CN1119518A - Guide miniature anticancer light bullet - Google Patents
Guide miniature anticancer light bullet Download PDFInfo
- Publication number
- CN1119518A CN1119518A CN 94116524 CN94116524A CN1119518A CN 1119518 A CN1119518 A CN 1119518A CN 94116524 CN94116524 CN 94116524 CN 94116524 A CN94116524 A CN 94116524A CN 1119518 A CN1119518 A CN 1119518A
- Authority
- CN
- China
- Prior art keywords
- agent
- photosensitizer
- anticancer
- light
- emulsion
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to a guided miniature anticancer light bullet. It uses a new sensitization light source and a new photosensitizer of the photodynamic therapy affirmed by clinical curative effect as guide material, replaces the external laser and non-laser by chemical luminescent agent or chemical laser agent as sensitization light source, and transfers the emulsion made up by using new photosensitizer and cancerotropic material as continuous phase into the body via vena or skin, and then activates the photodynamic effect in the presence of oxygen with the use of the photosensitizer in the target organ to produce singlet oxygen to make selective aggression against the pathological changed tissue of the target organ, so that it can cure various malignant tumors, and can be used for controlling and curing virus infection, AIDS and parasitosis.
Description
Guide miniature anticancer light bullet is to carry out medicine efficacy screening with new photosensitizer as guide's thing with the new sensitization light source of the sure photodynamic therapy of clinical efficacy, obtains to have innovation academic thought and design concept novel derivatives synthetics.The invention belongs to the new drug development field.
Photodynamic therapy diagnosis and treatment tumor was applied to clinical achieving success in 1978, and existing nearly ten thousand cancer patient of the numerous countries in the world has accepted this treatment.Because photodynamic therapy has used hematoporphyrin derivative (HpD) to make photosensitizer, and make sensitization light source with the laser that action spectrum with it is output as the 630nm wavelength accordingly, thereby improved the curative effect of photodynamic therapy for malignant tumor, in the various tumor methods that emerge in an endless stream, taken the course of its own.No matter be independent application, still as the householder method of systematic treatments such as operative treatment, radiotherapy, chemotherapy, photodynamic therapy all can be brought into play the peculiar effect of its selective killing tumor cell.The approval photodynamic therapy is used for the treatment of bladder cancer at the beginning of the Canadian government 1993, and it is clinical that FDA (Food and Drug Adminstration) considers that also official approval is used for.Harvard University and Canadian Columbia University are all carrying out a kind of research of new photosensitizer-benzene derivatives of porphyrin (BPD), and it can reduce the medicine remaining quantity in the skin greatly, and the lucifuge phase can shorten to 3-5 days, the skin photosensitivity reaction promptly no longer occurs.In addition, the benzene derivatives of porphyrin enters to be organized very soon, and be feasible photodynamic action treatment the same day after the injection, and it can be used for the treatment of the more tumor of position, deep in theory.In JIUYUE, 1994 has been held the 5th international photodynamic therapy meeting at Fla., the content that discusses is except that the clinical practice problem of the mechanism of photodynamic therapy, target, also be provided with the ad hoc meeting that new photosensitizer is discussed especially, and propose a plan for the prospect of photodynamic therapy.In China, photodynamic therapy research is listed in " six or five ", " the Seventh Five-Year Plan " national science and technology research project, has also obtained very ten-strike, causes in the world to pay close attention to widely and attention.
But, from clinical practice and basic research over 20 years, no matter be specificity or therapeutic effect to tumor destruction, photodynamic therapy is still undesirable, therefore strengthened both at home and abroad the research of photodynamic therapy for cancer mechanism, the sensitization light source that active development is new strives to find more efficiently photosensitizer.
The present invention is directed to the above-mentioned shortcoming and defect that photodynamic therapy exists, adopt new chemiluminescence agent to replace laser and non-laser light source to make sensitization light source, also the phenyl ring coupling of photosensitizer and chemiluminescence agent can be formed the coenosarc thing of sensitization light source and photosensitizer, with carcinophilia material or monoclonal antibody is the synthetic Emulsion that continuous phase is made targeted delivery, improves the new sensitization light source and the targeting distributivity and the attainability of novel photosensitive agent.The coenosarc thing of this light source and photosensitizer, to have carcinophilia material such as monoclonal antibody continuous phase as emulsion carrier, avoided modern emulsion carrier to transmit the shortcoming of medicine, greatly reduce the medicine inlet in non-target organ and the skin, enter speeding up of target organ tissue, just started optical effect generation singlet oxygen in the target organ tissue in vivo the same day after the injection, similar directed guided missile is attacked at the tumor tissues of target organ, with abnormal structures such as enhancing selective killing tumors, reduce the purpose of normal structure damaged to greatest extent.By this carry out design concept novel and with " guide miniature anticancer light bullet " of its effect and mechanism name just can any position of diagnosis and treatment whole body malignant tumor.
Pursuit of the present invention comprises following four purposes:
First purpose is, chemiluminescence agent or visual chemical laser agent be delivered to the target area replaces external laser and non-laser to make sensitization light source in the body, in target organ, start photodynamic action by photosensitizer and produce singlet oxygen, similar directed guided missile is attacked at the tumor tissues selectivity of target organ, the malignant tumor that can treat former of any position of whole body and shift;
Second purpose is, improve drug targeting distributivity and attainability, make particularity Emulsion with carcinophilia material such as monoclonal antibody as continuous phase and chemiluminescence agent and photosensitizer, overcome the defective that emulsion carrier optionally concentrates in reticuloendothelial system or the macrophage etc. in a large number;
The 3rd purpose is, reduce body in the photosensitive side effect in pursuit photosensitizer targeted delivery, make great efforts synthetic a kind of with the chemiluminescence agent as coenosarc thing to the phenyl ring coupling photo etching hematoporphyrin derivative of adjacent basic magnesium bromide of bromine phenolic group or oxalate, reduce dosage and reduce cost, reach safe, efficient, economic purpose;
The 4th purpose is, adopt corresponding carcinophilia material or monoclonal antibody filler as the continuous phase or the continuous phase of Emulsion, be used for the control treatment to viral infection, acquired immune deficiency syndrome (AIDS) and parasitic disease, expanding photodynamic therapy is last purpose that the present invention pursues in the application of other field.
The principle of diagnosis and treatment tumor of the present invention and the mechanism of targeting are, guide miniature anticancer light bullet with photodynamic action is a kind of synthetic Emulsion of targeted delivery medicine, can be in vein, transdermal guide way target organ, in the presence of oxygen, sensitization light source starts photodynamic action by photosensitizer and produces singlet oxygen, similar directed guided missile is attacked at target organ pathological tissues (substrate that is acted on), but the tumor at any position of diagnosis and treatment whole body.Therefore, the essential condition that guide miniature anticancer light bullet produces biological effect is the substrate four elements that the existence of light source, photosensitizer, oxygen is arranged and acted on, i.e. photodynamic action reaction.The mechanism of its photodynamics is, be excited to behind the sensitiser absorption photon triplet [
3HPD], then energy is transferred to be in originally triplet ground state oxygen molecule (
3O
2), make it to be excited into active singlet oxygen with strong lethal effect (
1O
2).This singlet oxygen is the strong oxidizer of instantaneous existence, and it can combine with its bio-matrix A of retention, makes it strong oxidation and generates Aox, and concrete photodynamics course of reaction is:
HpD＋h
v—→
3(HpD)
3(HPD)＋
3O
2—→
1O
2＋HpD
1O
2＋A—→A
ox＋
3O
2
Because therefore singlet oxygen wrecks the cell of bio-matrix and tissue, thereby reach the purpose of treatment tumor.For the A of biological tissue, the photodynamics of photosensitizer itself is to normal structure and abnormal structure and zero difference.Therefore, photosensitizer as treatment usefulness, require the light toxic action to want big to tumor, and require the light toxic and side effects to want little or nothing to normal structure, this contradiction mainly is to solve by distributivity and the attainability of researching and developing new photosensitizer and the transmission of raising drug targeting except that the metabolism difference of utilizing different tissues to photosensitizer solves.Promptly utilize phenyl ring coupling, change the biological nature of photosensitizer, utilize carcinophilia material such as monoclonal antibody to make targeting Emulsion as continuous phase with photosensitizer and chemiluminescence agent.
In the photodynamic action process, tumor cell and the specific fluorescence that sent of tissue and normal cell with organize different, can determine that according to these discrepant optical parameters detected cell or tissue is that tumor also is non-tumor, thereby guide miniature anticancer light bullet also has the performance of diagnosing tumour.
The guiding mechanism of guide miniature anticancer light bullet is the two trend of a kind of tool concertedness drug-supplying system, the one, be positioned target site with Emulsion for the carrier transfer medicine, the 2nd, with carcinophilia material such as monoclonal antibody continuous phase, utilize antigen one antibody response to reach with the medicine cancerous cell that directly leads as Emulsion.The continuous phase component of Emulsion can directly influence all mechanism of action of Emulsion and Emulsion behavior in vivo, and the Emulsion of property is exactly to modify as the composition of carrier or to Emulsion continuous phase by changing Emulsion, reaches and improves its targeting.Secondly, Emulsion itself has the target administration function as carrier, is to utilize control, adjusting emulsion droplet mean diameter, particle size distribution, particle surface electric charge and electric weight method, makes water (W) and oil phase (O) be fused into best guiding Emulsion.The present invention experimental results show that some chemiluminescence agent such as chemiluminescent oxalate agent have the carcinophilia effect, with its oily liquid as Emulsion continuous phase and make its positively charged raising to tumor cell parent electro-affinity, control emulsion droplet grain diameter makes it arrive different target sites, tend to into spleen as emulsion droplet less than 50nm, bone marrow and tumor tissues are in 0.1～0.2 μ m emulsion droplet trend liver Kupffer lysosome; Stop greater than 1 μ m emulsion droplet trend lung; Can be greater than 15 μ m emulsion droplets respectively by intestinal, liver and kidney picked-up.The chemiluminescence agent that has not only has the function as sensitization light source in the body, but also has the specific function with the tumor cell affinity, has the close tumor-targeting effect that improves and revise Emulsion as Emulsion continuous phase.
In order to deepen the understanding of the present invention, now with reference to the accompanying drawings invention is illustrated.
Fig. 1 is that the guide miniature anticancer light bullet of chemiluminescence agent and photosensitizer one forms sketch map.By water (W) property photosensitizer and chemiluminescence agent as synthetics 1 to Cheng Gongyi phenyl ring of bromine phenolic group magnesium bromide coupling, mix the emulsifying agent 2 of hydrophile-lipophile balance value (HBL), insert oil phase (O) carcinophilia material such as monoclonal antibody as in the continuous phase 3, add Osmolyte regulator 4 usefulness mixing machines control emulsifying temperature and revolution emulsifying and generate Water-In-Oil (w/O) type Emulsion, then with dispersing emulsification machine carry out smart breast make the substep guidance guide miniature anticancer light bullet preset bullet; By the luminous catalyst 5 of water (w) property can be hydrogen peroxide 6, mix hydrophile-lipophile balance value (HBL) examples of suitable emulsifiers 2, insert the carcinophilia material of oil phase (O) such as monoclonal antibody as in the continuous phase 3, add Osmolyte regulator 4 usefulness mixing machines control emulsifying temperature and revolution emulsifying and generate Water-In-Oil (w/O) type Emulsion, carry out the catalysis bullet that smart breast is made the guide miniature anticancer light bullet of substep guidance with dispersing emulsification machine then, even the controlling agent that the chemiluminescence agent can be luminous.
Therefore, chemiluminescence agent of the present invention only could produce chemiluminescence reaction as sensitization light source under catalyst action, utilize this specific character of time difference that imports to have special meaning for starting photodynamic therapy, enter in-house retention amount of target organ and admission velocity according to chemiluminescence agent and photosensitizer, select Best Times to start photodynamic therapy, control treatment, can avoid damage normal structure.
Fig. 2 is that the guide miniature anticancer light bullet of chemiluminescence agent and photosensitizer split forms sketch map.By water (W) photosensitizer 1, the emulsifying agent 2 that mixes suitable hydrophile-lipophile balance value (HBL) is with catalyst 6 usefulness the mixing machine mixings of oil phase (O) chemiluminescence agent and control emulsifying temperature and revolution emulsifying generation oil-in-water (O/W) type Emulsion, and then the chemiluminescent oxalate agent 3 of inserting carcinophilia adds the guide miniature anticancer light bullet of emulsion type (O/W/O) the special type Emulsion of Osmolyte regulator, photosensitizer and catalyst in the oily liquids of continuous phase.
The guide miniature anticancer light bullet of one step guidance can also be made sensitization light source with visual chemical laser agent, continuous phase is mixed monoclonal antibody, formation has the drug delivery system of height targeting, the photosensitizer of decentralized photo starts the photodynamics reaction rapidly behind the arrival target site, guarantees to reduce to greatest extent the normal structure damaged.The guide miniature anticancer light bullet route of administration of one step guidance is good with subcutaneous or transdermal, and treatment has significant advantage to superficial tumor.
(1) photosensitizer: as the desirable photosensitizer of photodynamic action, at first must possess the high and strong physics and chemistry characteristics of cytotoxic effect of the absorption coefficient of light to a certain wavelength, and the absorption characteristic of photosensitizer itself can not be only considered in the selection of this optical wavelength, also must take into account the influence of the light through characteristic of biological tissue.For biological tissue, photosensitizer must infiltrate cyto-architectural sensitizing range and be only effectively, the photodynamic action of photosensitizer itself is to abnormal structure and normal structure and zero difference, therefore as the photosensitizer for the treatment of usefulness, require phototoxic action to want big to tumor tissues, and require the light toxic and side effects little to nonneoplastic tissue, and this contradiction is removed by utilizing the metabolism difference of different tissues to photosensitizer, i.e. and normal structure photosensitizer metabolism is fast, the retention time is short, it is fast to remove; Tumor tissues is slow to the photosensitizer metabolism, the retention time is long, it is slow to remove, utilize outside the metabolism time difference solves, the objective of the invention is to improve medicine location transmission method, promptly improving drug targeting distributivity and attainability solves, exploitation simultaneously can change the method for photosensitizer biological characteristics, be about to the phenyl ring coupling of photosensitizer and chemiluminescence agent, the medicine remaining quantity that reduces normal structure solves with the speed that quickening enters tissue.
1, hematoporphyrin derivative (HpD):
The photosensitizer that the present invention relates to uses hematoporphyrin derivative (HpD) at most the most generally, is a kind of mixture of the hemoporphyrin acetylate that is formed through glacial acetic acid one sulfuric acid treatment by hemoporphyrin.
(1) chemical property of hematoporphyrin derivative: hemoporphyrin extracts from hemoglobin, and its molecular weight is 598.7, and its molecular formula is C
34H
38O
6N
4, be kermesinus, soda acid two property, water insoluble, be soluble in acidity or the alkali organic solvent.To sensitivities such as oxidant, light.
(2) physical property of hematoporphyrin derivative: the peak wavelength of exciting light is 405nm in the human serum; The spectrum peak wavelength of emitting fluorescence is 630nm and 690nm, and the fluorescence of 630nm is stronger than 690nm's.Obviously, 405nm is the excellent diagnostics optical wavelength, and 630nm is the optimal treatment optical wavelength.
(3) biological nature of hematoporphyrin derivative: the hematoporphyrin derivative content distribution of each tissue in vivo is followed successively by gallbladder, lung, kidney, liver, intestinal, stomach, blood, adrenal gland, spleen, thymus, tumor, the heart, muscle, brain and bone.As time passes, the hemoporphyrin content ratio in the different tissues will change.After the injection 12～24 hours, the hemoporphyrin major part in the parenchyma of normal structure disappeared, was only keeping like some in reticuloendothelial system cell and connective tissue; The hemoporphyrin content of tissue such as kidney,liver,spleen did not have change in 3～24 hours, tumor cell then can reach the hematoporphyrin derivative retention 7 days.The notable difference of this hemoporphyrin retention time length in normal structure and tumor tissues is for the photodynamic therapy for malignant tumor provides advantageous conditions.
2, novel photosensitive agent-to bromine phenolic group magnesium bromide hematoporphyrin derivative: hematoporphyrin derivative and chemiluminescence agent are coupled at the ortho position to the phenyl ring of bromine phenolic group magnesium bromide, make its coenosarc synthetics that becomes chemiluminescence agent and photosensitizer, and make Emulsion as continuous phase with targeted delivery function with carcinophilia material or monoclonal antibody.
(1) chemical property: molecular weight 882.8, molecular formula are C
44H
39O
7N
4Br
2Mg is kermesinus.Meet catalyst and produce chemiluminescence, and start photodynamic action by the photosensitizer on same phenyl ring.
(2) physical property: mix different fluorescent agents and can produce light wave of all kinds from 200～700nm wavelength.
(3) biological nature: can reduce or avoid the medicine remaining quantity in the normal structure greatly, the lucifuge phase can shorten to 2 days, the skin photosensitivity reaction promptly no longer occurs.In addition, synthetics enters Tissue velocity to be accelerated, and just can give catalyst start photodynamic action and treat the same day after the injection.
3, other photosensitizer: the photosensitizer of use also can be with chromatography by HpD separate, remove irrelevant and poor efficiency composition, keep the stronger low-polarity constituents of known effect and be prepared into the PSD-007 that stablizes light sensitive effect; Can also be chlorin, alizarinopurpurin derivant etc.
(2) new sensitization light source: the new sensitization light source that the present invention relates to comprises chemiluminescence agent and chemical laser agent, is a kind of special light sources that can be delivered to the interior any target area of body and start photodynamic action at target organ.These two kinds of new sensitization light source can satisfy three conditions of photodynamic action, the one, the optimal wavelength of the photosensitizer action spectrum that the light positive of its wavelength is to use well; The 2nd, the light of this wavelength is again the stronger a kind of light source of penetration power that enters biological tissue; The 3rd, the light of this wavelength has certain light intensity.The used light intensity of the present invention be with reference to the U.S. in 1978 once extensive clinical test results: with the red light irradiation of effective wave band at 620～640nm, the efficient intensity that can arrive tumor 2cm is 0.5mw/cm
2, shine and just can kill 2cm in 20 minutes with interior whole tumors.Therefore, the light intensity used of the present invention in vivo the target area greater than 0.5mw/cm
2, irradiation time was greater than 0.5 hour.It between photodynamic action spectrum and the absorption spectrum inverse relation principle according to time and fluence rate, promptly utilize the continuous in vivo fluorescent lifetime of chemiluminescence agent long (more than 0.5 hour) can reach more than 6 times of external light source irradiation time, though fluence rate reduces than extracorporeal irradiation, but its light energy is accumulated increase, and the photodynamic action effect strengthens than extracorporeal irradiation.The characteristic of new sensitization light source is as follows:
1, chemiluminescence agent: chemiluminescence is meant in some chemical reactions a kind of disposable light source that directly chemical energy is converted into luminous energy, and this has essential difference with fluorescence and phosphorescence.
1) chemiluminescent oxalate agent:
(1) preparation method: leading in the course of reaction of nitrogen the oxalate with 1～5% (Bis oxalate) [-CO from start to finish
2C
6H (Cl)
3CO
2CH
2CH (CH
3)
2]
2Dissolve in the dimethyl phthalate, be heated to 150 ℃, to 130 ℃ of maintenances 3 hours, add fluorescent agent when being cooled to below 90 ℃, cooling gets final product.Meet catalyst action and produce chemiluminescence.
(2) chemical property: the chemiluminescent oxalate agent adds fluorescent agent as required can be red, green, yellow light wave of all kinds, and nontoxic, harmless, nothing heat, "dead" has close cancer trend.
(3) physical property: the emission spectra of chemiluminescent oxalate agent is adjusted into 620nm～640nm.
2) the new a pair of bromine phenolic group of chemiluminescence agent magnesium bromide:
(1) preparation method: in logical nitrogen overall process, p bromophenol is dissolved in the Carbon bisulfide, splashes into the magnesium bromide solution of Carbon bisulfide when cold, main product is to bromine phenolic group magnesium bromide.
(2) chemical property: extremely active to bromine phenolic group magnesium bromide, meet oxygen and can produce remarkable chemiluminescence, this diethyl ether solution to bromine phenolic group magnesium bromide is positioned in the air, the blue edge coloured light that is produced also can be finding of naked eye by day.
(3) physical property: emission spectra can be adjusted to green glow, the HONGGUANG of 400～700nm wavelength.
2. visual chemical laser agent:
1) with oxygen be the chemical laser agent of luminous source: Tokyo commercial development institute laser research center in 1989 is luminous source first in the world with oxygen, and successfully exploitation produces the red visual chemical laser of light wave concussion.
2) acetenyl (C
2H) chemical laser agent: acetenyl C
2H is in the past rarely known by the people, C
2H and O
2Reaction is also sent visible light, and spectrum has shown that product has CH, CO, CO
2, CH (A wherein
2△) spontaneous radiation can produce chemiluminescence to ground state CH (X), and near the chemical laser of the wavelength that sends 431nm, intensity I cL are that the concentration with CH this moment (A) is directly proportional.
Preparation method: with 248nm laser photolysis C
2The HBr molecule can produce C
2H:
C
2HBr→C
2H＋Br
(3), emulsifying agent: emulsification relates to the surface activity of emulsifying agent and chemical constitution, character and the effect between the two of emulsified thing.Conventional surfactant hydrophilic-lipophilic balance value (HBL) is as the foundation of selecting emulsifying agent for use on the theory of selection of emulsifying agent.Span (Span) is that surfactant HBL value can be used for preparing Water-In-Oil (O/w) type Emulsion 3～8.Tween (Tween) is that surfactant HBL value can be used for preparing oil-in-water (O/W) type Emulsion 8～16.The present invention with select for use experimental results show that nontoxic, easily molten and can be utilized fully by body, the natural phospholipid class (lecithin) of safety is as vein emulsion and the effective emulsifying agent of empirical evidence.
(4), Osmolyte regulator: for biological tissue, photosensitizer must infiltrate cyto-architectural sensitizing range and be only effectively.Promote Emulsion to see through the ability of skin, tumor cell and tumor tissues, the present invention selects for use Laurel nitrogen ketone (Azone) that the biomembrane lipoids is had SL and destruction, can promote hematoporphyrin derivative (HpD) and chemiluminescent oxalate agent and luminous catalyst to make the discontinuity or the cracking of tumor cell adipose membrane, the ability that increases by biological tissue enters the cell sensitizing range.
(5), stabilizing agent: Emulsion belongs to thermodynamic unstable system, and wild effects such as decentralized photo cohesion, inner phase shrinkage or expansion in sterilization and storage process, breast grain break, layering often have generation.One-level Emulsion and emulsion, because their structure differences, so their stability is also different.The present invention is to adopt the guiding anticancer light bullet of one-level Emulsion preparation substep guidance, and to the emulsion of the guide miniature anticancer light bullet of a step system conduction, for the stability that improves its Emulsion is mixed into gel with medicine and water soluble polymer such as polyacrylic acid, to improve the stability of Emulsion.
The present invention with the advantage that photodynamic therapy (PDT) and diagnosis and treatment tumor " magic bullet " are compared is:
1. the present invention compares with traditional tumor therapeuticing method, significantly advantage is that tumor tissues is had specific destruction, normal structure is not damaged, the function that has kept normal structure and organ to greatest extent, not only can the diagnosis and treatment primary tumo(u)r, but also can the diagnosis and treatment metastatic tumour, operative treatment, chemotherapy and radiocurable specificity is not high, side effect is big common drawback and the inconvenient factor of diagnosis and treatment program complexity have been overcome, relatively poor in the medical skill condition, before can't making correct diagnosis, just can carry out diagnoses and treatment and prophylactic treatment.
2. the present invention compares with photodynamic therapy, outstanding advantage is to have developed new sensitization light source can be delivered to any position of whole body, weak and the many diseased regions that are beyond one's reach of laser and non-laser light source penetrate tissue ability have been overcome, and light action underdosage and whole shortcomings of killing tumor cell, raising photodynamic action effect.
3. the present invention compares with traditional photosensitizer medication, biggest advantage is to have two tropism target administration propagation functions, improve the targeting and the distributivity of photosensitizer, strengthen the effect of photosensitizer effect, significantly reduce medicine remaining quantity in the skin, the short lucifuge phase of place the light toxic action no longer occurs to normal structure.
4. the present invention compares with the cancer " magic bullet " of controlling of existing drug delivery system (DDS), valuable advantage is that guidance quality shoots straight, that carries is miniature photoelastic to tumor cell and tumor tissues drug effect ensured sustained development long action time, lethality is strong, cheap, control crosslinked matching condition and can form multi-purpose guide miniature anticancer light bullet enforcement commercial production.
5. the particularity Emulsion pharmaceutical carrier that guide miniature anticancer light bullet of the present invention forms also has following advantage:
(1), has been established in the intravital safety of machine as luminous catalyst and as emulsifying agent such as lecithin etc. as the hematoporphyrin derivative (HpD) of photosensitizer as the chemiluminescence agent;
(2) water and oil phase can any mixed;
(3) by means of emulsifying agent, emulsifier unit, can the average emulsion droplet diameter of free regulating and controlling, particle size distribution;
(4) electrical property of emulsion droplet particle surface can freely be controlled;
(5) have rheological properties widely, make in the medicine of bag be difficult for oxidized, hydrolysis, increase stability of formulation;
(6) medicine that is insoluble in water can dissolve in oil phase;
(7) relax the zest of medicine to body tissue;
(8) attainability to the target area tissue, the distributivity of raising medicine;
(9) control diffusion makes drug release present slow releaseization, prolongs effective drug duration;
(10) reduce drug dose, reduce the preparation cost.
6. the Emulsion continuous phase of guide miniature anticancer light bullet of the present invention can be used monoclonal antibody and chemiluminescence agent, the crosslinked coupling of photosensitizer, photodynamic therapy is used for the diagnosis and the treatment of viral infection, acquired immune deficiency syndrome (AIDS) and parasitic disease, the new application of developing photodynamic therapy.
7. the present invention is except that the diagnosis and treatment that are applied to tumor separately, also can cooperate with traditional method and new therapy to reach synergism, as having the effect of obvious raising photodynamic action with hyperbaric oxygen therapy, light quantum blood therapy method Comprehensive Treatment.
Embodiment one: the guide miniature anticancer light bullet of substep guidance
With the chemiluminescence agent to bromine phenolic group magnesium bromide and photosensitizer hematoporphyrin derivative coenosarc synthetics, put in simple agitation device or the high-speed tissue mashing machine under the logical nitrogen of overall process (! ) add 1.5% Osmolyte regulator Laurel nitrogen ketone and purified lecithin 6 grams, 8000 rev/mins (rpm) stirs and formed uniform decentralized photo in 3 minutes under nitrogen current, moves on in the dispersing emulsification machine.Add the carcinophilia material and can be monoclonal antibody (McAb) in decentralized photo as continuous phase, ultrasonic emulsator is handled, and microscopy is carried out in sampling, Water-In-Oil (w/o) Emulsion to the particle diameter 1 μ m.Under the liquid level nitrogen current, filter filterable Emulsion embedding, in every bottle 25 milliliters through the BG filter.
With same close cancer material monoclonal antibody is continuous phase, with catalyst hydrogen peroxide (H
2O
2) make Water-In-Oil (w/o) targeted delivery Emulsion.
Hematoporphyrin derivative (HpD) is made water preparation with the chemiluminescence agent to bromine phenolic group magnesium bromide, with Water-In-Oil (w/o) type Emulsion, carcinophilia material and monoclonal antibody as continuous phase, collaborative targeting with two tropisms, the hematoporphyrin derivative of target organ tumor tissues (HpD) concentration is significantly higher than the water preparation administration of no guidance quality, can overcome the light toxic and side effects of photosensitizer effectively and change the shortcoming of retention in organs such as liver, spleen, lymphs.
Chemiluminescence intensity is directly proportional with the amount of catalyst, and its fluorescent lifetime and catalytic amount are inversely proportional to.Adjust the ratio of the injection rate of chemiluminescence agent and catalyst as required, fluorescent lifetime can be controlled in 0.5～8 hour.
The guide miniature anticancer light bullet of embodiment two: one steps guidance
The guide miniature anticancer light bullet of preparation one step guidance adopts two step emulsion processes, the first step is got purified photosensitizer hematoporphyrin derivative (HpD) 80ml earlier and is added lipophilic emulsifier while stirring and be mixed with the brownish red colostrum, move on to then in the Rinsing Area of supersonic generator, made oil-in-water (O in ultrasonic 8 minutes
1/ w) type Emulsion; Second step got 100 milliliters of chemiluminescent oxalate agent and adds lecithin 6 gram and Osmolyte regulator Laurel nitrogen ketone 2.5%, and heated and stirred is even, slowly pours (the O that is made by luminous catalyst and photosensitizer hematoporphyrin derivative under constantly stirring
1/ w) in the type Emulsion, mix 2 milliliters monoclonal antibody, change over to then in the Rinsing Area of supersonic generator, ultrasonic 8 minutes, form red multiple emulsion (O
1/ w/O
2) the guide miniature anticancer light bullet of a step guidance.
This product donor harmony in the exterior topical can be a continuous phase with monoclonal antibody, guarantees to have the targeting effect of height.
Description of drawings
Fig. 1. the guide miniature anticancer light bullet of chemiluminescence agent and photosensitizer one forms sketch map
1. 3 pairs of bromine phenolic group of photosensitizer 2. emulsifying agents magnesium bromide chemiluminescence agent, 4. Osmolyte regulators, 5. luminous catalyst 6. hydrogen peroxide
Fig. 2. the guide miniature anticancer light bullet of chemiluminescence agent and photosensitizer split forms sketch map
1. photosensitizer 2. emulsifying agents 3. chemiluminescent oxalate agent 4. Osmolyte regulators 5. luminous catalyst 6. hydrogen peroxide
Claims (9)
1. one is carried out the medicine efficacy screening development with the new sensitization light source of the sure photodynamic therapy of clinical efficacy and new photosensitizer as guide's thing, invention with guide miniature anticancer light bullet of innovation academic thought and design concept novelty is characterized in that, replace the laser and the non-laser of extracorporeal irradiation to make sensitization light source with chemiluminescence agent or chemical laser agent, with novel photosensitive agent, emulsifying agent, luminous catalyst, Osmolyte regulator is made with the target administration Emulsion with dual tropism of close cancer material as continuous phase, through vein, transdermal imports in the body and is positioned target organ, in the presence of oxygen, start photodynamic action generation singlet oxygen by importing the in-house photosensitizer of target organ, similar directed guided missile carries out the selectivity attack at the pathological tissues of target organ, make the pathological tissues cell impaired and downright bad, it is injury-free to keep normal structure to greatest extent, malignant tumor that can any position of diagnosis and treatment whole body also can be used for viral infection, the control treatment of acquired immune deficiency syndrome (AIDS) and parasitic disease.
2. guide miniature anticancer light bullet according to claim 1 is characterized in that described new sensitization light source comprises that can make the Emulsion targeted delivery replaces external laser and non-laser to do the chemiluminescence agent and the visual chemical laser agent of sensitization light source with catalyst action generation chemiluminescence in body.
3. guide miniature anticancer light bullet according to claim 1 is characterized in that, described chemiluminescence agent according to photosensitizer optimal treatment optical wavelength add different fluorescent agents can be made into required wavelength and photochromic and in vivo can be more than continuous luminous half an hour, light intensity can reach 0.5mw/cm
2The sensitization light source of photodynamic action.
4. guide miniature anticancer light bullet according to claim 1 is characterized in that, described chemiluminescence agent only just produces chemiluminescence with luminous catalyst action the time, the incorporation of fluorescent lifetime length and intensity and catalyst and concentration are directly proportional as to chemiluminescence agent such as bromine phenolic group magnesium bromides.
5. guide miniature anticancer light bullet according to claim 1 is characterized in that, the luminous catalyst of described chemiluminescence agent is to be oxidant with the hydrogen peroxide, in the photodynamic therapy process with can replace hydrogen peroxide to make the even more ideal light intensity of the luminous generation of the intravital chemiluminescence agent of machine and the hyperbaric oxygen therapy of photodynamic effect.
6. guide miniature anticancer light bullet according to claim 1 is characterized in that, described chemiluminescence agent becomes the coenosarc thing with the photosensitizer coupling, produces a kind of new photosensitizer and new sensitization light source as bromine phenolic group magnesium bromide is become the synthetics of common phenyl ring with the hematoporphyrin derivative coupling.
7. guide miniature anticancer light bullet according to claim 1 is characterized in that, described carcinophilia material can be make sensitization light source and photosensitizer have dual tropism target administration Emulsion can be delivered to any position in the body the cellularity sensitizing range, can reduce photodynamic action the light toxic and side effects make the monoclonal antibody of Emulsion as continuous phase.
8. guide miniature anticancer light bullet according to claim 1 is characterized in that described chemical laser agent can be with 248nm laser photolysis C
2The HBr molecule is produced and is produced luminous its intensity with oxygen reaction.
9. guide miniature anticancer light bullet according to claim 1 is characterized in that, described treatment viral infection, acquired immune deficiency syndrome (AIDS) and parasitic disease are that target area generation photodynamic action selective killing pathological tissues is made dual tropism target administration Emulsion with corresponding monoclonal antibody as continuous phase in vivo.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 94116524 CN1119518A (en) | 1994-09-30 | 1994-09-30 | Guide miniature anticancer light bullet |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 94116524 CN1119518A (en) | 1994-09-30 | 1994-09-30 | Guide miniature anticancer light bullet |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1119518A true CN1119518A (en) | 1996-04-03 |
Family
ID=5037940
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 94116524 Pending CN1119518A (en) | 1994-09-30 | 1994-09-30 | Guide miniature anticancer light bullet |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1119518A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000007933A1 (en) * | 1998-08-05 | 2000-02-17 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | Device and method for the production of singlet oxygen |
-
1994
- 1994-09-30 CN CN 94116524 patent/CN1119518A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000007933A1 (en) * | 1998-08-05 | 2000-02-17 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | Device and method for the production of singlet oxygen |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Xie et al. | Emerging combination strategies with phototherapy in cancer nanomedicine | |
| Bovis et al. | Improved in vivo delivery of m-THPC via pegylated liposomes for use in photodynamic therapy | |
| CN109481680B (en) | Composite nano photosensitizer capable of being repaired internally and externally as well as preparation method and application thereof | |
| Tian et al. | A pH-activatable and aniline-substituted photosensitizer for near-infrared cancer theranostics | |
| Pan et al. | Photosensitive drug delivery systems for cancer therapy: Mechanisms and applications | |
| Wen et al. | One-for-all phototheranostics: Single component AIE dots as multi-modality theranostic agent for fluorescence-photoacoustic imaging-guided synergistic cancer therapy | |
| Sun et al. | Advanced techniques for performing photodynamic therapy in deep-seated tissues | |
| CN101102766B (en) | Novel derivatives of porphyrin, particularly chlorins and/orbacteriochlorins, and uses thereof in photodynamic therapy | |
| CN1842322A (en) | Non-polar photosensitizer formulations for photodynamic therapy | |
| CN101130082A (en) | Novel photosensitive agent with function of carrying oxygen | |
| CN108159422A (en) | A kind of preparation method of self assembly drug-loading system and its compound formulation | |
| CN102961337B (en) | Preparation method of target compound nano particle | |
| CN103491980B (en) | Utilize OPK therapeutic agent or the diagnostic agent of region of ultra-red light | |
| CN106362152A (en) | Material for tumor photothermic treatment and preparation method and application thereof | |
| US20210228719A1 (en) | Triplet-triplet energy transfer with light excitation at long wavelengths and methods thereof | |
| US20120323163A1 (en) | Methods of using dual-effect liposome in therapy | |
| Nishiwaki et al. | New method of photosensitizer accumulation for photodynamic therapy in an experimental liver tumor | |
| CN1119518A (en) | Guide miniature anticancer light bullet | |
| CN101850118B (en) | Preparation method and application in preparation of photodynamic therapy medicines of fat-soluble photosensitizer loaded on inorganic salt carrier | |
| CN110051632B (en) | Enhanced photodynamic anti-tumor nano drug delivery system and preparation method and application thereof | |
| Barr et al. | Photodynamic therapy with ALA: a clinical handbook | |
| US6495585B2 (en) | Method for treating hyperproliferative tissue in a mammal | |
| CN110115763A (en) | A kind of multi-functional liposome and the preparation method and application thereof of near infrared light activation | |
| CN113499312A (en) | Supramolecular core-shell compound, supramolecular drug-loaded core-shell compound, and preparation methods and applications of supramolecular core-shell compound and supramolecular drug-loaded core-shell compound | |
| CN111214656A (en) | Photothermal targeting nano-drug for treating breast cancer and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |