CA2339384C - Improved method for targeted topical treatment of disease - Google Patents
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Abstract
A method and apparatus for topical treatment of diseased tissue, including topical or systemic application of a PDT agent to diseased tissue, followed by topical application of light (24).
Description
W000/07515 PC'T/US99/17515 Improved Method For Targeted Topical Treatment Of Disease BACKGROUND OF THE INVENTION
The present invention is related to a method and apparatus for topical treatment of tissue, particularly diseased tissue, using photodynamic therapy (PDT) and a PDT agent.
More specifically, the present invention is directed to a method and apparatus for topical or systemic application of the PDT agent to the diseased tissue and then topical application of light to the diseased tissue.
PDT was developed to treat cancer and other diseases with the promise of limiting the invasiveness of the therapeutic intervention and lessening potential collateral damage to normal, non-diseased tissue. Key elements ofPDT include either selective application or selective uptake of a photosensitive agent into the diseased tissue and site-directable application of an activating light. PDT agents are typically applied systemically (for example, via intravenous injection or oral administration) or via localized topical application directly to diseased tissues (for example, via topical creams, ointments, or sprays). Subsequent to administration of the agent (typically 30 minutes to 72 hours later), an activating light is applied to the disease site, locally activating the agent, and destroying the diseased tissue. Light is typically applied by direct illumination of the site, or by delivery of light energy to internal locations using a fiberoptic catheter or similar means.
Most current PDT regimens are based on systemic appiication of porphyrin-based agents or topical or systemic application of psoralen-based agents. Examples of porphyrin-based agents include porfimer sodium (PHOTOFRIN ), hematoporphyrin-derivative (HPD), or SnET2. PHOTOFRIN is one of the few agents currently licensed by the FDA. Porphyrin-based agents generally are derived from complex mixtures of natural or synthetically prepared materials. Many components of porphyrin-based agents are lipophilic. As a result of this lipophilicity, porphyrin-based agents have shown a slight tendency to preferentially accumulate in some tumors. However, the targeting of such agents to diseased tissue is still unacceptably low when compared to uptake in normal tissue, (i.e., 2-lOx greater uptake in diseased tissue relative to normal tissue).
Further, porphyrin-based agents were developed primarily as a result of a desire to have agents that are compatible with highly-penetrating activating light so as to enable
The present invention is related to a method and apparatus for topical treatment of tissue, particularly diseased tissue, using photodynamic therapy (PDT) and a PDT agent.
More specifically, the present invention is directed to a method and apparatus for topical or systemic application of the PDT agent to the diseased tissue and then topical application of light to the diseased tissue.
PDT was developed to treat cancer and other diseases with the promise of limiting the invasiveness of the therapeutic intervention and lessening potential collateral damage to normal, non-diseased tissue. Key elements ofPDT include either selective application or selective uptake of a photosensitive agent into the diseased tissue and site-directable application of an activating light. PDT agents are typically applied systemically (for example, via intravenous injection or oral administration) or via localized topical application directly to diseased tissues (for example, via topical creams, ointments, or sprays). Subsequent to administration of the agent (typically 30 minutes to 72 hours later), an activating light is applied to the disease site, locally activating the agent, and destroying the diseased tissue. Light is typically applied by direct illumination of the site, or by delivery of light energy to internal locations using a fiberoptic catheter or similar means.
Most current PDT regimens are based on systemic appiication of porphyrin-based agents or topical or systemic application of psoralen-based agents. Examples of porphyrin-based agents include porfimer sodium (PHOTOFRIN ), hematoporphyrin-derivative (HPD), or SnET2. PHOTOFRIN is one of the few agents currently licensed by the FDA. Porphyrin-based agents generally are derived from complex mixtures of natural or synthetically prepared materials. Many components of porphyrin-based agents are lipophilic. As a result of this lipophilicity, porphyrin-based agents have shown a slight tendency to preferentially accumulate in some tumors. However, the targeting of such agents to diseased tissue is still unacceptably low when compared to uptake in normal tissue, (i.e., 2-lOx greater uptake in diseased tissue relative to normal tissue).
Further, porphyrin-based agents were developed primarily as a result of a desire to have agents that are compatible with highly-penetrating activating light so as to enable
2 treatment of deep-seated cancerous tumors. For example, porphyrin-based agents are typically activated using light at wavelengths from 600-750 nm, which may penetrate tissue to a depth of 1 cm or more. In contrast, light at wavelengths below 600 nm will penetrate tissue only to a depth much less than 1 cm.
However, the dark toxicity of most porphyrin-based agents is high. Dark toxicity is the cellular toxicity in the absence of activating light. Only a small increase in cytotoxicity is achieved upon illumination which necessitates high dosages of agent in order to effect treatment in specific tissues. Moreover, the systemic clearance time, which is the duration subsequent to agent administration wherein significant agent concentrations are present in skin and other external tissues, can extend from weeks to months, forcing patients to avoid exposure to bright light or sunlight for extensive periods in order to avoid serious skin irritation and other complications. Systemic administration also necessitates a delay of between 30 min to 72 hours between agent administration and light activation, essentially precluding the possibility of immediate treatment of diseased tissue upon detection of such diseased tissue. Further, detection and treatment of gastrointestinal diseases, such as Barrett's esophagus) requires at least two endoscopic procedures: one procedure to diagnose, and a subsequent procedure to treat the diseased tissue with light following administration of a PDT agent.
The absence of a significant difference between light and dark cytotoxicity and the low preferential concentration ratio of most common PDT agents necessitates use of high agent dosages. For example, the dosage for treatment of an adult male 'with PHOTOFRIN may require greater than 100 mg of agent at a cost of more than $5,000 for the agent alone. This large dose also gives rise to a significant potential for development of adverse side effects in healthy tissue (such as skin phototoxicity) that may remain for several weeks. Also, since porphyrin-based agents are activated with light at wavelengths greater than 600 nm (i.e., near infrared light (NIR)), procedures based on porphyrins + NIR can subject the patient to significant risk of serious complications due to the tissue penetration potential of such NIR light. Complications can include perforation of internal structures, such as the esophagus during treatment of esophageal disease, due to undesirable activation of the agent present in healthy tissue layers which are beyond the topical treatment site.
Additionally, porphyrin-based PDT agents achieve light-activated cytotoxicity via type-II mechanisms, typically the conversion of cellular OZ into cytotoxic singlet oxygen.
SUBSTITUTE SHEET (RULE 26)
However, the dark toxicity of most porphyrin-based agents is high. Dark toxicity is the cellular toxicity in the absence of activating light. Only a small increase in cytotoxicity is achieved upon illumination which necessitates high dosages of agent in order to effect treatment in specific tissues. Moreover, the systemic clearance time, which is the duration subsequent to agent administration wherein significant agent concentrations are present in skin and other external tissues, can extend from weeks to months, forcing patients to avoid exposure to bright light or sunlight for extensive periods in order to avoid serious skin irritation and other complications. Systemic administration also necessitates a delay of between 30 min to 72 hours between agent administration and light activation, essentially precluding the possibility of immediate treatment of diseased tissue upon detection of such diseased tissue. Further, detection and treatment of gastrointestinal diseases, such as Barrett's esophagus) requires at least two endoscopic procedures: one procedure to diagnose, and a subsequent procedure to treat the diseased tissue with light following administration of a PDT agent.
The absence of a significant difference between light and dark cytotoxicity and the low preferential concentration ratio of most common PDT agents necessitates use of high agent dosages. For example, the dosage for treatment of an adult male 'with PHOTOFRIN may require greater than 100 mg of agent at a cost of more than $5,000 for the agent alone. This large dose also gives rise to a significant potential for development of adverse side effects in healthy tissue (such as skin phototoxicity) that may remain for several weeks. Also, since porphyrin-based agents are activated with light at wavelengths greater than 600 nm (i.e., near infrared light (NIR)), procedures based on porphyrins + NIR can subject the patient to significant risk of serious complications due to the tissue penetration potential of such NIR light. Complications can include perforation of internal structures, such as the esophagus during treatment of esophageal disease, due to undesirable activation of the agent present in healthy tissue layers which are beyond the topical treatment site.
Additionally, porphyrin-based PDT agents achieve light-activated cytotoxicity via type-II mechanisms, typically the conversion of cellular OZ into cytotoxic singlet oxygen.
SUBSTITUTE SHEET (RULE 26)
3 Because cellular O, levels can be readily depleted during activation of a type-Il PDT
agent, use of such agents mandates relatively low intensity illumination and thus relatively long illumination durations in order to allow 02 levels to remain sufficient throughout the duration of light activation. For example, in the treatment of Barrett's esophagus with PHOTOFRIN , light intensities typically must be held well below 100-150 mW/cmZ
during treatment, necessitating illumination periods of 10-20 minutes or more.
Numerous practitioners have also found with type-II agents that it is equally important to avoid any tissue manipulation that might compromise blood circulation at the treatment site during illumination, again in order to avoid potential depletion of available O2.
Thus, careful control of the illumination apparatus and procedure is critical in order to assure that proper light intensities are delivered without affecting tissue in a manner that might affect blood circulation.
Barrett's esophagus is a perfect example of a superficial disease that is an attractive candidate for PDT as it occurs in a location that is difficult to access via conventional surgical means but is readily accessible using endoscopic catheters. It is a condition in which chronic acid reflux from the stomach irritates the esophagus at the gastro-esophageal junction, causing epithelial tissue in the esophagus to proliferate. Patients with Barrett's esophagus have a significantly increased risk of developing esophageal cancer.
The FDA has approved PDT (PHOTOFRIN with light at 630 nm) to destroy the proliferating tissue in Barrett's patients. Similar regimens can also be used to remove esophageal stricture caused by esophageal cancer.
A common method for treatment of Barrett's esophagus using PDT is shown in cross-sectional form in Fig. 1(a). The esophagus 10 has a proximal tissue surface 12 and a distal tissue surface 14. In the example shown in Fig. 1(a), a portion of esophagus 10 is healthy tissue 16 while another portion is diseased tissue 18. Typically, a non-compliant balloon 20 inserted into the esophagus 10 is used to stabilize the tissue to be treated. The balloon is filled with gas or liquid so that it will expand to a known radius (nearly filling the esophagus) while avoiding dilation of the esophagus. Such dilation could cause restriction of blood flow to the treatment site which could compromise the 02 supply during light activation. An optical fiber inserted into the center of the balloon 20 serves as a light source 22 to provide a uniform light intensity at the surface of the balloon. The outer structure of this balloon 20 may be composed of a material that scatters activating light 24 or may be transparent to the activating light.
SUBSTITUTE SHEET (RULE 26)
agent, use of such agents mandates relatively low intensity illumination and thus relatively long illumination durations in order to allow 02 levels to remain sufficient throughout the duration of light activation. For example, in the treatment of Barrett's esophagus with PHOTOFRIN , light intensities typically must be held well below 100-150 mW/cmZ
during treatment, necessitating illumination periods of 10-20 minutes or more.
Numerous practitioners have also found with type-II agents that it is equally important to avoid any tissue manipulation that might compromise blood circulation at the treatment site during illumination, again in order to avoid potential depletion of available O2.
Thus, careful control of the illumination apparatus and procedure is critical in order to assure that proper light intensities are delivered without affecting tissue in a manner that might affect blood circulation.
Barrett's esophagus is a perfect example of a superficial disease that is an attractive candidate for PDT as it occurs in a location that is difficult to access via conventional surgical means but is readily accessible using endoscopic catheters. It is a condition in which chronic acid reflux from the stomach irritates the esophagus at the gastro-esophageal junction, causing epithelial tissue in the esophagus to proliferate. Patients with Barrett's esophagus have a significantly increased risk of developing esophageal cancer.
The FDA has approved PDT (PHOTOFRIN with light at 630 nm) to destroy the proliferating tissue in Barrett's patients. Similar regimens can also be used to remove esophageal stricture caused by esophageal cancer.
A common method for treatment of Barrett's esophagus using PDT is shown in cross-sectional form in Fig. 1(a). The esophagus 10 has a proximal tissue surface 12 and a distal tissue surface 14. In the example shown in Fig. 1(a), a portion of esophagus 10 is healthy tissue 16 while another portion is diseased tissue 18. Typically, a non-compliant balloon 20 inserted into the esophagus 10 is used to stabilize the tissue to be treated. The balloon is filled with gas or liquid so that it will expand to a known radius (nearly filling the esophagus) while avoiding dilation of the esophagus. Such dilation could cause restriction of blood flow to the treatment site which could compromise the 02 supply during light activation. An optical fiber inserted into the center of the balloon 20 serves as a light source 22 to provide a uniform light intensity at the surface of the balloon. The outer structure of this balloon 20 may be composed of a material that scatters activating light 24 or may be transparent to the activating light.
SUBSTITUTE SHEET (RULE 26)
4 PDT agent present in tissue located proximal to the balloon (on the proximal tissue surface 12) is thereby activated by light emitted from the surface of the balloon 20.
Because the balloon 20 is non-compliant, it is possible to estimate the light intensity at the surface of the balloon based on geometrical properties of the balloon and knowledge of the light emitting properties of the light source 22. A fiberoptic diffuser tip is an example of such a light source. However, since the external surface of the balloon 20 generally will not conform exactly to the shape of the esophagus, it is not possible to accurately estimate light intensity at all points along the circumference of the proximal tissue surface 12.
Moreover, should the light field present at the proximal tissue surface 12 be uneven, for example due to non-uniform light emitting properties of the light source 22 or incorrect location of the light source 22 in the esophagus 10, uneven treatment may result. In extreme cases, such uneven treatment can compromise tissue sufficiently to result in tissue perforation and patient death.
As shown in Fig. 1(b), activation of the PDT agent in the esophageal tissue upon illumination will produce a treatment zone 26 which will generally include the entire zone of diseased tissue 18 in Fig.1(a) and may extend radially and circumferentially a significant distance beyond the margins of the zone of diseased tissue 18. In fact, use of NIR light for agent activation can result in formation of a treatment zone that extends a significant distance from the proximal tissue surface 12 to the distal tissue surface 14 of the esophagus 10. This is a consequence of the large penetration depths characteristic ofNIR
light and the presence of a significant systemic concentration of agent in healthy tissue.
In extreme cases, this enlargement of the treatment zone can compromise healthy tissue sufficiently enough to result in tissue perforation and patient death.
This example of the use of PDT for treatment of superficial lesions illustrates a number of disadvantages of current methods and apparatus. For example:
(1) Systemic agent application is costly due to high agent dosage requirements;
(2) Systemic agent application results in sensitization of healthy tissue outside of the desired treatment zone;
(3) Systemic agent application results in prolonged skin photosensitization;
(4) Systemic agent application requires significant delay between disease diagnosis and disease treatment in order for the agent to reach the diseased tissue while clearing out of the surrounding healthy tissue;
SUBSTITUTE SHEET (RULE 26)
Because the balloon 20 is non-compliant, it is possible to estimate the light intensity at the surface of the balloon based on geometrical properties of the balloon and knowledge of the light emitting properties of the light source 22. A fiberoptic diffuser tip is an example of such a light source. However, since the external surface of the balloon 20 generally will not conform exactly to the shape of the esophagus, it is not possible to accurately estimate light intensity at all points along the circumference of the proximal tissue surface 12.
Moreover, should the light field present at the proximal tissue surface 12 be uneven, for example due to non-uniform light emitting properties of the light source 22 or incorrect location of the light source 22 in the esophagus 10, uneven treatment may result. In extreme cases, such uneven treatment can compromise tissue sufficiently to result in tissue perforation and patient death.
As shown in Fig. 1(b), activation of the PDT agent in the esophageal tissue upon illumination will produce a treatment zone 26 which will generally include the entire zone of diseased tissue 18 in Fig.1(a) and may extend radially and circumferentially a significant distance beyond the margins of the zone of diseased tissue 18. In fact, use of NIR light for agent activation can result in formation of a treatment zone that extends a significant distance from the proximal tissue surface 12 to the distal tissue surface 14 of the esophagus 10. This is a consequence of the large penetration depths characteristic ofNIR
light and the presence of a significant systemic concentration of agent in healthy tissue.
In extreme cases, this enlargement of the treatment zone can compromise healthy tissue sufficiently enough to result in tissue perforation and patient death.
This example of the use of PDT for treatment of superficial lesions illustrates a number of disadvantages of current methods and apparatus. For example:
(1) Systemic agent application is costly due to high agent dosage requirements;
(2) Systemic agent application results in sensitization of healthy tissue outside of the desired treatment zone;
(3) Systemic agent application results in prolonged skin photosensitization;
(4) Systemic agent application requires significant delay between disease diagnosis and disease treatment in order for the agent to reach the diseased tissue while clearing out of the surrounding healthy tissue;
SUBSTITUTE SHEET (RULE 26)
5 PCT/US99/17515 (5) Systemic agent application provides PDT practitioners with limited control over the site of agent delivery and concentration;
(6) Systemic agent application results in uneven treatment due to uneven partitioning of the agent into the diseased tissues;
(7) Use of type-II agents requires slow and lengthy agent activation to avoid depletion;
(8) Use of type-II agents requires careful tissue handling to avoid restriction of blood flow and the resultant O2 depletion during tissue illumination; and
(9) Use oftype-II agents, when commonly combined with NIR activating light, results in excessive treatment depths in most topical applications, adversely affecting surrounding healthy tissue.
Therefore, it is an object of the present invention to provide new methods and apparatus for an improved application of PDT while increasing the efficacy and safety of the procedure and reducing the cost of treatment.
SUMMARY OF THE PRESENT INVENTION
The present invention is directed to a method and apparatus for topical treatment of diseased tissue, including topical or systemic application of a PDT agent to diseased tissue, followed by topical application of light. In general, the method involves the steps of applying a PDT agent to diseased tissue to form a treatment zone; purging excess agent; and applying light to the treatment zone to activate agent associated with the diseased tissue. The light penetrates the treatment zone while minimizing activation of the agent outside the treatment zone.
In a preferred embodiment, Rose Bengal is the PDT agent.
In a further embodiment, the PDT agent is directly applied only to the treatment zone. Alternatively, the PDT agent can be applied systemically.
In a still further embodiment, the depth of activation of the PDT agent is controlled by proper selection of wavelength of activating light so as to avoid activation of agent that may be present in underlying healthy tissues.
In yet a further embodiment, the diseased tissue is diagnosed before applying the PDT agent.
In another embodiment, detection and treatment of a lesion may be effected in a short time period using a single procedure (such as endoscopy) instead of by separate diagnostic and therapeutic procedures.
SUBSTITUTE SHEET (RULE 26) In another embodiment, treatment rate is not limited by oxygen-dependent mechanisms.
In another embodiment, heat is also applied to the treatment zone to increase efficacy of activation of the agent.
In still another embodiment, activating light is delivered through a "balloon"
or other delivery apparatus located at the disease site.
In another embodiment, the method of the present invention can be used for treatment of disease in the gastrointestinal tract.
The method of the present invention can also be used for treatment of disease in vessels of the circulatory system.
The present invention is also directed to an apparatus for topical treatment of diseased tissue.
Accordingly, the present invention is directed to a method and apparatus to improve the evenness of light delivery, and to improve the safety and efficacy and reduce the cost of PDT, for treatment of Barrett's esophagus and other conditions.
The invention in a broad aspect seeks to provide an endoscopic apparatus for topical treatment of diseased tissue located within a body comprising applicator means for applying a PDT agent to the diseased tissue so as to form a treatment zone, and means for purging excess agent from the treatment zone prior to photoactivation of residual PDT
agent. There is a source of light to activate the PDT agent in the, wherein the light , is able to penetrate the diseased tissue while minimizing activation of the agent outside the diseased tissue, the light having a wavelength between approximately 400-600 nm.
The invention also pertains to the use of such apparatus for the treatment of diseased tissue located within a body.
6a BRIEF DESCRIPTION OF THE DRAWINGS
In describing the preferred embodiments, reference is made to the accompanying drawings wherein:
FIGURE 1(a) shows a cross-sectional view ofan esophagus illustrating a common method for treatment of Barrett's esophagus using PDT;
FIGURE 1(b) iltustrates the treatment zone of the method of Figure 1(a);
FIGURE 2(a) illustrates an example of an embodiment of the present invention for treatment of diseased esophageal tissue;
FIGURE 2(b) illustrates an alternate example of the embodiment of Figure 2(a);
FIGURE 2(c) illustrates an additional alternate example of the embodiment of Figure 2(a);
FIGURE 3(a) illustrates an example of another embodiment for the treatment of disease in vessels of the circulatory system; and FIGURE 3(b) illustrates an alternate example of the embodiment of Figure 3(a) wherein the PDT agent is directly applied to the diseased tissue.
DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED
EMBODIMENTS
The method and apparatus of the present invention is applicable to improved treatment of various dermatologic afflictions, such as psoriasis or skin cancer, and to diseased tissues at sites within the body, such as disease of the digestive or respiratory tracts. The present invention can also be used for the treatment of other anatomical sites, including intra-abdominal, intra-thoracic, intra-cardial, intra-circulatory, intra-cranial, and the reproductive tract.
In general, the method of the present invention involves one or more of the following steps. Initially, disease is diagnosed using, for example, histologic examination, or by measurement of the autofluorescence properties of diseased tissue or by detecting selective uptake of an indicator agent, such as a fluorescent dye or a PDT
agent, into such diseased tissue. Thereafter, a sufficient quantity of a topical or systemic formulation of a desired PDT agent is applied to the disease site so as to cover, perfuse, or saturate the diseased tissue. After a brief accumulation period to allow the agent to coat, perfuse, or otherwise become active within the diseased tissue, excess agent is purged or flushed from the disease site, and a substantially uniform light field is applied to the disease site in order to activate the agent associated with the diseased tissue.
For treatment of superficial diseased tissue, the wavelength of the light is preferably chosen so as to allow optical penetration into the diseased tissue but to minimize further optical penetration beyond the diseased tissue into underlying healthy tissue.
For example, visible light in the spectral region between 400-600 nm may be used to afford shallow penetration depths on the order of several millimeters or less. Use of such light affords efficacy in agent activation in superficial diseased tissues while simultaneously minimizing potential for deleterious photosensitization of underlying tissue. Preferably, laser light is used. It can be delivered by fiberoptic catheters. Alternatively, light can be delivered by direct illumination. Other alternate light source configurations and delivery apparatus include fiberoptic bundles, hollow-core optical waveguides, and liquid-filled waveguides.
Alternate light sources, including light emitting diodes, micro-lasers, monochromatic or continuum lasers or lamps for production of activating light, and continuous wave or pulsed lasers or lamps. Either single-photon or two-photon excitation methods can be used for agent activation. A more detailed explanation of such excitation methods is given SUBSTITUTE SHEET (RULE 26) WO 00/07515 PCT/iJS99/17515 in commonly assigned Canadian Patent File No. 2.252,783 filed October 28. 1997 which may be referred to for fiirther details.
Furthermore, the time and order of the applications of the agent and light can also be varied. For example, application of the agent and the light treatment regimen can be repeated one or more times to eliminate residual diseased tissue. Further, for some applications, an increased delay between agent application and light treatment can be beneficial. Additionally, the step of diagnosing can almost immediately be followed by the steps of applying a PDT agent, purging excess agent and applying light so that said method of diagnosis and treatment is done in a single procedure. If PDT agent uptake is used to diagnose or detect diseased tissue, the step of diagnosing can be immediately followed by the step of applying activating light. Alternatively, there may be an indefinite.
delay between diagnosis and PDT treatment.
Preferably Rose Bengal is used as the PDT or photosensitizing agent as it is inexpensive, non-toxic, has a proven safety record in human use, has significant intrinsic lipophilic properties, exhibits both type-I and type-II PDT response and therefore can be activated by type-I, oxygen-independent mechanism and is strongly phototoxic upon activation with light between 500 nm and 600 nm. Because of its 02-independent response, Rose Bengal is compatible with high intensity light activation, which reduces treatment time relative to porphyrin-based agents. More specifically, Rose Bengal is optimally activated using light between 500 nm and 600 nm, which is sufficient for activation of superficial diseased tissue and substantially avoids the potential for activation of underlying healthy tissues. An example of such a PDT agent is a solution of Rose Bengal formulated with a suitable lipophilic delivery vehicle, such as I-octanol or liposomes.
Alternatively, other PDT agents, including type-I or type-II agents can be used.
Examples of such standard PDT agents include psoralen derivatives; porphyrin and hematoporphyrin derivatives; chlorin derivatives; phthalocyanine derivatives;
rhodamine derivatives; coumarin derivatives; benzophenoxazine derivatives;
chlorpromazine and chlorpromazine derivatives; chlorophyll and bacteriochlorophyll derivatives;
pheophorbide a (Pheo a); merocyanine 540 (MC 540); Vitamin D; 5-amino-laevulinic acid (ALA);
photosan; pheophorbide-a (Ph-a); phenoxazine Nile blue derivatives including various phenoxazine dyes; PHOTOFRIN; benzoporphyrin derivative mono-acid; SnET,; and WO 00/07515 PC7'/US99/17515 LutexT'. The inventors of the present invention believe that all present and futiire PDT agents will work in the method and apparatus of the present invention.
Additionally, the present invention is not limited to the use of one PDT
agent.
Instead, more than one PDT agent can be used during a treatment regimen.
In a further embodiment, the PDT agent used in the present invention can include at least one targeting moiety. Examples of such targeting moieties include DNA, RNA, amino acids, proteins, antibodies, ligands, haptens, carbohydrate receptors or complexing agents, lipid receptors or complexing agents, protein receptors or complexing agents, chelators, and encapsulating vehicles. Such targeting moieties may be used to improve the selectivity of agent delivery to diseased tissue, and can function either by association with the photosensitizing PDT agent (for exampie where the PDT agent is encapsulated in a vehicle composed of the targeting moiety) or by attachment to the photosensitizing PDT agent (for example where the PDT agent is covalently attached to the targeting moiety).
In a further preferred embodiment, the PDT agent is applied directly to the diseased tissue. Employment of direct topical application provides a number of advantages. In particular, it affords improved targeting of the agent specifically to the diseased tissue, reduces the required latency period between agent administration and light activation and thereby shortens the treatment cycle, substantially eliminates the potential for systemic photosensitization, reduces agent consumption, and reduces the overall potential for side effects from exposure to the agent. Preferably, the agent is applied as a topical spray or wash. After a brief accumulation period (generally not to exceed 30 minutes), the excess agent is removed from the tissue surface by flushing with liquid, such as with water or saline. Following this flushing, it is preferred that the residual agent associated with the diseased tissue be activated by illumination of the diseased site with visible light between 400 nm and 600 nm. Optically, the light can be applied as discussed supra.
Alternatively, the PDT agent can be applied systemically. For example, this application may be via intravenous injection or parenteral administration (such as by consumption of a tablet or liquid formulation of the PDT agent).
In a further embodiment, heat can be applied to the treatment zone to increase PDT
effectiveness via hyperthermia. Heat can be applied, for example, through the use of a.
heated liquid in an illumination balloon, a transparent heating pad positioned between the illumination source and the tissue, or simultaneous illumination of the treatment site with infrared energy.
Examples of some of these embodiments of the present application are shown in cross-sectional form in Figs. 2(a), 2(b), and 2(c).
Fig. 2(a) illustrates an example of a treatment of diseased esophageal tissue using a non-compliant balloon 20 illumination apparatus. Initially, a treatment zone 30 is identified. This can be done for example via endoscopic examination of the esophagus and visual or spectroscopic identification of zones of diseased tissue. Such identification can include detection of histologic changes or other visual indicators of disease, detection of changes in autofluorescence, or detection of uptake of PDT or other agents into diseased tissue. Following identification of the treatment zone 30, PDT agent is applied to the identified diseased tissue. This agent can be applied, for example, via systemic application or more preferably, by direct spray application using a nozzle or other means provided at the distal end of an endoscope. Excess agent is subsequently purged from the site by, for example, natural systemic clearance or by flushing with liquid.
A transparent, non-compliant balloon apparatus 20 is then inserted into the esophagus so as to span the treatment zone 30. The non-compliant balloon 20 is filled with gas or liquid to a pre-determined pressure so as to establish a desired pre-determined radius. Visible light 24 is then uniformly delivered radially to the treatment site through the walls of the balloon 20 using a light source 22, such as for example a fiberoptic diffuser, located along the central axis of the balloon.
Additionally, the balloon 20 can be filled with a scattering medium, such as a dilute solution of intralipid, so as to improve the uniformity of light intensity delivered at the surface of the balloon. Further, the balloon 20 can be composed of or include a material that scatters the light 24 delivered at the surface of the balloon so as to further improve the uniformity of light intensity delivered at the surface of the balloon.
Examples of such a material include a material that is naturally translucent, such as latex; a polymer that includes particulate scattering materials; or a polymer with a roughened surface.
In the example illustrated in Fig. 2(a), the intensity of the light source 22 is operated at a pre-determined level for a pre-determined duration based on the filled radius of the non-compliant balloon 20 and the desired light intensity and light dose at the surface of the balloon.
SUBSTITUTE SHEET (RULE 26) An alternate example of this embodiment is shown in cross-sectional form in Fig.
2(b), where diseased esophageal tissue is treated using an enlarged non-compliant balloon 40. In this example, following identification of diseased tissue, PDT agent is applied to the identified diseased tissue. Excess agent is subsequently purged from the site.
A transparent, non-compliant balloon apparatus 40 is then inserted into the esophagus so as to span the treatment zone 30. The non-compliant balloon 40 is filled with gas or liquid so as to substantially distend or slightly dilate the esophagus, eliminating folding of the esophageal surface and thereby presenting a more uniform tissue surface 12 for illumination. Fill pressure is measured to establish the radius of the filled balloon.
Visible light 24 is then uniformly delivered radially to the treatment site through the walls of the balloon using a light source 22, such as for example a fiberoptic diffuser, located along the central axis of the balloon.
Additionally, the balloon 40 can be filled with a scattering medium, such as a dilute solution of intralipid, so as to improve the uniformity of light intensity delivered at the surface of the balloon. Further, the balloon 40 can be composed of or include a material that scatters the light 24 delivered at the surface of the balloon. Examples of such materials include material that is naturally translucent, such as latex; a polymer that includes particulate scattering materials; or a polymer with a roughened surface.
The pressure used to fill the balloon is measured and used to establish the operational radius of the filled balloon, and the intensity of the light source 22 is operated at a level that is selected based on the operational radius of the filled non-compliant balloon 40 so as to deliver a desired light intensity and light dose at the surface of the balloon. It is preferred in this alternate embodiment that sufficient pressure be used so as to minimize folding of the treated esophageal region without significantly dilating the esophagus so as to avoid potential stenosis or other non-specific irritation of esophageal tissue.
An additional alternate example of this embodiment is shown in cross-sectional form in Fig. 2(c), where diseased esophageal tissue is treated using a compliant balloon 50. In this example, following identification of diseased tissue, PDT agent is applied to the identified diseased tissue. Excess agent is subsequently purged from the site.
A transparent, compliant balloon apparatus 50 is then inserted into the esophagus so as to span the treatment zone 30. The compliant balloon 50 is filled with gas or liquid so as to fill, distend or slightly dilate the esophagus, substantially eliminating non-uniform SUBSTITUTE SHEET (RULE 26) contact between the esophageal surface and the balloon and thereby presenting a uniform tissue surface for illumination. Fill pressure is measured to establish the approximate radius of the filled balloon. Visible light 24 is then uniformly delivered radially to the treatment site through the walls of the balloon 50 using a light source 22, such as for example a fiberoptic diffuser, located along the central axis of the balloon.
Additionally, the balloon 50 can be filled with a scattering medium, such as a dilute solution of intralipid, so as to improve uniformity of light intensity delivered at the surface of the balloon. Further, the balloon 50 can be composed of or include a material that scatters the light 24 delivered at the surface of the balloon. Examples of such materials include material that is naturally translucent, such as latex; a polymer that includes particulate scattering materials; or a polymer with a roughened surface.
The pressure used to fill the balloon is measured to establish the operational radius of the filled balloon. Thus, in this example, the intensity of the light source 22 is operated at a level that is selected based on the operational radius of the filled compliant balloon 50 so as to deliver a desired light intensity and light dose at the surface of the balloon.
Preferably, in this alternate embodiment, sufficient pressure is used so as to minimize folding of the treated esophageal region without significantly dilating the esophagus (to avoid potential stenosis or other non-specific irritation of esophageal tissue).
For the treatment of disease in vessels of the circulatory system (such as arterial or venous plaque), Figs. 3(a) and 3(b) illustrate an alternate preferred embodiment of the present invention In the specific example of Fig. 3(a), a photosensitive agent is applied parenterally or via intravenous injection. The agent accumulates in diseased tissue of the vessel wall 60 to form a treatment zone 62. This agent is chosen based on preferential concentration in diseased material present at the desired treatment zone. After a brief accumulation period, a light 64 is applied to the disease site in order to activate the agent associated with the diseased material. This application may be effected by using a fiberoptic catheter 66 or similar means having a focusing, collimating, or diffi.csing terminus for spatial control of light delivery. The fiberoptic catheter 66 is able to deliver the light 64 directly to the treatment zone 62 so that the light can be applied topically. To minimize potential optical penetration into underlying healthy tissue, it is preferred that visible light in the spectral region between 400-600 nm be used so as to effect shallow penetration depths on the order of several millimeters or less. Use of such light affords efficacy in agent activation SUBSTITUTE SHEET (RULE 26) in superficial diseased material while simultaneously minimizing potential for deleterious photosensitization of the underiying tissue.
Alternatively, the photosensitive agent administration can be effected via localized, direct application of an agent to diseased material in the treatment zone 62, as illustrated in Fig. 3(b). Agent administration may be readily effected via an agent delivery device 68, such as a capillary tube, attached to and terminating near the end of the fiberoptic catheter 66, that is used to deliver a small quantity of agent, as a stream 70 or other flow, directly to or in the vicinity of the treatment zone 62. Alternately, this delivery device 68 may be separate from the fiberoptic catheter 66, thereby facilitating independent position of the respective termini of the light delivery fiberoptic catheter 66 and the agent delivery device 68. In either embodiment, delivery of a small quantity of photosensitive agent to diseased material in the treatment zone 62 is followed, after a short accumulation period, with application of light 64 to the disease site in order to activate agent associated with diseased material.
Preferably, in these example embodiments, Rose Bengal is used as the photosensitizing agent. Rose Bengal is optimally activated using light between 500 nm and 600 nm, which is sufficient for activation of superficial diseased material and substantially avoids potential for activation of underlying healthy tissues. Further, this agent is compatible with high intensity activating light, which may thereby be used to substantially reduce treatment times over that required with other agents, such as Type-II
PDT agents.
This description has been offered for illustrative purposes only and is not intended to limit the invention of this application, which is defined in the claims below.
What is claimed as new and desired to be protected by Letters Patent is set forth in the appended claims.
SUBSTITUTE SHEET (RULE 26)
Therefore, it is an object of the present invention to provide new methods and apparatus for an improved application of PDT while increasing the efficacy and safety of the procedure and reducing the cost of treatment.
SUMMARY OF THE PRESENT INVENTION
The present invention is directed to a method and apparatus for topical treatment of diseased tissue, including topical or systemic application of a PDT agent to diseased tissue, followed by topical application of light. In general, the method involves the steps of applying a PDT agent to diseased tissue to form a treatment zone; purging excess agent; and applying light to the treatment zone to activate agent associated with the diseased tissue. The light penetrates the treatment zone while minimizing activation of the agent outside the treatment zone.
In a preferred embodiment, Rose Bengal is the PDT agent.
In a further embodiment, the PDT agent is directly applied only to the treatment zone. Alternatively, the PDT agent can be applied systemically.
In a still further embodiment, the depth of activation of the PDT agent is controlled by proper selection of wavelength of activating light so as to avoid activation of agent that may be present in underlying healthy tissues.
In yet a further embodiment, the diseased tissue is diagnosed before applying the PDT agent.
In another embodiment, detection and treatment of a lesion may be effected in a short time period using a single procedure (such as endoscopy) instead of by separate diagnostic and therapeutic procedures.
SUBSTITUTE SHEET (RULE 26) In another embodiment, treatment rate is not limited by oxygen-dependent mechanisms.
In another embodiment, heat is also applied to the treatment zone to increase efficacy of activation of the agent.
In still another embodiment, activating light is delivered through a "balloon"
or other delivery apparatus located at the disease site.
In another embodiment, the method of the present invention can be used for treatment of disease in the gastrointestinal tract.
The method of the present invention can also be used for treatment of disease in vessels of the circulatory system.
The present invention is also directed to an apparatus for topical treatment of diseased tissue.
Accordingly, the present invention is directed to a method and apparatus to improve the evenness of light delivery, and to improve the safety and efficacy and reduce the cost of PDT, for treatment of Barrett's esophagus and other conditions.
The invention in a broad aspect seeks to provide an endoscopic apparatus for topical treatment of diseased tissue located within a body comprising applicator means for applying a PDT agent to the diseased tissue so as to form a treatment zone, and means for purging excess agent from the treatment zone prior to photoactivation of residual PDT
agent. There is a source of light to activate the PDT agent in the, wherein the light , is able to penetrate the diseased tissue while minimizing activation of the agent outside the diseased tissue, the light having a wavelength between approximately 400-600 nm.
The invention also pertains to the use of such apparatus for the treatment of diseased tissue located within a body.
6a BRIEF DESCRIPTION OF THE DRAWINGS
In describing the preferred embodiments, reference is made to the accompanying drawings wherein:
FIGURE 1(a) shows a cross-sectional view ofan esophagus illustrating a common method for treatment of Barrett's esophagus using PDT;
FIGURE 1(b) iltustrates the treatment zone of the method of Figure 1(a);
FIGURE 2(a) illustrates an example of an embodiment of the present invention for treatment of diseased esophageal tissue;
FIGURE 2(b) illustrates an alternate example of the embodiment of Figure 2(a);
FIGURE 2(c) illustrates an additional alternate example of the embodiment of Figure 2(a);
FIGURE 3(a) illustrates an example of another embodiment for the treatment of disease in vessels of the circulatory system; and FIGURE 3(b) illustrates an alternate example of the embodiment of Figure 3(a) wherein the PDT agent is directly applied to the diseased tissue.
DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED
EMBODIMENTS
The method and apparatus of the present invention is applicable to improved treatment of various dermatologic afflictions, such as psoriasis or skin cancer, and to diseased tissues at sites within the body, such as disease of the digestive or respiratory tracts. The present invention can also be used for the treatment of other anatomical sites, including intra-abdominal, intra-thoracic, intra-cardial, intra-circulatory, intra-cranial, and the reproductive tract.
In general, the method of the present invention involves one or more of the following steps. Initially, disease is diagnosed using, for example, histologic examination, or by measurement of the autofluorescence properties of diseased tissue or by detecting selective uptake of an indicator agent, such as a fluorescent dye or a PDT
agent, into such diseased tissue. Thereafter, a sufficient quantity of a topical or systemic formulation of a desired PDT agent is applied to the disease site so as to cover, perfuse, or saturate the diseased tissue. After a brief accumulation period to allow the agent to coat, perfuse, or otherwise become active within the diseased tissue, excess agent is purged or flushed from the disease site, and a substantially uniform light field is applied to the disease site in order to activate the agent associated with the diseased tissue.
For treatment of superficial diseased tissue, the wavelength of the light is preferably chosen so as to allow optical penetration into the diseased tissue but to minimize further optical penetration beyond the diseased tissue into underlying healthy tissue.
For example, visible light in the spectral region between 400-600 nm may be used to afford shallow penetration depths on the order of several millimeters or less. Use of such light affords efficacy in agent activation in superficial diseased tissues while simultaneously minimizing potential for deleterious photosensitization of underlying tissue. Preferably, laser light is used. It can be delivered by fiberoptic catheters. Alternatively, light can be delivered by direct illumination. Other alternate light source configurations and delivery apparatus include fiberoptic bundles, hollow-core optical waveguides, and liquid-filled waveguides.
Alternate light sources, including light emitting diodes, micro-lasers, monochromatic or continuum lasers or lamps for production of activating light, and continuous wave or pulsed lasers or lamps. Either single-photon or two-photon excitation methods can be used for agent activation. A more detailed explanation of such excitation methods is given SUBSTITUTE SHEET (RULE 26) WO 00/07515 PCT/iJS99/17515 in commonly assigned Canadian Patent File No. 2.252,783 filed October 28. 1997 which may be referred to for fiirther details.
Furthermore, the time and order of the applications of the agent and light can also be varied. For example, application of the agent and the light treatment regimen can be repeated one or more times to eliminate residual diseased tissue. Further, for some applications, an increased delay between agent application and light treatment can be beneficial. Additionally, the step of diagnosing can almost immediately be followed by the steps of applying a PDT agent, purging excess agent and applying light so that said method of diagnosis and treatment is done in a single procedure. If PDT agent uptake is used to diagnose or detect diseased tissue, the step of diagnosing can be immediately followed by the step of applying activating light. Alternatively, there may be an indefinite.
delay between diagnosis and PDT treatment.
Preferably Rose Bengal is used as the PDT or photosensitizing agent as it is inexpensive, non-toxic, has a proven safety record in human use, has significant intrinsic lipophilic properties, exhibits both type-I and type-II PDT response and therefore can be activated by type-I, oxygen-independent mechanism and is strongly phototoxic upon activation with light between 500 nm and 600 nm. Because of its 02-independent response, Rose Bengal is compatible with high intensity light activation, which reduces treatment time relative to porphyrin-based agents. More specifically, Rose Bengal is optimally activated using light between 500 nm and 600 nm, which is sufficient for activation of superficial diseased tissue and substantially avoids the potential for activation of underlying healthy tissues. An example of such a PDT agent is a solution of Rose Bengal formulated with a suitable lipophilic delivery vehicle, such as I-octanol or liposomes.
Alternatively, other PDT agents, including type-I or type-II agents can be used.
Examples of such standard PDT agents include psoralen derivatives; porphyrin and hematoporphyrin derivatives; chlorin derivatives; phthalocyanine derivatives;
rhodamine derivatives; coumarin derivatives; benzophenoxazine derivatives;
chlorpromazine and chlorpromazine derivatives; chlorophyll and bacteriochlorophyll derivatives;
pheophorbide a (Pheo a); merocyanine 540 (MC 540); Vitamin D; 5-amino-laevulinic acid (ALA);
photosan; pheophorbide-a (Ph-a); phenoxazine Nile blue derivatives including various phenoxazine dyes; PHOTOFRIN; benzoporphyrin derivative mono-acid; SnET,; and WO 00/07515 PC7'/US99/17515 LutexT'. The inventors of the present invention believe that all present and futiire PDT agents will work in the method and apparatus of the present invention.
Additionally, the present invention is not limited to the use of one PDT
agent.
Instead, more than one PDT agent can be used during a treatment regimen.
In a further embodiment, the PDT agent used in the present invention can include at least one targeting moiety. Examples of such targeting moieties include DNA, RNA, amino acids, proteins, antibodies, ligands, haptens, carbohydrate receptors or complexing agents, lipid receptors or complexing agents, protein receptors or complexing agents, chelators, and encapsulating vehicles. Such targeting moieties may be used to improve the selectivity of agent delivery to diseased tissue, and can function either by association with the photosensitizing PDT agent (for exampie where the PDT agent is encapsulated in a vehicle composed of the targeting moiety) or by attachment to the photosensitizing PDT agent (for example where the PDT agent is covalently attached to the targeting moiety).
In a further preferred embodiment, the PDT agent is applied directly to the diseased tissue. Employment of direct topical application provides a number of advantages. In particular, it affords improved targeting of the agent specifically to the diseased tissue, reduces the required latency period between agent administration and light activation and thereby shortens the treatment cycle, substantially eliminates the potential for systemic photosensitization, reduces agent consumption, and reduces the overall potential for side effects from exposure to the agent. Preferably, the agent is applied as a topical spray or wash. After a brief accumulation period (generally not to exceed 30 minutes), the excess agent is removed from the tissue surface by flushing with liquid, such as with water or saline. Following this flushing, it is preferred that the residual agent associated with the diseased tissue be activated by illumination of the diseased site with visible light between 400 nm and 600 nm. Optically, the light can be applied as discussed supra.
Alternatively, the PDT agent can be applied systemically. For example, this application may be via intravenous injection or parenteral administration (such as by consumption of a tablet or liquid formulation of the PDT agent).
In a further embodiment, heat can be applied to the treatment zone to increase PDT
effectiveness via hyperthermia. Heat can be applied, for example, through the use of a.
heated liquid in an illumination balloon, a transparent heating pad positioned between the illumination source and the tissue, or simultaneous illumination of the treatment site with infrared energy.
Examples of some of these embodiments of the present application are shown in cross-sectional form in Figs. 2(a), 2(b), and 2(c).
Fig. 2(a) illustrates an example of a treatment of diseased esophageal tissue using a non-compliant balloon 20 illumination apparatus. Initially, a treatment zone 30 is identified. This can be done for example via endoscopic examination of the esophagus and visual or spectroscopic identification of zones of diseased tissue. Such identification can include detection of histologic changes or other visual indicators of disease, detection of changes in autofluorescence, or detection of uptake of PDT or other agents into diseased tissue. Following identification of the treatment zone 30, PDT agent is applied to the identified diseased tissue. This agent can be applied, for example, via systemic application or more preferably, by direct spray application using a nozzle or other means provided at the distal end of an endoscope. Excess agent is subsequently purged from the site by, for example, natural systemic clearance or by flushing with liquid.
A transparent, non-compliant balloon apparatus 20 is then inserted into the esophagus so as to span the treatment zone 30. The non-compliant balloon 20 is filled with gas or liquid to a pre-determined pressure so as to establish a desired pre-determined radius. Visible light 24 is then uniformly delivered radially to the treatment site through the walls of the balloon 20 using a light source 22, such as for example a fiberoptic diffuser, located along the central axis of the balloon.
Additionally, the balloon 20 can be filled with a scattering medium, such as a dilute solution of intralipid, so as to improve the uniformity of light intensity delivered at the surface of the balloon. Further, the balloon 20 can be composed of or include a material that scatters the light 24 delivered at the surface of the balloon so as to further improve the uniformity of light intensity delivered at the surface of the balloon.
Examples of such a material include a material that is naturally translucent, such as latex; a polymer that includes particulate scattering materials; or a polymer with a roughened surface.
In the example illustrated in Fig. 2(a), the intensity of the light source 22 is operated at a pre-determined level for a pre-determined duration based on the filled radius of the non-compliant balloon 20 and the desired light intensity and light dose at the surface of the balloon.
SUBSTITUTE SHEET (RULE 26) An alternate example of this embodiment is shown in cross-sectional form in Fig.
2(b), where diseased esophageal tissue is treated using an enlarged non-compliant balloon 40. In this example, following identification of diseased tissue, PDT agent is applied to the identified diseased tissue. Excess agent is subsequently purged from the site.
A transparent, non-compliant balloon apparatus 40 is then inserted into the esophagus so as to span the treatment zone 30. The non-compliant balloon 40 is filled with gas or liquid so as to substantially distend or slightly dilate the esophagus, eliminating folding of the esophageal surface and thereby presenting a more uniform tissue surface 12 for illumination. Fill pressure is measured to establish the radius of the filled balloon.
Visible light 24 is then uniformly delivered radially to the treatment site through the walls of the balloon using a light source 22, such as for example a fiberoptic diffuser, located along the central axis of the balloon.
Additionally, the balloon 40 can be filled with a scattering medium, such as a dilute solution of intralipid, so as to improve the uniformity of light intensity delivered at the surface of the balloon. Further, the balloon 40 can be composed of or include a material that scatters the light 24 delivered at the surface of the balloon. Examples of such materials include material that is naturally translucent, such as latex; a polymer that includes particulate scattering materials; or a polymer with a roughened surface.
The pressure used to fill the balloon is measured and used to establish the operational radius of the filled balloon, and the intensity of the light source 22 is operated at a level that is selected based on the operational radius of the filled non-compliant balloon 40 so as to deliver a desired light intensity and light dose at the surface of the balloon. It is preferred in this alternate embodiment that sufficient pressure be used so as to minimize folding of the treated esophageal region without significantly dilating the esophagus so as to avoid potential stenosis or other non-specific irritation of esophageal tissue.
An additional alternate example of this embodiment is shown in cross-sectional form in Fig. 2(c), where diseased esophageal tissue is treated using a compliant balloon 50. In this example, following identification of diseased tissue, PDT agent is applied to the identified diseased tissue. Excess agent is subsequently purged from the site.
A transparent, compliant balloon apparatus 50 is then inserted into the esophagus so as to span the treatment zone 30. The compliant balloon 50 is filled with gas or liquid so as to fill, distend or slightly dilate the esophagus, substantially eliminating non-uniform SUBSTITUTE SHEET (RULE 26) contact between the esophageal surface and the balloon and thereby presenting a uniform tissue surface for illumination. Fill pressure is measured to establish the approximate radius of the filled balloon. Visible light 24 is then uniformly delivered radially to the treatment site through the walls of the balloon 50 using a light source 22, such as for example a fiberoptic diffuser, located along the central axis of the balloon.
Additionally, the balloon 50 can be filled with a scattering medium, such as a dilute solution of intralipid, so as to improve uniformity of light intensity delivered at the surface of the balloon. Further, the balloon 50 can be composed of or include a material that scatters the light 24 delivered at the surface of the balloon. Examples of such materials include material that is naturally translucent, such as latex; a polymer that includes particulate scattering materials; or a polymer with a roughened surface.
The pressure used to fill the balloon is measured to establish the operational radius of the filled balloon. Thus, in this example, the intensity of the light source 22 is operated at a level that is selected based on the operational radius of the filled compliant balloon 50 so as to deliver a desired light intensity and light dose at the surface of the balloon.
Preferably, in this alternate embodiment, sufficient pressure is used so as to minimize folding of the treated esophageal region without significantly dilating the esophagus (to avoid potential stenosis or other non-specific irritation of esophageal tissue).
For the treatment of disease in vessels of the circulatory system (such as arterial or venous plaque), Figs. 3(a) and 3(b) illustrate an alternate preferred embodiment of the present invention In the specific example of Fig. 3(a), a photosensitive agent is applied parenterally or via intravenous injection. The agent accumulates in diseased tissue of the vessel wall 60 to form a treatment zone 62. This agent is chosen based on preferential concentration in diseased material present at the desired treatment zone. After a brief accumulation period, a light 64 is applied to the disease site in order to activate the agent associated with the diseased material. This application may be effected by using a fiberoptic catheter 66 or similar means having a focusing, collimating, or diffi.csing terminus for spatial control of light delivery. The fiberoptic catheter 66 is able to deliver the light 64 directly to the treatment zone 62 so that the light can be applied topically. To minimize potential optical penetration into underlying healthy tissue, it is preferred that visible light in the spectral region between 400-600 nm be used so as to effect shallow penetration depths on the order of several millimeters or less. Use of such light affords efficacy in agent activation SUBSTITUTE SHEET (RULE 26) in superficial diseased material while simultaneously minimizing potential for deleterious photosensitization of the underiying tissue.
Alternatively, the photosensitive agent administration can be effected via localized, direct application of an agent to diseased material in the treatment zone 62, as illustrated in Fig. 3(b). Agent administration may be readily effected via an agent delivery device 68, such as a capillary tube, attached to and terminating near the end of the fiberoptic catheter 66, that is used to deliver a small quantity of agent, as a stream 70 or other flow, directly to or in the vicinity of the treatment zone 62. Alternately, this delivery device 68 may be separate from the fiberoptic catheter 66, thereby facilitating independent position of the respective termini of the light delivery fiberoptic catheter 66 and the agent delivery device 68. In either embodiment, delivery of a small quantity of photosensitive agent to diseased material in the treatment zone 62 is followed, after a short accumulation period, with application of light 64 to the disease site in order to activate agent associated with diseased material.
Preferably, in these example embodiments, Rose Bengal is used as the photosensitizing agent. Rose Bengal is optimally activated using light between 500 nm and 600 nm, which is sufficient for activation of superficial diseased material and substantially avoids potential for activation of underlying healthy tissues. Further, this agent is compatible with high intensity activating light, which may thereby be used to substantially reduce treatment times over that required with other agents, such as Type-II
PDT agents.
This description has been offered for illustrative purposes only and is not intended to limit the invention of this application, which is defined in the claims below.
What is claimed as new and desired to be protected by Letters Patent is set forth in the appended claims.
SUBSTITUTE SHEET (RULE 26)
Claims (13)
1. An endoscopic apparatus for topical treatment of diseased tissue located within a body comprising:
applicator means for applying a PDT agent to said diseased tissue so as to form a treatment zone;
means for purging excess agent from said treatment zone prior to photoactivation of residual PDT agent; and a source of light to activate said PDT agent in said treatment zone, wherein said light is able to penetrate said diseased tissue while minimizing activation of said agent outside said diseased tissue, said light having a wavelength between approximately 400-600 nm.
applicator means for applying a PDT agent to said diseased tissue so as to form a treatment zone;
means for purging excess agent from said treatment zone prior to photoactivation of residual PDT agent; and a source of light to activate said PDT agent in said treatment zone, wherein said light is able to penetrate said diseased tissue while minimizing activation of said agent outside said diseased tissue, said light having a wavelength between approximately 400-600 nm.
2. The apparatus of claim 1 wherein said PDT agent is Rose Bengal.
3. The apparatus of claim 1 wherein said PDT agent includes a targeting moiety.
4. The apparatus of claim 3 wherein said targeting moiety is selected from the group comprising DNA, RNA, amino acids, proteins, antibodies, ligands, haptens, carbohydrate receptors or complexing agents, lipid receptors or complexing agents, protein receptors or complexing agents, chelators, and encapsulating vehicles.
5. The apparatus of claim 1 wherein said light is applied via a balloon catheter apparatus.
6. The apparatus of claim 5 wherein said balloon catheter apparatus is non-compliant.
7. The apparatus of claim 6 wherein said non-compliant balloon catheter apparatus is enlarged so as to substantially distend said treatment zone.
8. The apparatus of claim 5 wherein said balloon catheter is compliant.
9. The apparatus of claim 5 wherein said balloon catheter is filled with a scattering medium.
10. The apparatus of claim 5 wherein said balloon catheter comprises a material that scatters light.
11. The apparatus of claim 1 wherein said light is applied by direct illumination.
12. The apparatus of claim 1 wherein said light is applied by a light source selected from the group comprising fiberoptic bundles, hollow-core optical waveguides, liquid-filled waveguides, light emitting diodes, micro-lasers, monochromatic lasers, continuum lasers, lamps, continuous wave lasers, and pulsed lasers.
13. The use of the apparatus as defined in any one of claims 1-12 for topical treatment of diseased tissue located within a body.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13004198A | 1998-08-06 | 1998-08-06 | |
| US09/130,041 | 1998-08-06 | ||
| PCT/US1999/017515 WO2000007515A1 (en) | 1998-08-06 | 1999-08-02 | Improved method for targeted topical treatment of disease |
Publications (2)
| Publication Number | Publication Date |
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| CA2339384A1 CA2339384A1 (en) | 2000-02-17 |
| CA2339384C true CA2339384C (en) | 2008-07-08 |
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| CA002339384A Expired - Lifetime CA2339384C (en) | 1998-08-06 | 1999-08-02 | Improved method for targeted topical treatment of disease |
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| EP (1) | EP1109506A4 (en) |
| JP (1) | JP2002522111A (en) |
| KR (1) | KR20010072307A (en) |
| CN (1) | CN1132557C (en) |
| AR (1) | AR021750A1 (en) |
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| MX (1) | MXPA01001336A (en) |
| TW (1) | TW396030B (en) |
| WO (1) | WO2000007515A1 (en) |
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| US7390668B2 (en) * | 1996-10-30 | 2008-06-24 | Provectus Pharmatech, Inc. | Intracorporeal medicaments for photodynamic treatment of disease |
| US6493570B1 (en) * | 1998-11-02 | 2002-12-10 | Photogen, Inc. | Method for improved imaging and photodynamic therapy |
| ATE406157T1 (en) | 1999-08-13 | 2008-09-15 | Provectus Pharmatech Inc | IMPROVED TOPICAL MEDICATIONS AND METHODS FOR THE PHOTODYNAMIC TREATMENT OF DISEASES |
| US20040039242A1 (en) * | 2002-04-02 | 2004-02-26 | Seedling Enterprises, Llc | Apparatus and methods using visible light for debilitating and/or killing microorganisms within the body |
| US20050053895A1 (en) | 2003-09-09 | 2005-03-10 | The Procter & Gamble Company Attention: Chief Patent Counsel | Illuminated electric toothbrushes emitting high luminous intensity toothbrush |
| EP1541091A1 (en) * | 2003-12-10 | 2005-06-15 | EL.EN. S.p.A. | Device for treating tumors by laser thermotherapy |
| US20080045859A1 (en) * | 2006-08-19 | 2008-02-21 | Fritsch Michael H | Devices and Methods for In-Vivo Pathology Diagnosis |
| US20100130909A1 (en) * | 2007-01-09 | 2010-05-27 | Health Research, Inc. | Treatment of barrett's esophagus using photodynamic therapy |
| DE102008047640B4 (en) * | 2008-09-17 | 2012-10-25 | Anton Kasenbacher | Use of a laser processing device for ablation of tooth material |
| WO2011097458A2 (en) * | 2010-02-04 | 2011-08-11 | University Of Rochester | Devices and methods for conforming photodynamic therapy to specific anatomic locations |
| WO2014015274A1 (en) | 2012-07-20 | 2014-01-23 | The General Hospital Corporation | Methods for tissue passivation |
| US10292381B2 (en) | 2012-07-20 | 2019-05-21 | The General Hospital Corporation | Vessel treatment systems, methods, and kits |
| US10549112B2 (en) | 2012-07-20 | 2020-02-04 | The General Hospital Corporation | Apparatus for tissue irradiation and methods and kits utilizing the same |
| JP6434911B2 (en) * | 2012-10-08 | 2018-12-05 | ウニヴェルジテート ライプチッヒ | Device for treating the sclera |
| EP2967743A4 (en) * | 2013-03-15 | 2016-11-30 | Gen Hospital Corp | Apparatus for tissue irradiation and methods and kits utilizing the same |
| JP6169275B2 (en) | 2013-07-18 | 2017-07-26 | ザ ジェネラル ホスピタル コーポレイション | Vascular treatment system, vascular treatment method, and vascular treatment kit |
| DE102015225400A1 (en) * | 2015-12-16 | 2017-06-22 | Vimecon Gmbh | Swiveling ablation catheter |
| CN107213554B (en) * | 2017-07-17 | 2019-11-19 | 尚华 | A kind of liquid light conduction device of intervention |
| CN107376132B (en) * | 2017-07-17 | 2020-02-04 | 尚华 | Novel optical fiber catheter and preparation method thereof |
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| JPS5940830A (en) * | 1982-08-31 | 1984-03-06 | 浜松ホトニクス株式会社 | Apparatus for diagnosis of cancer using laser beam pulse |
| JPS63111886A (en) * | 1986-10-29 | 1988-05-17 | 呉羽化学工業株式会社 | Cancer remedy apparatus using optical diode |
| US5346670A (en) * | 1986-12-24 | 1994-09-13 | British Technology Group U.S.A. Inc. | Phthalocyanine and tetrabenztriazaporphyrin reagents |
| US4973848A (en) * | 1989-07-28 | 1990-11-27 | J. Mccaughan | Laser apparatus for concurrent analysis and treatment |
| US5034613A (en) * | 1989-11-14 | 1991-07-23 | Cornell Research Foundation, Inc. | Two-photon laser microscopy |
| US5576013A (en) * | 1995-03-21 | 1996-11-19 | Eastern Virginia Medical School | Treating vascular and neoplastic tissues |
| IT1275571B (en) * | 1995-07-19 | 1997-08-07 | Consiglio Nazionale Ricerche | FLUOROGENIC SUBSTRATES SUSCEPTIBLE FOR PHOTOACTIVATION AFTER ENZYMATIC TRANSFORMATION SUITABLE FOR DIAGNOSIS AND PHOTODYNAMIC CANCER THERAPY |
| US5797868A (en) * | 1996-07-25 | 1998-08-25 | Cordis Corporation | Photodynamic therapy balloon catheter |
| US5814008A (en) * | 1996-07-29 | 1998-09-29 | Light Sciences Limited Partnership | Method and device for applying hyperthermia to enhance drug perfusion and efficacy of subsequent light therapy |
| US5829448A (en) | 1996-10-30 | 1998-11-03 | Photogen, Inc. | Method for improved selectivity in photo-activation of molecular agents |
| US20010003800A1 (en) * | 1996-11-21 | 2001-06-14 | Steven J. Frank | Interventional photonic energy emitter system |
| US5827269A (en) * | 1996-12-31 | 1998-10-27 | Gynecare, Inc. | Heated balloon having a reciprocating fluid agitator |
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1999
- 1999-08-02 MX MXPA01001336A patent/MXPA01001336A/en active IP Right Grant
- 1999-08-02 CN CN998110493A patent/CN1132557C/en not_active Expired - Lifetime
- 1999-08-02 WO PCT/US1999/017515 patent/WO2000007515A1/en not_active Application Discontinuation
- 1999-08-02 AU AU53917/99A patent/AU750633B2/en not_active Expired
- 1999-08-02 IL IL14127399A patent/IL141273A0/en unknown
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- 1999-08-02 KR KR1020017001602A patent/KR20010072307A/en not_active Application Discontinuation
- 1999-08-02 BR BR9912773-3A patent/BR9912773A/en not_active IP Right Cessation
- 1999-08-02 EP EP99939669A patent/EP1109506A4/en not_active Withdrawn
- 1999-08-02 CA CA002339384A patent/CA2339384C/en not_active Expired - Lifetime
- 1999-08-05 AR ARP990103908A patent/AR021750A1/en unknown
- 1999-08-26 TW TW088113402A patent/TW396030B/en not_active IP Right Cessation
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| KR20010072307A (en) | 2001-07-31 |
| MXPA01001336A (en) | 2002-04-24 |
| AU5391799A (en) | 2000-02-28 |
| HK1039555A1 (en) | 2002-05-03 |
| TW396030B (en) | 2000-07-01 |
| IL141273A0 (en) | 2002-03-10 |
| BR9912773A (en) | 2001-10-16 |
| CN1132557C (en) | 2003-12-31 |
| AR021750A1 (en) | 2002-08-07 |
| AU750633B2 (en) | 2002-07-25 |
| JP2002522111A (en) | 2002-07-23 |
| EP1109506A4 (en) | 2009-09-09 |
| CA2339384A1 (en) | 2000-02-17 |
| EP1109506A1 (en) | 2001-06-27 |
| CN1317952A (en) | 2001-10-17 |
| HK1039555B (en) | 2004-05-07 |
| WO2000007515A1 (en) | 2000-02-17 |
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