AU696682B2 - Apparatus for an efficient photodynamic treatment - Google Patents

Description

P/00/011 Regulation 3.2

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT Invention Title: APPARATUS FOR AN EFFICIENT PHOTODYNAMIC TREATMENT a The following statement is a full description of this invention, including the best method of performing it known to us: GH&CO REF: P24009-A:PJT:RK un -1A- The present invention relates to an apparatus for invivo treatment of tumors. More particularly, the invention relates to an improved apparatus for an efficient photodynamic therapy as an in-vivo treatment of tumors.

BACKGROUND OF THE INVENTION As known Photodynamic Therapy (hereinafter referred to as PDT), is recognised as an usefu'l treatment for certain solid tumors, including skin cancer and internal organs such as colon, vagina, bladder and others. The PDT treatment is based on a systemic or topical administration of a tumor-localizing photosensitizer reagent, such as porphirin, aminolevulinic acid (ALA), phtalocyanin, chlorine etc., which after illumination and excitation with visible light in the presence of oxygen, give rise to highly reactive and cytotoxic singlet molecular oxygen which leads to tumor regression (see Figure 1).

In our previous U.S. Patent No. 5,344,434, an apparatus for a PDT treatment was described. The apparatus comprises the following components: 20 a Xe-lamp possessing a narrow beam light with half angle divergence of up to 100, possessing an intensity of at least 2mW/nm with a special region in the range of 610 to 750 nm; e_ *e a glass lense to focus the beam of the light; a red filter to provide a spectral region of above 610 nm; a 450 dichroic mirror to remove produced heat, and a light guide in the range of 3 to 12 mm diameter, which provides a minimum irradiance of 50 mW/cm 2 The apparatus described in the above patent was found to be useful with a wide variety of photosensitizers contrary to what is claimed in some prior patent applications such as German 411 2275 41 and PCT 94/09850, that a narrow band filtering, does enable excitation of specific photosensitizers only. In additon to that, the broad band excitation mentioned in the invention described in our above prior U.S. patent, enables utilization 15 of PDT photo-products, having an absorption maxima eo extended by 30 to 50 nm from the absorption maxima of the photosensitizer.

The Xe short arc and metal halide short arc lamps are most preferred beiig able to produce the arc image of 20 the highest radiance. However, these lamps are very inefficient generators of spectral energy. Thus, with a Xe lamp of 300 W input electrical energy only about 50 W are transformed into light, i.e. from ultra-violet to near infra-red, while other 250 W are transformed into

I

heat. The available spectral intensity in the spectral interval of 100 nm bandwidth is only 5 W. Therefore, in order to produce a spectrally filtered intensity, 45 W of undesired light must be filtered out. In this manner, the overall balance shows that only 2% of the electrical input are transformed into the desired spectral output, while the balance of 295 W of heat and unwanted light are most undesirable.

It is also known that PDT involves damage to the tumor vascular bed, which in turn causes disruption of tumor blood flow and ultimately to a tissue necrosis. The vascular damage produced by the PDT treatment in the tumor, reduces its efficiency in cooling the tumor.

Hyperthermia or heating of the tumor to the moderate temperature of up to 460 has been proven to be of clinically value. It has been published (S.Kimmel et.al, Lasers Surgery medicine, 12: 432-440, 1992) that a combination of PDT with Hyperthermic therapy (hereafter referred to HPT) will result a 40% decrease of the irradiation dose required to produce vascular damage.

Various mechanisms for the synergism of PDT and HPT, were suggested which can be concluded as follows: The PDT treatment increases the heat sensitivity of -4the tumor cells, due to a decrease of the pH.

The HPT enhances the photosensitization due to an increased blood flow.

The damage repair inactivation by each of the modalities enhances another effect.

Among other disadvantages of the heat and unwanted light, it should be mentioned the failure which might occur to the lamp, to the optical and electronics elements as well as the hazards to the operating personnel of the apparatus.

There are some prior patents which deal with the problem of cooling means, such as Xenon lamps, in order to decrease the disadvantages involved by their use. Thus, according to the U.S. Patent No. 4,298,005, it is suggested to use a ventilator for cooling the housing of the apparatus.

In the U.S. Patent No. 5,036,242, it is suggested a liquid-cooled lamp, having a passage for the flow of the liquid coolant and a passage for heated fluid outlet; the liquid-air heat exchanger is positioned in the flow circuit conduit by heat exchange with air.

In a very recent U.S. Patent No. 5,285,363, it is suggested a method and device for removing heat generated from a Xenon-lamp, by using a heat transfer unit which 5 is located adjacent to a mirror positioned in the path of the beam to transmit infrared light.

The above brief review of the prior art, clearly indicates the long felt need for an improved apparatus to deal with the subject of the present invention.

In one aspect the present invention relates to an improved apparatus for an efficient treatment of tumors which substantially overcomes the disadvantages of the known apparatus. In another aspect the present invention 10 relates to an improved apparatus for an efficient treatment of tumors wherein the unwanted light is removed while the generated heat is dissipated.

BRIEF DESCRIPTION OF THE INVENTION 15 The invention relates to an efficient apparatus for a therapeutic treatment of malignant solid tumors, consisting of a combined photodynamic therapy and hyperthermic therapy which comprises: a lamp possessing a narrow beam light; a "hot" mirror; an optical glass lenses system; a dichroic filter having at least transmittance above 600 nanometers.

S:\24009a -6a glass fiber optics bundle, and an effective air-cooling system to provide an internal temperature in the apparatus of not above 46oC.

BRIEF DESCRIPTION OF THE FIGURES.

Figure 1, illustrates a typical absorption spectra of photosensitizers.

Figure 2, illustrates a typical absorption spectra of tissue constituents.

Figure 3, is a schematic illustration of the improved apparatus according to the present invention which combines the PDT and HPT treatments of solid tumor.

Figure 4, illustrates the spectral distribution of a preferred embodiment.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

I

e 2 e* *oe 2 e e ft Hyperthermia has been proved to be selectively lethal to various malignant cells in the range of 41 0 C to 46 0

C,

thus being considered to be of a clinical value.

According to the preferred embodiment of the present invention, it was found that the combination of PDT and HPT when applied simultaneously, is much more effective and provides better results than the two separate individual treatments. The benefit from this combination, besides the decrease of about 40% of the irradiation dose required to produce vascular damage is also a better penetration.

The photochemical reaction enhancement at elevated temperatures which results from the PDT, does produce a strong cytotoxic effect and reduces the required treatment dosage. On the other hand, the thermal penetration depth in the tissue which is generally in the range of 3 to 7 nm, is higher than the optical penetration of between 1 to 3 mm at 630 nm. Therefore, shallow tumors i i might be treated by PDT alone, but an efficient treatment could not be achieved in case of deeper tumors.

It was found that the apparatus according to the present invention, produces a moderate heating of the tumor to a temperature in the range of between 41 to 46oC and most preferably to about 450C. This effect called hyperthermia, imparts a synergistic effect when combined with the PDT treatment. As a result, the overall efficiency in treating deep tumors is greatly enhanced.

According to a most preferred embodiment, the treatment will consist from the administration of between 100 to 150 mw/cm 2 of red radiation in the range of between 600 to 750 nm band and simultaneously a heating of the tumor to a temperature of up to 460C. The total time of treatment will be about 20 minutes, including only about

I

)il~P minutes of pure PDT, reaching the above maximum temperature and a simultaneous HPT treatment for about minutes.

The hyperthermal treatment may be obtained by a direct heating of the tumor. However, for a better control of the maximum temperature produced, an optical irradiation is preferred. For example, by a simultaneous irradiation at 1.2 to 1.7 um, the required heating of a tumor could be produced with a irradiance of only 30 to 70 mw/sq.cm.

for a period of about 20 minutes. A preferred apparatus S. according to the present invention is characterized by a simultaneous illumination in the range of between 600 to 750 nm in the "red" and between 1200 to 1700 nm in the Snear infra-red. The ratio between the power emitted in the "red" to the power emitted in the near Infra-red is preferably between 2:1 and 5:1 and most preferably between 3:1. A preferred mode for applying the heating is by a C02 laser or NdYaG laser. The resulting spectrum of the preferred embodiment is shown in Figure 4.

DETAILED DESCRIPTIOQNOF THE FIGURES.

Figure 1, illustrates typical absorption spectra of monomeric porphyrin, chlorins and phthalocyanines.

9) o o r Figure 2, illustrates typical absorption spectra of melanin, hemoglobin, oxyhemoglobin and water which involves the mechanisms for the synergistic effect which may include several contributions.

Figure 3, describes the apparatus according to the present invention which comprises the following main components: A lamp possessing a narrow beam light with half angle divergence of up to 100, having an intensity of at least 20mW/nm at a spectral region in the range of 600 to 750 nm and intensity of at least 2 mW/nm in the spectral region of 1200 to 1700 nm.

A "hot"mirror", comprising a hard all-dielectric filter coating deposited on a TEMPAX glass, having a transmittance of at least 60% in the range of 600 to 750 nm and at least 5% in the range of 1200 to 1700 nm range, while reflecting the radiation between the 750 to 1200 nm range.

According to a preferred embodiment, the angle of the mirror relative to the axis may be varied in order to change the ratio of the transmittance in those two bands.

The ratio between the transmittance at the 600 to 750 nm and 1200 to 1700 nm may be changed by rotating the mirror from its axis, between 00 and 450 relative to the optical axis.

An optical glass lenses system to focus the beam of the light, preferably with a broad band Anti- Reflection coating for the visible spectrum.

comprising a hard all-dielectric coating.

A dichroic filter comprising a hard all-dielectric coating having at least 60% transmittance above 600nm.

A glass fiber optics bundle, having an input diameter in the range of 1 to 12 mm, preferably 6 mm and length of 0.5 m to 2.5 m and most preferably 1.5 m, as a separate unit or as a part of endoscope.

An effective air-cooling system for the removal of the unwanted light and dissipation of the 20 generated heat, so that the internal temperature in the apparatus will not exceed 500C. According S. to a preferred embodiment, this cooling is obtained by two or more fans, which provides an 11 internal temperature in the apparatus of not above 465C. The most preferred embodiment includes 4 fans to dissipate hot air and an inlet system for ambient air.

A power supply; A timer to control the length of exposure.

An electronic control card.

Figure 4, illustrates the "red" dual band spectral distribution, correlating the normalized o spectrum as a function of wavelength (in nanometers).

From Figure 2, the following conclusions can be drawn: The absorption of oxyhemoglobin in the 600-750nm range does result in a temperature increase which causes an increase in molecular oxygen concentration due to dissociation. This effects counter the effect of oxygen depletion during the PDT.

The absorption of hemoglobin in the blood vessels is in the range of 600 to 750 nm,which produces an increase in the temperature and an enhanced PDT reaction rate.

The clinical results in three different hospitals using the apparatus according to the present invention for skin cancer treatments of 150 patients, show a success of 85% even after one single treatment.

-12- The apparatus according to the present invention, can be also incorporated in other systems, thus providing additional useful functions as known in the art. Thus for instance, by adding a violet filter in the range of 400-450 nm, using the means of the filter wheel, it could be used for excitation of photosensitizers in the photodynamic diagnostics. On the other hand, the incorporation of a green filter in the spectral range of 505-590 nm using the means of the filter wheel, may be used for the superficial PDT treatment or for various dermatologic applications such as removal of tatoos and portwine stains.

The addition of distal hand-piece to the fiber optics bundle for dermatologic application, will enable a substantially uniform illumination of up to 3 cm diameter tumors.

.Fluorescence spectrometer enabling real-time fluorescence measurements excited by violet filter, can be used for cancer diagnostics known in the art as "optical "o 20 biopsy".

Other functions which could incorporate the apparatus according to the present invention are: Endoscopes for different applications, such as colon, bronchi, gastro, etc.

-13- RGB (red-green-blue) and CCD (charge-coupled-device) cameras to provide multi-spectral vieweing through the above endoscopes.

The addition of white filter in the spectral range of between 400 to 700 nm using the means of the filter wheel may be used for the endoscopic observation.

The apparatus was found also to be used with a broad types of photosensitizers as known in the art and also when narrow band filters enable excitation of only specific photosensitizers. Furthermore, the broad band 15 excitation used in the present invention, enables the utilization of PDT photoproducts, having the absorption maxima removed by 30 to 550 nm from the absorption maxima of the photosensitizer used.

While the invention has been described and illustrated in respect to some particular features, it should be understood that the description does not limiting it, a person skilled in the art after reading the present specification, will be in a position to insert slight modifications, without being outside the invention as covered by the appended Claims. Thus for example, modifications to the electronic components: g, h and i, (see Figure 3) will enable pulsed high power operations -14of the above device in the dermatological applications such as portwine stains and tattos removal.

0 tt Je me M B

IN

Claims (21)

1. An apparatus for an efficient simultaneous photodynamic and hyperthermic treatment comprising: a lamp operative to emit a narrow beam light along an optical axis, said light having an intensity of at least about 20 mw/nm throughout a red spectral region of 600 to 750 nm and at least about 2 mw/nm throughout a near infrared spectral region of 1200 to 1700 nm; a "hot" mirror having a transmittance of at least about 60% in said red spectral region and at least about in said near infrared spectral region while reflecting the radiation in the range of 750-1200 nm; and a dichroic filter having at least 15 transmittance above about 600 nm while having a negligible transmittance below about 600 nm; said mirror and said filter being disposed along said optical axis to filter said light so as to produce an output beam including only wavelengths passed by said 20 mirror and said filter.

2. The apparatus of claim 1, wherein said beam has a half angle divergence of up to about 25

3. The apparatus of claim 1, wherein said mirror includes a hard all-dielectric filter coating deposited on a TEMPAX glass.

4. The apparatus of claim 1, wherein said filter is made of a hard, all-dielectric coating deposited on glass.

The apparatus of claim 1, further comprising: a glass lens system between said mirror and said filter.

6. The apparatus of claim 5, wherein said lens S system includes an anti-reflection coating. 16

7. The apparatus of claim 1, further comprising: a glass fiber optics having a diameter between about 1 and about 12 mm, for directing said output beam at a target.

8. The apparatus of claim 1, further comprising: an air cooling system, to dissipate heat produced by said lamp, which provides an internal temperature in the apparatus of at most about 500C.

9. The apparatus of claim 8, wherein said air cooling system includes at least two fans and wherein said internal temperature is at most about

10. The apparatus of claim 1, wherein said mirror is tiltable relative to said axis to change the ratio of transmittance in said red spectral region to transmittance in said near infrared spectral region. 20

11. The apparatus of claim i, wherein the ratio between power emitted in said output beam in said red spectral region to power emitted in said output beam in said near infra-red spectral region is between about 2:1 and about 5:1.

12. A method of treating a patient simultaneously with photodynamic therapy and hyperthermic therapy, comprising the steps of: generating broad band light; bandpass filtering said broad band light to produce visible light at wavelengths below about 750 nm and near infrared light at wavelengths between about 1200 nm and about 1700 nm while blocking wavelengths between about 750 nm and about 1200 nm; and directing said visible light and said near infrared light at the patient.

13. The method of claim 12, wherein said generating 17 of said broad band light is effected using a lamp which emits a beam of said broad band light having an intensity of at least about 20 mw/nm at wavelengths between 600 nm and 750 nm and at least about 2 mw/nm at wavelengths between 1200 nm and 1700 nm.

14. The method of claim 12, wherein said bandpass filtering is effected using a "hot" mirror having a transmittance of said visible light of at least about and a transmittance of said near infrared light of at least about 5% while reflecting said broad band light in said range of 750-1200 nm.

The method of claim 12, further comprising the 15 step of: low pass filtering of said visible light.

16. The method of claim 16, wherein said low pass filtering is effected using a dichroic filter having at least 60% transmittance at wavelengths above about 600 nm while having a negligible transmittance at wavelengths below about 600 nm.

17. The method of claim 12, wherein said visible 25 radiation has an intensity of between about 100 mw/cm 2 and about mw/cm 2

18. The method of claim 12, wherein said directing of said light at the patient is effected for about 15 minutes.

19. The method of claim 12, wherein said directing of said light at the patient is effected in a manner that heats a portion of the patient whereon said light is incident to at most about 46 0 c.

The method of claim 12, wherein said visible Rlight and said near infrared light are directed at the patient at certain power levels, said power level of said 18 visible light being between about twice said power level of said near infrared light and about five times said power level of said near infrared light.

21. An apparatus for an efficient simultaneous photodynamic and hyperthermic treatment, the apparatus being substantially as described herein with reference to Example 3. Dated this 8th day of July 1998 ENERGY SYSTEMS CORPORATION LTD By their Patent Attorneys GRIFFITH HACK e e ABSTRACT OF I f*L INVLN'g ION. Hip present i nvention relates to an i mpro5vod apparatus for a therapeutic t reaLmen t of m~al i'jinan t solIi d t umors,, cunsisting of a com~bined phcwudynaimic therapy arid hyper'- thermic treatmnorit, said apparatvs comprisingJ A lamp poasessing a narrow beam lighlt, a mirror, an optical ~j1a I le s sys tem, a d i roi c f-1-1 tr a 9ol,.ss; tibor opt ics bundle aridl an foutive a! -cool irv~s~;~n.ri ppciratus provide~s the admitisi rat icn betweeni 100 to 150 rnw/cm 2 of red radiation in the ranqa of b,_i a'eon b&G0~ LU 7!)0 nm barnd at a -tempera tur e c~f uip to 4u0;C. Cl inic,al results from threu different hospitals show thAt by thiS appara~tus a succest., of more than 65% wieroa a ~e ven ~~~attur ona~ -,inglie trL~trt1nt.