WO2014079972A1

WO2014079972A1 - Device for photodynamic treatment

Info

Publication number: WO2014079972A1
Application number: PCT/EP2013/074469
Authority: WO
Inventors: Morten Groseth
Original assignee: Photocure Asa
Priority date: 2012-11-23
Filing date: 2013-11-22
Publication date: 2014-05-30
Also published as: GB201221123D0

Abstract

The invention relates to a device for use in the photodynamic treatment of a body cavity or hollow organ of the body such as the bladder and to the use of such a device in the photodynamic treatment of abnormalities, disorders or diseases of the internal surfaces of said body cavity or hollow organ, such as of the bladder. The device comprises: an expandable structure for insertion within the body, wherein the expandable structure is arranged to be placed within the body cavity or hollow organ such that expansion of the structure will result in mechanical distention of the body cavity or hollow organ, and wherein the expandable structure is arranged such that light emitted within the body cavity or hollow organ when it has been distended by expansion of the expandable structure will irradiate an internal surface of said body cavity or hollow organ.

Description

DEVICE FOR PHOTODYNAMIC TREATMENT

This invention relates to a device for use in the photodynamic treatment of a body cavity or hollow organ of the body such as the bladder and to the use of such a device in the photodynamic treatment of abnormalities, disorders or diseases of the internal surfaces of said body cavity or hollow organ, such as of the bladder.

Photodynamic treatment (PDT) is a relatively new technique for the treatment of pre-cancerous conditions, cancer and non-cancerous diseases. PDT involves the administration of a photosensitiser or a precursor thereof to an area of interest. The photosensitiser or precursor thereof is taken up into the cells, where a precursor of a photosensitiser is converted into a photosensitiser. Upon exposure of the area of interest to light, the photosensitiser is excited, usually from a ground singlet state to an excited singlet state. It then undergoes intersystem crossing to a longer-lived excited triplet state. One of the few chemical species present in tissue with a ground triplet state is molecular oxygen. When the photosensitiser and an oxygen molecule are in proximity, an energy transfer can take place that allows the photosensitiser to relax to its ground singlet state, and create an excited singlet state oxygen molecule. Singlet oxygen is a very aggressive chemical species and will very rapidly react with any nearby biomolecules.

Ultimately, these destructive reactions will kill cells through apoptosis or necrosis, whereby for instance cancer cells are selectively killed. The mechanisms are still not fully understood, but studies suggest that the clinical result, e.g. the selectivity for cancerous cells, is not due to selective uptake by cancerous cells. Rather, there are similar levels of uptake in all cell types, but the processes of conversion and elimination are different in malignant cells and in metabolically active cells in general, such as inflamed or infected cells, leading to a concentration gradient between cancerous and normal tissue.

Various photosensitisers and precursors of photosensitisers are known and described in the art.

Typical photosensitisers include dyes like hypericin and PVP hypericin, psoralens, porphyrins such as hematoporphyrins, protoporphyrins, uroporphyrins, coproporphyrins, benzoporphyrins or deuteroporphyrins, in particular Photofrin® (profimer sodium), photosan III or verteporfin; chlorins, including bacteriochlorins and isochlorins such as chlorine e6, talaporfin or temoporfin and phthalocyanines such as aluminium- and silicon phthalocyanines.

Typical precursors of photosensitisers include 5-aminolevulinic acid (5-ALA) and certain derivatives thereof, e.g. 5-ALA N-derivatives where 5-ALA is chemically modified at the amino-group, or 5-ALA esters. Such compounds are intracellular^ converted to . .

protoporphyrins, such as protoporphyrin IX (PplX), which are photosensitisers. Currently several pharmaceutical products comprising 5-ALA or 5-ALA esters are in clinical use for PDT. One of them is Metvix®, a topical dermal product in the form of a cream comprising 5-ALA methyl ester (Galderma, Switzerland) for the photodynamic treatment of actinic keratosis and basal cell carcinoma. Another known product is Levulan Kerastick® (DUSA Pharmaceuticals, Canada), a solution for the photodynamic treatment of actinic keratosis which contains 5-ALA.

It is known to use 5-ALA esters clinically for the detection of cancer in the bladder. In the known technique, Hexvix® (Ipsen SA, France and Photocure ASA, Norway), a solution comprising 5-ALA hexyl ester, is instilled into the bladder and the bladder surface is exposed to blue light. In response, PplX displays a red fluorescence which is detected. Cancerous cells display a higher fluorescence than normal cells and hence cancerous lesions can be detected. This technique is known as photodynamic diagnosis (PDD).

5-ALA, 5-ALA hexyl ester and several other photosensitisers such as Photofrin® have been used experimentally in pre-clinical and clinical studies for the photodynamic treatment of bladder cancer (for review: N. Yavari et al., Can J Urol. 201 1 , 18(4), 5778-86). The management of superficial cancerous lesions in the bladder is challenging: when considered slightly aggressive, the disease may recur for many years and lead to a progressive loss of bladder function; whereas when aggressive, it may progress to an invasive tumour and lead to death in up to one third of the cases. Standard therapies are based on transurethral bladder resection and/or fulguration of all visible tumours, in association with different modalities of topical chemo- or immunotherapy, i.e. agents that are instilled into the bladder such as mitomycin C or bacillus Calmette-Guerin (BCG). However, such therapies fail in certain patients and there is thus a need for alternative and/or adjuvant treatment such as PDT. Photodynamic therapy offers treatment of the entire internal bladder surface which is crucial since bladder cancer often grows multifocally.

The internal surface of the bladder, i.e. the bladder wall, is not smooth, but consists of a series of ridges known as rugae, which are produced by folding of the bladder wall. The function of the rugae is to allow the bladder to expand when needed. When the bladder is not full, the rugae are folds in the tissue. However, as the bladder fills with urine, it expands by unfolding the rugae. When the bladder empties again, it refolds and the rugae increase to their former size. For bladder PDT, these rugae present a challenge since the whole bladder wall needs to be exposed to light such that all cancerous lesions are exposed to light and no cancerous lesions are missed. . .

In the prior art, this problem was addressed as follows: either the bladder was filled with sufficient volume of liquid, e.g. saline solution to produce a smooth bladder wall (R. Skyrme et al., BJU Int. 2005, 95(5), 1206-1210) or a continuous irrigation with saline solution was maintained during the whole PDT procedure at a flushing pressure sufficient to distend the bladder without folds (A. Johansson et al., Proc. of SPIE Vol. 7380,

73801 S1-S9, 2009).

Both procedures are quite cumbersome, since the bladder size/volume varies from patient to patient and the filling volume or flushing pressure for continuous irrigation has to be determined for each patient before the PDT procedure. Also, the bladder volume has to be controlled during the course of the PDT procedure, usually by suprapubic ultrasound (see for instance R. Waidelich et al., Urology 2003, 61 (2), 332-337). Not only the complexity but also the size/diameter of the part of the equipment which is inserted into the patient's urethra and bladder increases with the presence of one or more lumen to introduce or circulate the saline solution in the bladder and thus patients may need general anaesthesia during PDT (see R. Waidelich, supra) or spinal anaesthesia (R. Skyrme et al., BJU Int. 2005, 95(5), 1206-1210).

There thus remains a need for a better procedure and better equipment to carry out PDT of the bladder and other similar body cavities or hollow organs.

According to a first aspect the present invention provides a device for use in the photodynamic treatment of a body cavity or hollow organ of the body, the device comprising: an expandable structure for insertion within the body, wherein the expandable structure is arranged to be placed within the body cavity or hollow organ such that expansion of the structure will result in mechanical distention of the body cavity or hollow organ, and wherein the expandable structure is arranged such that light emitted within the body cavity or hollow organ when it has been distended by expansion of the expandable structure will irradiate an internal surface of said body cavity or hollow organ.

Surprisingly, it has been found by the inventor that the use of a specific device with these features, which reliably ensures the distention of the body cavity or hollow organ, significantly improves and simplifies PDT of the internal surfaces of the body. The term "body cavity/hollow organ" refers to such cavities/organs that have non-smooth surfaces or rugae. This includes the vagina, the stomach, the intestines, the bladder and the gallbladder, and preferably refers to the bladder. The term "body cavity/hollow organ" should preferably be understood to exclude blood vessels, and hence in preferred embodiments the device is not for treatment of blood vessels.

It is envisaged that this device will be of particular use in the treatment of the bladder, preferably in the photodynamic treatment of the bladder, but also for use in other . .

types of treatments which require a fully extended bladder or in other types of

manipulations of the bladder, e.g. surgical interventions, which require access to the whole internal surface of the bladder. The device will eliminate the prior art requirement for liquid (saline) to distend the bladder wall in PDT. Hence, in a preferred embodiment the device is for treatment of the bladder.

The term "mechanical distention" refers to the expansion of the body cavities/hollow organs by the mechanical action of the expandable structure. It is preferably that distention occurs to such extent that the internal surface of the body cavity/hollow organ is

substantially, or completely, smooth and substantially, or completely, without folds. Hence, in preferred embodiments the expandable structure is arranged to be able expand to such an extent that the walls of the body cavity or hollow organ of interest will be stretched to result in an internal surface which is substantially, or completely, smooth and without folds. To this end the expandable structure, at least when expanded, may have a size and/or shape selected to target the body cavity or hollow organ of interest.

For example, in the preferred embodiment for treatment of the bladder the expandable structure may be arranged to expand into a generally spherical shape, whereas for treatment of the stomach the expandable structure may be arranged to expand into an oblate spheroid (or lentile) of larger size. The volume of a full (i.e. expanded) bladder is about 100 ml and up to 650 ml, e.g. about 500 ml, more often 140 to 380 ml and most often around 250 to 300 ml and its expanded shape closely resembles that of a sphere. Hence for the bladder the expandable structure may be arranged to expand to generally spherical shape with a diameter of about 5.8 cm and up to about 1 1 cm, e.g. about 10 cm, preferably about 6.4 cm to about 9 cm and more preferably with a diameter of about 7.8 to 8.4 cm. Further details regarding the preferred form of the expandable structure are set out below.

The expandable structure is preferably located at the distal end of the device, and hence there may be no part of the device extending in the distal direction beyond the expandable structure. This makes the device well adapted for mechanical distention of a cavity or hollow organ of the body since there will be no part protruding beyond the expandable structure that might otherwise cause discomfort or potential injury when impinging on the wall of the cavity or hollow organ during expansion. For example, when the expandable structure is spherical in shape there would be no part at the distal end extending beyond the surface of the sphere.

The term "distal" is intended to refer to a direction away from the physician (or other medical personnel using the device), which is also the direction of insertion of the device . .

into the body. A proximal direction would hence the direction toward the physician, and the opposite end of the device to the distal end.

Light which is emitted within the body cavity or hollow organ to irradiate an internal surface of the body cavity or hollow organ may be emitted from within the expandable structure or from parts of the expandable structure. If light is emitted from within the expandable structure, then the expandable structure should be arranged to permit at least part of the light to pass through it. Hence, in preferred embodiments the expandable structure does not include any elements of significant size that are not transparent to at least a part of the light, preferably to the part of the light, i.e. wavelength(s), of interest for the PDT. The expandable structure may for example comprise a transparent balloon or membrane in order to achieve this, such elements being transparent to wavelengths of interest for the PDT that the device is intended for use with. However, in preferred embodiments the expandable structure is a non-occluding structure, by which is meant a structure with openings that hence permits generally undisrupted passage of light from within the expandable structure to internal surfaces of the body cavity or hollow organ distended by the expandable structure. As well as providing undisrupted passage of light a non-occluding structure of this type will also allow for passage of bodily fluids (e.g. in case of the bladder or the stomach) and hence in some cases can allow for normal operation of the body cavity/hollow organ to some extent whilst the photodynamic treatment with the device is ongoing.

Preferably the expandable structure has a mechanism that moves from an unexpanded to an expanded configuration. For example the mechanism may comprise flexible, rotatable and/or translatable wires. The expanded configuration of the wires may be an open structure similar to an umbrella or it may be a closed cage-like structure. The mechanism may expand by means of a folding structure similar to an umbrella.

In a particularly preferred embodiment the mechanism comprises multiple flexible wires located at different points around a longitudinal axis of the device, wherein the mechanism expands by the wires flexing outwardly away from the axis into curves for pushing against the walls of the body cavity or hollow organ. The longitudinal axis is the axis along the device between the proximal and distal ends. The wires are hence arranged about a distal part of this axis. These flexible wires may each have distal and proximal ends (being ends located toward the distal end of the device and toward the proximal end of the device) coupled to respective distal and proximal couplings, one or both of the couplings being arranged to move so that one coupling moves relative to the other to decrease the distance between the couplings. Reducing the distance between the ends of the flexible wires will cause the wires to flex by applying a buckling force to the wires and . .

hence expand the structure. The coupling may for example both move toward one another or the proximal coupling may be arranged to move toward the distal coupling (or vice versa). The wires are subject to buckling as a result of compression arising from the relative movement of the couplings. An outwardly flexing/buckling of the wires may be ensured by the wires being initially slightly outwardly bowed and/or by a blocking member that prevents inward bowing of the wires. With this arrangement, the wires may be joined to one or both of the distal and proximal couplings by pivoted joints.

In an alternative arrangement the expandable structure may expand by movement of a folding structure similar to an umbrella as mentioned above. In this case the mechanism of the structure may comprise wires each attached at one end to a coupling with a pivoted connection and with the other end of the wires moving freely. Each of the wires may be pivotally and slidably connected to a shaft running along a longitudinal axis of the expandable structure. For example the wires have a pivot part way along the length thereof connected to a rod that itself is pivotably connected to a slider on the shaft, in this way forming a simple umbrella type structure. The expandable structure may alternatively be more complex and include several folding elements linked together as is known for example for compact folding umbrellas.

With wires spaced about a longitudinal axis of the device the curved wires may form an expanded structure having a shape that approximates to a surface of revolution of which each wire is a generatrix. Thus, in the unexpanded state the surface of revolution formed by the wires would be cylindrical with the wires being straight or alternatively almost straight with some curvature to ensure outward buckling and lying along the surface. As the wires flex outwardly buckling then the surface of revolution will expand first into a shape similar to a prolate spheroid or vesica piscis and then, with further movement of the coupling(s), to an approximation of a sphere and finally into an oblate shape like an oblate spheroid or pumpkin shape. The exact shape of the mechanism as it expands will be determined by the characteristics of the wires and of the joints to the couplings and it will be appreciated that different shapes could be generated by constraints on movement of the wires at the couplings and by wires that have different stiffness along the length of the wires.

The couplings may comprise rings or plates with the wires attached by pivoting or pin joints around a circumference of the couplings. The device preferably comprises actuator elements attached to the couplings to move the couplings toward one another and thereby actuate the mechanism of the expandable structure. In a preferred embodiment these actuator elements comprise rods and/or strings passing along the device from the couplings at the distal end to the proximal end in order to allow the user to operate the . .

mechanism by manipulation of the rods and/or strings. For example, in one embodiment the coupling at the distal ends of the wires may be connected to an actuator element extending along the device and being accessible at the proximal end of the device (or coupled to a control mechanism at the proximal end), so that pulling of the actuator element moves the distal coupling toward the proximal coupling. Alternatively, or in addition, the proximal coupling may be connected to an actuator element extending along the device and being accessible at the proximal end of the device (or coupled to a control mechanism at the proximal end), so that pushing of the actuator element moves the distal coupling toward the proximal coupling. As mentioned earlier, it is only essential for one of the couplings to move in order to flex the wires, the other coupling may remain fixed.

However for some applications it may be useful for both couplings to be controllable by actuator elements.

The device may hence include a distal part comprising the expandable structure, along with a proximal part that is, in use, outside of the body and allows for control of the expansion of the expandable structure. The expandable structure and the proximal part are preferably joined by an elongate section, which may be covered with a protective cover/sheath.

In a preferred embodiment, the mechanism of the expandable structure can be locked in its position, for example by a locking element that prevents movement of the actuator elements. This is advantageous in order to prevent accidental expansion or collapse of the expandable structure.

The mechanism may for example comprise four to twenty flexible wires, or more for larger devices. Preferred embodiments may utilise eight to sixteen flexible wires. What is required is for the wires to be sufficiently numerous to spread the load applied to the internal walls of the body cavity or hollow organ such that this surface is stretched to remove folds/rugae and the like without risk of damage to the body tissue as a result of the force applied by the wires. It is preferred for the wires to be symmetrically spaced about the longitudinal axis.

Preferably the mechanism moves elastically between the unexpanded and expanded configuration such that when no force is applied the mechanism will revert to one of the unexpanded or the expanded configuration. Typically it is preferred for the mechanism to revert to its unexpanded configuration. This allows the device to be inserted into the body cavity or hollow organ in a stable unexpanded configuration without the need to any force to be applied to the mechanism of the expandable structure. Thus, in the preferred embodiment above including multiple flexible wires that expand by flexing . _

outwardly it is preferred for the wires to be generally straight when no force is applied and for them to deform elastically as they flex outwardly into the expanded configuration.

The wires and/or couplings may be made of metal and/or of a polymer material. In some preferred embodiments the wires and/or couplings are made of a polymer material that does not interfere with the light used for irradiation in PDT, i.e. which permits suitable wavelength(s) in a sufficient amount to be transmitted therethrough to provide the required light dose to the entire internal surface of the body cavity/hollow organ. In a preferred embodiment, said polymer material is a transparent polymer material. In a more preferred embodiment, said polymer material is a transparent polymer material which has light scattering and/or light diffusing properties.

As noted above, the expandable structure is arranged so that light emitted within the body cavity or hollow organ irradiates an internal surface of the body cavity or hollow organ. Preferably the light can irradiate the entire internal surface, although for some applications only parts of the internal surface may be irradiated. The light which is emitted within the body cavity or hollow organ to irradiate the internal surface of the body cavity or hollow organ may be emitted within the expandable structure or from the expandable structure. In the latter case, the expandable structure comprises a light emitter. In the former case, the device according to the invention is used in combination with or comprises a light emitter which emits light within the expandable structure. The light emitter may be included in the device or may not be included in the device, i.e. a separate light emitter.

In a preferred embodiment, the device of the invention comprises a light emitter which, when the device is in use, emits light within the body cavity or hollow organ and irradiates the internal surface of said body cavity or hollow organ.

This may be a light emitter which emits light from an internal light source (a light source that is inside the body cavity or hollow organ when the device is in use) or alternatively it may be a light emitter which emits light from an external light source (a light source that is external to the body when the device is in use).

Embodiments where the light source is inside the body cavity/hollow organ are preferred since they allow the patient to sit in a chair and stand up/sit down or may even allow the patient to move around.

The light source may be connected to a power supply, such as a utility power supply (optionally with a power transformer, if required) or preferably a disposable or rechargeable battery. The type of battery may be dependent on the light source and the fluence rate of the light emitted by the light source.

In one arrangement the light emitter is part of a light guide, preferably an optical fibre, that directs light from an external light source to said light emitter. . .

In a preferred embodiment, the light emitter is located at the distal end (i.e. tip) of the light guide or optical fibre. This arrangement is suitable for the bladder, gallbladder and stomach. Preferably, the tip of the optical fibre is adapted to distribute light

homogeneously onto the internal surface of the body cavity/hollow organ. This can be achieved by selecting a suitable geometry for the tip of the optical fibre and/or by using scattering or diffusing materials. For use in the bladder and other quasi-spherical hollow organs, the optical fibre is preferably equipped with a tip that is adapted to emit light in a spherical manner, for example by use of a spherically shaped tip or by a tip comprising a light scattering or diffusing material. In a preferred embodiment, for use in the bladder and other quasi-spherical hollow organs the tip of the optical fibre is located within the expandable structure so as to be centrally positioned within said hollow organ. Hence, the tip of the optical fibre may be at a centre of the volume of the expandable structure.

In another preferred embodiment, the light emitter is located along at least a part of the length of a light guide, preferably an optical fibre, i.e. light is emitted along the part of the light guide/optical fibre that is, when the device is in use, located in the body cavity or hollow organ. This embodiment is suitable for the intestines.

In another arrangement the mechanism of the expandable structure, e.g. the multiple wires, comprise an optical fibre which emits light along at least a part of the length of the wires, preferably along the whole length of the wires.

In a preferred embodiment, each wire comprises an optical fibre which preferably emits light along the whole length of said wire. In another preferred embodiment, the couplings - in addition to the wires - comprise an optical fibre which emits light around at least a part of the circumference of the couplings, preferably around the whole of the circumference of the couplings. In these arrangements, the wire and/or coupling material is preferably a polymer material. In a preferred embodiment, the polymer has light scattering or light diffusing properties which promotes the homogeneous distribution of the light onto the internal surface of the body cavity or hollow organ. In a preferred

embodiment, an optical fibre is embedded in the polymer material of the wire and preferably also in the polymer material of the couplings such that light is emitted in all directions, i.e. also towards the direction of the part of the internal surface the wire and the couplings are in contact with.

The term "optical fibre" includes conventional optical fibres like waveguides or light pipes which are designed to conduct light issuing from a light source coupled to the proximal end of the optical fibre to its distal end. The optical fibre may be a single optical fibre or several optical fibres, i.e. a bundle of optical fibres. The term "optical fibre" further . .

includes organic light emitting diode fibres (OLED fibres) such as those described in US 6,538,375. The optical fibre is preferably flexible.

When using an optical fibre, a light source needs to be coupled to the optical fibre and the light source is preferably outside the body. Such light source may for instance be one or more light bulbs (e.g. a xenon bulb) or light emitting diodes or a laser. Non-laser light sources such as light bulbs or light emitting diodes may be preferred for safety reasons, if the PDT is carried out outside of the operating theatre, e.g. at the hospital ward or at an outpatient facility. Since the outer material of the optical fibre may come into contact with body tissue, the outer material may be a protective material (layer, sheet, casing) that protects the optical fibre when handled and/or in use and which is suitable for use in human patients.

In an alternative arrangement the light emitter may be a light emitting strand which includes a single light emitting element or preferably a plurality of light emitting elements. The light emitting elements are preferably light emitting diodes (LEDs), e.g. organic LEDs (OLEDs) or light emitting electrochemical cells (LECs) as described in A. Sandstrom et al., Nat. Commun. 3, 2012, 1002. Hence in this arrangement the light emitter is the light source. If a plurality of light emitting elements is used, the elements may be connected in parallel or preferably in series. The light emitting elements may be located at the distal end of the strand or clustered around the distal end of the strand (most suitable for bladder, gallbladder, stomach) or may be located or distributed along the length of the part of the strand which is inserted into the body cavity/hollow organ (most suitable for the intestines or vagina). The strand is preferably flexible. In a preferred embodiment, for use in the bladder and other quasi-spherical hollow organs the distal end (tip) of the strand is centrally positioned within said hollow organ. Thus, the strand may be located along the axis of the device at the distal end thereof, and may comprise light emitting elements centrally within the expandable structure.

In an alternative arrangement, the mechanism of the expandable structure, e.g. the multiple wires, comprise light emitting elements which emit light along at least a part of the length of the wires, preferably along the whole length of the wires. In a preferred embodiment, each wire comprises light emitting elements, preferably along the whole length of the wires. In another preferred embodiment, the couplings - in addition to the wires - comprise light emitting elements which emit light from at least a part of the circumference of the couplings, preferably the whole of the circumference of the couplings.

In these arrangements, the light emitting elements are arranged in such a way that the light emitted from those elements homogeneously irradiates the internal surface of the body cavity or hollow organ. This may be done by covering the light emitting elements with . .

a material which has diffusing properties, such as medical grade silicon comprising pigments or materials described in US 2009/0198173. With the use of a diffusing material, a single light emitting element will irradiate a larger portion of the internal surface of the body cavity/hollow organ than without it. As a result, fewer light emitting elements are necessary to achieve a homogeneous irradiation. This is a benefit if LEDs, OLEDs or LECs are used since less heat is generated from such light emitting elements when the device is in use and heat generation management is easier if their number is kept as small as possible. The light emitting elements may be placed on the side of the wire/coupling which faces the interior of the body cavity/hollow organ or, in addition, also on the side of the wire/coupling which faces the internal surface of the body cavity/hollow organ.

If the light emitting element is an OLED or LEC, the light emitting element may be placed on opposite sides of the wire (or coupling), e.g. the side that faces the interior of the body cavity/hollow organ and the side which faces the internal surface of the body cavity/hollow organ, and polymer material (which may be identical with the wire and/or coupling material) may be used to cover the light emitting element. In a preferred embodiment, the OLED or LEC is embedded in the polymer material of the wire/coupling such that light emitted from the OLED or LEC is emitted in all directions, i.e. also towards the direction of the part of the internal surface the wire or coupling is in contact with.

Preferably the polymer material has light scattering and/or light diffusing properties.

When using a light emitting strand, the light source is inside the body and hence the strand and/or the light emitting elements are preferably covered with a protective material (layer, sheet, casing) which protects the strand/light emitting elements. Preferably, the material has also insulating properties. In one preferred embodiment, the material has also diffusing properties to enhance homogeneity of the light emission. Alternatively, the material is a clear material which does not impact the light emission.

The optical fibre or light emitting strand may be permanently located within and integrated with the device, for example within the expandable structure or as a part of the expandable structure. Alternatively, the device may comprise a lumen to insert a separate light emitter, e.g. an optical fibre or light emitting strand and means to lock the position of the light emitter when it in place.

The device according to the first aspect of the invention may be inserted into the body cavity/hollow organ either through a catheter or an endoscope which is suitable to be inserted into said body cavity/hollow organ, e.g. a cystoscope if the body cavity/hollow organ is the bladder or a gastroscope if the body cavity/hollow organ is the stomach. Other lumen of the catheter or working channels of the endoscope may be used to insert means to irradiate the body cavity/hollow organ (i.e. separate light emitters) and/or means to - - manipulate the body cavity/hollow organ, e.g. means to take biopsy samples, means to remove diseased tissue or means to ablate tissue and/or means to instil or introduce something into the body cavity/hollow organ such as instilling or introducing a fluid or a drug and/or means to drain fluids form the body cavity/hollow organ.

If a working channel of an endoscope equipped with means to irradiate a body cavity/hollow organ is used for inserting the device into the body cavity/hollow organ, then said means to irradiate the body cavity/hollow organ could be used for photodynamic treatment of the body cavity/hollow organ, e.g. by coupling the means to irradiate said body cavity/hollow organ to an optical fibre. Alternatively, when those means are not suitable for carrying out PDT (e.g. if the emitted fluence rate is too low or the wavelength of the light is not suitable), those means could be adapted or changed in order to make them suitable for carrying out PDT, e.g. by using a filter or set of filters to use a specific wavelength. In another embodiment, the catheter or endoscope may be equipped with a lumen or working channel which allows the insertion of a light emitter, e.g. an optical fibre or light emitting strand suitable to irradiate the internal surface of the body cavity/hollow organ in such a way that PDT can be carried out.

The device may further include a hollow elongate, preferably flexible catheter body having a proximal and a distal end and comprising a lumen for insertion of the expandable structure into said body cavity or hollow organ.

The catheter body may comprise one or more further lumens fluidly connected to the body cavity or hollow organ. This may include a lumen for draining fluid from said body cavity or hollow organ, e.g. into a collection bag coupled to the lumen when in use. This may alternatively or additionally include a lumen coupled to e.g. a syringe or infusion bag to instil a liquid/fluid into said body cavity or hollow organ. For instance, when in use in the bladder, there may be a need to drain urine from the bladder. If PDT is carried out after removal of superficial tumours, blood may be present in the bladder. Since blood absorbs light, the presence of blood may impact the PDT procedure and thus there may be a need to rinse the bladder from blood by instilling a fluid, e.g. saline, into the bladder and drain the bladder thereafter. Further, it may be beneficial to fill the bladder with a liquid, e.g. a buffer or saline before the expandable structure is inserted. The liquid will help to extend the bladder and the expandable structure, once inside the bladder and expanded, will ensure that the bladder stays expanded. This minimizes the risk that the bladder wall is injured when the expandable structure is expanded. The liquid may remain in the bladder and e.g. serve as a diluent or solvent for a photosensitiser or precursor thereof which is either introduced into the bladder or which is part of the expandable structure. Alternatively, the liquid may be drained from the bladder. A single lumen may be used both for drainage and . .

instillation. Preferably, a first lumen may be used for instillation and a second lumen may be used for drainage.

The outer diameter of the catheter body may be generally dependent on its use and is comparable to similar catheters of the art: for catheters to be used in fairly large organs like the stomach (i.e. inserted into the esophagus and ultimately into the stomach), the catheter may have a larger outer diameter than if inserted through the urethra into the bladder. The outer diameter is preferably small enough to fit within the portion of the body to which it is inserted to (esophagus, urethra) and to house internally contained

components and lumens.

In preferred embodiments the catheter body comprises a preferably flexible plastic or polymeric material suitable for medical use in general and catheter bodies in particular. Appropriate materials may include silicones, latex, rubbers, polyurethanes and

combinations of these materials. Depending on its use, the catheter body may have an antiseptic coat to prevent bacterial infection of the body cavity/hollow organ or other body tissue it comes in contact with, e.g. the urethra.

The invention also extends to the device of the first aspect or preferred

embodiments thereof as discussed above when in a kit form comprising the device with the expandable structure and optionally the catheter body and/or a pharmaceutical

composition comprising a photosensitiser or precursor thereof for photodynamic treatment. Suitable photosensitisers and precursors of photosensitisers and pharmaceutical compositions comprising such photosensitisers and precursors of photosensitisers, i.e. suitable formulations of such photosensitisers and precursors of photosensitisers, are discussed below.

Viewed from a second aspect, the invention provides a method comprising use of the device of the first aspect in the photodynamic treatment of a body cavity or hollow organ. The method includes the use of a device having any or all of the preferred features set out above.

The method includes insertion of the device to an appropriate extent into the body cavity or hollow organ of interest, mechanically distending the body cavity or hollow organ by expansion of the expandable structure, and irradiating an internal surface of the body cavity or hollow organ with light.

In a third aspect, the invention provides a method of photodynamic treatment of a body cavity or hollow organ, the method comprising: administering a composition comprising a photosensitiser or precursor of a photosensitiser to a patient in need of said treatment, inserting the device according to the invention or at least the expandable structure of the device into the body cavity or hollow organ of interest, mechanically . .

distending the body cavity or hollow organ by expansion of the expandable structure and irradiating an internal surface of the body cavity or hollow organ with light. The method may include use of a device having any or all of the preferred features set out above. The administration of the photosensitiser or precursor of the photosensitiser and the insertion of the device may happen simultaneously or sequentially.

This method is considered inventive irrespective of the device used to distend the body cavity or hollow organ and therefore, viewed from a fourth aspect, the invention provides a method of photodynamic treatment of a body cavity or hollow organ, the method comprising: mechanically distending the body cavity or hollow organ and irradiating an internal surface of the body cavity or hollow organ with light. The method may optionally include use of a device having any or all of the preferred features set out above.

In the methods of the second, third and fourth aspects the location and degree of expansion of the device may be checked by suitable imaging modalities, e.g. ultrasound imaging, x-ray or magnetic resonance imaging, e.g. when metal is used as a material for the mechanism of the expandable structure.

The device is preferably inserted into the body cavity/hollow organ through a catheter or an endoscope, preferably through a flexible catheter or endoscope and more preferably through a catheter body, preferably a flexible catheter body, which may be a part of the device and may have features as discussed above.

In the methods of the second, third and forth aspect, there may optionally be an incubation time after administering a photosensitiser or precursor of a photosensitiser to a patient in need of said treatment. Such incubation time is further discussed below.

The photodynamic treatment includes the administration of a photosensitiser or a precursor of a photosensitiser. This may be achieved in a separate procedure prior to or after the insertion of the device, e.g. by systemic administration or local administration, i.e. administration to the body cavity or hollow organ of interest. Alternatively the

photosensitiser or precursor of photosensitiser may be administered to the body cavity or hollow organ by contact of the expandable structure or other parts of the device with the internal surface of the body cavity or hollow organ. Example procedures are set out in more detail below, along with details of suitable photosensitisers or precursors of

photosensitisers.

A preferred embodiment of the device will now be described by way of example only and with reference to the accompanying drawings, in which:

Figure 1 shows an example device with an expandable structure unexpanded; Figure 2 shows the device of Figure 1 with the expandable structure expanded into a spherical shape . .

Figure 3 is a schematic illustration of a light emitter embedded in a wire of an expandable structure; and

Figure 4 is a schematic illustration of a similar light emitter using light emitting strand with LEDs.

The device of Figures 1 and 2 is an example that is intended for use in PDT of the bladder, but it will be appreciated that the principles and construction of this example could readily be adapted to provide for treatment of other body cavities or hollow organs. The device comprises a distal end 2 and proximal end 4. At the distal end 2 is an expandable structure 6 that can be moved from an unexpanded configuration as shown in Figure 1 to an expanded configuration as shown in Figure 2 in order to thereby mechanically distend the body cavity or hollow organ into which it is inserted, in this example the bladder.

The expandable structure 6 has a mechanism comprising multiple flexible wires 8 each of which has a distal end and proximal end connected to a distal coupling 10 and proximal coupling 12. The wires 8 are connected by pivoting joints to the couplings 10, 12 such what when the couplings 10, 12 are moved closer together as shown in Figure 2 the wires flex outwardly to form the expanded shape of the expandable structure. This shape is a volume of revolution of which each wire 8 is a generatrix.

The device also includes an elongate section 14 extending between the proximal and distal ends of the device. In use the distal end 2 with the expandable structure 6 would be inserted into the bladder, for example by passing along the urethra into the bladder, with the elongate section 14 extending back to the proximal end 4, which would remain outside of the body, i.e. allowing operation/manipulation of the expandable structure 6 when inside the bladder from outside the body.

The expandable structure 6 is actuated by an actuator element 16 that consists of a slidable rod or tube passing along the elongate section 14 from the distal coupling 10 to the proximal end 4 of the device. The actuator element 16 is shown in full in Figure 2, whereas Figure 1 just shows the parts that are outside of the elongate section 14. Once the device has been inserted into the required location within the body then the expandable structure 6 can be operated by manipulation of the actuator element 16. The proximal end of the actuator element 16 is moved relative to the elongate section 14 in order to increase the distance X as shown in Figure 1 by the arrows A. This pulls the distal coupling 10 closer to the proximal coupling 12 and hence flexes the wires 8 outwardly in the direction of the arrow B. The size of the expanded structure can be controlled by controlling the distance X and the force applied to the internal walls of the bladder can also be controlled to some extent by control of the force applied by the movement A. . .

When the expandable structure 6 has been appropriately deployed it can be fixed in place by a locking element (not shown) that fixes the distance X. The PDT treatment can then be carried out by emitting light from a light emitter within the expandable structure 6 in order to irradiate the internal surface of the bladder. The device includes a light emitter 18 and a connector 20 passing from the light emitter 18 to the proximal end 4 of the device. As discussed above the light emitter 18 (and hence the connector 20) can take various forms. In Figures 1 and 2 the light emitter 18 is shown as a point source of light at the centre of the expandable structure. This might be a light emitting element or cluster of light emitting elements (LEDs, OLEDs or LECs) or a tip of an optical fibre. If a light emitting element is used then the connector 20 can be an electrical connector for supplying power and/or control signals. The power source for supplying the power could be located on the patient, e.g. in a small pocket which is strapped to the hip or thigh. If the light emitter 18 is the tip of an optical fibre then the connector 20 is the optical fibre, which would be connected outside of the device to a light source, e.g. a laser.

In alternative embodiments the light emitter 18 could be a length of optical fibre arranged to emit light along its length, an elongate OLED element, or a light emitting strand with discrete light emitting elements such as LEDs. Figures 3 and 4 show possible arrangements where light emitters 18 of this type are incorporated into parts or the whole length of the wires 8 of the expandable structure. In the arrangement shown schematically in Figure 3 the light emitter 18 is an optic fibre or an OLED or LEC element that is embedded into a wire 8 made of a polymer material 24. The polymer material 24 preferably has light scattering/diffusing properties in order to evenly distribute light from the light emitter 18 within the wire 8. Figure 4 is a schematic illustration of a similar light emitter 18 which takes the form of a light emitting strand 18 embedded in the wire 8 and having LEDs 26 spaced along its length. The wire 8 is once again made of a polymer material 24. The LEDs 26 are located on the wire so as to be on a side of the wire 8 that faces an internal surface 22 of the body cavity or hollow organ when the expandable structure is expanded. LEDs 26 may also be located on the side facing away from the internal surface 22.

The device, or at least the expandable structure of the device, can be inserted into the body by means of a catheter or the like and in some embodiments the catheter is a part of the device, either integrated with the device or supplied in kit form. The device will pass along a lumen of the catheter and the catheter may have other functions as described above.

The device of the preferred embodiments is intended for use in PDT. The preferred

PDT procedure starts with the administration of the photosensitiser or precursor of . .

photosensitiser, i.e. with the administration of a pharmaceutical composition comprising a photosensitiser or a precursor of a photosensitiser. The mode of administration is dependent on which photosensitiser or precursor is used. Typically, administration can be done systemically, i.e. parenterally (infusion, injection), enterally (oral or rectal

administration) or topically to the body cavity or hollow organ of interest. Photofrin®, for instance, is preferably intravenously administered while ALA and ALA-esters are preferably topically or enterally administered, e.g. instilled as a solution into the body cavity/hollow organ (e.g. to the bladder), applied topically to the internal surface of the body cavity/hollow organ (e.g. to the vagina), orally ingested (e.g. stomach, intestines) or rectally administered (intestines).

To obtain a pharmaceutical composition suitable for administration to a patient, photosensitisers or precursors of photosensitisers are formulated with compatible excipients that are known in the art as described for instance in WO 96/28412, WO 99/53962, WO 2009/07481 1 , WO 2010/072419, WO 2010/142456, WO 2010/142457, WO 201 1/161220 and WO 2012/004399. For parenteral administration the photosensitiser or precursor of photosensitiser can be formulated as a solution, preferably aqueous solution. For enteral administration, the photosensitiser or precursor of photosensitiser can be formulated as a solid for oral administration, e.g. a pill, tablet, powder, granulate, capsule or as a solid for rectal administration, e.g. a suppository. Alternatively, the photosensitiser or precursor of photosensitiser can be formulated as a semi-solid for oral or rectal administration, e.g. a gel, emulsion, foam or ointment. Further, the photosensitiser or precursor of photosensitiser can be formulated as a liquid for oral administration, e.g. a solution, suspension, syrup or for rectal administration, e.g. an enema. For topical administration, the photosensitiser or precursor of photosensitiser can be formulated as a liquid, e.g. a solution such as an aqueous and/or alcoholic solution or suspension, as a semi-solid, e.g. a cream, emulsion, lotion, ointment, gel, foam and paste or as a solid, e.g. a transdermal patch.

Alternatively, the expandable structure of the device according to the invention may be coated with the photosensitiser or precursor of photosensitiser, preferably in the form of a dry deposit or film, such as described in WO 2012/004399.

In general, any known photosensitisers or precursors thereof can be used in a method of PDT wherein the devices according the preferred embodiments are used.

Typical such photosensitisers include dyes like hypericin and PVP hypericin, psoralens, porphyrins such as hematoporphyrins, protoporphyrins, uroporphyrins, coproporphyrins, benzoporphyrins or deuteroporphyrins, in particular Photofrin® (profimer sodium), photosan III or verteporfin; chlorins, including bacteriochlorins and isochlorins . .

such as chlorine e6, talaporfin or temoporfin and phthalocyanines such as aluminium- and silicon phthalocyanines.

Typical such precursors of photosensitisers include 5-aminolevulinic acid (5-ALA) and certain derivatives thereof, e.g. 5-ALA N-derivatives or 5-ALA esters, preferably derivatives or pharmaceutically acceptable salts thereof disclosed in WO 96/28412, WO 02/10120, WO 2005/092838 or WO 2009/077960, all of which are incorporated by reference.

The term "5-ALA" denotes 5-aminolevulinic acid, i.e. 5-amino-4-oxo-pentanoic acid. The term "precursor of 5-ALA" denotes compounds which are converted metabolically to 5-ALA and thus are essentially equivalent thereto. Thus the term

"precursor of 5-ALA" covers biological precursors for protoporphyrin in the metabolic pathway for haem biosynthesis.

The term "derivative of 5-ALA" denotes chemically modified 5-ALA, i.e. 5-ALA having undergone a chemical derivation such as substitution of a chemical group or addition of a further chemical group to modify or change any of its physico-chemical properties such as solubility or lipophilicity. Chemical derivation is preferably carried out at the carboxy group of 5-ALA, at the amino group of 5-ALA or at the keto group of 5-ALA, more preferably at the carboxy group or the amino group of 5-ALA. Preferred derivatives include esters, amides and ethers of 5-ALA, most preferred 5-ALA esters.

The term "pharmaceutically acceptable salt" denotes a salt that is suitable for being used in the semi-solid pharmaceutical product and which fulfils the requirements related to for instance safety, bioavailability and tolerability (see for instance P. H. Stahl et al. (eds.) Handbook of Pharmaceutical Salts, Publisher Helvetica Chimica Acta, Zurich, 2002)

Preferred derivatives of 5-ALA are esters of 5-ALA which are optionally N- substituted. Those compounds in which the 5-amino group is unsubstituted, i.e. 5-ALA esters, are particularly preferred. Such compounds are generally known and described in the literature see, for example, WO 96/28412 and WO 02/10120 to Photocure ASA, WO 03/041673 and in N. Fotinos et al., Photochemistry and Photobiology 2006, 82, 994-1015, the contents of which are incorporated herein by reference.

Esters resulting from a reaction of 5-ALA with unsubstituted or substituted alkanols, i.e. alkyi esters and substituted alkyi esters, and pharmaceutically acceptable salts thereof, are especially preferred derivatives of 5-ALA for use in the preferred embodiments.

5-ALA esters and pharmaceutically acceptable salts thereof for use in the preferred embodiments may be prepared by any conventional procedure available in the art, e.g. as described in WO 96/28412, WO 02/10120, WO 03/041673 and in N. Fotinos et al., . .

Photochemistry and Photobiology 2006, 82, 994-1015 and the cited literature references therein.

The 5-ALA esters may be in the form of a free amine, e.g. -NH₂, -NHR² or -NR²R² or preferably in the form of a pharmaceutically acceptable salt. Such salts preferably are acid addition salts with pharmaceutically acceptable organic or inorganic acids. Suitable acids include, for example, hydrochloric, nitric, hydrobromic, phosphoric, sulphuric, sulfonic and sulfonic acid derivatives, the salts of ALA-esters and the latter acids are described in WO2005/092838 to Photocure ASA, the entire contents of which are incorporated herein by reference. A preferred acid is hydrochloride acid, HCI. Further preferred acids are sulfonic acid and sulfonic acid derivatives. Procedures for salt formation are conventional in the art and are for instance described in WO2005/092838.

For bladder PDT, one preferred photosensitiser is PVP hypericin and preferred precursors of a photosensitiser are 5-ALA or 5-ALA esters. More preferred is the use of an aqueous solution of PVP hypericin which is instilled into the bladder or as a coating on the expandable structure, e.g. in the form of a dry deposit or film. Further, more preferred is the use of a pharmaceutically acceptable salt of the hexyl ester of 5-ALA (HAL), most preferably in the formulation of Hexvix®, i.e. a solution of the hydrochloride salt of HAL in an aqueous buffer or as a coating on the expandable structure, e.g. in the form of a dry deposit or film.

The concentration of the photosensitisers or precursors of photosensitisers herein described in a pharmaceutical compositions for use in PDT procedures wherein the devices of the preferred embodiments are used depends upon the nature of the

photosensitiser or precursor of photosensitiser, the nature of the composition, the mode of administration, the organ and condition to be treated, and the subject to which it is administered and may be varied or adjusted accordingly. For precursors of

photosensitisers, such as 5-ALA and derivatives of 5-ALA, generally, concentration ranges of 0.01 to 50% by weight, such as 0.05 to 20% by weight, or 1 to 10% by weight, e.g. 1 to 5% by weight, are suitable. For bladder PDT, Hexvix® is suitable, which is instilled into the bladder as a 8 mM solution of the hydrochloride salt of HAL in an aqueous buffer (2 mg/ml; 0.2% by weight) or PVP hypericin is suitable which is instilled into the bladder (total amount of 0.25 mg hypericin bound to 25 mg PVP, reconstituted in 50 ml physiological sodium chloride solution (A. Kubin et al., Photochem Photobiol 2008, 84(6), 1560-1563).

Since precursors of photosensitisers first have to be intracellular^ converted to photosensitisers, e.g. ALA and ALA-esters to protoporphyrins, such as protoporphyrin IX (PplX), it is preferred to have a delay between the administration of such compounds and . -

the start of the irradiation (incubation time or waiting time). The incubation time is generally 5 min to up to 12 hours, such as 10 min to 2 hours or 15 min to 1 hour.

If the device includes a catheter body then the catheter body can be inserted into the body cavity/hollow organ and a lumen therein may be used to instil/administer the photosensitiser or precursor of a photosensitiser to the body cavity/hollow organ. During the incubation time, the catheter may preferably be kept in place, i.e. inside the body cavity/hollow organ. Alternatively, it is withdrawn. After the incubation time, the body cavity/hollow organ is distended by means of the expandable structure and the now smooth internal surface of the body cavity/hollow organ is irradiated with light.

Alternatively, a catheter or a working channel of an endoscope may be used to instil/administer the photosensitiser or precursor of a photosensitiser to the body cavity/hollow organ and the same catheter or endoscope can be used to insert the device into the body cavity/hollow organ. During the incubation time, the catheter or endoscope may preferably be kept in place, i.e. inside the body cavity/hollow organ. Alternatively, it is withdrawn. After the incubation time, the body cavity/hollow organ is distended by means of the expandable structure and the now smooth internal surface of the body cavity/hollow organ is irradiated, either by the means of a light emitter that is an integral part of the device according to the invention or by means of a separate light emitter, as described before. A separate light emitter may be inserted into the body cavity/hollow organ, e.g. either via another lumen in a catheter or another working channel of the endoscope.

Prior to PDT, it may be necessary and/or advantageously to empty the body cavity/hollow organ, e.g. to empty the intestines by help of a bowel cleansing procedure, the bladder by draining urine or the stomach from food by fasting.

During PDT, body fluids such as urine or gastric acid may be drained from the body cavity/hollow organ by means of a drainage lumen which may be an integral part of the device, e.g. an integral part of the catheter body. Alternatively, a drainage lumen may be part of a catheter or endoscope which was used to insert the device into the body cavity/hollow organ. Further, during PDT there may be the need to rinse the body cavity/hollow organ, e.g. from blood or to drain fluids from the cavity/hollow organ, e.g. urine or gastric acid. Rinsing may be done by installing a rinse medium, e.g. saline by means of an instillation lumen which may be an integral part of the device, e.g. an integral part of the catheter body. Alternatively, an instillation lumen may be part of a catheter or endoscope which was used to insert the device into the body cavity/hollow organ. Draining may be done by a draining lumen which may be the same or different from the installation lumen and which may be an integral part of the device, e.g. an integral part of the catheter _ _

body. Alternatively, a draining lumen may be part of a catheter or endoscope which was used to insert the device into the body cavity/hollow organ.

For the PDT procedure, various light-related parameters can be varied: the type of light emitter and light source, the wavelength of the light which is used for irradiation, the light intensity (fluence rate), which is however often a non-changeable instrumental parameter of the light source and the light dose are the most important of such parameters. The irradiation time is a result of the fluence rate (determined by the output power of the light source) and the light dose which needs to be provided to achieve the desired treatment effect.

Several types of light emitters/light sources are known in the art and have been used for PDT. Generally, lamps such as lamps comprising one or more light bulbs, fluorescent tubes or light emitting diodes may be used. Alternatively, lasers or laser diodes may be used. For PDT of the bladder, lamps comprising short arc xenon bulbs which were coupled to an optical fibre, i.e. a quartz fibre, have been used (A. Johansson et al., Proc. of SPIE Vol. 7380, 73801 S1 -S9, 2009 or R. Waidelich et al., Urology 2003, 61 (2), 332-337). Also lasers coupled to an optical fibre have been used: R. Skyrme et al., BJU Int. 2005, 95(5), 1206-1210 used a surgical KTP/YAG laser while Kriegmair et al., Br J Urol 1996, 77(5), 667-671 used an argon ion laser pumped dye laser.

The selected wavelength depends on the type of photosensitiser used for the PDT procedure. In general, the selected wavelength should of course be suitable to excite (i.e. activate) the photosensitiser. Absorption spectra from photosensitisers known in the art are available in the literature, e.g. the absorption spectrum of PplX, the photosensitiser which is the result of cellular conversion of precursors like 5-ALA or derivatives of 5-ALA, like 5- ALA esters, is disclosed in for instance US 6645230, Fig. 9. M. Manyak et al., J. Endourol 17(8), 2003, 633-639 describe the use of red light irradiation at 630 nm to excite porfimer sodium (Photofrin®). N. Yavari et al., Can J Urol 18(4), 201 1 , 5778-5786 provide in Table 1 an overview over the main activation wavelength of various photosensitisers and precursors of photosensitisers. For precursors like 5-ALA or derivatives of 5-ALA, like 5- ALA esters, irradiation with wavelengths of light in the range of 300 - 800 nm, e.g. 400 - 700 nm and 500 - 700 nm has been found particularly effective.

Red light (600 - 670 nm) is known to penetrate well into tissue and the use of red light in the PDT procedure may thus be useful to destroy abnormalities, e.g. neoplastic tissue, in deeper tissue layers. For the destruction of superficial lesions, blue light (400 - 500 nm) which is typically used in photodynamic diagnosis or green light (500 - 560 nm) may be used. . -

Alternatively, different wavelengths may be used to efficiently destroy both superficial and deeper lesions. For instance white light irradiation has been used in bladder PDT with precursors like 5-ALA or derivatives of 5-ALA, like 5-ALA esters (see for instance A. Johansson et al., Proc. of SPIE Vol. 7380, 73801 S1-S9, 2009 or R. Waidelich et al., Urology 2003, 61 (2), 332-337).

The PDT procedure can be carried out either with providing a high light dose or a low light dose. Generally, high light doses are 50 J/cm² and above, e.g. 50 J/cm² to 200 J/cm² or preferably 50 J/cm² to 100 J/cm², while low light doses are below 50/cm², e.g. 10 J/cm² to 40 J/cm² and preferably 25 J/cm² to 35 J/cm².

100 J/cm² was for instance used by A. Johansson et al., Proc. of SPIE Vol. 7380,

73801 S1-S9, 2009 or R. Waidelich et al., Urology 2003, 61 (2), 332-337 in the

photodynamic treatment of lesions in the bladder with 5-ALA hexyl ester and 5-ALA, respectively. Both groups describe that such light doses result in photobleaching (i.e. photomodification and phototransformation) of the photosensitiser and that with a bleaching of 10% of the initial photosensitiser concentration, 90% of the overall inducible therapeutic effect was initiated. An additional advantage of high light doses and thus photobleaching is that a change in the applied light dose (i.e. a light dose which is actually higher than the applied light dose due to backscatter of the light from the bladder wall) has only a minor influence on the therapeutic effect and therefore, precise light dosimetry and highly homogeneous light distribution is not necessary (see R. Waidelich, supra, page

336). A simple method to check for bleaching is offered with photodynamic diagnosis: blue light which is used in the photodynamic detection of lesions in the bladder may be used to irradiate the bladder wall at the end of the PDT procedure: with photobleaching, none or only little of the characteristic red fluorescence of PplX can be detected.

PDT with low light doses has also been described, e.g. by R. Skyrme et al., BJU Int.

2005, 95(5), 1206-1210 who used 10, 15 and 25 J/cm² in PDT of bladder lesions with 5- ALA and by M. Manyak et al., J. Endourol 17(8), 2003, 633-639 who used 20-25 J/cm² in PDT of bladder lesions with porfimer sodium. An advantage of low light doses is that they usually require shorter irradiation times and thus shorter PDT procedures.

PDT may be carried out using a dosimeter which allows the exact determination of light dose provided to the patient. However, especially where high light doses are used which results in photobleaching, the use of a dosimeter is not necessary for the reasons stated above. A dosimeter may be a part of the device according to the invention.

An alternative approach to PDT is to select the light intensity (fluence rate) and to carry out the irradiation for such a time that the desired light dose is provided. In general, for a given light dose the irradiation will generally be applied for a short time with a high . .

light intensity, i.e. a high fluence rate, or for a longer time with a low light intensity, i.e. low fluence rate. The latter is preferred for a PDT procedure where the patient is not anaesthetised or only locally anaesthetised since this is beneficial in terms of reduced discomfort to the patient and may also enhance the efficacy of the treatment. However, if the PDT is carried out under anaesthesia and/or while the patient is immobilized, irradiation applied for a short time with a high light intensity, i.e. a high fluence rate may be preferred. The fluence rate is depending on the means of irradiation, i.e. what kind of light source is used. The fluence rate may be an immanent apparatus parameter which cannot be chosen by the user of the light source. However, if the fluence rate can be chosen, for a low fluence rate procedure, fluence rates below 50 mW/cm² are preferred, more preferred 1-30 mW/cm² and most preferred 2 to 20 mW/cm², e.g. 10 mW/cm² or 15 mW/cm². For a high fluence rate procedure, fluence rates above 50 mW/cm² are preferred, more preferred 50 to 70 mW/cm². With low fluence rate, the PDT procedure could be carried out without anaesthesia, which would allow the patient to sit in a chair or even move around, especially if a device is used with light emitting elements or in combination with light emitting elements, i.e. an internal light source.

In a preferred embodiment of the device according to the invention, wherein the device comprises a light emitter which, when the device is in use, emits light within the body cavity or hollow organ and irradiates the internal surface of said body cavity or hollow organ, the device further comprises a control circuit, such as a microcontroller or microprocessor, for regulating the irradiation provided by the light emitter. The control circuit of the lamp system may be activated by a switch. In a preferred embodiment the control circuit comprises a timer. The light emitter can then be programmed to begin illumination at a pre-determined time interval after activation. This ensures that sufficient time has passed from activation to the start of illumination, for example, in order to allow the absorption or build up of a photosensitiser from a precursor. The length of illumination can also be strictly controlled as the control circuit can be arranged to switch off illumination after a pre-determined light dose has been delivered. If 5-ALAL or a derivative of 5-ALA has been used as a precursor of a photosensitiser, to allow further build-up of protoporphyrins after the first illumination, the device may repeat the illumination (re-PDT) after a certain period of time, e.g. 3 hours.

In addition the control circuit may be arranged to provide pulsed illumination. This can be achieved by providing a function generator within a microprocessor. Pulsed light may be advantageous in ensuring that no unacceptable heating of tissue occurs. In addition, providing intervals in illumination enhances tissue oxygenation and the effect of PDT. Further if 5-ALAL or a derivative of 5-ALA has been used as a precursor of a . .

photosensitiser it allows for the re-accumulation of protoporphyrins in surviving cells that can be treated with repeated illuminations. The frequency and length of the pulses can be chosen according to the requirements of the treatment regime and set within the control circuit.

In one embodiment, the control circuit can be programmed by the user. This enables the length, strength and illumination pattern to be adjusted to suit individual treatments. Suitable re-writable memory forms include EPROM, EEPROM, flash etc.

However, the control circuit memory is preferably read only (ROM) and programmed at the time of manufacture.

Access to the control circuit could be achieved by means of a user interface on the device. Alternatively, the control circuit may comprise a receiver for connection to a remote terminal. In this preferred way, specific program commands can be communicated from the remote terminal, e.g. a computer, to the control circuit which enable the user to set and incubation time/ initial delay period, light dose, number and length of light pulses or to choose from two or more fluence rates, e.g. low and high fluence rates, choose from different wavelengths, etc.

Preferably program commands are transmitted to the device by means of a wireless connection. For example, the receiver may be an infra-red or radio wave receiver. This has the advantage that a physical input port is not necessary and instead the control circuit can be permanently sealed within the device.

Preferably the control circuit further comprises a feedback system. This enables the control circuit to make adjustments in the treatment program to account for deviations in expected light emitter performance.

For example, the feedback system may comprise a light monitor or other direct or indirect monitor to measure the light dose that has been given to the patient. In such systems the control circuit may be programmed to switch off the light emitter after a predetermined light dose has been provided to the patient rather than after a pre-determined time.

Alternatively a dosimeter may override the timer in the event that the light emitter does not operate as expected. For example, if the power supply is faulty the output of the light emitter may be reduced. Therefore it will be necessary to continue illumination beyond the pre-determined time in order to provide the complete light dose. Conversely if the power output of the light emitter is stronger than anticipated the illumination can be stopped ahead of the pre-determined time interval, or the duration of each pulse can be shortened to prevent overheating of tissue. . .

Another optional feature of the control circuit is one or more performance indicator lights for informing a user whether the device has operated correctly or whether a fault has occurred. The control circuit may be arranged to provide a signal to the user when treatment is complete to indicate that the device can be removed. For example an acoustic and/or visual signal may be provided, such as an alarm sound and/or a light signal.

Preferably some or all of the above mentioned features of the control circuit are contained in a microprocessor.

Advantageously, the device is designed for a single-use and for disposal after that single use. The device may include one or more features that promote single-use and/or prevent repeat use. For example, if the power source is a battery, said power source may be arranged to provide power that is only sufficient for a single-use, i.e. such that the power source is depleted after the required treatment is complete. The power source may be arranged so as not to be re-charged, and/or the control circuit may lack access to recharge the power source. The control circuit may be arranged to prevent re-use by means of features of its programming and/or it may include a deactivation mechanism that destroys circuitry or software when triggered.

Generally, during PDT the patient may be kept in local or general anaesthesia. The abnormalities, disorders and diseases which may be treated with

photodynamic treatment using devices according to the preferred embodiments include any malignant, pre-malignant and benign abnormalities or disorders on the internal surface of a body cavity or hollow organ which are responsive to photodynamic treatment.

As used herein the term "treatment" or "therapy" encompasses curative as well as prophylactic treatment or therapy.

In general, cells which are metabolically active are responsive to photodynamic treatment with a photosensitiser or precursor of a photosensitiser. Examples of

metabolically active cells are cells that undergo an abnormal growth pattern such as increased number of cells/increased cell proliferation (hyperplasia), wherein the cells of a hyperplastic growth remain subject to normal regulatory control mechanisms; abnormal maturation and differentiation of cells (dysplasia); and abnormal proliferation of cells (neoplasia), wherein genetically abnormal cells proliferate in a non-physiological manner which is unresponsive to normal stimuli. Other examples of metabolically active cells are inflamed cells.

The devices according to the invention are preferably used in photodynamic treatment of neoplasms and tumours (benign, pre-malignant and malignant) on internal surfaces of body cavities and hollow organs. Examples of such neoplasms and tumours - - on internal surfaces of body cavities and hollow organs are neoplasms in the bladder, the colon, the stomach and the gallbladder.

Further, the devices according to the invention are preferably used in photodynamic treatment of abnormalities, disorders or diseases associated with viral, bacterial and fungal infections of internal surfaces of body cavities and hollow organs such as vaginal or cervical intraepithelial neoplasia (associated with the human papilloma virus), stomach cancer (associated with the bacterium Helicobacter pylori) and pseudomembranous colitis (associated with the bacterium Clostridium difficile).

In addition, the devices according to the invention are preferably used in

photodynamic treatment of abnormalities, disorders or diseases associated with inflamed cells. Inflammation is usually a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process and thus often associated with an infection.

Examples are inflammatory colitis (e.g. inflammatory bowel disease, ulcerative colitis and Crohn's disease)

The internal surfaces which may be treated by photodynamic treatment wherein the devices according to the invention are used are the internal surfaces of body cavities and hollow organs that comprise rugae, preferably the bladder, the gallbladder, the intestines, the stomach, and the vagina.

Claims

CLAIMS:

1. A device for use in the photodynamic treatment of a body cavity or hollow organ of the body, the device comprising: an expandable structure for insertion within the body, wherein the expandable structure is arranged to be placed within the body cavity or hollow organ such that expansion of the structure will result in mechanical distention of the body cavity or hollow organ, and wherein the expandable structure is arranged such that light emitted within the body cavity or hollow organ when it has been distended by expansion of the expandable structure will irradiate an internal surface of said body cavity or hollow organ.

2. A device as claimed in claim 1 , wherein the body cavity or hollow organ is the vagina, the stomach, the intestines, the bladder or the gallbladder and the expandable structure is arranged to be able to expand the body cavity of hollow organ to such extent that its internal surface is smooth and without folds.

3. A device as claimed in claim 1 or 2, wherein the body cavity or hollow organ is the bladder and the expandable structure takes a generally spherical shape in its expanded configuration

4. A device as claimed in claim 1 , 2 or 3, wherein the expandable structure is located at a terminal distal end of the device and there is no part of the device extending in the distal direction beyond the expandable structure.

5. A device as claimed in any preceding claim, wherein the expandable structure has a mechanism comprising flexible, rotatable and/or translatable wires that move from an unexpanded to an expanded configuration.

6. A device as claimed in claim 5, wherein the mechanism comprises multiple flexible wires located at different points around a longitudinal axis of the device, and wherein the mechanism expands by the wires flexing outwardly away from the axis into curves for pushing against the walls of the body cavity or hollow organ.

7. A device as claimed in claim 6, wherein the curved wires form an expanded shape that approximates to a surface of revolution of which each wire is a generatrix.

8. A device as claimed in claim 6 or 8, wherein the flexible wires each have distal and proximal ends coupled to respective distal and proximal couplings, at least one of the couplings being arranged to move toward the other to thereby outwardly flex the wires by applying a buckling force to the wires.

9. A device as claimed in claim 8 wherein the couplings comprise rings or plates with the wires attached by pivoting or pin joints around a circumference of the couplings.

10. A device as claimed in claim 8 or 9, comprising actuator elements attached to the couplings to move the couplings toward one another and thereby actuate the mechanism of the expandable structure.

1 1 . A device as claimed in claim 10, wherein the actuator elements comprise rods and/or strings passing along the device from the couplings at the distal end to the proximal end in order to allow the user to operate the mechanism by manipulation of the rods and/or strings.

12. A device as claimed in any of claims 5 to 1 1 , wherein the wires and/or couplings are made of a polymer material that does not interfere with the light used for irradiation in PDT, preferably of a transparent polymer material, more preferably of a transparent polymer material that has light scattering and/or light diffusing properties.

13. A device as claimed in any preceding claim, wherein the expandable structure can be locked in its expanded configuration and/or its unexpanded configuration, preferably by a locking element.

14. A device as claimed in any preceding claim, wherein expandable structure moves elastically between its unexpanded and expanded configurations such that when no force is applied it reverts to one of the unexpanded or the expanded configuration.

15. A device as claimed in claim 14, wherein the expandable structure reverts elastically to its unexpanded configuration.

16. A device as claimed in any preceding claim comprising a light emitter which, when the device is in use, emits light within the body cavity or hollow organ and irradiates the internal surface of said body cavity or hollow organ.

17. A device as claimed in claim 18, wherein the light emitter is located within the expandable structure, preferably centrally within the expandable structure.

18. A device as claimed in claim 16 or 17, wherein the light emitter is part of a light guide, preferably an optical fibre, that directs light from an external light source to the light emitter.

19. A device as claimed in claim 18, wherein the light emitter is at a distal end of the light guide, preferably of the optical fibre.

20. A device as claimed in claim 18, wherein the light emitter is located along at least a part of the length of the light guide, preferably of the optical fibre.

21 . A device as claimed in claim 16 or 17, wherein the light emitter is a light emitting strand which includes a single light emitting element or preferably a plurality of light emitting elements.

22. A device as claimed in claim 21 wherein the light emitting element(s) are located at the distal end of the strand or along the length of the part of the strand which, when the device is in use, is inside the body cavity or hollow organ.

23. A device as claimed in claim 22, wherein the light emitting elements are LEDs, OLEDs or LECs.

24. A device as claimed in any preceding claim, comprising a hollow elongate, preferably flexible, catheter body having a proximal and a distal end and comprising a lumen for insertion of the expandable structure into said body cavity or hollow organ.

25. A device as claimed in claim 29, wherein the catheter body comprises one or more further lumens fluidly connected to the body cavity or hollow organ.

26. A kit comprising a device as claimed in any of claims 1 to 25 and a composition comprising a photosensitiser or precursor of a photosensitiser for photodynamic treatment of the internal surface of a body cavity or hollow organ.

27. A method comprising use of the device or kit of any preceding claim in the photodynamic treatment of the internal surface of a body cavity or hollow organ.

28. A method of photodynamic treatment of the internal surface of a body cavity or hollow organ, the method comprising: administering a composition comprising a photosensitiser or precursor of a photosensitiser to a patient in need of said treatment, inserting the device or at least the expandable structure of the device according to claims 1 to 25 into the body cavity or hollow organ of interest, mechanically distending the body cavity or hollow organ by expansion of the expandable structure of said device and irradiating an internal surface of the body cavity or hollow organ with light.