that ensures blood drainage, drug delivery to the target blister wall region, and removal of the drug solution after treatment (in addition to the mechanisms illustrated by FIGS. 3-7). Exemplary FIG. 9 is an explanatory diagram of one embodiment of this type. In one embodiment, the device includes three balloons along a wire with a proximal balloon surrounding the tube for use in a method of treatment, the method comprising inflating a central balloon to drain blood in a region designated for treatment, then inflating two end balloons to block the vascular treatment region, and then deflating the central balloon while filling the void with a fluid introduced through the tube, e.g., a drug solution. In other words, in the first stage: Step 1: the central balloon is inflated to drain any blood area, and in Step 2, the distal and proximal balloons are inflated. The second stage may include deflating the central balloon and introducing a drug formulation into the central region (hatched area) after draining the blood. FIG. 10 is an illustration of one embodiment of this type. The present invention is not intended to be limited to the means by which the balloon is deflated. In one embodiment, deflation is effected by aspirating the saline present in the inflated balloon.

[0022] In one embodiment, the device is formed between two balloons and includes a hollow void (hard boundary) that exists longitudinally between the upper portions of these two balloons along with a void that is longitudinally positioned between these two balloons and allows blood flow between the balloons. Each balloon has a plurality of holes, for example, pores, along their luminal sides and is filled with a drug solution, for example, a sirolimus solution in 100% DMSO or a mixture of DMSO and saline, and there is little leakage from the holes when moving through the blood vessel to the treatment area. When the device is deployed at the location where it is held in place, the balloons expand just sufficiently and simultaneously so that the side walls with holes come into firm contact with the blood vessel wall, and then a pressure, for example, an extrusion force, is generated to allow the balloons to expand and inject the drug solution from the balloons into the blood vessel wall tissue through the holes. The absorption of DMSO into the blood vessel wall 20 is intended to be rapid with high delivery efficiency. The void between the two balloon tubes is sufficient to allow a continuous blood through-flow that must ensure that the drug solution does not come into contact with the blood flow, and thus there is no loss of drug due to the flushing of blood flow through this region compared to the losses using conventional drug-coated balloons (DCBs). FIG. 11 is an illustration of an example of this type of embodiment.

[0023] In one embodiment, a delivery system includes a medical-grade flexible hollow plastic tube with pores drilled in the outer circumference of the tube and a fluid-impermeable end enclosure. When filled with a fluid, such as a DMSO drug formulation, a delivery system is provided in which the fluid does not move through the pores. When deployed in the treatment area, the pores are adjacent to the blood vessel wall and not in the main flow of blood. Such a plastic hollow tube, when deployed in a blood vessel, has an outer boundary made of a very thin, flexible plastic or fabric (impermeable to the fluid) that responds to shear pressure generated by the blood flow in the central region. The hydrostatic pressure of the blood presses the outer region of the tube material against the blood vessel wall, and at the same time, presses the drug formulation against the blood vessel wall tissue through the pores. In other words, after slowly moving the blood through the narrow opening during deployment and then holding the tube in place, when the blood presses against the blood vessel wall for delivery of the active agent, the blood enters the larger and more extensive opening with greater force and volume, and the tube begins to contract due to the loss of fluid introduced into the peripheral blood vessel tissue. FIG. 12 is an illustration of an example of this type of embodiment.

[0024] In one embodiment, for the treatment of a hypertrophied blood vessel wall region, such as an atherosclerotic plaque, PAD, etc., a treatment method using the device described herein includes the preparation of a blood vessel wall covered with plaque intended for a treatment in the form of restoring blood flow through the plaque using either angioplasty or atherectomy. Thus, in a preferred embodiment, the treatment method incorporates angioplasty or atherectomy prior to treatment with the device described herein to combine the complete procedure with the method of using the device. In one embodiment, atherectomy includes, but is not limited to, rotational atherectomy, transcatheter atherectomy, and directional coronary atherectomy. In one embodiment, atherectomy is used for applications below the knee.

[0025] There are at least two ways to stop the migration of emboli distally occurring in the limbs to the devices used for treatment. One is blood filtration, in other words, filtration using a device with a filter attached or a device with a distal protection filter. One is the removal of disrupted tissue using a catheter so as not to allow the distal migration of emboli downstream of the blood flow. Another method is a method by using a method for treating atherosclerosis, which includes a chemical method of dissolving or removing atherosclerotic plaques in combination with delivering a treatment to the vessel wall in contact with the plaque using the device described herein. In one embodiment, the device described herein having pores or holes on its outer surface provides a large amount of chemical substances through a hypodermic tube (injection through the central part of the hypodermic tube and perfusion into the blood vessel through the fine holes (pores) shown in FIG. 12). The injection is carried out for a period long enough for the chemical agent to dissolve the target lesion (for example, 1 to 100 minutes, more typically 2 to 30 minutes), but short enough not to cause clinical problems associated with blood flow cessation. When sufficient disintegration of the target lesion is achieved, the fragmented lesion is discharged through a drainage catheter. When the lesion is removed, the flow recovers sufficiently, the particles / emboli are discharged, and then the drug solution can be injected into the target area. An aspect of this embodiment includes a hypodermic tube to maintain a low-profile delivery system and also enables passage through difficult lesions, also known as "pushability". The drainage catheter includes an opening cavity in the inner part between two balloons to remove blood and emboli, and its connected proximal balloon to stop the flow. Another aspect of this embodiment is a restraining catheter that stretches (slides) over a hypodermic tube containing pores to enable drug discharge of various lengths from the opening holes not covered by the surrounding catheter to provide therapeutic agents for different lesion lengths using one device / system. FIG. 13 is an illustration of an embodiment of this type.

[0026] For a better understanding of the mechanisms and advantages of the present disclosure, reference is also made to other subsections, including the detailed description of exemplary embodiments of devices, systems, compositions, and methods of treatment, and to the accompanying drawings. Further, the compositions and methods described herein, including the treatment of patients with DMSO as part of a pharmaceutical formulation, may also include commercially available devices in which exemplary elements are described herein and shown in the figures.

[0027] In one embodiment, the present invention contemplates a delivery system comprising a delivery device including first, second, and third ports, wherein the first port is configured to supply fluid through a first channel to inflate an angioplasty balloon, the second port is configured to supply fluid through a second channel to inflate a distal balloon to block blood flow, and the third port is configured to supply fluid through a third channel in the hypodermic tube to supply a treatment solution to a blood vessel. In one embodiment, the treatment solution comprises rapamycin encapsulated in a nanocarrier. In one embodiment, the channels are disposed within a hypodermic tube. FIG. 29 is an illustration of one embodiment of this type.

[0028] In another embodiment, the present invention contemplates a delivery system comprising a delivery device including first, second, and third ports, wherein the first port is configured to supply fluid through a first channel in a hypodermic tube to inflate an angioplasty balloon, the second port is configured to supply fluid through a second channel in the hypodermic tube to inflate a distal balloon to block blood flow, and the third port is configured to supply fluid through a third channel in the hypodermic tube to supply a treatment solution to a blood vessel. In one embodiment, the treatment solution comprises rapamycin encapsulated in a nanocarrier.

[0029] The following embodiments are merely illustrative. One or more embodiments may be combined to provide devices, treatment steps, and to overcome or solve problems associated with current devices and treatments, including but not limited to, PAD and other medical treatments of blisters, and the use of current devices and treatments. This patent or application file contains at least one color drawing. Copies of this patent or patent application publication, which include a color drawing(s), will be provided by the United States Patent and Trademark Office upon request and payment of the fee.

Brief Description of the Drawings

[0030]

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[0031] Definitions As used herein, "patency" refers to a state of being open, expanded, or unobstructed. As used herein, "hypotube" refers to a small-diameter tube used for medical applications, typically having one or more hollow channels. As used herein, "catheter" refers to a tube used for medical applications, which may be solid or have a central opening channel, and the opening channel includes one or more openings (e.g., holes, pores, etc.). As used herein, "microcatheter" refers to a catheter tube having a diameter of 0.70 - 1.30 mm. As used herein, "intima" refers to the layer of the blood vessel wall including arteries and veins. As used herein, "neointima" or "neointimal" refers to a new or hypertrophied layer of the intima. Neointimal hyperplasia or growth refers to pathologic vascular remodeling after intervention by proliferation of vascular smooth muscle cells and migration into the intimal layer, which results in vascular wall thickening and a progressive loss of vascular patency that can lead to recurrence of vascular obstruction. As used herein, "growth inhibitor" includes any compound that inhibits or reduces growth or hyperplasia. Pharmaceutical compositions that have been shown to impede revascularization (inhibit neointimal growth) include drugs such as sirolimus, temsirolimus, everolimus, dexamethasone, alteplase (TPA), and paclitaxel. As used herein, "radiopaque substance" refers to a substance that is impervious to radiation, e.g., visible on a radiograph and under fluoroscopy (the opposite of radiopaque). As used herein, "radiopaque agent" refers to the property or characteristic of a substance, typically a dense metallic powder, that is radiopaque to radiation such as X-rays. As used herein, "atherectomy" refers to a procedure that utilizes a catheter having a sharpened blade at its distal end to remove plaque from a blood vessel. As used herein, "endarterectomy" refers to the surgical removal of a portion of the inner wall of an artery, along with any occlusive deposits, performed on arteries and blood vessels that supply blood to the legs. As used herein, "restenosis" generally refers to the narrowing of the blood vessel diameter that results in restricted blood flow. As used herein, "target lesion revascularization" refers to any procedure, for example, performed to restore vascular patency after late vascular loss due to in-stent restenosis (ISR). DETAILED DESCRIPTION OF THE INVENTION

[0032] The present invention generally relates to pharmaceutical compositions, methods, and devices / systems for treating vascular diseases. More particularly, the present invention relates to medical methods, devices, and kits for distributing drugs to peripheral vascular tissue for treating neointimal growth. More specifically, the described present invention aims to overcome the drawbacks of existing treatment methods for peripheral arterial disease (PAD). The devices and methods of the present invention are for reducing one or more pathological conditions; reducing treatment complications in the treated patient population, reducing the target lesion revascularization (TLR) rate; and reducing the patient population that requires any type of leg amputation, particularly for patients with PAD related to below-the-knee (tibial) arteries, for example, patients with clinical indications for treatment below the knee (e.g., claudication and / or critical limb ischemia (CLI)), and patients with complex pathological conditions are specifically contemplated for treatment.

[0033] In one embodiment, the present invention contemplates the use of solution-based techniques and dissolves a growth inhibitory drug, such as rapamycin, also known as sirolimus and Rapamune® (registered trademark), in a solvent, such as dimethyl sulfoxide (DMSO), which is used as a penetration enhancer in other pharmaceutical formulations. In some embodiments, by using DMSO, drug coating of balloons with solid (amorphous or crystalline) rapamycin (registered trademark) (sirolimus) having the undesirable side effects described herein can be omitted. Further, rapamycin (registered trademark) may be encapsulated in polymeric or lipid nanoparticles for its good solubility at the tissue surface for deep penetration, whereby the treatment process of the blood vessel wall becomes easier, more effective (with fewer undesirable side effects), more realistic, less laborious, and more cost-effective than current treatments. In one embodiment, rapamycin is introduced into or onto the nanoparticles. In one embodiment, rapamycin is incorporated during nanoparticle generation. In one embodiment, rapamycin is encapsulated in a plurality of nanoparticles. In one embodiment, rapamycin is encapsulated in gelatin nanoparticles (GNP).

[0034] DMSO itself has anti-inflammatory properties and is currently used as a solvent for chemotherapeutic agents. It has been successfully used in human rheumatic, pulmonary, gastrointestinal, neurological, urinary, and skin diseases. DMSO further shows a protective effect in animal models of arterial diseases such as middle cerebral artery occlusion, cerebral hypoperfusion-related neuronal death, mercuric chloride-induced kidney injury, and chemical liver injury. Recent reports have proposed that DMSO reduces ischemic brain injury through both anti-inflammatory properties and free radical scavenging properties. Application of 70% - 90% DMSO easily penetrates the skin. DMSO is known as a tissue penetration enhancer for diffusing many drugs such as morphine sulfate, penicillin, steroids, and insulin across membranes into tissues and cells. The relief by drugs delivered by DMSO is almost instantaneous and reported to last up to 6 hours.

[0035] A fundamental problem with existing mechanisms currently on the market for delivering an active agent, such as a drug, to a vascular target tissue is that the active agent is typically not water-soluble and thus remains in the solid phase when deployed for treatment. Therefore, the kinetics of transporting the drug into the target tissue are not very effective. The composition of the active agent containing DMSO of the present invention described herein is intended to address the fundamental drawbacks of existing drug-coated balloons and stents by placing the drug in a solution phase containing DMSO and enabling effective penetration into the target tissue. Furthermore, the present invention describes a method for treating lesions of various lengths. Embodiments of the present invention provide an effective amount of the drug necessary to treat the target tissue by penetrating the vascular tissue to the depth required for treatment with little loss of the drug in the circulation, while at the same time. Embodiments of the present invention also intend to provide consistency in drug penetration into the target tissue extending throughout the length of the lesion.

[0036] To improve blood flow to tissues downstream from an occluded blood vessel, various revascularization methods may be used to bypass the occluded area or to reopen the occluded artery. Arterial bypass surgery can be an effective treatment for atherosclerotic or stenotic or narrowed arteries due to other causes. However, this is a highly invasive surgery, costly, and requires substantial hospitalization and recovery time. Mechanical revascularization methods using balloon angioplasty, atherectomy, stent placement, or surgical endarterectomy can be used to open or dilate arteries. As an example, percutaneous transluminal angioplasty (PTA), commonly called balloon angioplasty, is not overly costly and is less dramatic than bypass surgery. In addition, the effectiveness of balloon angioplasty has been improved by the introduction of stents that involve the placement of a scaffold structure within the artery after treatment by balloon angioplasty. Stents have some advantage in suppressing acute re-occlusion of the artery and in reducing substantial restenosis that results in hyperplasia of cells within the vessel wall.

[0037] Current standard treatments, and the most studied treatments, for cardiovascular disease and more specifically peripheral artery disease typically incorporate some type of active agent to inhibit neointimal hyperplasia (PAD). Methods for incorporating an active agent, for example a drug, into these devices usually involve coating the outside of the balloon that is used to treat PAD. These coatings typically involve incorporating a solid-phase drug and / or active agent onto the surface of a plastic and / or metal device including the outer balloon surface, and modifying the surface to attach the drug, as well as other elements designed to provide the medical device and drug during the manufacturing process and to allow release into the blood vessel for treatment. A common element for making such medical devices is the use of excipients to attach the drug in its solid state. However, there are many problems associated with incorporating active agents in this way. Starting with the manufacturing process, it is extremely difficult to obtain a consistent, uniform coating, and thus it is difficult to supply an effective dose on the surface of the device.

[0038] During clinical use, the device may have a friable or brittle coating, which presents additional problems during use. When the device is removed from the packaging container, the device is manipulated before or during insertion into the patient, which may cause cracks or breaks in the active agent coating of these devices. When the device is inserted into the patient and then deployed, there are also many operations that can break the coating. When the device is deployed, for example, both the stent and the balloon are mechanically manipulated, which also breaks the coating and causes delamination. The balloon expands or is mechanically manipulated and does not provide a vascular wall targeted treatment that includes a specific effective amount that does not enter the blood circulation beyond the treatment area, and here too, the coating is broken and delamination occurs.

[0039] As previously described herein, due to the brittleness of the coating material and the nature of the solid phase of the drug embedded in the coating, a small percentage of the embedded drug ultimately reaches the inner diameter of the target tissue. The remainder of the drug, excipients, and other components of the delaminated coating end up somewhere distal to the target tissue in the vasculature beyond the treatment area. Furthermore, the mechanical disruption caused by the insertion of one or more devices into the blood vessels and subsequent passage through the blood vessels, balloon inflation, and stent deployment until they reach the treatment area conditions the blood vessels. Thus, stretching of the blood vessels, tissue disruption can cause microthrombi, damage the target tissue, and cause particles to flow from the tissue and target lesion to the distal vasculature, where they can occlude small blood vessels. Some of the active agent is applied to the device in an amount greater than necessary due to active agent delamination from the device before and during treatment, tissue injury, and loss of the active agent to the blood stream, wasting expensive active agent. Accordingly, one of several objectives described herein is to provide a device having an effective amount of an active agent as a coating, or a device that delivers an effective amount of an active agent to a target vascular wall, for effective treatment of the vascular wall. In a preferred embodiment, the active agent does not enter the circulating blood stream beyond the treatment area.

[0040] The present invention as described is intended to address the above-mentioned drawbacks of existing procedures. Embodiments have clinical indications for patients with, for example, lower extremity peripheral artery disease (PAD), claudication, which literally means "dragging the foot," which is one of the symptoms of critical limb ischemia (CLI) that significantly reduces blood flow due to severe occlusion of the arteries in the lower extremities, and patients with PAD associated with complex medical conditions such as coronary artery disease (CAD), PAD associated with diabetes, specifically intended to treat patients with PAD related to the infrapopliteal (tibial) artery. Advantages of using the devices, systems, and methods described herein include, but are not limited to, demonstrating excellent patency at six months with a reduction in pathological conditions and complications in the patient population being treated, such as a reduction in the target lesion revascularization (TLR) rate; and a reduction in the patient population that requires some type of leg amputation, etc.

[0041] Exemplary Method of Use of the Devices of the Invention In one embodiment, a device as shown in FIG. 29 is provided. FIG. 29 shows an exemplary schematic diagram of one embodiment including a delivery device 101, a port 102 for supplying saline through a connected hypo tube 108 including a channel through an opening 122 for inflating and deflating the angioplasty balloon 116; a port 104 for supplying saline to the distal balloon 114 through a connected hypo tube 110 including a channel for supplying saline through holes and / or pores 120 located at the cut end 118 for inflating the distal balloon; a port 106 through a connected hypo tube 112 including a channel for supplying a drug into a blood vessel such as an artery, and a complete delivery system including a heat shrinkable tube 130.

[0042] Figures 30A - 30E show an exemplary method using the embodiment of device 101 shown in FIG. 29. Port 102 for supplying saline through hypo - tube 108 connected through an opening 122 for inflating and deflating balloon 116 for angioplasty; port 104 for supplying saline through hypo - tube 110 connected for supplying saline to distal balloon 114 through holes and / or pores 120 where saline flows through holes and / or pores 120 located at the cut end 118 for inflating the distal balloon; port 106 through which a hypo - tube 112 connected for supplying drugs into a blood vessel such as an artery passes. Figure 30A shows an exemplary delivery device 101 inserted into an affected blood vessel, such as an artery, with a part of its wall represented by two parallel black lines surrounding device 101. The balloon 116 for constrictive angioplasty is positioned adjacent to the target tissue, for example, at a location where plaque is present on the arterial wall of the blood vessel. Figure 30B shows an exemplary distal balloon inflated to occlude a blood vessel such as an artery. The distal balloon 114 is introduced through port 104 and the connected hypo - tube 110 and discharges saline through opening 122 as shown by the saline represented by the spiral lines inside distal balloon 114. Figure 30C shows an exemplary angioplasty balloon 116 inflated to reduce the size of the target tissue, such as to reduce plaque size. The angioplasty balloon 116 is introduced through port 102 and the connected hypo - tube 108 and exits through opening 122. Figure 30D shows an exemplary deflated angioplasty balloon 116 within the blood vessel. Figure 30E shows an exemplary drug distribution adjacent to a target tissue such as plaque. The drug is administered through drug port 106 connected to hypo - tube 112 and pores 120. The administered drug is represented by wavy lines in the front part of distal balloon 114 and in the target tissue area such as plaque. Device 101 is removed by contracting distal balloon 114 after drug delivery and then removing device 101 from the blood vessel.

[0043] Description of Preferred Embodiments As described above, treatment of neointimal growth can include a chemical or surgery to first remove the occlusion (prior to treatment of the target tissue with the treatment solution). Such surgery includes angioplasty. The treatment devices, systems, compositions and methods are not limited to coronary arteries, but the following examples use coronary arteries as a model for angioplasty. In practice, these examples of treatment devices, systems, compositions and methods are also intended for the treatment of PAD and are preferred.

[0044] Angioplasty or percutaneous coronary intervention (PCI) is a procedure used to open blocked coronary arteries caused by coronary artery diseases such as atherosclerosis. It restores blood flow to the myocardium without performing open-heart surgery. Angioplasty can be performed in emergency situations such as when a patient is having a heart attack. In the case of angioplasty, a long, thin tube (catheter) is inserted into a blood vessel and guided into the blocked coronary artery. The catheter has a small balloon at its tip. When the catheter is in place, the balloon is inflated in the narrow area of the coronary artery. This presses plaque or blood clots against the side of the artery, creating more space for blood flow. When blood pressure drops, intracellular Ca 2+ concentration decreases, causing relaxation of smooth muscle cells and vasodilation of arterioles. Ultimately, this endothelium-independent myogenic control maintains the radial wall stress of arterioles at a stable level and constitutes one of the pathways for controlling vascular tone. Accordingly, due to the variability of the disease for each patient, in some cases, but not limited to, angioplasty (a procedure to widen an artery) may be performed prior to atheredectomy (a procedure in which plaque is removed from inside the artery) before a treatment method including drug-coated balloon (DCB) therapy. However, due to the potential harmful side effects of angioplasty, some embodiments of the present invention aim to minimize or reduce the need to perform angioplasty to remove plaque. Further, the variability of the disease also results in differences in the length of the blood vessel wall that requires treatment. Thus, in one preferred embodiment, the drug delivery device of the present invention may be shortened or lengthened to treat multiple patients having desired blood vessel wall regions of different lengths with one device. Accordingly, the need to have multiple devices for different fixed lengths of treatment regions is overcome.

[0045] As described herein, a) the use of commercially available balloons in small blood vessels is problematic but can be addressed by using the devices and systems of the present invention described herein; b) embolization during procedures for treating small blood vessels is a concern but can be addressed by filters at the distal end; c) hypo tubes (having narrow hollow channels) are better than thin wires in terms of strength; further, they can be useful for deploying filters and for delivering pharmaceutical formulations using the devices, systems, compositions and methods described herein. In one embodiment, there is a desire to use one or a limited number of devices and systems for treating blood vessels of different lengths.

[0046] Treatment of atherosclerotic plaque before treatment. Certain embodiments of the multi-step process include, but are not limited to, the following during the insertion and removal of a medical device into a blood vessel as described below: 1) Occlusion of blood flow downstream of the target vascular tissue, e.g., cessation of blood flow at the distal end. If necessary, blood flow is allowed to enter at the other proximal end. This can be done using a hypo tube having a filter deployed like an umbrella at the distal end (non-limiting examples of umbrellas are shown in FIGS. 15-20). 2) Treatment of occlusion. This can be done using chemical substances such as amines and alcohol solvents, chelating agents, papain enzymes, etc. Alternatively, occlusion can be treated by performing surgical angioplasty or atherectomy, including those by the devices and methods described in this specification that include the following; 3) Removal of particles (such as potential emboli and necrotic cell debris) by a drainage catheter (non-limiting examples of the drainage catheter are shown in FIGS. 8-9); 4) Optionally, perform additional steps of flushing (washing) described in this specification (a non-limiting example of washing is shown in FIG. 1); 5) Introduction of a penetration enhancer, such as a DMSO + rapamycin formulation, together with a therapeutic agent, for delivery to the target tissue for a required period (2 - 30 minutes) (since blood flow is not blocked at other ends, in the presence of blood). This can be done by several non-limiting means including introduction of fluid through the narrow channel of a hypodermic tube; through balloon-assisted drug delivery; or through plastic tube drug delivery, etc. 6) Removal of the entire system from the patient. The following is an example of a means for blood flow occlusion in step 1 above.

[0047] Exemplary occlusion Occlusafe (trademark) - temporary occlusion balloon catheter: Challenges of large lesions: Large lesions respond partially to current TACE treatments because of insufficient embolization uptake. Multiple or combined treatments are required to achieve complete success. · Flow distribution: Through the pressure gradient effect, balloon occlusion by Occlusafe provides the ability to redistribute blood flow and access capillary circulation, resulting in increased accumulation of therapeutic agents in the target lesion with minimal off-target embolization. · Access to capillary circulation: Balloon occlusion by Occlusafe (trademark) enables improved visualization of the target lesion with better uptake of embolization and better visualization of the target lesion. The following are non-limiting examples for use in step 2 above, i.e., chemicals for treating the blood vessel wall.

[0048] Minimization or elimination of the need for angioplasty to remove plaque prior to treatment. In some embodiments, the present invention contemplates a method of avoiding vascular disorders. The following section includes a description of non-limiting options that can be used as alternatives to angioplasty. Such alternatives can be performed as embodiments before or during the method of using the balloon therapy described herein.

[0049] Removal of calcification using chemical methods Example 1. Use of amines and alcohol solvents: Phospholipids are known to play an important role in bovine pericardium in in vivo calcification. Ca in extracellular fluid 2+ molecules are thought to bind to phosphorus molecules in phospholipids, which are abundant in the pericardial cell membranes of dead cells and form calcium phosphate crystals. This indicates that phospholipid substances can be a starting point (a place where something occurs and grows) for calcification. A study was conducted to evaluate the effect of in vivo treatment of glutaraldehyde (GA)-fixed pericardium calcification with amino compounds and alcohol solvents. Treatment with amino compounds alone resulted in a dramatic decrease in Ca 2+ and inorganic phosphate (IP) concentrations. The amine compounds used were urazol and glutamic acid, as well as several solvents (ethanol or octanediol containing octanol) that reduce the phospholipid content in bovine pericardium tissue. Anti-calcification treatment with glutamic acid, urazol, and the solvent significantly prevented in vivo calcification without deteriorating the physical properties of bovine pericardium. (Interact Cardiovasc Thorac.Surg. 2011 Jun,12(6),903-7; doi:10.1510 / icvts.2010.259747.)

[0050] Example 2. Use of chelating agents: Chelating agents such as disodium ethylenediaminetetraacetate (EDTA), diethylenetriaminepentaacetic acid (DTPA), and sodium thiosulfate (STS) can reverse elastin calcification by directly removing calcium (Ca 2+ ) from calcified tissue to form soluble calcium complexes. The chelating abilities of EDTA, DTPA, and STS on the removal of calcium from hydroxyapatite (HA) powder, calcified porcine aortic elastin, and calcified human aorta were tested. The tissue structure did not change during chelation. In an animal model of aortic elastin-specific calcification, local periadventitial delivery of EDTA loaded on poly(lactic-co-glycolic acid) (PLGA) nanoparticles was further shown to regress elastin-specific calcification in the aorta. Taken together, the data indicate that elastin-specific intimal vascular calcification can be reversed by chelating agents. (Calcif Tissue Int. 2013 Nov;93(5); doi:10.1007 / s00223-013-9780-0)

[0051] Example 3. Papain enzyme: Papain is an enzyme extracted from Carica papaya, such as products sold under the trademark name "Papase" by Warner-Chilcott Laboratories, a division of Warner-Lambert Company, Morris Plains, N.J., 07950. Papain does not affect bone calcium in vivo, but liquefies or dissolves calcium and then utilizes the natural circulation process to remove irritating calcium deposits from joints or tissue areas without the need for surgical procedures or subcutaneous tissue injections that could cause further damage, thereby completely removing abnormal inactive calcium deposits located under the skin of animals or other organisms and dissolving the inactive calcium. This component also reduces swelling, aids the flow of blood to affected areas, and supports the natural body circulation process that bathes these areas. (Acta Orthop.Scand. 1977, 48(2), 143-9; doi:10.3109 / 17453677708985125.)

[0052] The following are additional means of improving blood flow. 1. Peripheral vasodilators Peripheral vasodilators refer to drugs used to treat conditions that affect the blood vessels in external (peripheral) parts such as the extremities and legs. For example, they are used to treat peripheral arterial disease and Raynaud's phenomenon. They relieve the symptoms of these conditions by dilating the blood vessels and preventing them from narrowing further. These drugs are usually prescribed after attempts at self-help measures have not improved the symptoms. Other vasodilatory means are described in a study reporting treatment options for chronic thromboembolic pulmonary hypertension (CTEPH) that is inoperable for endarterectomy or is recurrent / persistent after endarterectomy (i.e., inoperable CTEPH). Treatment options include pulmonary vasodilators or balloon pulmonary angioplasty (BPA) (Kalra et al. 2020). These authors compared the efficacy and safety outcomes of BP with or without pulmonary vasodilators to pulmonary vasodilator therapy alone in patients with inoperable CTEPH. Findings reporting outcomes in more than five patients with inoperable CTEPH and randomized trial data were sought. A single-arm random-effects meta-analysis was performed. These authors concluded that both BPA and pulmonary vasodilators improve the functional and hemodynamic outcomes of patients with inoperable CTEPH. BPA may provide greater functional and hemodynamic improvement, but this technique has risks associated with invasive surgery. To clearly examine the roles of BPA and pulmonary vasodilators for beneficial treatment of patients with inoperable CTEPH, long-term follow-up and higher-quality randomized data from more patients are needed. However, one problem with using vasodilators is that their effects are generally transient. Furthermore, there is a need for treatment of the vessel wall that rapidly destroys plaque to avoid the need to open the artery multiple times to remove plaque from the same area, rather than opening the artery to temporarily remove plaque.

[0053] 2. Chemical treatment: In this embodiment, an exemplary blood vessel wall treated with DMSO is the thoracic aorta. Debons et al. examined the effect of dimethyl sulfoxide (DMSO) on cholesterol-induced atherosclerotic lesions in rabbits. Rabbits fed an atherogenic diet and not administered DMSO had extensive aortic lesions covering 82 ± 5% of the surface area of the thoracic aorta. Aortic lesions were inhibited in approximately 50% of rabbits given 2% (dose, 1.5 g / kg) DMSO and were substantially absent in most rabbits given 4% (dose, 3.5 g / kg), 5% (dose, 5.5 g / kg), and 6% (dose, 9.1 g / kg) DMSO. Food intake in rabbits fed an atherogenic diet was not inhibited by DMSO. Debons, et al., J Pharmacol Exp Ther. 1987 Nov;243(2):745-57.

[0054] 3. Laser angioplasty: Laser angioplasty is used to treat severely ischemic patients who are not candidates for bypass surgery. One report is a study that concluded that laser-assisted angioplasty was extremely effective in limb salvage and revascularization in patients who were not suitable for bypass surgery. Chen et al.Chapter 11-Laser Atherectomy,Endovascular Surgery(Fourth Edition)2011,Pages 107-115.Available online 27 December 2010.More specifically, 145 patients with severely ischemic limbs were enrolled at 14 facilities in the United States and Germany. The treatment included balloon angioplasty with optional stent placement after laser atherectomy. Stents were implanted in 45% of the limbs. At 6-month follow-up, limb salvage was achieved in 110 of 119 surviving patients (92%) or 93% of all limbs (118 / 127). Another report is Yang et al.,”Endovascular Debulking of Human Carotid Plaques by Using an Excimer Laser Combined With Balloon Angioplasty:An ex vivo Study.” Front Cardiovasc Med.,2021, which examined the safety and efficacy of excimer laser application for lesion debulking of human carotid atherosclerotic plaques by investigating distal debris, plaque lumen enlargement, and micro-morphology of the plaque surface. For example, see the exemplary flow diagram shown in FIG. 14. The authors of Yang found that treatment group 3 (laser + balloon) resulted in the highest lumen enlargement (5.40±4.51mm 2 ) compared to 4.05±3.20 and 3.77±2.55mm in the other two groups respectively 2showed an increase in lumen. Both devices caused disruption to the plaque vessel surface. Furthermore, laser ablation exposed the subendothelial fibers, i.e., disrupted the endothelium, and balloon angioplasty caused fissures in the vessel surface. The average damage amount was 3,611±1,475.4 in group 1 (laser only), 2,828±1,266.7 in group 2 (balloon only), and 4,400±2,567.9 in group 3 (laser + balloon). More than 90% of the distal debris was smaller than 10 μm. Group 2 resulted in the most debris with a ferret diameter (maximum caliper diameter) ≧40 μm, and group 1 had the least. The authors concluded that excimer laser ablation can significantly increase lumen enlargement in carotid artery plaques with severe stenosis. The excimer laser combined with balloon angioplasty achieved the greatest lumen dilation.

[0055] 4. Coronary artery bypass grafting: Coronary artery bypass grafting (CABG) surgery, also known as coronary artery bypass or bypass surgery, is a surgical procedure to restore normal blood flow to blocked coronary arteries. Normal coronary arteries transport blood to the myocardium itself rather than within the major circulatory system. CABG is often indicated when the coronary arteries have a 50 - 99% occlusion. The occlusions to be bypassed are usually due to arteriosclerosis, atherosclerosis, or both. Arteriosclerosis is characterized by thickening, loss of elasticity, and calcification of the arterial wall, and in most cases, results in a general narrowing of the affected coronary artery. Atherosclerosis is characterized by yellowish plaques of cholesterol, lipids, and necrotic cell debris deposited in the inner layer of the wall of large or medium-sized coronary arteries, and in most cases, results in a partial occlusion of the affected artery. Either condition can restrict blood flow if it causes a cross-sectional narrowing of at least 50%. Cleveland Clinic:Coronary Artery Bypass Surgery(my.clevelandclinic.org / health / treatments / 16897-coronary-artery-bypass-surgery).Downloaded 2-18-2022.

[0056] 5. Reperfusion Therapy: Reperfusion therapy typically refers to medical procedures to restore blood flow through or around an occluded artery after a heart attack (myocardial infarction (MI)). Reperfusion therapy includes medications and surgery. The medications are thrombolytics and fibrinolytic agents used in a process called thrombolysis. The surgery performed can be percutaneous coronary intervention (PCI) followed by minimally invasive endovascular procedures such as coronary angioplasty. Angioplasty is used as the insertion of a balloon to open an occluded artery, with the possible additional use of one or more stents. The other surgery performed is more invasive bypass surgery to graft arteries around the occlusion. Barron et al. concluded that reperfusion therapy, used either with administration of thrombolytics or immediate angioplasty, is a clearly beneficial therapy for patients presenting with myocardial infarction, but it has not yet been fully utilized. Their data suggest that 24% of those patients eligible for reperfusion therapy are not receiving this proven therapy. Specifically, elderly female patients without chest pain, and those at greatest risk of in-hospital mortality, were least likely to receive reperfusion therapy. The findings of randomized controlled trials must be translated into clinical practice in order for reperfusion therapy to realize its maximum potential in reducing cardiovascular mortality. Barron et al., Circulation Volume 97, Issue 12, 31 March 1998; Pages 1150 - 1156.

[0057] 6. Filters at the Distal End of Medical Devices: To assist in preventing embolization during endovascular surgery, an embolic protection device (EPD) has been developed. The risk of distal embolization in the carotid artery, saphenous vein grafts, and thrombotic lesions affecting patients with acute coronary syndrome is considered significant. EPDs have been designed and clinically tested for these procedures, but their use in other vascular regions during surgery is questioned due to increased costs, potential risks of complications, and the perceived lack of significance of distal embolization in these vascular beds. Several commercially available EPDs are described herein and shown in FIGS. 15 - 20. The following are non - limiting examples for use in step 5 above, introducing penetration enhancers such as DMSO + rapamycin formulations, etc.

[0058] Concentration of DMSO for rapamycin delivery Rapamycin has been found to be most stable in DMSO at - 20 °C over several months. Rapamycin solutions in DMSO can be further diluted in saline, PBS, or distilled water. Current data indicate that the minimum concentration of DMSO (the concentration at which precipitation or deposition of the solution does not occur) that enables rapamycin to remain soluble in saline is 20% (v / v) of the total volume. Mixing of rapamycin solution in DMSO in saline must be in a specific order so that rapamycin does not precipitate from the solution, which has been found to be the case when DMSO is at a final volume of 20% or less after dilution. Saline is suggested to be added to the rapamycin solution in DMSO and not the other way around. The best working solution is considered to be 50 / 50 DMSO / water, i.e., 50% DMSO in the solution. This is assumed to be effective even if blood is used instead of saline.

[0059] Other chemicals as penetration enhancers 1. N - vinylpyrrolidone (NMP) N-Methyl-2-pyrrolidone (NMP) is an aprotic polar solvent and is miscible with most common solvents including water and alcohols. NMP can be well distributed in the human stratum corneum. In tissues, it acts by changing the solvent properties of membranes and is used to create a "reservoir" within the skin membrane. It has also been used as a skin penetration enhancer in many topical formulations at concentrations up to 40% without any skin sensitization. (Asian journal of pharmaceutical sciences 8(2013)110-117; doi:10.1016 / j.ajps.2013.07.014)

[0060] 2. Ionic liquids: Currently, ionic liquids (ILs) are a class of compounds that are intensively studied for biomedical applications - more specifically, for transdermal drug delivery. Based on the reported use of ILs as chemical penetration enhancers (CPEs), there has been a continuous interest in ILs for transdermal drug delivery. ILs have been shown to enhance transcellular and paracellular transport across the skin by circumventing the barrier properties of the stratum corneum (SC) using mechanisms such as disruption of cell integrity, fluidization, and creation of diffusion pathways, as well as extraction of lipid components in the SC. (Pharmaceutics 2019,11,96; doi:10.3390 / pharmaceutics11020096 and International Journal of Pharmaceutics 516(2017)45-51; doi:10.1016 / j.ijpharm.2016.11.020). Professor Samir Mitragotri's laboratory has shown extensively that an ionic liquid / deep eutectic solvent consisting of choline and geranic acid (CAGE) exhibits features that make it a potential candidate for the effective treatment of warts. CAGE has been shown to exhibit deep penetration into the skin (Bioengineering & Translational Medicine, 6(2); doi:10.1002 / btm2.10191 and Advanced Materials, 1901103; doi:10.1002 / adma.201901103). The same laboratory has also synthesized various other ionic liquid / deep eutectic solvent systems for deep tissue penetration applications (PNAS, 2014, 111(37)13313-13318; doi:10.1073 / pnas.1403995111).

[0061] 3. Lipids and Liposomes: Drugs with insufficient water solubility are a challenge for formulation researchers in terms of solubility and bioavailability. Lipid and liposome-based drug delivery systems (LBDDS) have attracted much attention because they exhibit effective size-dependent properties. Also, due to the obvious advantages of higher biological compatibility and versatility, LBDDS are at the forefront. These systems are commercially available for formulating pharmaceuticals for topical, oral, pulmonary, or parenteral delivery. Lipid formulations can be modified in various ways to meet a wide range of product requirements regarding disease state, route of administration, and cost, product stability, toxicity, and efficacy. Lipid-based carriers are safe and efficient, and thus they have proven to be attractive candidates for pharmaceutical formulations, as well as for vaccines, diagnostics, and nutraceuticals (Journal of Pharmaceutics Vol.2014; doi:10.1155 / 2014 / 801820, Therapeutic Delivery, 2(11), 1485-1516; doi:10.4155 / tde.11.105, Int.J.Mol.Sci.2020, 21, 3248; doi:10.3390 / ijms21093248, and Front.Pharmacol.; doi:10.3389 / fphar.2015.00286).

[0062] The system of the present invention includes, but is not limited to, the use of some medical devices during the treatment method. Merely by way of example, in one embodiment, as described herein, the system for the treatment of PAD includes a wire that deploys a filter present distally in addition to a hypo tube surrounded by a balloon, using a catheter for introducing an active agent and simultaneously stopping the proximal blood flow. In one embodiment, a device is provided that includes two balloons, a proximal and a distal one, for directly delivering a treatment solution (DMSO + drug formulation, e.g., DMSO + rapamycin formulation, etc.) to the wall of a blood vessel and at the same time preventing or reducing the mixing of the formulation with the blood. After the balloons are deployed, the inflow of fluid through a hollow tube through one of the balloons introduces a fluid such as a drug formulation, a cleaning fluid, etc. through an isolated void between the balloons. Conversely, fluids such as blood, the post-treatment drug formulation, the cleaning fluid, etc. may also be removed. Exemplary Figure 1.

[0063] In one embodiment, the device provided herein maximizes the amount of space occupied by the balloon within the inner diameter of the blood vessel. Thereby, the DMSO + drug formulation can be present against the wall of the target blood vessel, minimizing the exposure of the formulation to the blood flow. Alternatively, in one embodiment, the device provided herein minimizes the void within the balloon. Exemplary Figure 2. In certain embodiments, it can accommodate as much as possible the variations in the length of the blood vessel and address the number of lumens required to inflate the balloon and deliver the drug. Additionally, steps are taken to address any plugs formed from the inflation and deployment of the balloon in relation to the target tissue. In one embodiment, a method is provided for directly delivering a DMSO + drug formulation, e.g., a DMSO + rapamycin formulation, to the wall of a blood vessel and at the same time preventing or reducing the mixing of the formulation with the blood using an inner balloon within an outer balloon, where the outer balloon has holes for directly introducing the DMSO + drug formulation into the blood vessel wall. The balloon may be inserted by a wire or a hollow hypodermic tube. Step 1 is to drain the blood. Exemplary Figure 3.

[0064] In certain embodiments, it addresses the potential formation of tissue destruction and plugs during deployment. Additionally, steps are taken to limit the length of the blood vessel being treated. In further embodiments, it has a delivery system that can sufficiently deliver the formulation of the active ingredient even in blood vessels with a smaller diameter of less than 4 mm. The loss of the formulation and the formation of plugs when removing the device after treatment are both problems associated with most balloon-based delivery systems, and this is also addressed. In one embodiment, a low-profile system includes a small balloon or other mechanical occlusion mechanism attached to the distal or proximal end of a guidewire or hypo tube to stop or inhibit further blood movement within a blood vessel. In this embodiment, blood flow is inhibited or stopped for a specified period of time until after the release of a treatment solution (including, but not limited to, a DMSO + rapamycin formulation) into the blood stream. When the treatment solution mixes with the blood upstream from the occlusion mechanism, the blood vessel can be treated in the stopped blood for a period of, for example, 2 - 30 minutes, and the drug formulation is more readily absorbed by the vascular target region. This type of embodiment has several distinct advantages, including 1) a low-profile system by use of a small hypo tube as a wire for delivering the balloon / delivery system to the target site, and 2) substantially having the ability to deliver the delivery system to the target vasculature regardless of the size or length of the blood vessel by simply varying the location where the balloon is inflated along the hypo tube wire. The ability to treat very small blood vessels with minimal disruption to the vasculature, and thus minimize any potential emboli formed during the procedure itself, is one advantage of using this method. Exemplary Figure 4.

[0065] Further, in this embodiment, the presence of a distal filter can be used for a number of beneficial results including preventing any emboli formed during balloon deployment or upon contraction of the balloon during or after treatment and upon removal of the device by entry of the DMSO drug combination into the blood stream. In one embodiment, the device includes a combination of a wire and a hypodermic tube attached at its distal end to a balloon or other mechanical occlusion device. A small hypodermic tube surrounding the wire is used to deliver drugs through a plurality of holes, i.e., perforated hypodermic tube. As the drug flows through the hypodermic tube, the drug escapes into the vascular structure including blood. An additional feature of this device is a means to vary the length or distance that the drug is introduced into the vascular structure, thus enabling treatment of lesions of different lengths using the same device. In a further embodiment, an additional tube, e.g., a catheter, is provided to block the flow of a treatment solution (e.g., DMSO + rapamycin) to avoid treatment of that portion of the blood vessel and then to surround a portion of the perforated hypodermic tube to cover some of the holes in the hypodermic tube that target treatment of a specific length of blood vessel. Exemplary FIG. 5.

[0066] In one embodiment, the balloon is moved proximally to prevent blood flow. In some embodiments, the filter is positioned distally from the balloon to prevent embolisms. Exemplary FIG. 6.

[0067] In one embodiment, the balloon is positioned proximally to block blood flow while at the same time a distal hypodermic tube having a perforated side surface perfuses the drug into the blood vessel. Exemplary FIG. 7.

[0068] In one embodiment, the device and / or system further includes one or more hypo tubes, wires, balloons together with a micro catheter as an occlusion mechanism at the distal end of the treatment area, and the balloon occludes the proximal end of the treatment area. In a further embodiment, the catheter extrudes a treatment formulation into a vascular region targeted for treatment. In some embodiments, a radiopaque substance in a fluid, such as iodine, may be added to the DMSO + rapamycin formulation, and pieces of the radiopaque substance adhering to the inside of the wire, catheter, balloon, etc. provide a means for a clinician to clearly identify the area of the blood vessel being treated during surgery using an X-ray or other radiation emitting device. The radiopaque substance includes, but is not limited to, salts or compounds or nanoparticles of small molecular weight containing iodine, barium, tantalum, bismuth, or gold. Exemplary Figure 8.

[0069] Further included in this embodiment is a catheter for discharging a thrombus or embolus after completion of the treatment method. The catheter can also be used in place of a hypo tube to deploy a fluid, such as a drug solution, and to discharge residual blood or treatment residues in the treatment area, such as emboli, debris, etc. The distance of the catheter from the balloon is adjusted to accommodate the treatment of lesions of various lengths. In one embodiment, the device includes the embodiments described in FIGS. 3 - 7 and further includes an additional mechanism of a balloon surrounding the hypo tube or catheter for ensuring blood drainage, drug delivery to the target blister-like wall region, and removal of the drug solution after treatment. Exemplary Figure 9.

[0070] In one embodiment, the device includes three balloons along a wire with a proximal balloon surrounding the tube for use in a method of treatment, the method comprising inflating a central balloon to displace blood in a region designated for treatment, then inflating two end balloons to occlude the vascular treatment region, and then deflating the central balloon while filling the void with a fluid introduced through the tube, e.g., a pharmaceutical solution. In other words, in a first stage: Step 1: the central balloon is inflated to displace any blood, and in Step 2, the distal and proximal balloons are inflated, and the second stage may include deflating the central balloon and introducing a pharmaceutical formulation into the central region (hatched region) after displacing the blood. Exemplary Figure 10.

[0071] In certain embodiments, steps are taken to address destruction of the target lesion and retraction of the device. Additionally, steps are taken to address the number of lumen profiles required for a system to function. Additionally, steps are taken to limit the length of the blood vessel being treated. For example, see FIG. 13. In one embodiment, the device includes a hollow void (hard boundary) longitudinally above one another with a void longitudinally positioned between these two balloons that allows blood flow between these balloons. Each balloon has a plurality of holes, e.g., pores, along their luminal sidewalls and is filled with a drug solution, e.g., a sirolimus solution in 100% DMSO or a mixture of DMSO and saline, such that there is little leakage from the holes when moving through the blood vessel to the treatment area. When the device is deployed at the location where it is held in place, the balloons expand just sufficiently and simultaneously such that the sidewalls with holes are in firm contact with the blood vessel wall, and then pressure, e.g., an extrusion force, is created to allow the balloons to expand and extrude the drug solution from the balloons through the holes into the blood vessel wall tissue. Absorption of DMSO into the blood vessel wall is intended to be rapid with high delivery efficiency. The void between the two balloon tubes is sufficient to allow a continuous through-flow of blood that must ensure that the drug solution does not come into contact with the blood flow, and thus there is no loss of drug due to a flush of blood flow through this area as compared to losses with conventional drug-coated balloons (DCBs). Exemplary FIG. 11.

[0072] In one embodiment, a delivery system includes a medical-grade flexible hollow plastic tube having pores drilled in the outer perimeter of the tube and a fluid-impermeable end enclosure, such that when filled with a fluid, e.g., a DMSO drug formulation, the fluid does not move through the pores. When deployed in the treatment area, the pores are adjacent to the vessel wall and not in the main flow of blood. Such a plastic hollow tube, when deployed in a blood vessel, has an outer boundary of very thin, flexible plastic or fabric (impermeable to the fluid) that responds to shear pressure generated by the blood flow in the central region, with the hydrostatic pressure of the blood pressing the outer region of the tube material against the vessel wall and simultaneously pressing the drug formulation against the vessel wall tissue through the pores. In other words, after slowly moving blood through the narrow openings during deployment and then holding the tube in place, when the blood enters the larger force and larger opening as the tube is pressed against the vessel wall for delivery of the active agent, the tube begins to contract due to the loss of fluid introduced into the surrounding vessel wall tissue. Exemplary FIG. 12.

[0073] In one embodiment, for the treatment of hypertrophied vessel wall regions, e.g., atherosclerotic plaques, PAD, etc., a treatment method using the devices described herein includes the preparation of a vessel wall covered with plaque intended for a treatment in the form of restoring blood flow through the plaque using either angioplasty or atherectomy. Thus, in a preferred embodiment, the treatment method incorporates angioplasty or atherectomy prior to treatment with the devices described herein to combine the complete procedure with the method of using the device. In one embodiment, atherectomy includes, but is not limited to, rotational atherectomy, transcatheter atherectomy, and directional coronary atherectomy. In one embodiment, atherectomy is used for applications below the knee. There are at least two ways to stop the migration of emboli that occur distal to the device used in the treatment to the extremities. One is blood filtration, in other words, filtration using a device with a filter attached, or a device equipped with a distal protection filter. Another is the removal of disrupted tissue using a catheter so as not to allow the distal migration of emboli downstream of the blood flow. Yet another method is by using a method for treating atherosclerosis, which includes a chemical method of dissolving or removing atherosclerotic plaques in combination with delivering a treatment fluid to the vessel wall in contact with the plaque using the device described herein. In one embodiment, the device described herein having fine holes in the outer surface provides a large amount of chemicals (injection through the central part of the hypodermic tube and perfusion into the blood vessel through the fine holes (pores) shown in FIG. 12) through the hypodermic tube. The injection is carried out for a period long enough for the chemical agent to dissolve the target lesion but short enough not to cause clinical problems associated with blood flow stoppage. When sufficient disintegration of the target lesion is achieved, the fragmented lesion is discharged through the drainage catheter. When the lesion is removed, the flow recovers sufficiently, the particles / emboli are discharged, and then the drug solution can be injected into the target area. Aspects of this embodiment include a hypodermic tube for holding a low-profile delivery system and also enable passage through difficult lesions, also known as "pushability performance". The drainage catheter having an opening cavity is present in the internal area between the two balloons so that blood and emboli can be removed along the connected proximal balloon for stopping the flow. The restraining catheter that expands and contracts on the hypodermic tube containing holes / apertures allows various lengths for enabling drug discharge of various lengths from the opening holes, but is not discharged from these holes covered by the surrounding catheter, providing treatment means for different lesion lengths using one device / system. See exemplary FIG. 13.

[0074] Accordingly, in one embodiment, means are provided for varying the length and / or distance into the vasculature into which a drug is introduced, and thus for accommodating variations in lesion length. In this embodiment, treatment of lesions of various lengths is contemplated to be achieved in several ways. In some embodiments, the flow of solvent from a solvent delivery channel, such as a hypo tube (or other examples, e.g., a delivery catheter, conduit, channel, etc.), is varied by including a sleeve / catheter or hypo tube that slides over the solvent delivery channel to increase or decrease the flow. Accordingly, in a preferred embodiment, the sleeve and the solvent delivery channel move relative to each other. In other words, if holes are present in the solvent delivery channel, the sleeve (e.g., catheter) prevents the solvent from exiting through the holes on the side of the solvent delivery channel.

[0075] The use of the invention described herein is not intended to be limited to lesion lengths, and in fact, lesions of various lengths can be treated. Table 1 below shows exemplary lesion lengths that can be treated. In one embodiment, the lesions that can be treated range from 11 to 26 mm.

Table 1

[0076] Cationic gelatin nanoparticle (GNP) delivery of drugs In some embodiments, drug-loaded nanoparticles (e.g., nanoparticle-encapsulated drugs) are delivered intra-arterially. In some embodiments, the drugs (not limited to drugs) are included for treatment of the vessel wall, such as plaques covering the inside of the arterial wall. In a preferred embodiment, drug delivery is achieved using the device of the present invention.

[0077] Synthesis and characterization data of prepared gelatin nanoparticles (GNP) Next, data obtained during the preparation of non-loaded gelatin nanoparticles (GNP) and non-loaded cationic gelatin nanoparticles (GNP) are described. Non-loaded GNP are prepared without drugs. 1. Preparation of non-filled cationic gelatin nanoparticles (GNP) In one embodiment, non-filled cationic gelatin nanoparticles were prepared using a two-step desolvation method. Briefly, gelatin (2.5 g, type B; Bloom value: 300 g) was dissolved in ultrapure water (50 mL) while stirring at 600 rpm for 30 minutes in a 40 °C water bath. As described herein, the Bloom value refers to the strength of a gel or gelatin as the number of grams called the Bloom value. Most gelatins have a Bloom value between 30 and 300 g. The higher the Bloom value, the higher the melting point and gelling point of the gel, and the shorter the gelling time. In this first desolvation step, acetone (50 mL) was slowly added to the gelatin solution, and the mixture was stirred at 600 rpm for an additional 30 minutes. After the precipitate or mass settled to the bottom of the beaker, the clear supernatant (which contains lower molecular weight gelatin) was discarded. While continuously stirring, the settled precipitate was dissolved in fresh ultrapure water (50 mL), and the pH was adjusted to 2.5 - 3 by the addition of 2N hydrochloric acid (1.5 mL). Thereafter, using a dropping funnel, acetone (140 mL) was added dropwise while stirring with a magnetic stirrer at 600 rpm, and then, to stabilize the nanoparticles, a solution of glutaraldehyde (12.6 mL, 50% concentration) in acetone (20 mL) was added dropwise to perform the second desolvation step. Thereafter, the entire suspension was stirred at 600 rpm for 12 hours. Thereafter, the nanoparticles were centrifuged at 14000 rpm for 30 minutes to collect the nanoparticles. The pellet was redispersed in deionized (DI) water by sonication at 30 °C for 30 minutes, and then centrifuged to remove glutaraldehyde and acetone. This purification step was repeated at least two more times. Finally, the obtained GNP pellet was freeze-dried overnight and collected as a grayish-white powder (2.0 g, 80% yield). The obtained cationic GNP was stored at 4 °C and analyzed for the size of the NPs. See FIGS. 31 and 32 for data on these cationic GNP. Non-limiting examples of nanoparticles include poly(lactic-co-glycolic acid) (PLGA) nanoparticles, such as gelatin-poly(lactic-co-glycolic acid) nanoparticles, and gelatin nanoparticles (GNPs) described herein.

[0078] 2. Preparation of Sirolimus-Loaded Cationic GNP Drug loading tests were performed by incorporating sirolimus simultaneously with nanoparticle preparation (e.g., encapsulation of sirolimus). In this test, a sirolimus:gelatin ratio of 1:35 was used to achieve a high drug loading efficiency. Briefly, gelatin (100 mg, type B; Bloom value: 300 g) was dissolved in ultrapure water (50 mL) while stirring at 600 rpm for 30 minutes in a water bath at 40°C. In this first desolvation step, acetone (5 mL) was slowly added to the gelatin solution, and the mixture was stirred at 600 rpm for an additional 30 minutes. After the precipitate or mass had settled to the bottom of the beaker, the clear supernatant (containing lower molecular weight gelatin) was discarded. While continuously stirring, the settled precipitate was dissolved in fresh ultrapure water (5 mL), and the pH was adjusted to 2.5 - 3 by adding 2N hydrochloric acid (150 μL). Subsequently, a sirolimus solution (300 μL) prepared by dissolving sirolimus (10 mg) in DMSO (1 mL) at room temperature was added dropwise. The gelatin-drug solution was homogenized by stirring with a magnetic stir bar for 15 minutes. Thereafter, acetone (15 mL) was added dropwise using a glass pipette while stirring at 600 rpm, and then glutaraldehyde (120 μL, 50% concentrated solution) was added dropwise as a cross-linking agent for nanoparticle stabilization. Subsequently, the second desolvation step was performed by stirring the entire suspension at 600 rpm for 12 hours. Thereafter, the nanoparticles were centrifuged at 14,000 rpm for 30 minutes to collect the nanoparticles. The supernatant was immediately subjected to visible-ultraviolet spectrophotometry to evaluate the amount of free sirolimus that was not encapsulated. The pellet was redispersed in DI water by sonication at 30°C for 30 minutes and centrifuged to remove all glutaraldehyde and acetone. This purification step was repeated two more times. Finally, the obtained GNP pellets were lyophilized overnight and collected as a grayish-white powder (80 mg, 80% yield). The obtained sirolimus-encapsulated cationic GNP was stored at -20 °C, and the encapsulation efficiency and capacity were analyzed.

[0079] 3. Sirolimus Encapsulation in GNP Tests To analyze an unknown amount of sirolimus, the inventors prepared a calibration curve using visible-ultraviolet spectroscopy. A known amount of sirolimus was dissolved in a mixture of water and ethanol (1:1 (v / v)), and a stock solution was prepared at a final concentration of 1.0 mg / mL. The calibration curve ranged from 50 ng / mL to 2 μg / mL. The absorbance at 288 nm corresponded to sirolimus. The concentration was plotted against each absorbance that generated an R 2 value of 0.9999, and a linear curve was obtained. The calibration curve was used to calculate the unknown amount of sirolimus. See Figure 31, the sirolimus calibration curve and encapsulation analysis.

[0080] Capture Efficiency: After centrifuging the sirolimus-loaded GNP at 14,000 rpm, the amount of non-loaded sirolimus in the supernatant was quantified by spectrophotometry at 288 nm. The drug capture efficiency (EE) was calculated according to the following formula:

Equation

[0081] Loading Efficiency Similarly, the loading efficiency can also be calculated using the following formula:

Equation

Table 2

[0082] 4.2-week kinetic release of sirolimus The release of sirolimus from GNP was monitored in phosphate-buffered saline (PBS; pH 7.4) at 37 °C with gentle shaking. Briefly, 1 ml of GNP nanoparticles (1 mg / ml) was transferred into a dialysis bag (10 kDa cutoff; Sigma-Aldrich) and immersed in 10 ml of release buffer. At predetermined time intervals, 0.5 ml of the release buffer was taken out for measurement and the same amount of fresh buffer was added back. The solution was measured for the presence of sirolimus at 280 nm using visible-ultraviolet spectrophotometry. The concentration of sirolimus present in the withdrawn buffer was measured using the calibration curve shown in Figure 33. The release kinetics showed a sustained release of sirolimus (15% of the initial dose) over a 2-week period. The release kinetics of sirolimus from cationic GNP under sink conditions (i.e., related to the dissolution test method) are shown (see Figure 34).

[0083] 5. Cell viability analysis To evaluate the cytotoxic potential of empty cationic GNP, THP-1 and RAW264.7 cell lines were used. Cells were maintained in DMEM containing stable glutamine with 10% fetal bovine serum (FBS) and 1x penicillin-streptomycin mixture. Cells were grown at 37 °C in a 5% CO2 humidified incubator. The effect of empty GNP on cell viability was analyzed by MTT ([3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay). First, THP-1 and RAW264.7 cells were seeded in 96-well plates (1x10 4Cells / well). After 24 hours of incubation, the cells were treated with empty GNP. Untreated cells were used as a control. At the end of specific incubation times (24 hours, 48 hours, and 72 hours), the medium was replaced with 100 μL of fresh growth medium, and then 10 μL of MTT solution (5 mg / mL) was added. After 4 hours of incubation, the medium containing MTT in the wells was carefully discarded, and 100 μL of DMSO was added to solubilize the formazan crystals formed by the reaction in the live cells. Absorbance was measured at 540 nm using a UV spectrophotometer. See the cell viability test results in Figure 35.

[0084] Experiment Example 1 below describes and evaluates the sirolimus treatment of isolated porcine arteries. Example 1 Materials and Methods 1. Exemplary reagent and material sources. Sirolimus / rapamycin (>98%, AdooQ Bioscience), ascomycin (>98%, AdooQ Bioscience), (see Figure 26), dimethyl sulfoxide (DMSO, 99.9%, Sigma Aldrich). Methanol (>99.9%, Sigma Aldrich), and ammonium acetate (>99.9%, Sigma Aldrich) HPLC grade. All other reagents were of analytical grade and were used without further purification. 2. Equipment and analysis conditions Sirolimus / rapamycin was analyzed using an LC-MS / MS system consisting of an Agilent 1290 (San Jose, CA, USA) and an Agilent LC 1200 binary pump system (Agilent Technologies, Santa Clara, CA, USA) coupled to an electrospray ionization triple quadrupole mass spectrometer (Agilent 6460, San Jose, CA, USA) with a turbo ion spray interface in negative ionization mode. Ascomycin was used as the internal standard (IS). A Gemini 5μm NX-C18 110Å, LC column with a Security Guard (trademark) column (4.0mm x 3.0mm) and a polar RP 80A column (50 x 2mm, Phenomenex, Torrance, CA, USA) were utilized to optimally separate sirolimus and the internal standard from endogenous substances in porcine carotid arteries. The mobile phase was a mixture of 20 mM ammonium acetate (A) and methanol (B). Sample separation was performed using a flow rate of 0.2 mL / min and a gradient condition of 10 minutes (0 - 1 minute: 20% B, 1 - 6 minutes: 100% B, 6 - 7 minutes: 100% B, 7.1 - 10 minutes: 20% B). The injection volume was 5 μL for calibration and carotid samples. The selected reaction monitoring transitions of m / z 912.5 → 371.2 and m / z 790.5 → 530.3 were applied to sirolimus and IS, respectively. Mass data were acquired using Analyst software version 1.5.2 (Applied Biosystems - SCIEX, Concord, ON, Canada). Data analysis was processed using SCIEX OS offline software version 1.6 (Applied Biosystems - SCIEX, Concord, ON, Canada). The operating parameters of the LC-MS / MS system are listed in Table 3. [Table 3] 3. Solutions and Validation Samples Sirolimus / rapamycin was dissolved in acetonitrile to prepare a stock solution (1 mg / mL). Including 2 ng / μL of IS, it was gradually diluted by the stepwise dilution method using calibrated pipettes (2 - 20 μL, 10 - 100 μL, and 100 - 1000 μL) to obtain working stock dilutions with decreasing concentrations (1, 2.5, 5, 10, 25, 50, 100, 250, 500, 1000 pg / μL). These solutions were used for mass spectrometry optimization of DMSO and carotid homogenates, calibration curve preparation, and quality control standards. These stock solutions and stock dilutions were stored at -20 °C respectively. Exemplary calibration data are shown in Figures 27A, 27B, and 27C. 4. Rapamycin Delivery in the Carotid Artery Sirolimus / rapamycin was dissolved in DMSO to prepare a stock solution with a final concentration of 100 mg / mL and stored at -80 °C. Porcine carotid arteries were washed 5 times in PBS (1x) to remove all blood and fluid, and then they were cut into lengths of 40 mm. The surface area (SA) of the artery was calculated to be 628 mm 2 (lateral SA 円筒 = 2πrh; π = 3.14, r = 2.5 mm, and h = 40 mm). The rapamycin solution was dissolved in DMSO to prepare 1256 μg / mL (2 μg / mm 2 ). One of the carotid arteries was ligated at one end, then filled with 0.5 mL of the rapamycin solution ([rapamycin]0 = 628 μg / mL), and the open end was ligated. After a 5-minute treatment, the solution was drained, and the artery was washed with 5 x 0.2 mL of PBS (1x) and collected for analysis as well. Similar experiments were performed as biological replicates. Then, for use as a model, the artery and the wash were analyzed for the presence of sirolimus / rapamycin to compare the amount absorbed by the tissue with the amount washed away. 5. Sample Preparation: Tissue Homogenization The treated and untreated porcine carotid artery segments (100 mg, 2 mm) were minced using a surgical blade in methanol and transferred to a 2 ml tube containing a total of 1 ml of methanol and 100 μL of internal standard (1 ng / ml). This tube contained garnet beads / fragments for homogenizing the tissue. Next, the arterial fragments were disrupted using a Qiagen Tissue Lyser LT at 50 Hz for 10 minutes. The supernatant was completely dried under a gentle nitrogen stream using a nitrogen evaporator. The sample was resuspended in 100 μL of DMSO and placed in an inserted universal autosampler vial prior to analysis. The concentrations of rapamycin in the artery and washes were found to be 19.28 μg / mL (30.13% of the total drug in the 2 mm artery) and 3.14 μg / mL (0.5% of the total drug in the 40 mm artery).

[0085] Results:

Table 4

[0086] Example 2 Summary of data from animal experiments The purpose of this non - Good Laboratory Practice (GLP) study was to test paclitaxel and sirolimus, mitotic drugs that penetrate vascular tissue. A porcine model was employed for the in - vivo study to evaluate the penetration of the drug formulations and their residence time in the blood vessels over a two - week period. The study consisted of three female Yorkshire pigs (50 - 60 kg) that survived for 1, 7, and 14 days. For each survival time point, one animal was euthanized and the drug present in the artery and local toxicity were investigated by high - performance liquid chromatography (HPLC) and histology. Whole blood at baseline and endpoints was collected for each animal into tubes containing anticoagulants such as citrate or heparin.

[0087] Formulations: Two different formulations were prepared: 1. Paclitaxel was dissolved in pure medical-grade DMSO to obtain a final concentration of 1 mg / mL. 15 mg of paclitaxel was dissolved in 15 mL of DMSO. 0.5 mL of this formulation, which constitutes 500 mg of paclitaxel, was injected into each test site. 2. Sirolimus was encapsulated in gelatin nanoparticles (GNP). In the calculation, 100 mg of GNP contained 3 mg of sirolimus. 100 mg of GNP was dispersed in DMSO (1:1 (v / v)) in 15 mL of physiological saline. The final concentration of sirolimus at the time of injection was 160 mg.

[0088] There were 8 test sites for each animal (4 for paclitaxel and 4 for sirolimus), and all test sites were performed by accessing both the left and right femoral arteries. The animals were sedated, prepared in a sterile operating room (OR), and placed in the dorsal recumbent position. An incision of 5 - 8 cm was made along with the femoral (or cervical) artery, and the surrounding muscle and perivascular fascia were incised to expose the artery. After the artery was exposed, the following is an exemplary method for the drug test: · Marks were made on approximately 10 - 20 mm test sites (4 for each site). · Both ends of the test site were occluded to stop blood flow. · Blood was drained from the test site using a catheter. · The test site was filled with the designated drug solution for that site (e.g., 0.5 mL). · The test site was exposed to the solution and held for 5 minutes. · After 5 minutes, the drug formulation was drained. · Normal blood flow was restored. The above steps were repeated for each of the 8 sites for each animal (4 sites on each side). The paclitaxel formulation was injected on the right side of the animal, and sirolimus was injected on the other side (left).

[0089] Observation: 1. All animals were found to be healthy on the day of necropsy. However, at t = 24 hours, the first animal was found to have a harmful reaction of severe edema around the right - leg surgery (paclitaxel injection). When the surgeon incised the suture, a large amount of dead tissue and blood clots were observed around the delivery site. The occurrence of this edema and blood clots around the delivery site could be due to either the surgery or the influence of pure DMSO and the high dose of paclitaxel. On the other hand, the left leg injected with sirolimus - encapsulated nanoparticles dispersed in 50% DMSO in physiological saline was found to have no edema or blood clots near the delivery site. The absence of this harmful reaction suggests that the surgery did not cause edema or blood clots. However, the harmful reaction could be due to the presence of paclitaxel and DMSO. 2. However, no harmful reactions were observed in the animals on the 7th day. The animals were healthy and no edema was observed. The same absence of reaction was also observed in the animals on the 14th day. 3. Blood samples were collected before necropsy and stored at - 80°C. Every day, eight femoral arteries (four from each leg) were collected, and two of each 1 - cm length were stored at - 80°C in HPLC - grade methanol until drug isolation, and the other two of each were stored for histology. Along with the arteries, 0.5 cm of muscle tissue around the test site of the right leg was collected for HPLC for paclitaxel quantification.

[0090] Results: The HPLC facility isolated paclitaxel by the usual method and isolated sirolimus after an additional step of enzymatic digestion of GNP with trypsin at 37°C, and then each of them was analyzed by liquid chromatography - tandem mass spectrometry (LC - MS - MS). 1. Paclitaxel in both arteries on day 1 with final concentrations of 12 ng / g in the first artery and 5.2 ng / g in the second artery was detected by LC-MS / MS. The solution of the formulation in the test site discharged 5 minutes later was evaluated by LC-MS / MS, and 15% (75 mg) of the initial concentration of the injected paclitaxel solution was detected. This suggests that 85% (425 mg) of the paclitaxel was absorbed by the tissue. Only a few nanograms were detected at 24 hours, which could indicate that nearly 100% of the DMSO carried paclitaxel as a carrier from that site to other regions of the leg muscle.

[0091] All publications and patents mentioned in the above specification are hereby incorporated by reference into this specification. Various modifications and variations of the described methods and systems of the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the present invention. Although the present invention has been described with specific preferred embodiments, it should be understood that the claimed invention should not be unduly limited to such specific embodiments. Indeed, various modifications of the described methods for practicing the invention that are obvious to those skilled in the art of drugs, cell biology, molecular biology, biochemistry, chemistry, or related fields are intended to be included within the scope of the following claims.

Claims

1. A method of treating a target tissue indicative of neointimal growth in a blood vessel of a subject, comprising: a) occluding the blood vessel of the subject with a device, wherein at least a part of the device is disposed downstream of the target tissue indicative of neointimal growth, and the part stops blood flow at the distal end of the blood vessel; b) introducing a treatment solution comprising rapamycin and dimethyl sulfoxide (DMSO) to contact the target tissue for a certain period of time; and c) removing the device from the blood vessel, thereby restoring blood flow at the distal end of the blood vessel.

2. The method according to claim 1, wherein the device is a hypodermic tube comprising a channel, and the channel has one or more openings.

3. The method according to claim 2, wherein the treatment solution is introduced in step b) through the channel of the hypodermic tube and through the one or more openings.

4. The method according to claim 2, wherein the hypodermic tube comprises a filter.

5. The method according to claim 4, wherein the filter is deployed like an umbrella at the distal end and stops blood flow at the distal end.

6. The method according to claim 2, wherein the part of the device disposed downstream is an inflatable balloon connected to the hypodermic tube.

7. The method according to claim 1, wherein the blood vessel comprises a partial or complete occlusion at or near the target tissue.

8. The method according to claim 7, further comprising performing a procedure to remove or reduce the occlusion before step b).

9. The method according to claim 8, wherein the procedure is a chemical procedure that dissolves at least a part of the occlusion.

10. The method according to claim 9, wherein the chemical procedure comprises delivering a chemical substance through the channel of the hypodermic tube for a certain period of time, and the hypodermic tube further comprises fine holes, whereby the occlusion is perfused by the chemical substance entering through the fine holes.

11. The method according to claim 8, wherein the procedure is a surgical operation.

12. The method according to claim 11, wherein the surgical operation is an angioplasty.

13. The method according to claim 11, wherein the surgical operation is an atherectomy.

14. The method according to claim 13, wherein the atherectomy is selected from the group consisting of rotational atherectomy, transcatheter atherectomy, and directional coronary atherectomy.

15. The method according to claim 8, further comprising removing particles generated by the procedure after the procedure for removing or reducing the occlusion but before step b).

16. The method according to claim 15, wherein the particles are potential emboli and they are removed by a drainage catheter.

17. The method according to claim 1, wherein the blood vessel is a popliteal blood vessel.

18. The method according to claim 1, wherein the target tissue showing neointimal growth is in a blood vessel below the knee of the subject.

19. The method according to claim 1, wherein the device has a connected proximal balloon disposed upstream to block proximal blood flow.

20. The method according to claim 1, wherein the rapamycin is encapsulated in a nanocarrier.

21. The method according to claim 20, wherein the nanocarrier is selected from the group consisting of polymer and lipid nanocarriers.

22. The method according to claim 20, wherein the rapamycin is encapsulated in a plurality of nanoparticles.

23. The method according to claim 22, wherein the rapamycin is encapsulated in gelatin nanoparticles.

24. A method for treating a target tissue showing neointimal growth in a blood vessel of a subject, comprising: a) providing a device comprising a hypodermic tube including a channel and one or more openings, the hypodermic tube having a connected distal balloon; b) introducing the device into the blood vessel of the subject, at least a part of the device being disposed downstream of the target tissue showing neointimal growth, the part including the connected distal balloon; c) inflating the connected distal balloon, thereby stopping blood flow at the distal end of the blood vessel; d) introducing a treatment solution containing a growth inhibitor into the hypodermic tube and through the one or more openings such that the treatment solution contacts the target tissue for a certain period; e) inflating the connected distal balloon, removing the device from the blood vessel, thereby restoring blood flow at the distal end of the blood vessel.

25. The method according to claim 24, wherein the treatment solution contains rapamycin and dimethyl sulfoxide (DMSO).

26. The method according to claim 24, wherein the treatment solution comprises rapamycin encapsulated in a nanocarrier.

27. The method according to claim 26, wherein the nanocarrier is selected from the group consisting of polymeric and lipid nanocarriers.

28. The method according to claim 24, wherein the treatment solution is encapsulated in a plurality of nanoparticles.

29. The method according to claim 28, wherein the rapamycin is encapsulated in gelatin nanoparticles.

30. The method according to claim 24, wherein the blood vessel comprises a partial or complete occlusion in or near the target tissue.

31. The method according to claim 30, further comprising performing a procedure to remove or reduce the occlusion prior to step d).

32. The method according to claim 31, wherein the procedure comprises delivering a chemical solution that dissolves at least a portion of the occlusion, the chemical solution being different from the treatment solution.

33. The method according to claim 32, wherein the chemical solution is delivered through the channel of the hypodermic tube and through the one or more openings, whereby the occlusion is perfused with the chemical solution for a period of time.

34. The method according to claim 31, wherein the procedure is a surgical procedure.

35. The method according to claim 34, wherein the surgical procedure is an angioplasty.

36. The method according to claim 34, wherein the surgical procedure is an atherectomy.

37. The method according to claim 36, wherein the atherectomy is selected from the group consisting of rotational atherectomy, transcatheter atherectomy, and directional coronary atherectomy.

38. The method according to claim 30, further comprising removing particles generated by the procedure after the procedure for removing or reducing the occlusion but before step d).

39. The method according to claim 38, wherein the particles are potential emboli and are removed by a drainage catheter.

40. The method according to claim 24, wherein the blood vessel is a popliteal blood vessel.

41. The method according to claim 24, wherein the target tissue exhibiting neointimal growth is in a blood vessel below the knee of the subject.

42. The method according to claim 24, wherein the device further comprises a connected proximal balloon disposed upstream of the target tissue.

43. The method of claim 42, further comprising, after step b), inflating the connected proximal balloon to occlude proximal blood flow. **Claim 44** i) A hypotube having a channel, the channel having one or more openings and having a connected distal balloon and a connected proximal balloon; ii) A drainage catheter having an open cavity in an internal portion between the distal and proximal balloons; and iii) A system including a restriction catheter that allows for various lengths to accommodate different lesion lengths. **Claim 45** The system of claim 36, wherein the restriction catheter is configured to cover the hypotube that delivers the therapeutic agent. **Claim 46** The system of claim 37, wherein the restriction catheter is moved substantially distally relative to the distal balloon to limit the amount and location of the therapeutic agent eluted by the hypotube, thereby allowing for the various lengths of the blood vessel and the lesion therein. **Claim 47** A delivery system including a delivery device having first, second, and third ports, wherein the first port is configured to supply fluid through a first channel for inflating an angioplasty balloon, the fluid for inflating the angioplasty balloon, the second port is configured to supply fluid through a second channel for inflating a distal balloon to occlude blood flow, and the third port is configured to supply fluid through a third channel for supplying a treatment solution into a blood vessel. **Claim 48** The method of claim 47, wherein the treatment solution includes rapamycin encapsulated in a nanocarrier. **Claim 49** The method of claim 47, wherein the first channel is within a first hypotube, the second channel is within a second hypotube, and the third channel is within a third hypotube.

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