Endoluminal phototherapy of tumors

Abstract

Intravascular photodynamic therapy (PDT) of target tumor tissue is disclosed. The PDT method may be vascular targeted photodynamic therapy (VTP) or any other form of PDT in which the concentration of photosensitizer in the vascular endothelium is not phototoxic. The disclosed PDT is performed within a blood vessel near the target tissue or organ, and the light-diffusing portion of the optical fiber that delivers the irradiation is positioned within the inflatable balloon portion of a balloon catheter that expands during irradiation to block blood flow.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 427,867, filed November 2022 with the USPTO, the entirety of which is incorporated herein by reference. [Technical Field]

[0002] The presently disclosed subject matter is in the general field of photodynamic therapy (PDT), and in particular in the field of vascular-targeted photodynamic therapy (VTP). [Background technology]

[0003] Photodynamic therapy (PDT) is a form of phototherapy that involves the dynamic interaction of photosensitizing drugs, oxygen, and light to induce cell death. In classical PDT, photosensitizing drugs administered to a subject preferentially accumulate in tumor tissue due to the enhanced permeability and retention (EPR) effect, and can subsequently further accumulate in rapidly proliferating cancer cells. Activation of the photosensitizer by application of light at specific wavelengths restricted to the tumor site generates short-lived reactive oxygen species (ROS) by interacting with local oxygen, resulting in apoptosis or necrosis of cancer cells. Currently, the most commonly used sensitizers preferentially accumulate in tumor tissue and are activated upon uptake by cancer cells. Furthermore, the active ROS generated by these sensitizers is singlet oxygen, which oxidizes proteins and lipids essential for cell survival (type II mechanism), thereby triggering cell death by apoptosis or necrosis, resulting in non-thermal tumor ablation.

[0004] Vascular-targeted photodynamic therapy (VTP) is a photodynamic therapy in which photosensitizers are applied shortly after intravenous administration while the photosensitizer is still present in the bloodstream. Some VTP drugs, such as ledaporfin or visudyne (verteporfin), are delivered in liposomes and rapidly taken up by vascular endothelial cells. Tumor irradiation then induces endothelial cell death, vascular thrombosis, and blood flow cessation. In contrast, bacteriochlorophyll derivatives (Bchl-D), such as padeliporfin (also known by the codename WST11), are water-soluble VTP drugs that are noncovalently bound to serum albumin and are neither taken up by tumor endothelium nor extravasated until excreted. Irradiation of the tumor vascular bed is typically performed using light in the red to near-infrared range delivered through an optical fiber connected to a laser, activating circulating Bchl-D. Activated Bchl-D generates hydroxyl and superoxide radicals (type I mechanism), resulting in local hypoxia and the production of endogenous nitric oxide. This initiates a chain of biological processes, resulting in tumor vasoconstriction, followed by destruction and cell death, ultimately leading to coagulation necrosis of tumor tissue, while normal blood vessels, particularly those larger than 40 microns in diameter, are preserved. Following endothelial and cancer cell necrosis, antitumor immunity is activated, leading to complete eradication of the irradiated tumor. WST11-VTP has recently been named Padeliporfin ImPACT (Immune Photo-Activated Cancer Therapy).

[0005] overview This description relates to intravascular photodynamic therapy (PDT) of targeted tumor tissue, typically performed within blood vessels, such as major blood vessels near the tumor. According to one preferred embodiment of this disclosure, the PDT method is vascular-targeted photodynamic therapy (VTP). Other exemplary embodiments include immuno-photoactivated cancer therapy (ImPACT) and PDT that targets photosensitizing drugs absorbed by cancer cells.

[0006] The term "PDT" as used herein refers to all of these types of PDTs, preferably VTPs. Also, although PDTs may be referred to in the following description, it should be understood that this is a specific embodiment of the present disclosure and is not intended to limit the present disclosure, which applies to the entire scope described above.

[0007] The terms "PDT drug," "PDT effective drug," "photosensitizing drug," and the like are meant to refer to an agent or combination of agents that can be administered to a subject and activated by light to generate chemically reactive species (typically, but not limited to, reactive oxygen species).

[0008] The terms "PDT effective light", "photosensitizing effective light" and the like refer to light that has the effect of activating a PDT effective drug.

[0009] The term "about" refers to a quantity that may deviate from the stated quantity by up to 10%, 15%, or 20%.

[0010] In accordance with this disclosure, it has been recognized that light delivery via optical fibers positioned within the lumenal space of large blood vessels, such as arteries or other tubular organs, can be safely used to initiate PDT, particularly in tumor VTPs containing accessible major blood vessels, but that circulating photosensitizing drugs can significantly attenuate emitted light due to light absorption by blood-borne elements such as hemoglobin (which peaks at 780 nm), which can be a limiting factor for such therapeutic treatments. More specifically, the attenuation of light reaching the vessel wall is roughly proportional to the vessel diameter, and correspondingly, there is an inverse relationship between this diameter and the amount of light reaching the tumor tissue surrounding that vessel. Some light may be absorbed by the circulating photosensitizing drug, and the thicker the blood layer between the optical fiber and the vessel wall, the greater the attenuation (based on the Beer-Lambert law or the light diffusion model (when scattering is included)). As a result, the light fluence required to activate the photosensitizing drug within the tumor is reduced as it passes through the vessel wall, resulting in particularly low effective photosensitizing drug in tumor VTPs. It is further understood that, according to this disclosure, such attenuation can be avoided by temporarily blocking blood from the irradiated portion of the blood vessel with a balloon catheter, and then irradiating the drug-sensitizing effective light from within the inflated inflatable balloon portion. In this manner, the irradiated light reaches the vessel wall with only slight attenuation, passes through the inflatable balloon portion made of a transparent or translucent material, and then proceeds through the vessel wall to the tumor. This manner also avoids any negative effects that may arise from the interaction of light with a photosensitizing drug circulating through the vessel where light irradiation is performed, because such interaction occurs only outside the vessel.

[0011] In other words, according to the present disclosure, the blood layer between the light diffusing element at the distal end of the illumination optical fiber and the vessel wall, which traditionally optically separates this element from the vessel wall and thus reduces radiation damage, but which may potentially induce localized damage within the vessel, is safely thinned or eliminated by the procedures described herein, thereby allowing light to penetrate the vessel wall and reach the tumor, causing ablation of the tumor surrounding such vessel.

[0012] The present disclosure provides catheter systems and catheter assemblies assembled from elements of the catheter systems useful in PDT procedures, treatment systems including the catheter systems or assemblies, and PDT methods, all of which are independent aspects of the present disclosure. As will be appreciated, one skilled in the art will no doubt recognize that an embodiment described with respect to one aspect may also be applicable to one or more of the others.

[0013] One aspect of this disclosure provided is a catheter system comprising an optical fiber, a balloon catheter, and a flushing channel, each extending axially between a proximal end and a distal end.

[0014] The optical fiber can be optically coupled at its proximal end to a light source, typically emitting light effective for PDT (at a wavelength effective for PDT, depending on the nature of the photosensitizing drug used, and at a sufficient intensity). It also has a cylindrical light-diffusing portion (or sometimes referred to as a "light diffuser") at its distal end configured to scatter light transmitted through the fiber, so that at least a portion of it is transmitted from the light-diffusing portion in a non-axial, particularly radial, direction. One or more fiber-associated imaging markers are attached to the end of the fiber, as described in more detail below, and are useful for tracking the position of the light-diffusing portion (for proper imaging) and thus ensuring correct positioning before light irradiation begins. The distal markers also provide an indication of the position of the fiber tip within the balloon catheter, particularly with respect to extending beyond the distal end of the flushing channel.

[0015] Various types of optical diffusers may be used in accordance with this disclosure. These include diffusers that scatter light approximately evenly in all radiation directions, front-facing diffusers that emit a circular beam, and side-firing diffusers in which the beam is directed to only one side. Additionally, the term "diffuser" in this disclosure may also refer to other light-emitting elements at the distal end of a light-emitting fiber. These include clear-cut fibers (polished or cleaved) that emit light as a Gaussian or super-Gaussian beam, conical emitters that emit a ring-shaped light pattern forward from the center of the fiber, and lensed fibers that emit a beam with a larger divergence angle forward. For other optical emitters, scattering may also refer to the propagation of light rays determined through a surface, reflective, or refractive medium.

[0016] The balloon catheter is fluidly connectable at its proximal end to a pressure fluid source (liquid or gas, which may include a contrast agent) and has an inflatable balloon portion at its distal end. One or more balloon-associated imaging markers attached to the catheter are associated with the inflatable balloon portion and, like the fiber-associated imaging markers, are useful for tracking the position of the inflatable balloon portion, thus ensuring proper positioning both in the blood vessel and in the position of the optical fiber's light-diffusing portion within the balloon before light irradiation begins. The balloon catheter also has a working channel, as is conventionally known.

[0017] The flushing channel may be constituted by the working channel described above (a non-limiting example), or by a separate tube that can be fitted into and extend through the working channel of the balloon catheter. The flushing channel can be fluidly connected at its proximal end to a source of flushing physiological solution, where the term "flushing physiological solution" is used interchangeably with "flushing solution" and is meant to encompass any compatible physiological solution, including saline, saline with other additives, etc. This is intended to cool the light-diffusing portion of the optical fiber, which heats up upon irradiation, prevent blood from entering the open working channel where the fiber is located (which must remain open to allow balloon placement using a guidewire), and separate the highly absorbent blood from the diffuser at the distal-most end of the system or assembly disclosed herein. The flushing channel extends between a liquid-tight proximal end and an open distal end, allowing flushing fluid to flow along the flushing channel and exit the distal end toward the artery distal to the inflatable balloon portion of the balloon catheter. The flushing channel is sized to accommodate an optical fiber introduced through the liquid-tight proximal end, allowing the flushing solution to flow along the entire length of the introduced optical fiber between the proximal and distal ends of the flushing channel.

[0018] The imaging marker, according to one embodiment, is an X-ray marker, which may be configured as an annular metallic element, or in certain cases, for example, as a metallic rod near the distal tip of the fiber, although, as can be seen from other embodiments, the imaging marker may be configured differently, such as a polymer-based X-ray marker, or may be adapted for other imaging techniques, such as ultrasound-based imaging.

[0019] The inflatable balloon portion typically has a wall that is transparent or translucent to the irradiating light and may be adapted to allow at least 50% of the incident light to pass through.

[0020] In some embodiments, the system includes an auxiliary catheter, fluidly connectable at its proximal end to a source of auxiliary fluid, typically contrast saline (i.e., saline containing a contrast agent, which may comprise approximately 10% of the total solution), which can be used as an imaging aid to position the inflatable balloon portion at its intended distal location and as a means to provide a fluid barrier between the balloon and blood in the artery at the proximal end of the balloon. It has a catheter lumen extending between a liquid-tight proximal end and an open distal end. The lumen is sized to accommodate a balloon catheter introduced through the liquid-tight proximal end, allowing auxiliary fluid to flow from the proximal end to the distal end even when the balloon catheter is accommodated. The auxiliary catheter has a length such that, when the balloon catheter is accommodated, the distal end of the balloon catheter, including the inflatable balloon portion, extends beyond the distal portion of the auxiliary catheter.

[0021] It should be noted that contrast agents may be incorporated into the flushing fluid according to some embodiments of this disclosure.

[0022] Typically, one or two fiber-related imaging markers and one or two balloon-related imaging markers may be present. The imaging markers may be positioned at defined locations, with at least one fiber-related imaging marker at a defined location relative to the light-diffusing portion and at least one balloon-related imaging marker at a defined location relative to the inflatable balloon portion. The defined locations are typically near the proximal or distal end of each portion. In some embodiments, two fiber-related imaging markers and / or two balloon-related imaging markers may be present. When two such markers are provided in a set, they are typically positioned on either side of each portion. Each marker is useful as image-based positional guidance to confirm that the optical fiber's optical diffuser is axially positioned within the inflatable balloon portion of the balloon catheter. When two fiber-related imaging markers are positioned on either side of the light-diffusing portion and two balloon-related imaging markers are positioned on either side of the inflatable balloon portion, the axial distance between the two fiber-related imaging markers and the distance between the two balloon-related imaging markers may be different, thereby enabling a comprehensive view and ensuring that the two markers in one set do not overlap with each other. In other words, the distance D1 between two fiber-related imaging markers and the distance D2 between two balloon-related imaging markers are different, with D1 typically being shorter than D2. However, it is also possible for D1 and D2 to be substantially the same. In that case, proper positioning of the light-diffusing portion and the inflatable balloon portion is ensured by "merging" the two sets of images. The light-diffusing portion is typically shorter than the inflatable balloon portion, allowing its position to be within the axial limits of the inflatable balloon portion.

[0023] A catheter assembly is another aspect of the present disclosure and includes elements of a catheter system that are assembled together to extend coaxially from proximal to distal. All of the above embodiments are applicable with respect to assembly.

[0024] A treatment system is another aspect of the present disclosure, which may include the catheter systems previously described, which may be assembled together to form the assembly described above, or may include an already pre-assembled catheter assembly.

[0025] The treatment system also includes a light source for emitting light at an appropriate wavelength, particularly visible, near-infrared, or SWIR, configured for coupling to the proximal end of the optical fiber. This range may include light in the range of about 350 nm to 1600 nm, particularly within the range of about 400 nm to 800 nm. The light source, e.g., a laser, is typically (but not exclusively) adapted to emit a narrow band of light. For example, in the case of a bacteroclophyll derivative, a suitable laser emits light with a center wavelength of about 750-75 nm, with a bandwidth typically less than 4 nm. The power of the laser light incident on the proximal end of the optical fiber is typically up to about 2 watts.

[0026] The treatment system may include a source of contrast saline solution fluidly connectable to the proximal end of the auxiliary catheter. Additionally, the flushing solution and the balloon inflation solution may also include a contrast agent. The treatment systems disclosed herein may also include a photosensitizing drug.

[0027] A method of photodynamic therapy (PDT) to a target site within a subject is a further aspect of this disclosure, comprising the following elements in the order listed or any other suitable order: For example, systemic administration of a photosensitizing drug as described in (a) may occur before, during, or after insertion of an assembly as described in (b), and may also occur during a therapeutic induction phase as described in (c). The method includes the following elements:

[0028] (a) A photosensitizing drug is administered systemically to the subject. This can be accomplished by intravenous administration, but other methods are also possible. The photosensitizing drug can be, for example, a bacteriochlorophyll derivative that absorbs and can sensitize light at wavelengths of approximately 750-756 nm. A specific example of such a photosensitizing drug is padeliporfin (also known as WST11). Another example is verteporfin, which is sensitized by light at wavelengths of approximately 680-700 nm, or ledaporfin, which is sensitized by light at wavelengths of approximately 740-760 nm. Other non-limiting examples include photofrin, phthalocyanine, ALA-Ppix, talaporfin, or temoporfin. (b) Inserting the assembly described herein through a blood vessel and guiding the inflatable balloon portion of the balloon catheter until it is near the target site, typically tangential to the target tissue, e.g., a tumor, and displacing the optical fiber axially to position the optical diffusing portion within the inflatable balloon portion. Optionally, this step may include adjusting the size and position of the balloon using standard radiology techniques, inflating the balloon, and then introducing a contrast agent via an auxiliary catheter. It should also be noted that rather than inserting the assembly in an assembled form, the assembly may be formed in situ, for example, by first inserting an auxiliary catheter, then inserting the balloon catheter from its proximal end through the lumen of the auxiliary catheter, and then inserting the optical fiber through the working channel of the balloon catheter. A typical insertion involves the use of a guidewire placed within the working channel of the balloon. Once the balloon is in place, the guidewire is removed from the working channel and the fiber is inserted. (c) Inducing a treatment phase, which includes substantially blocking blood flow through the vessel by inflating the inflatable balloon portion, for example, until the wall of the inflatable balloon portion contacts the vessel wall. This centers the fiber within the vessel. This phase further includes positioning the fiber with the light-diffusing portion using an imaging marker, passing a flushing fluid through the flushing channel, and irradiating the fiber with light of a wavelength and intensity suitable for activating the photosensitizing drug. The treatment phase may be performed for about 1, 2, 3, or 4 minutes to about 6, 7, 8, 9, 10, 11, or 12 minutes, with 5 minutes being a specific example. In some embodiments, treatment can last up to 20 or even 30 minutes.

[0029] In embodiments using padeliporfin, balloon placement (b) typically occurs prior to drug injection (a).

[0030] This method is typically performed while imaging at least a target site within the subject to ensure that the inflatable balloon portion is positioned adjacent to the target site and also to axially position the light diffusing portion within the inflatable balloon portion by properly aligning one or more fiber-associated imaging markers with one or more balloon-associated imaging markers.

[0031] If the fiber includes a distal marker, the distal marker on the fiber may be placed directly below or adjacent to the distal marker on the balloon.

[0032] If the fiber includes two sets of fiber-associated imaging markers on either side of the light diffusing portion and axially spaced a distance D1 from each other, and the balloon catheter includes two sets of balloon-associated imaging markers on either side of the inflatable balloon and axially spaced a distance D2 different from D1 from each other, then to properly align, the optical fiber is displaced axially until one of the sets is located on either side of the other. If D2 is greater than D1, then to properly align, the optical fiber is displaced axially until two fiber-associated imaging markers are located on either side of the two balloon-associated imaging markers.

[0033] Flushing saline can be continuously flushed through the flushing channel during the PDT procedure to prevent excessive heating of the optical fiber, especially the light diffusing portion.

[0034] The PDT method of the present disclosure is typically a VTP method for initiating tumor ablation by rapidly occluding and destroying tumor-associated blood vessels. One example is pancreatic cancer, where the distal end of the catheter assembly is guided into the superior mesenteric artery (SMA), superior mesenteric vein (SMV), celiac artery, or other large blood vessel accessible for catheter insertion near the pancreas.

[0035] An exemplary treatment regimen includes two or more repeated treatment phases (as described in (a) above) separated by rest phases in which the inflatable balloon portion is deflated, thereby eliminating transmission of light outside the vessel, and / or light irradiation is halted for a period of time, typically between about 0.5 or 1 minute and about 1.25, 1.5, 1.75, or 2 minutes, with about 1 minute being a specific example.

[0036] Other exemplary indications for using the systems or assemblies described herein include treatment of angiosarcoma, cancer-involved abdominal para-aortic lymph nodes, in and around the heart, or other vascularly accessible sites such as the brain, kidney, liver, lung, neck, muscle, and connective tissue, or treatment in the gallbladder or other hollow cavities containing fluid to be replaced. In addition to ablation, other treatments enabled by this delivery method may include altering tissue properties such as hardening, or localized chemical reactions through light activation.

[0037] Embodiment Some non-limiting embodiments of this disclosure are described in the following numbered paragraphs, which are intended to supplement, but not limit, the disclosure in the general description above.

[0038] 1. A catheter system, the system comprising: an optical fiber, a balloon catheter, and a flushing channel, each extending axially between a proximal end and a distal end; -Optical fiber is optically coupleable to a light source at a proximal end; a light diffusing portion at the distal end portion configured to scatter light transmitted through the fiber, such that at least a portion of the light is transmitted non-axially from the light diffuser; having one or more fiber-associated imaging markers at the end; -Balloon catheters fluidly connectable at a proximal end to a source of pressurized fluid; an inflatable balloon portion at a distal end portion; having one or more balloon-associated imaging markers associated with the inflatable balloon portion; and having a working channel. -Flushing channel at a proximal end fluidly connectable to a source of flushing solution; extending between a fluid-tight proximal end and an open distal end; a flushing channel sized to accommodate an optical fiber introduced through the fluid-tight proximal end and to allow flushing fluid to flow along the entire introduced length of the fiber between the proximal and distal ends of the flushing channel; The system may be comprised of a working channel or a separate tube attached to and extending through the working channel of the balloon catheter.

[0039] 2. The system of embodiment 1, wherein the flushing channel is a balloon working channel.

[0040] 3. The system of embodiment 1 or 2, wherein the imaging marker is an X-ray marker.

[0041] 4. The system of embodiment 3, wherein the imaging marker is a ring-shaped metallic element or a circular element.

[0042] 5. A system according to any one of embodiments 1 to 4, wherein the inflatable balloon portion has a transparent or translucent wall.

[0043] 6. The system of embodiment 5, wherein the wall allows at least 50% of the light incident thereon to pass through.

[0044] 7. A system according to any one of embodiments 1 to 6, comprising an auxiliary catheter, the auxiliary catheter being fluidly connectable at a proximal end to a fluid source; a catheter lumen extending between a fluid-tight proximal end and an open distal end, the catheter lumen being sized to accommodate a balloon catheter introduced through the fluid-tight proximal end and to allow fluid to flow from the proximal end to the distal end even when the balloon catheter is accommodated; The system has a length such that when the balloon catheter is housed, the distal end of the balloon catheter, including the inflatable balloon portion, extends beyond the distal portion of the auxiliary catheter.

[0045] 8. A system according to any one of embodiments 1 to 7, comprising at least one fiber-associated imaging marker at a defined position relative to the light-diffusing portion.

[0046] 9. The system of embodiment 8, comprising a fiber-associated imaging marker, typically at a known distance, near the proximal or distal end of the light-diffusing portion.

[0047] 10. The system of embodiment 8, comprising two fiber-associated imaging markers on either side of the light-diffusing portion.

[0048] 11. A system as described in any one of embodiments 1 to 10, comprising at least one balloon-associated imaging marker at a defined position relative to the inflatable balloon portion.

[0049] 12. The system of embodiment 11, comprising a balloon-associated imaging marker near the proximal or distal end of the inflatable balloon portion.

[0050] 13. A system according to any one of embodiments 1 to 10, comprising two balloon-associated imaging markers on either side of the inflatable balloon portion.

[0051] 14. A fiber-associated imaging marker at a defined position relative to the light-diffusing portion; A system as described in any one of embodiments 8 to 13, comprising two balloon-related imaging markers on either side of the inflatable balloon portion.

[0052] 15. The system of embodiment 14, comprising one fiber-associated imaging marker at the proximal end of the light-diffusing portion.

[0053] 16. Two fiber-associated imaging markers on either side of the light-diffusing portion and spaced apart from each other in the axial direction by a distance D1; A system as described in any one of embodiments 1 to 15, comprising two balloon-related imaging markers located on either side of the inflatable balloon portion and axially spaced from each other by a distance D2 different from D1.

[0054] 17. The system of embodiment 16, wherein D2 is greater than D1.

[0055] 18. The light diffusion portion is shorter than the inflatable balloon portion. 18. The system of any one of embodiments 1 to 17, wherein the optical fiber is axially displaceable within the flushing channel to axially align the light diffusing portion within the axial range of the inflatable balloon portion.

[0056] 19. A system according to any one of embodiments 1 to 18 for use in PDT, such as VTP (including immuno-photoactivated cancer therapy, i.e. ImPACT), or PDT / VTP targeted to the tumor parenchyma.

[0057] 20. A system described in any one of embodiments 1 to 19, wherein the optical fiber has a coupling member at the proximal end configured to optically couple to a light source emitting light of a therapeutically effective wavelength.

[0058] 21. A catheter assembly, the assembly comprising: an optical fiber; a balloon catheter having a working channel; and a flushing channel, all extending axially in a proximal to distal direction, each having a proximal end and a distal end; -Balloon catheters fluidly connectable at a proximal end to a source of pressurized fluid; an inflatable balloon portion at a distal end portion; having one or more balloon-related imaging markers associated with the inflatable balloon portion and having a working channel; -Flushing channel at a proximal end fluidly connectable to a source of flushing solution; extending between a fluid-tight proximal end and an open distal end; a flushing channel configured to receive an optical fiber introduced through the fluid-tight proximal end and to allow flushing fluid to flow around the entire introduced length of the fiber between the proximal and distal ends of the flushing channel; Defined by a working channel, or defined by a tube housed within and extending through the working channel, or defined by the lumen of a tube housed within the working channel; -Optical fiber is optically coupleable to a light source at a proximal end; a light diffusing portion at the distal end portion configured to scatter light transmitted through the fiber so that at least a portion of the light is transmitted non-axially from the light diffuser; one or more fiber-associated imaging markers at the end portion of the flushing channel; A catheter assembly, wherein the flushing fluid is contained within the flushing channel in a manner that allows the flushing fluid to flow along the entire length of the introduced fiber from the proximal end to the distal end of the flushing channel.

[0059] 22. The assembly of embodiment 21, wherein the flushing channel is the working channel.

[0060] 23. The assembly of embodiment 21 or 22, wherein the imaging marker is an X-ray marker.

[0061] 24. The assembly of embodiment 23, wherein the imaging marker is an annular or circular metal element.

[0062] 25. An assembly according to any one of embodiments 21 to 24, wherein the inflatable balloon portion has a transparent or translucent wall.

[0063] 26. The assembly of embodiment 25, wherein the wall allows at least 50% of the light incident thereon to pass through.

[0064] 27. An assembly according to any one of embodiments 21 to 26, comprising an auxiliary catheter, the auxiliary catheter being fluidly connectable at a proximal end to a fluid source; a catheter lumen extending between a fluid-tight proximal end and an open distal end, the catheter lumen being sized to accommodate a balloon catheter introduced through the fluid-tight proximal end and to allow fluid to flow from the proximal end to the distal end even when the balloon catheter is accommodated; The assembly has a length such that the distal end of the balloon catheter, including the inflatable balloon portion, extends beyond the distal portion of the auxiliary catheter.

[0065] 28. An assembly according to any one of embodiments 21 to 27, comprising at least one fiber-associated imaging marker at a defined position relative to the light-diffusing portion.

[0066] 29. The assembly of embodiment 28, comprising a fiber-associated imaging marker near the proximal or distal end of the light-diffusing portion.

[0067] 30. The assembly of embodiment 29, comprising two fiber-associated imaging markers on either side of the light-diffusing portion.

[0068] 31. An assembly according to any one of embodiments 21 to 30, comprising a balloon-associated imaging marker at a defined position relative to the inflatable balloon portion.

[0069] 32. The assembly of embodiment 31, comprising a balloon-associated imaging marker near the proximal or distal end of the inflatable balloon portion.

[0070] 33. An assembly according to any one of embodiments 21 to 32, comprising two balloon-associated imaging markers on either side of the inflatable balloon portion.

[0071] 34. A fiber-associated imaging marker at a defined position relative to the light-diffusing portion; 34. The assembly of any one of embodiments 21 to 33, comprising: two balloon-associated imaging markers on either side of the inflatable balloon portion.

[0072] 35. The assembly of embodiment 34, comprising one fiber-associated imaging marker at the proximal end of the light-diffusing portion.

[0073] 36. Two fiber-associated imaging markers on either side of the light-diffusing portion and spaced apart from each other in the axial direction by a distance D1; An assembly as described in any one of embodiments 21 to 35, comprising two balloon-related imaging markers on either side of the inflatable balloon portion and axially spaced from each other by a distance D2 different from D1.

[0074] 37. The system of embodiment 36, wherein D2 is greater than D1.

[0075] 38. The light diffusion portion is shorter than the inflatable balloon portion. An assembly described in any one of embodiments 21 to 37, wherein the optical fiber is axially displaceable within the flushing channel to axially align the light diffusing portion within the axial range of the inflatable balloon portion.

[0076] 39. An assembly according to any one of embodiments 21 to 38, for use in PDT, such as VTP (including immune photoactivated cancer therapy, i.e. ImPACT), or PDT / VTP targeted to the tumor parenchyma.

[0077] 40. An assembly described in any one of embodiments 21 to 39, wherein the optical fiber has, at its proximal end, a coupling member configured to optically couple to a light source that emits light of a therapeutically effective wavelength (e.g., effective to activate a photosensitizing drug).

[0078] 41. A treatment system comprising a catheter system according to any one of embodiments 1 to 20 or an assembly according to any one of embodiments 21 to 40.

[0079] 42. The system of embodiment 41, comprising a light source for emitting light in the ultraviolet, visible, NIR, and SWIR ranges (e.g., light in the range of approximately 350 nm to 6500 nm), and configured to be coupled to the proximal end of the optical fiber.

[0080] 43. The system of embodiment 41 or 42, wherein the light source emits narrow-band light.

[0081] 44. The system of embodiment 43, wherein the light source is a laser.

[0082] 45. An auxiliary catheter according to embodiment 7 or 27, 45. The system of any one of embodiments 41 to 44, further comprising a source of contrast saline solution fluidly connectable to the proximal end of the auxiliary catheter.

[0083] 46. ​​A system according to any one of embodiments 41 to 45, comprising a photosensitizing drug.

[0084] 47. A method of photodynamic therapy (PDT) of a target site within a subject, comprising: Systemically administering (e.g., intravenously administering) a photosensitizing drug to a subject; Inserting the assembly of any one of embodiments 19 to 36 through a blood vessel, axially advancing and guiding the inflatable balloon portion of the balloon catheter until it is near the target site, typically tangential to the target site, and axially displacing the optical fiber to position the optical diffusing portion within the inflatable balloon portion; and inducing a treatment step, the treatment step including inflating an inflatable balloon portion, passing a flushing solution through a flushing channel, and irradiating light via an optical fiber at a wavelength and intensity suitable for activating a photosensitizing drug.

[0085] 48. Imaging the target site; and axially positioning the light diffusing portion within the inflatable balloon portion by appropriately aligning one or more balloon-associated imaging markers with one or more fiber-associated imaging markers.

[0086] 49. The method of embodiment 47, wherein: the optical fiber includes two fiber-associated imaging markers on either side of the light-diffusing portion and spaced axially apart by a distance D1; the balloon catheter includes two balloon-associated imaging markers on either side of the inflatable balloon portion and axially spaced apart from each other by a distance D2 different from D1; A method in which the optical fibers are displaced axially until one of the sets is positioned between the other sets to achieve proper alignment.

[0087] 50.D2 is greater than D1, 50. The method of embodiment 49, wherein, for proper alignment, the optical fiber is axially displaced until the two fiber-associated imaging markers are positioned between the two balloon-associated imaging markers.

[0088] 51. A method according to any one of embodiments 47 to 50, comprising continuously flushing a flushing physiological solution through the flushing channel during the PDT procedure.

[0089] 52. The method of any one of embodiments 47 to 51, wherein the PDT is vascular-targeted photodynamic therapy (VTP).

[0090] 53. The method of embodiment 50, wherein the light source is a laser emitting light at a wavelength of about 750-756 nm and having an output power of up to about 2 watts.

[0091] 54. The photosensitizing drug is a bacteriochlorophyll derivative that has a major light absorption at about 750 to 756 nm and can generate oxygen radicals upon irradiation; 54. The method of embodiment 52 or 53, wherein the photosensitizing drug is administered intravenously to the subject at a predetermined time prior to the inflation of the inflatable balloon portion and the commencement of light irradiation.

[0092] 55. The method of embodiment 52 or 53, wherein the photosensitizing drug is padeliporfin, verteporfin, or ledaporfin.

[0093] 56. The method of any one of embodiments 47 to 55, wherein the photosensitizing drug is administered about 5 to 15 minutes (typically about 10 minutes) before light irradiation.

[0094] 57. The method of any one of embodiments 47 to 55, wherein the photosensitizing drug is administered about 5 to 30 minutes (typically about 10 minutes) before light irradiation.

[0095] 58. The target site is a tumor; The method of any one of embodiments 47 to 57, wherein the blood vessel is a major blood vessel passing near the tumor.

[0096] 59. The tumor is pancreatic cancer. 59. The method of embodiment 58, wherein the blood vessel is the superior mesenteric artery (SMA), the superior mesenteric vein (SMV), or other large vessel that can be catheterized near the pancreas.

[0097] 60. The method of embodiment 58 or 59, wherein the blood vessels are substantially tangential to the tumor.

[0098] 61. The method of any one of embodiments 47 to 60, wherein there are two or more treatment phases, optionally separated by rest phases, during which the inflatable balloon portion is deflated (light irradiation may or may not be discontinued during the rest phase).

[0099] 62. The treatment phase lasts from about 2 minutes to about 10 minutes. 62. The method of embodiment 61, wherein the resting step is from about 0.5 minutes to about 2 minutes.

[0100] 63. The method of any one of embodiments 47-62, wherein the inflatable balloon portion is inflated to substantially block blood flow through the blood vessel.

[0101] 64. The method of any one of embodiments 47-63, wherein the inflatable balloon portion is inflated to substantially block blood flow through the vessel and the fiber is centrally positioned within the vessel.

[0102] 65. The method of embodiment 63 or 64, wherein the inflatable balloon portion is inflated so that its wall contacts the vessel wall.

[0103] For a better understanding of the subject matter disclosed herein, and to illustrate how it may be carried out in practice, embodiments will now be described by way of non-limiting example with reference to the accompanying drawings, in which: [Brief explanation of the drawings]

[0104] For a better understanding of the subject matter disclosed herein, and to illustrate how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which: [Figure 1A] FIG. 1 is a general schematic diagram of a catheter assembly according to an exemplary embodiment of the present disclosure deployed within the body for performance of VTP within the pancreas. [Figure 1B] 1 shows the distal portion of the assembly relative to the target site. [Figure 1C] FIG. 1C is a detailed schematic diagram of a catheter system including the assembly shown in FIGS. 1A and 1B and portions thereof. [Figure 2] FIG. 1C is a schematic diagram of the ex vivo elements in the assembly of the system, showing it more realistically. [Figure 3] FIG. 3 is a schematic diagram of the distal portion of the assembly of FIGS. 1A-2. [Figure 4]1 illustrates a flowchart of an assembly deployment and VTP procedure implementation according to one embodiment of the present disclosure. [Figure 5] 1A-1D show schematic diagrams of the distal portion of an assembly in several operating states according to one embodiment of the VTP treatment regimen of the present disclosure. [Figure 6] 6 is a diagram illustrating the shading used on various elements in FIG. 5; [Figures 7A-7B] 10A-10C show images captured during real-time fluoroscopy utilizing imaged balloon-associated imaging markers and fiber-associated markers, respectively, to guide the inflatable balloon portion of the catheter and the optical diffuser to their proper placement within the confines of the balloon catheter. [Figure 8] FIG. 1 is a schematic diagram showing sites along the outer femoral artery wall (proximal and distal) where light intensity was measured using an isotropic probe to assess effective light exposure during the VTP procedure. [Figure 9] 1A-1C are histological images of the pancreas and other tissues following a VTP procedure as disclosed herein. DETAILED DESCRIPTION OF THE INVENTION

[0105] The following description describes exemplary embodiments that primarily focus on the VTP aspects of the present disclosure. It should be understood that the described embodiments are merely non-limiting examples of the full scope of the present disclosure, as defined and described above and in the appended claims.

[0106] 1A and 1B, a catheter assembly generally designated 100 is shown, including a proximal portion 102 outside the body and a distal portion showing only the optical fiber 104 inside the body. The assembly is inserted through the body wall at the point of insertion into the femoral artery, and then extended into the abdominal aorta with its distal optical diffusing portion 108 bent (the bend diameter may be less than 25 mm) and introduced into the superior mesenteric artery above the pancreas.

[0107] 1C, 2, and 3, Fig. 1C is a schematic diagram of a catheter system generally designated 110, including catheter assembly 100 and other system elements, all shown schematically. Fig. 2 is a more realistic view of the assembly elements of Fig. 1C that remain outside the body, and Fig. 3 is a schematic diagram of the distal end portion of the assembly.

[0108] The catheter system 110 of this embodiment includes a balloon catheter 114 with an optical fiber 112 and a working channel 116, all of which extend axially from proximal to distal directions and between their respective proximal and distal ends along an axis indicated by arrow 118 (which assumes a tortuous path in use).

[0109] A balloon catheter 114 (which may be, for example, a Powerflex™ or Saber™ (Cordis Medical, USA)) has a pressurized fluid conduit 120 surrounding a working channel 116 and is fluidly connected to a pressurized fluid source 122 (which may or may not contain contrast media), such as a manually operated device 122A (e.g., IN4130-BasxCOMPAK™, Merit Medical, USA) via a port 125 of a balloon Y-connector 126. Another port 127 of the balloon Y-connector is connected to an outlet port 131 of a hemostatic Y-connector 132, described below. The balloon catheter 114 has an inflatable balloon portion 128 at its distal end.

[0110] On either side of the working area of ​​the inflatable balloon portion 128, within the balloon volume, is an annular element formed on the inner wall of the balloon, which is comprised of a set of balloon-associated imaging markers 130, which in this particular example are X-ray markers, and thus become visible through X-ray imaging for determining the balloon's position. The two markers 130 are separated from each other by a distance D2. It should be noted that in other embodiments of the present disclosure, there may be only one such marker associated with either the proximal or distal end of the balloon portion, or there may be more than two such markers. The X-ray markers 130 may be made of a metal, such as gold, or a metal alloy.

[0111] As previously mentioned, the balloon catheter is formed with a working channel 116 that also functions as a flushing channel, the function of which will be described below. In the following description of this embodiment, the terms "working channel" and "flushing channel" may be used interchangeably. It should be noted that in other embodiments of the present disclosure, the flushing channel may be a dedicated conduit housed within the working channel.

[0112] At its proximal end, flushing channel 116 is fluidly coupled to outlet port 131 of hemostatic Y-connector 132, whose port 133 is coupled via coupling element 134 (which may be a controllable or one-way valve) to a source 136 of flushing saline (which may, in some embodiments, contain contrast agent), which may be a manually operated syringe 136A or an automated pump 136B. Working channel 116 has an opening 137 at its distal end so that the fluid therein is maintained at a pressure comparable to mean blood pressure (in practice, a slightly higher pressure is maintained to allow the flushing fluid to flow within the flushing channel from the liquid-tight proximal end to the open distal end and prevent backflow of blood). The hemostatic Y-connector 132 has a fluid-tight proximal end (achieved using a Tuohy-Borst adapter to prevent fluid leakage) and is configured to allow the fluid-tight introduction of the optical fiber 112 (e.g., CDS-23S, LifePhotonics GmbH, Germany) through the proximal end to maintain flushing solution pressure. The optical fiber 112 is sized to allow flushing solution to flow along the entire length of the fiber between the proximal and distal ends of the flushing channel. While a typical (but not limited to) outer diameter of the fiber is 0.75 mm, the diameter of the balloon working channel is 0.89 mm, allowing the fiber to be placed within the balloon and flushed with flushing solution. In one use, the optically diffusing portion 142 (see below) of the optical fiber 112 can become quite hot, and continuous flushing of the flushing solution exiting the distal open end 137 of the working channel 116 significantly cools the optically diffusing portion, preventing backflow of blood and hydrating the blood vessel.

[0113] The optical fiber 112 is optically connectable at its proximal end to a light source 140, typically a laser device 140A (e.g., ML7710, Modulight Inc., Finland). The optical fiber 112 has a light-diffusing portion 142 at its distal end configured to scatter light transmitted through the fiber, at least a portion of which is transmitted non-axially, specifically radially, from the optical diffuser. Associated with and flanking the light-diffusing portion are two imaging markers (typically, X-ray markers 144). These X-ray markers 144 are spaced apart by a fixed distance D1, which in this embodiment is different from and shorter than D2. This facilitates proper positioning of the optical diffuser relative to the inflatable balloon portion.

[0114] Inflatable balloon portion 128 is typically made of a transparent material, but in some embodiments may be translucent, allowing most of the light emitted from light diffusing portion 142 to pass through.

[0115] The system 110 also includes an auxiliary catheter 150, which may be a Cobra catheter, with a hemostatic Y-connector 152 at its proximal end. Again, a Tuohy-Borst adapter may be used to prevent fluid leakage. It includes a catheter lumen 154 extending between a fluid-tight proximal end defined by the Y-connector 152 and an open distal end 155, and accommodates a balloon catheter introduced through the fluid-tight proximal end. The catheter lumen 154 is sized to allow fluid to flow from the proximal end to the distal end. The lumen 154 is connected via a port 153 and a connecting element 156 in the Y-connector 152 to a contrast fluid source 158, which may be a manually operated syringe 158A filled with contrast media (typically, but not limited to, saline). This contrast fluid, which exits the open distal end 155 of the catheter 150, aids in the proper positioning of the auxiliary catheter and, therefore, the balloon catheter. The auxiliary catheter 150 has a shorter length than the balloon catheter 114 extending from the distal end 155 of the auxiliary catheter 150, as can be seen.

[0116] It should be noted that in certain uses and applications of the present disclosure, contrast agents may also be included in the balloon inflation fluid and / or flushing fluid.

[0117] Referring now to FIG. 4, this is a non-limiting example of a VTP procedure for a target site within a subject. It includes procedural steps 201-208, which may be performed in the order described, or in other embodiments, may be performed in a different suitable order. For example, administration of the photosensitizing drug by the system in step 206 may occur before, during, or after deployment of the assembly in step 201, or after assembling the elements in situ as described in steps 202-204, or during alignment of the light diffusing portion within the inflatable balloon portion during step 205, or even during treatment step 207. Therefore, as can be appreciated, the VTP procedure embodied in FIG. 4 is a non-limiting example.

[0118] In one embodiment, the assembly is assembled ex vivo and then deployed in the assembled configuration. This is represented by step 201, which involves inserting a VTP assembly as disclosed herein through a blood vessel and navigating the inflatable balloon portion of the balloon catheter until it is in proximity to the target site. Next, as represented by step 205, the optical fiber is positioned under imaging to ensure that the optically diffusing portion of the fiber is properly positioned within the inflatable balloon portion of the balloon catheter.

[0119] Alternatively, rather than deploying the assembly in an assembled state, the assembly may be assembled in situ, for example, as illustrated in steps 202-204. In this example, an auxiliary catheter is first inserted into each vessel and positioned, optionally with the aid of contrast, as illustrated in step 202. In the next step 203, a balloon catheter is inserted through the proximal end of the catheter lumen and displaced axially and distally to position its distal inflatable balloon portion at the intended treatment site. In the next step 204, an optical fiber is inserted through the working channel of the balloon catheter and displaced axially distally. The next step may be step 205, as already described above.

[0120] A guidewire may be used to position the auxiliary catheter and / or the balloon catheter, as is known per se. In the latter case, once the balloon portion is properly positioned, the guidewire can be removed and the optical fiber inserted.

[0121] As illustrated in step 205, imaging of at least the target region within the subject is performed to ensure proper positioning of the inflatable balloon portion adjacent to the target region and proper axial positioning of the optical fiber's light-diffusing portion within the inflatable balloon portion. This imaging-guided positioning is aided by imaging markers associated with the inflatable balloon portion and the optical fiber's light-diffusing portion, as shown in detail in FIG. 3 above. In an exemplary, non-limiting embodiment, the balloon catheter has two balloon-related markers on either side of the inflatable balloon portion, and the optical fiber has two fiber-related markers on either side of the light-diffusing portion, with the axial distance D1 between the two fiber-related markers being different and typically shorter than the distance D2 between the two balloon-related markers, allowing for comprehensive viewing of all markers without any set overlapping the other. Once the fiber-related markers are within the axial range of the balloon-related markers, proper alignment of the light-diffusing portion within the inflatable balloon portion is achieved.

[0122] To achieve proper alignment, the fiber is displaced axially while imaging until the fiber-associated marker is positioned axially within range of the balloon-associated marker.

[0123] In this embodiment, as illustrated in step 206, after the light-diffusing portion of the optical fiber in the inflatable balloon portion is properly positioned, a photosensitizing drug is systemically administered to the subject. This can be accomplished by intravenous administration, but other methods are also possible. The photosensitizing drug can be, for example, a bacteriochlorophyll derivative that can absorb and be sensitized to light at wavelengths of approximately 750-756 nm. Specific examples of such photosensitizing drugs include padeliporfin, or WST11. Other examples are verteporfin, which is sensitized by light at wavelengths of approximately 680-700 nm, or ledaporfin, which is sensitized by light at wavelengths of approximately 740-760 nm.

[0124] This may be followed by one or more treatment phases, including balloon inflation and light irradiation, as presented in step 207. Typically, there may be two or more treatment phases, separated by resting phases as needed, during which light irradiation may or may not be discontinued and the balloon is deflated to allow blood flow. The exemplary treatment regimen disclosed in FIG. 5 may include two or more treatment phases in which portions of the balloon are inflated, separated by resting phase segments as needed, during which brief deflation occurs. In this example, light irradiation occurs during the treatment phases and continues during the resting phases. In other embodiments of the present disclosure, light irradiation may be discontinued, typically during short resting phases. Once the clinically desired treatment regimen is complete, light irradiation is discontinued and the assembly disclosed herein is removed from the subject in step 208.

[0125] Referring now to Figures 5 and their legends in Figure 6, Figure 5 shows a schematic diagram of a non-limiting embodiment of the disclosed VTP treatment regimen. As previously described in Figure 4, the disclosed VTP procedure may include two or more treatment phases: balloon inflation and light irradiation. After proper positioning (the leftmost view in Figure 5), the inflatable balloon portion is typically inflated until the balloon wall contacts the vessel wall, substantially blocking blood flow through the vessel (artery or vein) (the second view from the left). Light is then applied at a wavelength and intensity appropriate to activate the photosensitizing drug, while a flushing solution is continuously flowed through the working channel to prevent overheating of the light-diffusing portion and backflow of blood, and the flushing solution is expelled from the open distal end of the working channel. After several minutes, typically about 5-10 minutes, the light irradiation may or may not be discontinued, and the flow of flushing solution may also be stopped, and the balloon is deflated (the third view from the left). This allows blood to flow through the vessel again, avoiding ischemic damage that can occur after prolonged blood occlusion. After a rest period, the inflatable balloon portion is reinflated, and light irradiation is resumed if it had previously been stopped. Meanwhile, flushing solution continues to flow through the working channel, and vascular ablation continues in the target tissue surrounding the vessel. The rest period is typically about 0.5 to 2 minutes, with about 1 minute being a specific example. This balloon inflation and light irradiation treatment regimen, followed by a rest period during which the balloon is deflated (with or without stopping light irradiation), may be repeated several times as needed.

[0126] It should be noted that while the disclosure herein focuses on the treatment of cancer (by PDT-mediated ablation of the associated blood vessels) and placement of the disclosed assemblies through arteries, this is not intended to be limiting, as the assemblies can also be placed through veins and used within the framework of treatments other than cancer indications. Furthermore, the disclosed assemblies can also be deployed through other lumens, and the target organ for treatment can be other than neoplastic tumors, such as the heart, gallbladder, urinary bladder, etc.

[0127] Additionally, a flow control valve or stopper, such as a one-way valve or a flow control pump, may be used in the catheter of the disclosed system.

[0128] Example To demonstrate the concept of safe and feasible ablation of tissue adjacent to major blood vessels with VTP (e.g., Padeliporfin ImPACT), the following treatment protocol was devised and tested. Preclinical safety evaluations used variations of the proposed protocol, as described in Example 1, and are also described in detail below.

[0129] material and method Assembling the laser system The optical fiber (LifePhotonic GmbH, Germany) was connected to a laser light source (ML7710 Modulite, Finland) via an SMA connector. The laser was configured to deliver a total power of 600 mW / cm through the diode. The diode output was measured using an external integrating sphere, as detailed below. The laser was set to "Ready" before light activation.

[0130] Fluoroscopic balloon deployment: This experiment was conducted in accordance with the Animal Welfare Law - Experiments in Animals 1994 and with the approval of the Institutional Animal Care and Use Committee (IACUC). Large White / Landrace sows (51–54 kg) were placed in a dorsal recumbent position. A 6 French (Fr) sheath was placed in the femoral artery using the Selidinger technique. The animals were administered heparin at a dose of 100–150 IU / kg. A 5 French (Fr) guiding catheter (Cobra C2, Merit Medical, USA) was placed in the orifice of the celiac artery, and angiography of the arteries (celiac and splenic) was performed to obtain baseline values ​​and measure the size of the target arteries. An exchange guidewire (Radiofocus™ 0.035" 260 cm, Terumo, Japan) was placed in the celiac artery (proximal splenic artery) or distal splenic artery. The guide catheter was withdrawn, and a Powerflex® dilatation catheter (Cordis Medical, USA) was placed in the proximal celiac artery or splenic artery (target artery), and the guidewire was withdrawn. As shown in Figures 7A and 7B, respectively, the optical fiber was inserted through the lumen of the balloon catheter and positioned using the imaging markers on the balloon and fiber so that the entire diffuser (3 cm long, 0.8 mm diameter) was contained within the balloon (4 cm long). Upon photoactivation, the balloon was inflated to the diameter of the artery, blocking blood flow and centering the fiber within the artery. Once the treatment regimen was completed, the fiber was withdrawn. In some experimental runs, the guide catheter was returned to the celiac ostium, and a second angiogram was performed to visualize and assess blood flow and any changes to the target artery. The catheter and sheath were withdrawn and the femoral artery was occluded by direct pressure for at least 20 minutes.

[0131] Preparation and administration of padeliporfin (WST11) for intraluminal VTP Padeliporfin (WST11) was dissolved in 5% sterile glucose solution under dim light prior to administration, according to the manufacturer's instructions, to a concentration of 10 mg / ml. After the optical fiber was placed at the target location, the animals were intravenously infused with padeliporfin solution using a syringe pump for 10 minutes, with a total dose of 4 mg / kg body weight. Immediately after the injection was completed, the laser was activated for 5 minutes, stopped for 1 minute, and then activated again for another 5 minutes (total irradiation time: 10 minutes). The balloon was inflated simultaneously with laser activation and deflated when irradiation was paused / completed. Figure 5, described above, shows a non-limiting example of the balloon inflation / deflation scheme. During irradiation, sterile saline was continuously infused into the balloon's working channel at a rate of approximately 1.6 ml / min. After completing the treatment regimen, the balloon catheter and fiber were removed. This procedure, from the start of the injection to the completion of treatment, was performed under dim lighting in an operating room. To ensure drug clearance, animals were kept under dim light until they recovered from anesthesia (approximately 1 h). Sham control animals underwent balloon and fiber deployment without the injection of padeliporfin and subsequent irradiation. The balloon was inflated and deflated according to the treatment protocol described above and then removed.

[0132] Autopsy and histopathology Animals were necropsied immediately after sacrifice (KCl injection 24 / 96 hours after treatment). Gross clinical observations were recorded. Photographs were taken when deemed necessary, including when macroscopic findings were confirmed.

[0133] For histopathological analysis, the irradiated artery segments were exposed and excised along with adjacent tissue. Additional organs were harvested as needed. The harvested tissues were fixed in 4% formalin for at least 3–5 days. For each treated arterial segment, 3–4 sections were cut at approximately 1 cm intervals and subjected to processing. Paraffin blocks were prepared, and 4–5 μm thick sections were cut and stained with hematoxylin and eosin. Tissue processing was performed in a certified laboratory.

[0134] Example 1: Preclinical Safety To evaluate the safety of the above treatment protocol, intra-arterial activation of padeliporfin was performed in two healthy female Yorkshire pigs (approximately 45 kg) using a 2 cm balloon laser catheter and a 1 cm diffuser. An 8 Fr (2.36 mm) transparent silicone balloon catheter was advanced through the femoral artery into the right external iliac artery. A laser fiber was then advanced into the balloon catheter. Heparin (100 IU / kg) and padeliporfin (4 mg / kg) were intravenously infused for 10 minutes. The balloon was inflated with 1 ml of 50% contrast medium, followed by 20 minutes of irradiation with a fiber laser (753 nm, 300 mW / cm). The balloon was periodically deflated (inflated for 1 minute every 5 minutes), and the catheter was flushed with saline to prevent clot formation and peripheral ischemia. Safety was assessed by post-treatment catheter angiography and necropsy. Catheter angiography after intra-arterial VTP showed no thrombus or arterial injury. Gross pathological examination showed no damage to the arterial wall.

[0135] Example 2: Preclinical light transmittance measurements. Next, the protocol described above in the "Materials and Methods" section was performed to measure and evaluate effective light transmittance. Therefore, immediately after the padeliporfin injection into the animal, the laser was activated at 753 nm. The light intensity on the exposed arterial wall, including the connective tissue, was measured using two identical probes, first with the balloon deflated and then with the balloon inflated, manually held against the external arterial wall, at the proximal and distal sites of the balloon using a 0.85 mm diameter spherical isotropic probe, as shown in Figure 8. To determine the photosensitizing drug concentration during the measurements, blood samples were taken at each light flow rate measurement. Similar measurements were performed before and after drug injection. These results showed a 10-fold increase in light intensity transmittance between the inflated and deflated balloon states, with the measured intensity increasing up to 740 mW / cm. 2 This shows that it has reached

[0136] Example 3: Preclinical Ablation Examples Next, we performed the treatment protocol described in the "Materials and Methods" section to evaluate its effectiveness for initiating pancreatic tumor ablation. As described, a cylindrical diffuser (3 cm long, 0.8 mm diameter) connected to an optical fiber capable of delivering up to 600 mW / cm of power was incorporated into an intravascular Cordis PowerFlex Pro® PTA dilatation catheter positioned at a selected site beginning at the celiac artery and continuing through the proximal splenic artery. This site was selected based on its proximity to the pancreatic tissue. After a 10-minute infusion of padeliporfin, the treatment protocol was initiated, as shown in Figure 5. During the resting phase(s), light irradiation was discontinued. The histological image selected for Figure 9 shows no damage to the vessel wall, but ablation of the pancreas was observed more than 5 mm away from the vessel. No irreversible changes were present in other tissue structures surrounding the pancreas (e.g., nerves, lymph nodes, etc.), demonstrating the selectivity and safety of the tested treatment protocol. In sham control animals exposed to the balloon inflation / deflation scheme without padeliporfin administration and laser activation, the pancreatic parenchyma adjacent to the artery appeared normal. The arterial wall showed near-preservation. Two foci of endothelial denudation with adjacent intimal necrosis were observed, which may indicate balloon injury.

Claims

1. 1. A catheter system comprising: an optical fiber; a balloon catheter; and a flushing channel, each extending axially between a proximal end and a distal end; said optical fiber, optically coupleable to a light source at a proximal end; a light diffusing portion at the distal end portion configured to scatter light transmitted through the fiber so that at least a portion of the light is transmitted non-axially from the light diffuser; having one or more fiber-associated imaging markers at the distal end portion; - the balloon catheter fluidly connectable at a proximal end to a source of pressurized fluid; an inflatable balloon portion at the distal end portion; having one or more balloon-related imaging markers associated with the inflatable balloon portion and having a working channel; - said flushing channel at a proximal end fluidly connectable to a source of flushing solution; extending between a fluid-tight proximal end and an open distal end; a flushing channel sized to accommodate the optical fiber introduced through the liquid-tight proximal end and to allow flushing fluid to flow along the entire introduced length of the fiber between the proximal and distal ends of the flushing channel; The system may be comprised of the working channel or a separate tube attached to and extending through the working channel of the balloon catheter.

2. The system of claim 1 , wherein the flushing channel is the working channel.

3. The system of claim 1 or 2, wherein the imaging marker is an X-ray marker.

4. The system of claim 3 , wherein the imaging marker is an annular metallic element.

5. 5. The system of claim 1, further comprising an auxiliary catheter, the auxiliary catheter is fluidly connectable at a proximal end to a fluid source; a catheter lumen extending between a fluid-tight proximal end and an open distal end, the catheter lumen being sized to accommodate the balloon catheter introduced through the fluid-tight proximal end and to allow the fluid to flow from the proximal end to the distal end even when the balloon catheter is accommodated; the balloon catheter has a length such that, when retracted, the distal end of the balloon catheter, including the inflatable balloon portion, extends beyond the distal portion of the auxiliary catheter.

6. the light diffusing portion is shorter than the inflatable balloon portion; 6. The system of claim 1, wherein the optical fiber is axially displaceable within the flushing channel to axially align the light diffusing portion within the axial extent of the inflatable balloon portion.

7. A system according to any one of claims 1 to 6 for use in vascular targeted photodynamic therapy (VTP) or any other photodynamic therapy (PDT) treatment.

8. the catheter assembly including an optical fiber, a balloon catheter with a working channel, and a flushing channel, all extending axially in a proximal to distal direction and each having a proximal end and a distal end; - the balloon catheter fluidly connectable at a proximal end to a source of pressurized fluid; an inflatable balloon portion at the distal end portion; having one or more balloon-related imaging markers associated with the inflatable balloon portion and having a working channel; - said flushing channel at a proximal end fluidly connectable to a source of flushing solution; extending between a fluid-tight proximal end and an open distal end; a flushing channel sized to accommodate the optical fiber introduced through the liquid-tight proximal end and to allow flushing fluid to flow around the entire introduced length of the fiber between the proximal and distal ends of the flushing channel; defined by the working channel, or by a tube housed within and extending through the working channel, or by the lumen of a tube housed within the working channel; said optical fiber, optically coupleable to a light source at a proximal end; a light diffusing portion at the distal end portion configured to scatter light transmitted through the fiber so that at least a portion of the light is transmitted from the light diffuser in a non-axial direction; one or more fiber-associated imaging markers at the distal end portion of the flushing channel; A catheter assembly, wherein the flushing fluid is contained within the flushing channel in a manner that allows the flushing fluid to flow along the entire length of the introduced fiber from the proximal end to the distal end of the flushing channel.

9. The assembly of claim 8 , wherein the flushing channel is the working channel.

10. 10. The assembly of claim 8 or 9, wherein the imaging marker is an X-ray marker.

11. The assembly of claim 10 , wherein the imaging markers are annular metal elements on either side of the light diffusing portion.

12. 12. An assembly according to any one of claims 8 to 11, comprising an auxiliary catheter, the auxiliary catheter is fluidly connectable at a proximal end to a fluid source; a catheter lumen extending between a fluid-tight proximal end and an open distal end, the proximal portion of the catheter extending out of the fluid-tight proximal end, the catheter lumen sized to allow the fluid to flow from the proximal end to the distal end; an assembly having a length such that the distal end of the balloon catheter, including the inflatable balloon portion, extends beyond the distal portion of the auxiliary catheter.

13. the light diffusing portion is shorter than the inflatable balloon portion; 13. The assembly of claim 8, wherein the optical fiber is axially displaceable within the flushing channel to axially align the light diffusing portion within the axial extent of the inflatable balloon portion.

14. A treatment system comprising the catheter system according to any one of claims 1 to 7 or the assembly according to any one of claims 8 to 13.

15. 1. A method of PDT of a target site in a subject, comprising: systemically administering to the subject a photosensitizing drug; inserting the assembly of any one of claims 8 to 14 through a blood vessel and advancing it axially until the inflatable balloon portion of the distal end portion of the balloon catheter is in the vicinity of the target site, and axially displacing the optical fiber to position the optical diffusing portion within the inflatable balloon portion; and inducing a treatment step, the treatment step including inflating the inflatable balloon portion, passing a flushing solution through the flushing channel, and irradiating light via the optical fiber at a wavelength and intensity suitable for activating the photosensitizing drug.

16. imaging the target site; and and axially positioning the light diffusing portion within the inflatable balloon portion by appropriately aligning the one or more fiber-associated imaging markers with the one or more balloon-associated imaging markers.

17. 17. The method of claim 15 or 16, comprising continuously flushing the flushing solution through the flushing channel during the PDT procedure.

18. 18. The method of claim 15 or 17, wherein the PDT procedure is VTP.

19. the photosensitizing drug for use in the PDT procedure is a bacteriochlorophyll derivative that has a primary light absorption at about 750-756 nm and is capable of generating oxygen radicals upon irradiation; the photosensitizing drug is administered intravenously to the subject for a predetermined time prior to the start of inflation of the inflatable balloon portion and light irradiation; 20. The method of claim 18, wherein the light source is a laser emitting light at a wavelength of about 750-756 nm and delivering a maximum of about 2 watts of power to the fiber.

20. 20. The method of claim 19, wherein the photosensitizing drug is padeliporfin, i.e., WST11.

21. 21. The method of any one of claims 15 to 20, wherein the photosensitizing drug is administered about 5 to about 15 minutes (typically about 10 minutes) before light irradiation begins.

22. the target site is a tumor; The method according to any one of claims 15 to 21, wherein the blood vessel is a major blood vessel passing near the tumor.

23. the tumor is pancreatic cancer; 23. The method of claim 22, wherein the blood vessel is the superior mesenteric artery (SMA) or the superior mesenteric vein (SMV).

24. 24. The method of claim 22 or 23, wherein the blood vessel is substantially tangential to the tumor.

25. 25. The method of any one of claims 15 to 24, comprising two or more treatment phases, during which the inflatable balloon portion is inflated and light irradiation is activated, separated by rest phases, during which the inflatable balloon portion is deflated.

26. the treatment phase lasts for between about 2 minutes and about 10 minutes; 26. The method of claim 25, wherein the resting step is from about 0.5 minutes to about 2 minutes.

27. 27. The method of any one of claims 15 to 26, wherein the inflatable balloon portion is inflated to substantially block blood flow through the blood vessel.

28. 28. The method of claim 27, wherein the inflatable balloon portion is inflated so that its wall contacts the vessel wall.

Images