Device for photodynamical therapy of cancer

Abstract

A method and device for photodynamic therapy for treating cancer. The method includes: providing a photodynamic therapeutic device for treating cancer. The provided device includes a plurality of light emitting diodes that are positionable in proximity of a patient's body and are adapted to provide a light fluence to a lesion area. The method also includes administering an effective dose of a photosensitizer in the lesion area; positioning the device in proximity to the patient's body; and irradiating the patient's body.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application 0.01 1 J/cm² and 100 J/cm².

The interdependence between power density and treatment duration brings with it limitations in the treatment procedure: Cancer cells exposed to irradiation at a power density lower than 1 mW/cm² are responsive. At a power density greater than 10,000 mW/cm², tissues are likely to undergo burning due to thermal effects. In other words, the aforesaid values of total energy density incident on the cancer tissue should be within the range of the energy density limited by the sensibility threshold on the low density side and tissue burning on the high density side.

Results of preclinical trials are presented in Tables 1 and 2. Table 1 depicts a set of experiments on mice. The presented data characterize power densities and energy densities which are incident on the cancer tissue. Treatment durations are also reported. Table 2 provides medical results of the experiment. In the column of number of mice with response to treatment, the first number corresponds to mice with a more than 50% reduction of tumour size following the treatment*. The second number is a total number of samples exposed to a specific light dose.

TABLE 1
	Joules	Time of	Light Intensity at
	delivered	treatment	tumor surface
Light dose	Joules/cm2	Seconds	mW/cm2
High dose light A	35	300	114
Low dose light B	7	60	114
Low dose light C	5	600	8.3
Low dose light D	0.01	1200	0.83

TABLE 2
	Tissue		Number of mice
	thickness**	Number of	with response to
Light dose	(cm)	treatments	treatment*
High dose light A	0	1	4/5
Low dose light B	0	3	8/10
Low dose light C	2	3	4/9
Low dose light D	4	3	2/10
Control-No light	0	0	0/10
**Tissue thickness refers to a thickness of pork tissue through which the cancer tumour
in the mouse was irradiated. The dimension of the tumour was larger than 1 cm.

Reference is now made to FIG. 7, presenting a remnant fibrous tissue following remission of a breast cancer tumour by photodynamic therapy using the light system of the present invention. There are no tumour cells visible. This figure is representative of the pathology to date in animals that have displayed remission in this experiment.

Reference is now made to FIG. 8, presenting experimental data concerning intensity profile depending on a penetration depth. It is shown that the penetration depth increases with extension of luminance body. As it appears from FIG. 8, 1 cm² luminance body provides power density 0.2 mW/cm² at penetration depth of about 4 cm, while the same power density is obtained at the penetration depth of about 8 cm with a 100 cm² luminance body.

Reference is now made to FIG. 9, presenting graphs of irradiance and fluence rate depending on luminous area. The irradiance and fluence rate curves were measured at fixed penetration depth. Pursuant to graph comparison, a most effective LED arrangement has the luminous surface greater than about 10 cm².

In Table 3, the first row corresponds to the luminous area with LEDs that were used in chicken breast experiment while the rest of the rows provide model treatment protocol applicable to human.

TABLE 3
1.875 LEDs/cm2		Mouse Study LEDs
3.75 W/cm2	LED power	Kilojoules delivered in
cm (X)	cm (Y)	cm2	Kilowatts	eff. @ 10%	60 s	3600 s (1 hr)		Applications
10	16	160	0.60	0.060	0.004	0.2	Panel
35	10	350	1.31	0.131	0.008	0.5	14″ × 4″	Arm
50	10	500	1.88	0.188	0.011	0.7	20″ × 4″	Thigh
90	10	900	3.38	0.338	0.020	1.2	36″ × 4″	Waist
90	15	1350	5.06	0.506	0.030	1.8	36″ × 6″	Waist
110	15	1650	6.19	0.619	0.037	2.2	43″ × 6″	Waist/Chest
130	15	1950	7.31	0.731	0.044	2.6	51″ × 6″	Waist/Chest

Similar to the previous table 3, in table 4, the first row corresponds to a luminous area with more powerful LEDs then that were used in chicken breast experiment. It should be emphasized that, geometric configuration of the device for photodynamic therapy is adapted for a specific tumour location in the patient's body.

TABLE 4
		Today's
		LEDs capability
1.875 LEDs/cm2		Kilojoules
3.75 W/cm2	LED power	delivered in
cm (X)	cm (Y)	cm2	Kilowatts	eff. @ 25%	60 s	3600 s (1 hr)		Applications
10	16	160	0.60	0.150	0.009	0.5	Panel
35	10	350	1.31	0.328	0.020	1.2	14″ × 4″	Arm
50	10	500	1.88	0.469	0.028	1.7	20″ × 4″	Thigh
90	10	900	3.38	0.844	0.051	3.0	36″ × 4″	Waist
90	15	1350	5.06	1.266	0.076	4.6	36″ × 6″	Waist
110	15	1650	6.19	1.547	0.093	5.6	43″ × 6″	Waist/Chest
130	15	1950	7.31	1.828	0.110	6.6	51″ × 6″	Waist/Chest

In Tables 5 and 6, estimated data concerning exposure doses provided to plurality of tumour locations by LED matrices of different LED packing density (1.875 LED/cm² and 10 LED/cm², respectively), The modern LED means provide an option of short pulse mode of the photodynamic therapy.

TABLE 5
1.875 LEDs/cm2		Future LEDs potential
3.75 W/cm2	LED power	Kilojoules delivered in
cm (X)	cm (Y)	cm2	Kilowatts	eff. @ 50%	60 s	3600 s (1 hr)		Applications
10	16	160	0.60	0.300	0.018	1.1	Panel
35	10	350	1.31	0.656	0.039	2.4	14″ × 4″	Arm
50	10	500	1.88	0.938	0.056	3.4	20″ × 4″	Thigh
90	10	900	3.38	1.688	0.101	6.1	36″ × 4″	Waist
90	15	1350	5.06	2.531	0.152	9.1	36″ × 6″	Waist
110	15	1650	6.19	3.094	0.186	11.1	43″ × 6″	Waist/Chest
130	15	1950	7.31	3.656	0.219	13.2	51″ × 6″	Waist/Chest

TABLE 6
10 LEDs/cm2		Future LEDs potential
20 W/cm2	LED power	Kilojoules delivered in
cm (X)	cm (Y)	cm2	Kilowatts	eff. @ 50%	60 s	3600 s (1 hr)		Applications
10	16	160	3.20	1.600	0.096	5.8	Panel
35	10	350	7.00	3.500	0.210	12.6	14″ × 4″	Arm
50	10	500	10.00	5.000	0.300	18.0	20″ × 4″	Thigh
90	10	900	18.00	9.000	0.540	32.4	36″ × 4″	Waist
90	15	1350	27.00	13.500	0.810	48.6	36″ × 6″	Waist
110	15	1650	33.00	16.500	0.990	59.4	43″ × 6″	Waist/Chest
130	15	1950	39.00	19.500	1.170	70.2	51″ × 6″	Waist/Chest

Reference is now made to FIGS. 10 (a and b), 11 (a and b) and 12 (a and b), presenting schematically operative principle of the present invention and. FIG. 10 shows a matrix of N×N LEDs 30, while FIGS. 11 and 12 correspond to LED matrices of M×M and K×K, respectively, thereat N<M<K.

It should be appreciated that there is a limitation of density of light intensity administered to the patient's body. The intensive narrow laser beam causes a burn. Consequently, a penetration depth of light used for photodynamic treatment is also limited according to Beer's law.

According to the present invention, an illuminated area of the patient's body 310 is two-dimensional. A growing number of side LEDs on a perimeter of the LED matrix also contribute into the resultant intensity in the target volume of a tumour 320. Light rays 330 originated from side LEDS reach the tumour 320. As seen in FIGS. 10b, 11b and 12b, the penetration depth grows with the matrix dimension. The described presentation is experimentally proved (see FIGS. 8 and 9). Specifically, in the model experiments on chicken breast, increase in the penetration depth from 4 cm up to 8 cm has been achieved.

An intermittent operation mode of the device is in the scope of the current invention. Intermitting active and inactive phases of illumination increases the performance of the drug because allows for cooling the skin during inactive phases to reduce heating effect of continuous light.

Some embodiments of the invention utilise a coolant loop that is in series with each segment of LEDs. The series configuration reduces water flow with increased resistance and the last segments will be the hottest depending on flow rate. The aforementioned is taken into consideration during the planning of the treatment schedule.

A parallel coolant loop is also contemplated in some embodiments of the invention where greater flow rates and possibly more consistently lower temperatures are required. The parallel configuration is defined by an arrangement of the invention whereby fluid enters all segments at the same time and leaves from all segments into a larger return tube.

In some embodiments of the invention ultimate control on the light output of the LEDs on each segment is provided: the output power to the unit may be altered in 0.1% steps from 0-100%

It is another objective of the invention to disclose treatment protocols for slowly raising the power level over the treatment area.

This might be important since as one penetrates a deep area, the closest flesh to the LED segment might receive a too powerful dosage and reduce drug effectiveness. On the other hand, a continuous low output may not achieve the depth of treatment. An optimal treatment protocol may be to gradually increase the light output over treatment time, allowing each measure of depth to receive the right amount of light until that depth is treated. Light is increased for deeper penetration in staged light increases.

In accordance with the current invention, a method of photodynamic therapy for treating cancer is disclosed. The aforesaid method comprises the steps of (a) providing a photodynamic therapeutic device for treating cancer; said device comprises a plurality of light emitting diodes positionable in proximity of a patient's body adapted to provide a light fluence to a lesion area and cooling means; (b) administering an effective dose of a photosensitizer in a lesion area of said patient's body; (c) positioning the device in proximity of said device to said patient's body; (d) irradiating said patient's body.

It is a core feature of the invention to provide the step of irradiating said lesion area which is characterized by power density ranging between 1 mW/cm² and 10,000 mW/cm² and treatment duration ranging between 100 sec and 3600 sec such that density of total energy incident to said lesion area is in a range between 0.01 1 J/cm² and 100 J/cm², thereat said step of irradiating said patient's body is performed by said photodynamic therapeutic device having a luminous surface of an area which is greater than 10 cm².

In accordance with a further embodiment of the current invention, the device positioned in proximity of said patient's body in a location is selected from the group consisting of a breast, an arm, a leg, a neck, an abdomen and any combination thereof.

In accordance with a further embodiment of the current invention, a mode of device operation is selected from the group consisting of a continuous mode, a pulse mode, an intermittent mode and any combination thereof.

In accordance with a further embodiment of the current invention, the step of positioning the device in proximity of said patient's body further comprises a step of preliminary positioning a silicon spacer therebetween.

In accordance with a further embodiment of the current invention, the step of irradiating at maximum light intensity at at least one wavelength is selected from the group consisting of: a wavelength of about 630 nm performed in coordination with said preceding step of administering an effective dose of a photosensitizer 5-aminolaevulinic acid (5-ALA); a wavelength of about 585 to about 740 nm performed in coordination with said preceding step of administering an effective dose of a photosensitizer 5,10,15,20-tetrakis(m-hydroxyphenyl) chlorin (Foscan); a wavelength of about 570 to about 670 nm is performed in coordination with said preceding step of administering an effective dose of a photosensitizer methyl aminolevulinate (Metvix); a wavelength of about 615 to about 800 nm performed in coordination with said preceding step of administering an effective dose of a photosensitizer Pd-bacteriopheophorbide (Tookad); a wavelength of about 600 to about 750 nm performed in coordination with said preceding step of administering an effective dose of a photosensitizer concentrated distillate of hematoporphyrins (Photofrin); a wavelength of about 450 to about 600 nm performed in coordination with said preceding step of administering an effective dose of a photosensitizer verteporfin (Visudyne) and any combination thereof.

In accordance with a further embodiment of the current invention, the step of irradiating is performed by said plurality of emitting diodes distributed along an inner surface of an annular structure.

In accordance with a further embodiment of the current invention, the step of irradiating is performed by LEDs grouped in a plurality of cooled units comprising at least two diodes; said cooled units are distributed along said inner surface of said annular structure.

In accordance with a further embodiment of the current invention, the step of positioning said device in proximity of said patient's breast further comprises a step of adjusting a length of said annular structure according to a patient's breast size.

In accordance with a further embodiment of the current invention, the step of positioning said device in proximity of said patient's breast further comprises steps of disposing said patient on a bearing surface in a prone position and putting in said patient's breast in said annular structure so that said annular structure embraces thereof and/or positioning the device in proximity of said patient's breast is performed frontally.

In accordance with a further embodiment of the current invention, the light intensity gradually increases over treatment time, allowing each measure of depth to receive an effective amount of light until that depth is treated.

In accordance with a further embodiment of the current invention, a device for photodynamic therapy for treating cancer is disclosed. The aforesaid device comprises a plurality of light emitting diodes postionable in proximity of a patient's body adapted to provide a light fluence to a lesion area and cooling means.

It is a core feature of the invention to provide the device having a luminous surface positioned in proximity of the patient's body part to be treated and having an area which is greater than 10 cm².

In accordance with a further embodiment of the current invention, the device is configured for irradiating said lesion area is characterized by power density ranging between 1 mW/cm² and 10,000 mW/cm² and treatment duration ranging between 150 sec and 3600 sec such that density of total energy incident to said lesion area is in a range between 0.01 1 J/cm² and 100 J/cm².

Claims

1. A method of photodynamic therapy for treating cancer; said method comprising the steps of:

a. providing a photodynamic therapeutic device for treating cancer;, said device comprises a copper circuit board, a plurality of light emitting diodes on said copper circuit board and positionable in proximity of a patient's body adapted to provide a light fluence to a lesion area and a passage connected to said copper circuit board to withdraw heat and accommodating a coolant circulating within said passage and removing heat generated by said plurality of light emitting diodes;, wherein said passage is connected in fluid communication to a feeding pipe;

b. administering an effective dose of a photosensitizer in a lesion area of said patient's body;

c. positioning the device in proximity of said lesion area of said patient's body, wherein said lesion area has an effective dose of a photosensitizer administered therein;

d c. irradiating said lesion area;

e d. transferring heat generated by said plurality of light emitting diodes through said copper circuit board to said passage; and

f e. removing said generated heat from said passage by said coolant circulating within said passage; wherein said step of irradiating said lesion area is characterized by power density at a skin surface overlaying the lesion area ranging between 1 200 mW/cm² and 10,000 3500 mW/cm² and treatment duration ranging between 150 sec and 3600 sec such that density of total energy incident to said lesion area is in a range between 0.01 J/cm² and 100 J/cm², thereat, wherein said step of irradiating said lesion area is performed by said photodynamic therapeutic device having a luminous surface of a total area which is greater than 10 from 31.25 cm² to 240 cm².

2. The method according to claim 1, wherein said device is positioned in proximity of said patient's body in a location selected from the group consisting of a breast, an arm, a leg, a neck, an abdomen and any combination thereof.

3. The method according to claim 1, wherein a mode of device operation is selected from the group consisting of a continuous mode, a pulse mode, an intermittent mode and any combination thereof.

4. The method according to claim 1, wherein said step of positioning the device in proximity of said patient's body lesion area further comprises a step of preliminary positioning a silicon spacer between the device and said patient's body.

5. The method according to claim 1, wherein said step of irradiating said lesion area includes irradiating at maximum light intensity at at least one wavelength selected from the group consisting and is performed in coordination with the photosensitizer that is administered within the lesion area and comprises at least one of:

a wavelength of about 630 nm performed in coordination with said preceding step of administering an effective dose of a with the photosensitizer being 5-aminolaevulinic acid (5-ALA);

a wavelength of about 585 to about 740 nm performed in coordination with said preceding step of administering an effective dose of a with the photosensitizer being 5,10,15,20-tetrakis(m-hydroxyphenyl) chlorin (Foscan);

a wavelength of about 570 to about 670 nm is performed in coordination with said preceding step of administering an effective dose of a with the photosensitizer being methyl aminolevulinate (Metvix);

a wavelength of about 615 to about 800 nm performed in coordination with said preceding step of administering an effective dose of a with the photosensitizer being Pd-bacteriopheophorbide (Tookad);

a wavelength of about 600 to about 750 nm performed in coordination with said preceding step of administering an effective dose of a with said photosensitizer being a concentrated distillate of hematoporphyrins (Photofrin); or

a wavelength of about 450 to about 600 nm performed in coordination with said preceding step of administering an effective dose of a with said photosensitizer being verteporfin (Visudyne) and any combination thereof.

6. The device method according to claim 1, wherein said step of irradiating is performed by said plurality of light emitting diodes distributed along an inner surface of an annular structure.

7. The method according to claim 6, wherein said step of irradiating is performed by LEDs said plurality of light emitting diodes are grouped in a plurality of cooled units comprising at least two of said plurality of light emitting diodes; said cooled units are distributed along said inner surface of said annular structure.

8. The method according to claim 1 6, wherein said step of positioning said device in proximity of said lesion area of said patient's body comprises positioning said device in proximity of said patient's breast, and wherein positioning said device in proximity of said patient's breast further comprises a step of adjusting a length of said annular structure according to a patient's breast size.

9. The method according to claim 1 8, wherein said step of positioning said device in proximity of said patient's breast further comprises steps of disposing said patient on a bearing surface in a prone position and putting in said patient's breast in said annular structure so that said annular structure embraces thereof and/or positioning the device in proximity of said patient's breast is performed frontally.

10. The method according to claim 1, wherein at said step of irradiating, light intensity gradually increases over treatment time, allowing each measure of depth to receive an effective amount of light until that depth is treated.

11. The method according to claim 1, wherein said copper circuit board is 0.005″ thick.

12. The method according to claim 1, wherein said photodynamic therapeutic device comprises a plurality of segments.

13. The method according to claim 12, wherein each segment contains 2 to 40 high power LEDs and would require up to 100 watts of heat removal for each segment.

14. The method according to claim 12, wherein said copper circuit board comprises a plurality of said copper circuit boards having a plurality of said plurality of light emitting diodes thereon, and wherein each segment contains one of said copper circuit boards.

15. The method according to claim 12, wherein said segments have a clear silicone spacer mat directly in front of the LEDs to protect and to remove the possibility of a lens of the LED directly coming into contact with the skin and causing direct heat transfer.

16. The method according to claim 15, wherein said clear silicone spacer mat is 0.3-0.5 cm thick.

17. The method according to claim 15, wherein the LEDs are soldered directly to the copper circuit board.

18. The method according to claim 1, wherein said coolant is not in direct contact with said light emitting diodes.