CN1958093A - Application of photosensitizer for high temperature focused ultrasonic sensitization agent - Google Patents
Application of photosensitizer for high temperature focused ultrasonic sensitization agent Download PDFInfo
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Abstract
An application of photosensistizer as the sensitizer of focused high-intensity ultrasonic therapy is disclosed. Said photosensitizer is activated by the focused high-intensity ultrasonic waves to generate photochemical reaction which can destroy the lesion tissue, so improving curative effect.
Description
Technical field
The invention belongs to the ultrasonic therapeutic technical field, more particularly, the present invention relates to the new purposes of photosensitizer as the high intensity focused ultrasound sensitizer.
Background technology
Photoactive substance is that a class contains photosensitive composition traditionally, can be activated by certain wavelength light any material that photooxidation reaction produces active oxygen takes place.Among the present invention related photosensitizer be contain photosensitive composition can selectivity very/neoplasm sex organization in retention and can be by the photoactivation of certain wavelength under produce the photoactive substance of active oxygen lethality proliferative tissue cell, be mainly used in the optical dynamic therapy of good/neoplasm disease.(Photodynamic Therapy PDT) is development in recent years oncotherapy new technique rapidly to optical dynamic therapy.Its basic skills is that photosensitizer is imported in the human body; make it behind certain hour morely in the tumor inner accumulated; this moment is with the rayed tumor locus of specific wavelength; in tissue under the participation of oxygen; cause photooxidation reaction, produce very active active oxygen species of chemical property or free radicals such as singlet oxygen, attack important biomolecule such as destroying albumen, lipid, nucleic acid; finally make death of neoplastic cells, reach therapeutic purposes.Photosensitizer commonly used among the PDT is a porphyrin substance, and its tetrapyrrole macro ring absorbs the 600-800nm HONGGUANG, causes photooxidation reaction.Photosensitizer also has phthalocyanine and derivant, chlorophyll and derivant thereof, quinones, endogenous photosensitizers 5-amino-laevulic acid, rose-red, polyacetylene class such as benzene alkynes in heptan three, thiophenes such as α thiophene, Chinese herbal medicine class such as hypocrellin derivant, psoralen class, curcumin, hypericin, pseudohypericin, emodin, riboflavin, aloe-emodin except porphyrin and derivant thereof.Described proliferative tissue is to become before the benign tumor tissue, malignant tumor tissue, cancer and non-tumprigenicity hyperplasia sex organization such as pathologic cicatrix, nevus flammeus, postangioplasty restenosis etc.
The high intensity focused ultrasound technology has obtained clinical approval as a kind of new method for the treatment of tumor and other diseases.It passes through concentration ultrasonic, on focus, form high strength, continuous ultrasound energy, thereby produce transient high temperature effect (70～100 ℃), cavitation effect, mechanical effect and sonochemical effect, optionally make the lesion tissue coagulation necrosis, the ability that makes tumor lose propagation, soak into and shift.
There are some researches show that ultrasound wave is in the process that tissue is propagated, its energy is exponential decay (people such as Liu Baoqin, Chinese ultrasound medicine magazine, 2002,18 (8): 565-568) with the increase of propagation distance.In addition, the energy attenuation that ultrasound wave is propagated in soft tissue comes self-organizing absorption, scattering, refraction, diffraction etc., wherein topmost energy loss come from absorb and scattering (Feng as if, the Wang Zhibiao chief editor, practical ultrasonic therapeutic, Beijing: Chinese science technical literature publishing house, 2002.14).Therefore, during tumor that utilization high intensity focused ultrasound technology treatment position is dark, volume is bigger, because that the decay of energy will cause arriving the energy of target area is on the low side, therapeutic efficiency descends, and treatment time prolongs.
Certainly, in order to improve therapeutic efficiency, though can merely strengthen the transmitting power of ultrasonic transducer,, the probability that the normal structure on the ultrasonic propagation passage is burnt has just increased greatly.
In addition, when the liver neoplasm that rib stops is arranged on utilization high intensity focused ultrasound technology treatment sound passage at present clinically, in order to increase the energy deposition of treatment target area, improve treatment speed and therapeutic effect, often to behind the rib on the excision sound passage, treat again, this runs counter to the theory of high intensity focused ultrasound non-invasive therapy, thus be difficult to obtain patient and doctor with can.
The existence of these factors must influence and limit high intensity focused ultrasound popularizing as a clinical applicable technology to a certain extent.Therefore, seek the high intensity focused ultrasound sensitizer and how further explore improve high intensity focused ultrasound to the therapeutic effect of malignant tumor and reduce its complication be high-strength focusing ultrasonic therapy good/neoplasm advancing of disease trend, also be the important research direction that high-strength focusing ultrasonic therapy is learned.
Summary of the invention
The objective of the invention is and photosensitizer will be used as the high intensity focused ultrasound sensitizer, improve high intensity focused ultrasound to very/neoplasm treatment of diseases effect and reduce the generation of its complication, expand the application of photosensitizer.
The technical scheme that realizes the object of the invention is the application of this photosensitizer as the high intensity focused ultrasound sensitizer, allow the photosensitizer selectivity very/neoplasm sex organization in retention, change the acoustic enviroment of target tissue by its selectivity target area retention effect, increase the target area ultrasound energy deposition, reduce high-strength focusing ultrasonic therapy dosage, activate photosensitizer generation phonochemical reaction with high intensity focused ultrasound and produce active oxygen and the irreversible damage pathological tissues, by sonochemistry mechanism strengthen high-strength focusing ultrasonic therapy good/neoplasm treatment of diseases effect.
Photosensitizer of the present invention be a kind of can selectivity very/neoplasm sex organization in the sensitizer of retention, not only can increase the target area ultrasound energy deposition by its selectivity target area retention effect, also can be activated and phonochemical reaction generation active oxygen take place and the irreversible damage pathological tissues by high intensity focused ultrasound, having the high intensity focused ultrasound enhancement effect, is a kind of energy collecting deposition harmony chemical sensitization high intensity focused ultrasound sensitizer.
In the present invention, described photosensitizer as sensitizer be safety non-toxic can selectivity very/neoplasm sex organization in retention and can be produced the photosensitizer that photooxidation reaction generates reactive oxygen species by light or sound activation, these materials are hydrophilic, lipophile, amphipathic photosensitizer.These materials are photosensitizer of intravenous injection, intra-arterial injection, local injection application.Described reactive oxygen species is a singlet oxygen.To not having too much restriction with the type of photosensitizer as high-strength focusing ultrasonic therapy, as long as this photosensitizer can be distributed in this target tissue by selectivity after being administered to target tissue, under the effect of high intensity focused ultrasound phonochemical reaction can take place, the therapeutic effect that strengthens high intensity focused ultrasound gets final product.Thereby, the photosensitizer that is used for the sensitizer of high-strength focusing ultrasonic therapy of the present invention is selected from porphyrin and derivant such as hemoporphyrin, benzoporphyrin derivative list acid ring A etc., phthalocyanine and derivant thereof such as zinc phthalocyanine and aluminum phthalocyanine etc., chlorophyll and derivant thereof such as pheophytin and chlorin and C.I. Natural Red 8 18, endogenous photosensitizers 5-amino-laevulic acid, rose-red, phycobniliprotein class photosensitizer such as phycoerythrin and phycocyanin etc., the quinones photosensitizer, fullerene, five nitrogen tooth derivatives class photosensitizer such as lutecium III five nitrogen teeth, polyacetylene class photosensitizer such as benzene alkynes in heptan three, thiophenes photosensitizer such as α thiophene, Chinese herbal medicine class photosensitizer such as hypocrellin and derivant thereof are (as hypocrellin A, hypocrellin B etc.), psoralen class and curcumin, hypericin, pseudohypericin, emodin, riboflavin, a kind of and wantonly two kinds or multiple mixture in the aloe-emodin etc., and any one or more photosensitizer and Chinese patent application numbers 200510000345.8 wherein, the applying date: arbitrary or multiple the combining of the high intensity focused ultrasound auxiliary agent that provides in the patent application on January 10th, 2005 and the photoactive substance that forms.Describedly combine the continuous phase that the high intensity focused ultrasound auxiliary agent that forms photoactive substance comprises that the discontinuous phase that is made of filmogen parcel core and aqueous medium constitute with photosensitizer, wherein said discontinuous phase is evenly dispersed in the described continuous phase, the particle diameter of described discontinuous phase is 5nm～15 μ m, preferred 8nm～10 μ m.The filmogen of described auxiliary agent has biocompatibility, and the material of described core adopts gas, liquid or nano grade biological compatibility solid.Wherein said filmogen is one or more materials in lipid, protide and the saccharide.Described lipid is selected from the 3-sn-phosphatidylcholine, 1 in the phospholipid; 2-two palmityls-sn-glyceryl-3-phosphatidyl glycerol base-sodium salt, 1; 2-distearyl acyl group-sn-glyceryl-3-phosphatidylcholine, 1; 2-two palmityls-sn-glyceryl-3-phosphatidyl acid-sodium salt, 1, one or more in 2-two palmityls-sn-glyceryl-3-phosphatidylcholine, Phosphatidylserine or the hydrogenated phospholipid acyl serine.The gas that described core material adopts is selected from air, nitrogen, one or more in carbon dioxide, fluorine carbon appropriate hydrocarbon gas or the alkanes gas.The liquid that described core material adopts is selected from C
5-C
6Alkane, C
5-C
12In fluorine carbon hydrocarbon, satisfied fatty acid, unsaturated fatty acid or the iodized oil one or more.
In addition, in order to make high intensity focused ultrasound sensitizer targeting of the present invention specific tumor tissues such as liver tumor, tumor of kidney, bone tumor, breast carcinoma and hysteromyoma etc., also can add the material that described tumor tissues or lesions position is had pathoklisis in as the photosensitizer of sensitizer, the targeting sensitizing agent that forms as the antibody of identification tumor, peptide etc. at this.
Utilize photoactive substance to increase the method for high-strength focusing ultrasonic therapy effect as sensitizer, be before high-strength focusing ultrasonic therapy is carried out in patient's target area 0～168 hour, by in intravenous drip or the target tissue directly mode such as injection give the above-described photoactive substance of patient infusion as sensitizer.
Widely used various photosensitizer and deutero-any photoactive substance thereof all can be used as high-strength focusing ultrasonic therapy sensitizer of the present invention in the photodynamic therapy field at present; In addition, phonochemical reaction takes place and produces reactive oxygen species in this class photoactive substance under ultrasonic activation, can damage the target tissue vascular endothelial cell, starts endogenous or extrinsic coagulation system thromboembolism blood capillary.Thereby the present invention also provides a kind of new method of utilizing photoactive substance combining ultrasonic embolotherapy tumor, nevus flammeus.Promptly utilize the method for photoactive substance as sensitizer combining ultrasonic ripple embolotherapy tumor, nevus flammeus, be before ultrasonic irradiation is carried out in patient's target area 0～168 hour, by in intravenous drip or the target tissue directly injection mode give the above-described photoactive substance of patient infusion.Described ultrasound wave is for focusing on treatment that maybe can not focus on or the ultrasound wave of diagnosing usefulness, and its energy can be a low-intensity or also high-intensity.
The various auxiliary agents of existing high intensity focused ultrasound enhanced sensitivity mainly are to increase target area ultrasound energy deposition effect according to it.Compare with existing high intensity focused ultrasound auxiliary agent, the photosensitizer that is used as the high intensity focused ultrasound sensitizer among the present invention has very/the selectivity retention effect of neoplasm sex organization, not only can increase the target area ultrasound energy deposition by selectivity, strengthen the high-strength focusing ultrasonic therapy effect but also can under ultrasonic activation, produce sonochemistry mechanism, significantly reduce high-strength focusing ultrasonic therapy dosage, reduce the generation of its complication.Its enhancement effect is that existing high intensity focused ultrasound auxiliary agent is incomparable.Utilize photosensitizer will make to treat deep tumor and under the situation of the rib that does not excise the patient, the liver tumor patient is effectively implemented high-strength focusing ultrasonic therapy and become possibility as sensitizer.
Description of drawings
Fig. 1 is the sketch map that ultrasonic activation photosensitizer generation phonochemical reaction generates active oxygen:
Fig. 2 is the applicating flow chart of the photosensitizer of embodiment 1 as the high intensity focused ultrasound sensitizer
Fig. 3 is the applicating flow chart of the photosensitizer of embodiment 2 as the high intensity focused ultrasound sensitizer
The specific embodiment
Below be non-limiting examples of the present invention:
Embodiment 1: the high intensity focused ultrasound enhancement effect of observing photosensitizer on the cultured cell in vitro: cultivate target cell: select breast cancer cell, be incubated in 37 ℃ of incubators that contain 5% carbon dioxide, saturation vapour with the RPMI1640 culture fluid routine that contains 10% calf serum; Then, the take the logarithm target cell (2 * 10 of trophophase
4) individual cell, adding photosensitizer such as hemoporphyrin hatched 12～16 hours in 37 ℃ of incubators that contain 5% carbon dioxide, saturation vapour, owing to there is part photosensitizer hemoporphyrin not engulfed by target cell, also be free in the culture fluid, so before ultrasonic irradiation, washing is removed hemoporphyrin remaining in the culture fluid for several times; Then, using ultrasound ripple irradiation target cell.Under the ultrasonic irradiation effect, photosensitizer hemoporphyrin generation phonochemical reaction generates reactive oxygen species (as shown in Figure 1).Strengthen the therapeutic effect of high intensity focused ultrasound.Experiment adopts mtt assay to observe the application dose that photosensitizer can significantly reduce high intensity focused ultrasound, improves the killing-efficiency of its pair cell.Show that photosensitizer has significant high intensity focused ultrasound effect of enhanced sensitivity.As shown in Figure 2.
In present embodiment 1, the photosensitizer of selecting is a kind of safety non-toxic, the selective fixed photosensitizer that is positioned at the proliferative tissue cell of energy, except hemoporphyrin, also it can be aluminum phthalocyanine, 5-amino-laevulic acid, hypocrellin derivant, single asparagine chlorin, De Kesafei quinoline lutecium, rose-red or hematoporphyrin monomethyl ether etc.
High intensity focused ultrasound is JC type high-intensity focus supersonic tumor therapy system (being produced by Haifu (HIFU) Technology Co. Ltd., Chongqing) in embodiment 1.JC type high-intensity focus supersonic tumor therapy system mainly is made up of five parts such as power-adjustable generator, B ultrasonic monitoring system, treatment probe, mechanical movement control system, therapeutic bed harmony coupling devices.
Embodiment 2: observe the high intensity focused ultrasound enhancement effect of photosensitizer at body: the photosensitizer hemoporphyrin is adopted in intravascular injection or the target tissue directly inject, when treating that its selectivity is distributed in target tissue, use the high intensity focused ultrasound effect and produce phonochemical reaction down, strengthen the therapeutic effect of high intensity focused ultrasound, reduce the generation of complication in the high-strength focusing ultrasonic therapy process.As shown in Figure 3:
Experimental rabbit is transplanted VX in embodiment 2
2The tumor model adopts intramuscular anesthesia, is fixed on the high-strength focusing ultrasonic therapy bed, { is produced by Haifu (HIFU) Technology Co. Ltd., Chongqing } with JC type high-intensity focus supersonic tumor therapy system experimental rabbit is carried out irradiation.JC type high-intensity focus supersonic tumor therapy system mainly is made up of five parts such as power-adjustable generator, B ultrasonic monitoring system, treatment probe, mechanical movement control system, therapeutic bed harmony coupling devices.
Experimental rabbit is transplanted VX
2Tumor model random packet is that blank group (giving normal saline), simple photosensitizer group (only give hemoporphyrin, do not carry out high intensity focused ultrasound irradiation), simple high intensity focused ultrasound irradiation group (only carry out high intensity focused ultrasound irradiation, do not give hemoporphyrin) and enhanced sensitivity group (give hemoporphyrin and carry out high intensity focused ultrasound irradiation).Adopt high intensity focused ultrasound to be with B ultrasonic prescan target tissue (to transplant VX at random
2Tumor), after the selected good aspect, along auricular vein input hemoporphyrin, row fixed point or linear fashion (line length 1cm, scanning, speed 3mm/s) are carried out the high intensity focused ultrasound damage to tumor tissue, record target area grey scale change, treatment time.
Dissected in 24 hours behind the irradiation and draw materials, measure the radial line (length and width, thick) in target tissue damage location coagulation necrosis district, with formula: long * 1/2 wide * 1/2, V=4/3 π * 1/2 is thick, calculates the size of coagulation necrosis.Calculate EEF (the available efficiency factor, energy efficiency factor) according to formula EEF=η Pt/V (J/mm3), and carry out comparing between A, B group and in the group.η represents the high-intensity focusing ultrasonic transducer focusing factor in the formula, and its reflection high-intensity focusing ultrasonic transducer is got η=0.7 to the ability that ultrasonic energy converges; P is a high intensity focused ultrasound source total acoustic power (W); T is treatment total time (s); V is lesion volume (mm3).After the photosensitizer effect was found in experiment, the efficiency factor of target tissue significantly descended; Illustrate that photosensitizer is the high intensity focused ultrasound sensitizer of function admirable.Measurement data is represented with meansigma methods ± SD, adopts SPSS 10.0 for windows statistical packages, the t check.The result is as shown in table 1 below, and wherein, in the following table, P has significant differences (annotate: P herein is an italic, is not power) on the statistics.
The comparison of the EEF of each group of table 1
| Group | EEF(J/mm 3) |
| Simple high intensity focused ultrasound | 332.8±120.2 |
| Hemoporphyrin adds the high strength focus supersonic | 13.6±10.1 * |
*Compare P＜0.01 in twos
Claims (14)
1. photosensitizer is as the application of high intensity focused ultrasound sensitizer.
2. photosensitizer according to claim 1 is as the application of high intensity focused ultrasound sensitizer, it is characterized in that allowing the photosensitizer selectivity very/neoplasm sex organization in retention, utilize the acoustic enviroment of its selectivity target area retention characteristic changing target tissue, increase the target area ultrasound energy deposition, reduce high-strength focusing ultrasonic therapy dosage, activate photosensitizer generation phonochemical reaction with high intensity focused ultrasound and produce active oxygen and the irreversible damage pathological tissues, strengthen optimum, the neoplasm treatment of diseases effect of high-strength focusing ultrasonic therapy by sonochemistry mechanism.
3. photosensitizer according to claim 2 is as the application of high intensity focused ultrasound sensitizer, it is characterized in that described photosensitizer as sensitizer be safety non-toxic can selectivity very/neoplasm sex organization in retention and can be produced the material that oxidation reaction generates active oxygen by light or sound activation, these photosensitizer can be hydrophilic, lipophile, amphipathic.
4, photosensitizer according to claim 3 is as the application of high intensity focused ultrasound sensitizer, but it is characterized in that described photosensitizer is the photosensitizer of intravenous injection, intra-arterial injection or local injection.
5, photosensitizer according to claim 3 is characterized in that being selected from porphyrin and derivant thereof as the photosensitizer of high-strength focusing ultrasonic therapy enhanced sensitivity as the application of high intensity focused ultrasound sensitizer, phthalocyanine and derivant thereof, chlorophyll and derivant thereof, endogenous photosensitizers 5-amino-laevulic acid, phycobniliprotein class photosensitizer, five nitrogen tooth derivatives class photosensitizer, the quinones photosensitizer, rose-red, fullerene, polyacetylene class photosensitizer, the thiophenes photosensitizer, Chinese herbal medicine class photosensitizer hypocrellin, psoralen class and curcumin, hypericin, pseudohypericin, emodin, riboflavin, a kind of and wantonly two kinds or multiple mixture in the aloe-emodin.
6, photosensitizer according to claim 5 is as the application of high intensity focused ultrasound sensitizer, the photoactive substance that it is characterized in that or multiple combine arbitrary with the high intensity focused ultrasound auxiliary agent of any one or more mixture in the described photosensitizer and form, should be included in simultaneously to add in this photosensitizer has the material of pathoklisis to form the targeting sensitizing agent to tumor tissues or lesions position.
7, photosensitizer according to claim 6 is as the application of high intensity focused ultrasound sensitizer, it is characterized in that the described continuous phase that the high intensity focused ultrasound auxiliary agent that forms sensitizing agent comprises that the discontinuous phase that is made of filmogen parcel core and aqueous medium constitute that combines with photosensitizer, wherein said discontinuous phase is evenly dispersed in the described continuous phase, and the particle diameter of described discontinuous phase is 5nm～15 μ m.
8, photosensitizer according to claim 7 is characterized in that as the application of high intensity focused ultrasound sensitizer the filmogen of described auxiliary agent has biocompatibility, and the material of described core adopts gas, liquid or nano grade biological compatibility solid.
9, photosensitizer according to claim 8 is as the application of high intensity focused ultrasound sensitizer, and the filmogen that it is characterized in that described auxiliary agent is one or more materials in lipid, protide and the saccharide.
10, photosensitizer according to claim 9 is as the application of high intensity focused ultrasound sensitizer; it is characterized in that described lipid is selected from the 3-sn-phosphatidylcholine, 1 in the phospholipid; 2-two palmityls-sn-glyceryl-3-phosphatidyl glycerol base-sodium salt, 1; 2-distearyl acyl group-sn-glyceryl-3-phosphatidylcholine, 1; 2-two palmityls-sn-glyceryl-3-phosphatidyl acid-sodium salt, 1, one or more in 2-two palmityls-sn-glyceryl-3-phosphatidylcholine, Phosphatidylserine or the hydrogenated phospholipid acyl serine.
11, photosensitizer according to claim 8 is characterized in that the gas that described core material adopts is selected from air, nitrogen, one or more in carbon dioxide, fluorine carbon appropriate hydrocarbon gas or the alkanes gas as the application of high intensity focused ultrasound sensitizer.
12, photosensitizer according to claim 8 is characterized in that as the application of high intensity focused ultrasound sensitizer the liquid that described core material adopts is selected from C
5-C
6Alkane, C
5-C
12In fluorine carbon hydrocarbon, satisfied fatty acid, unsaturated fatty acid or the iodized oil one or more.
13, according to of the application of the described photosensitizer of one of claim 1～12 as the high intensity focused ultrasound sensitizer, it is characterized in that it being before high-strength focusing ultrasonic therapy is carried out in patient's target area 0～168 hour, by in intravenous drip or the target tissue directly injection mode give the patient infusion photosensitizer.
14, photosensitizer according to claim 13 is as the application of high intensity focused ultrasound sensitizer, it is characterized in that utilizing photoactive substance as sensitizer combining ultrasonic ripple embolotherapy tumor, nevus flammeus, it is before ultrasonic irradiation is carried out in patient's target area 0～168 hour, by in intravenous drip or the target tissue directly mode such as injection give the patient infusion photosensitizer, described ultrasound wave is for focusing on treatment that maybe can not focus on or the ultrasound wave of diagnosing usefulness, and its energy can be a low-intensity or also high-intensity.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102233159A (en) * | 2010-05-06 | 2011-11-09 | 高春平 | Focused ultrasonic noninvasive sound powered tumor therapy system |
| CN103641712A (en) * | 2013-12-09 | 2014-03-19 | 哈尔滨医科大学 | Hydroxyl acetylated curcumin and application thereof in preparation of ultrasonic sensitive agent for treating atherosclerosis |
| CN108084311A (en) * | 2017-12-28 | 2018-05-29 | 宁波俐辰新能源有限公司 | A kind of ecologic planting nuisanceless light transmission film and its manufacturing method |
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2005
- 2005-11-04 CN CN 200510115551 patent/CN1958093A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102233159A (en) * | 2010-05-06 | 2011-11-09 | 高春平 | Focused ultrasonic noninvasive sound powered tumor therapy system |
| CN103641712A (en) * | 2013-12-09 | 2014-03-19 | 哈尔滨医科大学 | Hydroxyl acetylated curcumin and application thereof in preparation of ultrasonic sensitive agent for treating atherosclerosis |
| CN108084311A (en) * | 2017-12-28 | 2018-05-29 | 宁波俐辰新能源有限公司 | A kind of ecologic planting nuisanceless light transmission film and its manufacturing method |
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