CN114146086A - Application of verteporfin in preparation of anti-cancer pain medicine - Google Patents
Application of verteporfin in preparation of anti-cancer pain medicine Download PDFInfo
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- CN114146086A CN114146086A CN202210071021.7A CN202210071021A CN114146086A CN 114146086 A CN114146086 A CN 114146086A CN 202210071021 A CN202210071021 A CN 202210071021A CN 114146086 A CN114146086 A CN 114146086A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/409—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The invention relates to application of verteporfin in preparing a medicine for resisting cancer pain. The invention provides a new pharmaceutical application of verteporfin, and discovers that verteporfin has the effect of resisting cancer pain for the first time, and can be applied to preparation of a medicine for resisting cancer pain. Verteporfin accomplishes this by inhibiting the expression, aggregation and nuclear entry of the dorsal horn YAP and TAZ. The verteporfin is a targeted drug with high potential for resisting cancer pain, has pertinence in the treatment process, has a remarkable curative effect, is small in side effect and low in tolerance, provides a theoretical basis for researching the treatment strategy of the cancer pain, and provides an insertion point for preparing a novel drug for treating the cancer pain.
Description
Technical Field
The invention belongs to the technical field of biological medicines, relates to a new application of verteporfin serving as a medicine, and particularly relates to an application of verteporfin in preparation of an anti-cancer pain medicine.
Background
Cancer pain is widespread among cancer patients, and 75% to 90% of patients with metastatic or advanced cancer experience significant cancer pain. In certain cancers (e.g., pancreatic cancer, head and neck cancer, osteosarcoma), pain originates from the primary site of the cancer. However, in many common cancers, such as breast, prostate, kidney and lung, these tumors can rapidly metastasize to multiple bones of the body, including the vertebrae, ribs, hip, femur and tibia. This results in significant bone pain due to the many sites of metastasis.
Cancer pain is mainly manifested as moderate and severe spontaneous pain accompanied by a series of abnormal pain sensations to external stimuli, such as allodynia, mechanical, thermal, psychroalgia, etc. With the popularization and application of the three-step treatment principle of the world health organization and the NCCN guideline for adult cancer pain, the problems of drug safety, addiction, tolerance and the like exist through drug treatment such as steroid analgesics, tramadol, opioid analgesics and the like. Cancer pain has no specific targeted therapeutic target in clinical treatment, an effective analgesic method and an analgesic drug are lacked, the clinical effect is poor, 80% of cancer patients can relieve pain symptoms through standard and effective treatment, but 20% of cancer pain which is difficult to treat still exists, and the conventional drug is difficult to take effect.
CN101636391B discloses a prophylactic and/or therapeutic agent for neuropathic pain, which uses 2- [ (substituted-inden-7-yloxy) methyl ] morpholine or a pharmaceutically acceptable salt thereof as an active ingredient, for the following pain: allodynia, hyperalgesia, hyperesthesia, spontaneous pain, cancer pain, trigeminal neuralgia, phantom limb pain, post-herpetic pain, fibromyalgia syndrome, low and low pain in the waist and legs, thalalgia, atypical facial pain, pain associated with spinal cord injury, pain associated with multiple sclerosis.
CN108379263A discloses a pharmaceutical composition for treating cancer pain, which comprises the following active ingredients: diazepam, aminopyrine, antipyrine, barbital. When diazepam, aminopyrine, antipyrine and barbital are used together according to a certain proportion, the synergistic effect is achieved, the analgesic effect on the aspect of treating cancer pain is obvious, the advantages of small dosage, low toxic and side effect of the medicine and high compliance of patients are achieved, the life quality of cancer patients can be improved, and the treatment cost is reduced.
However, at present, there are few treatment strategies for cancer pain, and therefore, it is very meaningful to develop a drug which has a significant therapeutic effect and is targeted for treating cancer pain.
Verteporfin, the Chinese name Verteporfin, is trans- (+ -) -18-ethylene-4, 4 a-dihydro-3, 4-bis (carbomethoxy) -4a,8,14, 19-tetramethyl-23H, 25H-phenylporphyrin-9, 13-dipropyl ester chemically named 9-methyl (I) and 13-methyl (II). Verteporfin is clinically used for treating age-related macular degeneration. US2017043015(a1) discloses a method of crosslinking corneal collagen with verteporfin for treating eye disorders, compositions and methods for increasing corneal biomechanical strength using vertebroperfin-based photodynamic therapy (PDT), and more particularly, compositions and methods for crosslinking collagen in corneal tissue useful for treating corneal ectasia disorders.
Meanwhile, CN111956643A discloses the application of verteporfin in preparation of obesity drugs, and experiments prove that verteporfin relieves obesity by reducing adipose tissue content, thereby providing experimental basis for clinical treatment of pathological obesity. However, there are no reports of verteporfin relief of pain, especially cancer pain.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a new application of the drug verteporfin, in particular to an application of verteporfin in preparing the drug for resisting cancer pain.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides the use of verteporfin for the manufacture of a medicament for combating cancer pain.
Verteporfin, the chemical names of which are 9-methyl (I) and 13-methyl (II) -trans- (±) -18-ethylene-4, 4 a-dihydro-3, 4-bis (carbomethoxy) -4a,8,14, 19-tetramethyl-23H, 25H-benzoporphyrin-9, 13-dipropyl ester.
The invention discovers that the verteporfin has the effect of resisting cancer pain for the first time, and can be applied to preparing the medicine for resisting cancer pain. The verteporfin realizes the functions by inhibiting the expression, aggregation and nuclear entry of YAP and TAZ of spinal cord dorsal horn, wherein YAP is yes kinase related protein, and TAZ is transcription combined activator. Nerve injury caused by tumor compression or infiltration promotes the expression and accumulation of YAP or TAZ in spinal cord dorsal horn, causes central sensitization and causes pain. YAP or TAZ act like a "switch" in the development and progression of cancer pain, with increased levels leading to pain and decreased levels relieving pain. Therefore, the verteporfin is a targeted drug with high potential for resisting cancer pain, and has pertinence and obvious curative effect in the treatment process.
Preferably, the cancer pain includes pain caused by tumor compression or tumor infiltration at an early stage of cancer, and pain caused by tumor compression or tumor infiltration at an advanced stage in cancer.
The invention discovers for the first time that the verteporfin can be used for not only early cancer and delaying the occurrence and development of cancer pain, but also middle and late cancer and relieving cancer pain, and has wide application range.
Preferably, the manifestation of cancer pain comprises mechanical allodynia, thermal allodynia, spontaneous pain, allodynia.
Preferably, the verteporfin inhibits the expression of both YAP and TAZ proteins of the dorsal horn of the spinal cord.
In a second aspect, the present invention provides an anticancer pain medication comprising verteporfin.
Preferably, the dosage form of the medicament is any pharmaceutically acceptable dosage form, such as tablets, powders, suspensions, granules, capsules, solutions, enemas, emulsions and the like.
Preferably, the medicine further comprises pharmaceutically acceptable pharmaceutic adjuvants, wherein the pharmaceutic adjuvants comprise any one or a combination of at least two of a carrier, a diluent, an excipient, a filler, a binder, a wetting agent, a disintegrating agent, an emulsifier, a cosolvent, a solubilizer, an osmotic pressure regulator, a surfactant, a coating material, a coloring agent, a pH regulator, an antioxidant, a bacteriostatic agent or a buffering agent.
The combination of at least two of the above-mentioned components, such as the combination of diluent and excipient, the combination of emulsifier and cosolvent, the combination of filler and binder and wetting agent, etc., can be selected in any combination manner, and will not be described in detail herein.
The verteporfin can be loaded on a common medicinal carrier to be used as a medicament for resisting cancer pain, so that better biocompatibility, biological safety and medicinal effect are realized. The anticancer pain medicine can be independently administered or matched with auxiliary materials to be prepared into a proper dosage form for administration.
In a third aspect, the invention also provides an application of verteporfin in preparing a YAP protein inhibitor or a TAZ protein inhibitor.
In a fourth aspect, the invention also provides the use of verteporfin in the preparation of a YAP protein inhibitor or TAZ protein inhibitor for non-diagnostic and/or therapeutic purposes.
The research of the invention discovers that the CTGF expression of target genes of YAP and TAZ of spinal cord dorsal horn of cancer model rats is obviously reduced after the injection of verteporfin (abbreviated as VP) in the sheath, and based on the phenomenon, verteporfin can also be used for preparing YAP protein inhibitor or TAZ protein inhibitor aiming at non-diagnosis and/or treatment, and has long-term significance in other scientific research experiments.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a new pharmaceutical application of verteporfin, and discovers that verteporfin has the effect of resisting cancer pain for the first time, and can be applied to preparation of a medicine for resisting cancer pain. Verteporfin accomplishes this by inhibiting the expression, aggregation and nuclear entry of the dorsal horn YAP and TAZ. The verteporfin is a targeted drug with high potential for resisting cancer pain, has pertinence in the treatment process, has a remarkable curative effect, is small in side effect and low in tolerance, provides a theoretical basis for researching the treatment strategy of the cancer pain, and provides an insertion point for preparing a novel drug for treating the cancer pain.
Drawings
FIG. 1 is a graph showing the statistics of the results of mechanical pain sensitivity test in each group of rats in example 1;
FIG. 2 is a statistical chart showing the results of changes in the expression levels of YAP and TAZ in each group in example 2;
FIG. 3 is a Western blot of the various groups YAP and TAZ of example 2;
FIG. 4 is a statistical chart of the results of mechanosensitive assays in the groups of rats in example 3;
FIG. 5 is a statistical chart showing the sole landing time of rats in each group in example 3;
FIG. 6 is a statistical graph of lameness scores of the groups of rats in example 3;
FIG. 7 is a statistical graph showing the expression level of CTGF in the target gene of YAP/TAZ in spinal cord dorsal horn of rats of each group in example 3;
FIG. 8 is a graph showing the results of mechanical pain sensitivity test in each group of rats in example 4.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
The rats selected in the following examples were SD (Sprague Dawley, Sprague-Dow).
The following examples relate to groups including: TCI group (i.e., tibial medullary cavity inoculated with tumor cells), Sham group (i.e., Sham group, rat tibial medullary cavity inoculated with tumor cells that have been inactivated), TCI + verteporfin group (i.e., tumor cell inoculated group given injection of verteporfin).
The following examples relate to the fabrication of the TCI model and the Sham model, as follows: injecting Walker 256 breast cancer cells into SD rat abdominal cavity, collecting tumor-bearing rat ascites after 14 days, centrifuging at 1000rpm for 5min, discarding supernatant, rinsing with sterile PBS buffer (1000rpm × 5min) for 2-3 times, and resuspending tumor cells with PBS buffer to 1 × 10 concentration5Mu L of the cells are put in an ice box for standby. And taking the cells with the adjusted concentration to be subjected to water bath in boiling water for 10min to be used as inactivated cells. Rats were anesthetized with isoflurane and fixed in the supine position. At 1/3 in the middle of the left tibia, the skin was dissected along the long axis of the tibia, with 75% ethanol, and the muscles were separated to expose the bone surface of the tibia. Drilling a small hole on the bone surface by using a needle head of a 1mL syringe, then using a micro syringe with the volume of 20 mu L to enter a tibial bone marrow cavity through the small hole, and slowly injecting 5 mu L of tumor cells to establish a TCI model; while the same volume of inactivated cells was injected into the Sham model rats. After the injection is completed, the needle is retained for about 30s, and then the micro-syringe is pulled out. The needle hole is sealed by using sterile bone wax and dental cement, and a proper amount of erythromycin powder is smeared on the wound and then is sutured. The whole operation process is carried out according to the aseptic requirement. Namely, the TCI model and the Sham model are successfully established.
The following examples relate to the detection of mechanical hyperalgesia, which reflects the sensitivity of the rat to mechanical stimuli, and the lower the value, the more sensitive the rat to mechanical stimuli, and the specific method is as follows: mechanociception rats were challenged on their plantar skin with von frey and the pressure at which the rats contracted the foot reflex was recorded.
Example 1
Detection test for mechanical hyperalgesia (1)
The 28 male rats were randomly divided into TCI group (22), Sham group (6). The mechanorelgesia of each group of rats was measured 1 day before molding, 1 day after molding, 3 days, 5 days, 7 days, 10 days, 14 days, and 21 days, respectively, wherein the molding methods of the TCI group and Sham group were as described above, and the mechanorelgesia was measured as described above.
The test result is shown in fig. 1, after the rats are subjected to TCI modeling, the mechanical pain sensitivity of the TCI group is reduced, and the pain sensitivity of the Sham group is almost unchanged, which indicates that the rats have obvious cancerous pain after being inoculated with tumor cells, and the pain threshold value is gradually reduced along with time.
Example 2
Detection of expression of YAP and TAZ in rat spinal cord dorsal horn by Western blotting (1)
The following tests were carried out using rats whose tests were completed in example 1: the rats were decapped and sacrificed at 1 day, 3 days, 5 days, 7 days and 14 days after molding, respectively, and the rats L were taken out3-L5Corresponding spinal cord segments (i.e., the third, fourth and fifth lumbar segments of the spinal cord) were examined for expression of YAP and TAZ at spinal cord dorsal horn by immunoblotting.
As shown in the test results in FIG. 2 and FIG. 3, the YAP and TAZ contents of spinal cord dorsal horn of TCI group rats were significantly increased at 1 day, 3 days, 5 days, 7 days and 14 days after molding, while the YAP and TAZ contents of spinal cord dorsal horn of Sham group rats were not changed, which indicates that the YAP and TAZ contents of spinal cord dorsal horn of rats were significantly increased after tumor cell inoculation, and the inactivated tumor cell inoculation did not result in the YAP and TAZ contents of spinal cord dorsal horn of rats.
Example 3
Detection test for mechanical hyperalgesia (2)
18 male rats were randomly divided into TCI + PEG400, Sham, and TCI + verteporfin groups, 6 per group, and pre-fed for 7 days. The mechanical hyperalgesia of each group of rats was examined 1 day before molding, 1 day after molding, 3 days, 5 days, 7 days, 9 days, 12 days, 14 days, 21 days, respectively. Among them, the modeling method of the Sham group was the same as in example 1, and 20. mu.L of solvent PEG400 and 20. mu.L of verteporfin (0.45 mg of verteporfin dissolved in 20. mu.L of PEG400 per rat) were injected into sheaths of rats of the TCI + PEG400 group and the TCI + verteporfin group, respectively, on the 3 rd day after the modeling, and the administration was continued for 3 days. The method of detection of mechanical hyperalgesia is the same as in example 1.
The test result is shown in fig. 4, after the rats are subjected to TCI modeling, the mechanical pain sensitivity of the rats in the TCI group is reduced, the rats in the Sham group are almost unchanged, and the mechanical pain sensitivity of the rats in the TCI group can be remarkably inhibited by intrathecally injecting verteporfin in the early stage of modeling, which indicates that verteporfin can remarkably inhibit the generation and development of cancer pain, while the injection of the solvent PEG400 does not influence the pain threshold.
Evaluation of rat movement-induced pain behavior
The specific operation is as follows: the rats in example 3 were evaluated for exercise-induced pain behavior on day 14 after molding. Rats were placed in a clean plexiglass box (100X 60X 40cm), the affected limb was stroked, and the time during which the rat raised the affected limb during exercise was not used was observed and recorded for two minutes. Meanwhile, scoring is carried out according to the use condition of the affected limb when the rat moves: 0 min-normal use of affected limb; 1 point-light limp; 2 min-apparent lameness; 3 min-sometimes use the affected limb; 4 min-no affected limb at all. The statistical results are shown in fig. 5 and 6.
Spinal cord dorsal horn YAP/TAZ downstream gene expression quantity detection test
The specific operation is as follows: after rats were anesthetized with isoflurane on day 14 after molding, the heart was perfused with 0.1M PBS, the spinal cord dorsal horn from L3-L5 was taken, total RNA was extracted with RNA extraction kit and reverse-transcribed into cDNA, and CTGF gene expression level was detected by q-PCR method, with the results shown in fig. 7. Compared with the Sham group, the expression level of the downstream gene of the YAP/TAZ of the spinal cord dorsal horn of the rat in the TCI group is obviously increased at 14 days after the model building, and the expression level of the downstream gene of the YAP/TAZ of the spinal cord dorsal horn of the rat in the TCI + Verteporfin group is obviously reduced relative to the expression level of the downstream gene of the YAP/TAZ of the spinal cord dorsal horn of the rat in the TCI group.
Example 4
Detection test for mechanical hyperalgesia (3)
12 male rats were randomly divided into TCI + PEG400 and TCI + verteporfin groups, 6 per group, and pre-fed for 7 days. The mechanical hyperalgesia of each group of rats was examined 1 day before molding, 3 days, 5 days, 7 days, 9 days, 11 days, 13 days, 16 days, and 21 days after molding, respectively. On day 7 after molding, 20. mu.L of solvent PEG400 and 20. mu.L of verteporfin (0.45 mg of verteporfin dissolved in 20. mu.L of artificial cerebrospinal fluid is administered per rat) are injected intrathecally into rats in the TCI + PEG400 group and TCI + verteporfin group, respectively, and administration is continued for 3 days. The method of detection of mechanical hyperalgesia is the same as in example 1.
The test result is shown in fig. 8, after the rats are subjected to TCI modeling, the mechanical pain sensitivity of the rats in the TCI + PEG400 group is reduced, and the mechanical pain sensitivity of the rats subjected to TCI is remarkably reduced by intrathecally injecting verteporfin in the late stage of the modeling, which indicates that verteporfin can remarkably inhibit the development of cancer pain, and the injection of PEG400 does not affect the pain threshold.
The applicant states that the invention is illustrated by the above examples of the use of verteporfin according to the invention in the preparation of a medicament against cancer pain, but the invention is not limited to the above examples, i.e. it does not mean that the invention must be implemented by means of the above examples. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.
Claims (8)
1. Use of verteporfin in the manufacture of a medicament for treating cancer pain.
2. The use of claim 1, wherein the cancer pain comprises pain caused by tumor compression or tumor infiltration at an early stage of cancer, and pain caused by tumor compression or tumor infiltration at a late stage in cancer.
3. The use of claim 1 or 2, wherein the manifestation of cancer pain comprises mechanical, thermal, spontaneous, and allodynia.
4. The use of any one of claims 1 to 3, wherein verteporfin inhibits the expression of both YAP and TAZ proteins of the dorsal horn of the spinal cord.
5. An anti-cancer pain medication comprising verteporfin.
6. The anticancer pain medication of claim 5, wherein the dosage form of the medication is any one of the pharmaceutically acceptable dosage forms.
7. The anticancer pain medication of claim 5 or 6, further comprising pharmaceutically acceptable pharmaceutical excipients, wherein the pharmaceutical excipients comprise any one or a combination of at least two of a carrier, a diluent, an excipient, a filler, a binder, a wetting agent, a disintegrant, an emulsifier, a cosolvent, a solubilizer, an osmotic pressure regulator, a surfactant, a coating material, a colorant, a pH regulator, an antioxidant, a bacteriostatic agent or a buffer.
8. Application of verteporfin in preparing YAP protein inhibitor or TAZ protein inhibitor.
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| CN111956643A (en) * | 2020-09-15 | 2020-11-20 | 西安交通大学 | Application of verteporfin in preparation of obesity drug |
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