CN109172824A - A kind of pharmaceutical composition and preparation method thereof for treating cutaneous squamous cell carcinoma - Google Patents
A kind of pharmaceutical composition and preparation method thereof for treating cutaneous squamous cell carcinoma Download PDFInfo
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Abstract
The invention discloses a kind of pharmaceutical composition and preparation method thereof for treating cutaneous squamous cell carcinoma, which includes auxiliary material and active constituent, and the active constituent includes photosensitizer couplings and ethylenediamine tetra-acetic acid manganese disodium；Wherein ethylenediamine tetra-acetic acid manganese disodium and the mass ratio of photosensitizer couplings are 1:10-30；The photosensitizer couplings are made of chitosan, hyaluronic acid, photosensitizer by the molar ratio of 3:1:1；Wherein, hyaluronic acid is the identical wortmannin of molar ratio and Sodium Hyaluronate is compound obtains.Pharmaceutical composition prepared by the present invention can directly act on pathological tissues, and property is stablized, can attach to skin surface for a long time, be conducive to the release of drug, and the treatment works well.
Description
Technical field
The present invention relates to a kind of pharmaceutical compositions and preparation method thereof for treating cutaneous squamous cell carcinoma, belong to biology
Field of medicaments.
Background technique
Cutaneous squamous cell carcinoma (skim squamous cell carcinoma, SCC) is a kind of evil originating from epidermis
Property tumour, in Australian area, ultraviolet light irradiation is strong, and resident is mainly the white race, and SCC disease incidence may be up to 25
People/ten thousand.SCC is common in face, scalp, lower lip, the back of the hand etc., and site of disease easily forms ulcer, and basal part protuberance turns up, to trouble
The image and physical and mental health of person causes tremendous influence.With the increase of motion frequency outside household, the disease incidence of SCC increases year by year
Add, it has also become one of high-incidence tumour.Currently, clinical treatment SCC is mainly using operation excision and chemotherapy, still, both sides
There are still many deficiencies for method, and such as operation excision influences appearance, and has the risk of recurrence, and chemotherapeutics is cell toxicity medicament, right
Patient body has certain toxic side effect, can often cause vomiting, alopecia, anorexia, the symptoms such as immunity degradation, strong to patient's body and mind
Health brings injury.
Photodynamic therapy (Photodynamic Therapy, PDT) is a kind of new treatment to grow up for nearly 20 years
The method of malignant tumour.Its principle for treating tumour is to input photosensitizer after human body to irradiate lesion with the light of specific wavelength
Position, the singlet oxygen (singlet oxygen) or free radical (free radical) Oxidative demage tissue for recycling reaction to generate
With the various large biological molecules in cell, thus make cancer cell occur it is irreversible damage and it is dead.This method is successfully applied
In bladder cancer, the cancer of the esophagus, bronchiolar carcinoma, carcinoma of mouth, cutaneum carcinoma, nasopharyngeal carcinoma, pleura carcinoma mesothelial, liver cancer, laryngocarcinoma, breast cancer and
The treatment of the cancer of the brain etc..During killing tumor cell, photosensitizer plays decision as the carrier of energy and the bridge of reaction
The effect of property.
Photodynamic therapy has dual selection specificity to tumour, can directionally eliminate primary and recurrent tumour, seldom damage
Hurt normal tissue, toxic side effect is small, and patient can be made from the dangerous and simple and easy of general anesthesia.
Photosensitizer is considered as the core component of photodynamic therapy clinical treatment, up to the present, clinically mainly
Using having two generation photosensitizers, including first generation photosensitizer hematoporphyrin derivative (HpD), second generation photosensitizer etioporphyrin (ETIO) tin, methylene
Base orchid etc..However, developed photosensitizer still has shortcoming, in which:
First generation photosensitizer component is complicated, and easily causes skin photo sensitive reaction, and treatment depth is inadequate；The second generation is photosensitive
Though agent has very big improvement on the basis of the first generation, but still there are many defects, such as: Chinese invention patent (application number:
CN02806725.8, publication number: CN1531442) involved in quinone, water solubility is poor, and stability is poor in aqueous solution,
The adjustment amplitude of absorbing wavelength is less and molecular structure is not easy to be modified.
When with photodynamic therapy treatment cutaneous squamous cell carcinoma, tablet class photosensitive drug need to after patient takes, with
The circulatory system reaches pathological tissues, other auxiliary elements not only using duration, but also containing in drug are easy to make patient body
At unnecessary influence, injection class photosensitive drug is then relatively high to pharmaceutical properties requirement, and production cost is big, in contrast, frost
Agent formulation can not only directly act on pathological tissues, and property is stablized, and the normal time can attach to skin surface, be conducive to drug
Release.
Based on this, we have developed AKT and MAKP cell signal inhibitor-EtNBSe couplings, and combine ethylenediamine tetraacetic
Combination drug frost is made in manganese acetate disodium.
Summary of the invention
In view of the above technical problems, the present invention uses photosensitizer EtNBSe, and coupling AKT and MAKP cell signal inhibitor is made
For photosensitive drug core component, and compound creme class drug is made.The purpose of the present invention is to provide one kind can effectively improve light
Power curative effect reduces AKT the and MAKP cell signal inhibitor coupling EtNBSe photosensitizer combination drug frost of drug resistance, passes through light
Motivation therapy treats cutaneous squamous cell carcinoma.
The technical scheme is that providing a kind of for treating the pharmaceutical composition of cutaneous squamous cell carcinoma, the drug
Composition includes auxiliary material and active constituent, and the active constituent includes photosensitizer couplings and ethylenediamine tetra-acetic acid manganese disodium；Its
Middle ethylenediamine tetra-acetic acid manganese disodium and the mass ratio of photosensitizer couplings are 1:10-30；The photosensitizer couplings by chitosan,
Hyaluronic acid, photosensitizer are made by the molar ratio of 3:1:1；
Wherein, hyaluronic acid is the identical wortmannin of molar ratio and Sodium Hyaluronate is compound obtains；It is described
The chemical structural formula of photosensitizer are as follows:Wherein Et indicates ethyl.The photosensitizer
Be abbreviated as EtNBSe.
The manganese ion that ethylenediamine tetra-acetic acid manganese disodium contains can effectively facilitate photosensitizer and generate singlet oxygen, improve photosensitizer
Couplings kill the effect of close cancer cell.
Photosensitizer couplings of the invention include hyaluronic acid or salt (such as hyalomitome sodium), wortmannin, chitosan,
EtNBSe.Although new and composite construction can be formed between these substances, the degree of Covalent bonding together has not yet been reached, because
This, the present invention is referred to as couplings.It may be perovskite structure according to preliminary analysis.
Preferably, which is creme, and auxiliary material is cream base.
Preferably, the cream base by it is oily mutually and water phase emulsifies to obtain, by weight, oil mutually by 5-10 parts of lanolin,
1-10 parts of glycerin monostearate, 15-20 parts of albolene, 5-10 parts of atoleine compositions；Water phase by 30-50 parts of distilled water,
5-10 parts of glycerol, 2-4 parts of ethylparaben compositions.
Preferably, wherein ethylenediamine tetra-acetic acid manganese disodium and the mass ratio of photosensitizer couplings are 1:20.
The preparation method of described pharmaceutical composition, comprising the following steps:
(1) wortmannin of equimolar ratio is mixed with Sodium Hyaluronate, obtains hyaluronic acid；
(2) chitosan, hyaluronic acid, photosensitizer are mixed by the molar ratio of 3:1:1, are dissolved in organic solvent,
Ultrasonic vibration (80KHz) 5-20min, then be centrifuged, supernatant is taken, obtains photosensitizer couplings after dry；
(3) photosensitizer couplings are dispersed in the oily phase of cream base, ethylenediamine tetra-acetic acid manganese disodium is dispersed in frost
In the water phase of agent matrix, then by it is oily mutually and water phase emulsifies to obtain described pharmaceutical composition.
Preferably, in step (2), the rate of centrifugation is 6000~8000r/min.
The invention has the advantages that pharmaceutical composition prepared by the present invention can directly act on pathological tissues, property is steady
It is fixed, skin surface can be attached to for a long time, be conducive to the release of drug, and the treatment works well.
Detailed description of the invention
Fig. 1 is the autophagy scale of construction schematic diagram of A-431 cell generation after the processing of gradient concentration pharmaceutical composition.
Fig. 2 is the relative expression quantity signal of LC3b and Lamp in A-431 cell after the processing of gradient concentration pharmaceutical composition
Figure.
Fig. 3 is LC3b in A-431 cell, the column relational graph of Lamp relative expression quantity and pharmaceutical composition concentration.
Fig. 4 is after gradient concentration pharmaceutical composition is handled, and p-AKT, p-ERK, p-JNK and p-P38 are opposite in A-431 cell
Expression quantity schematic diagram.
Fig. 5 is p-AKT, p-ERK, p-JNK and p-P38 relative expression quantity and pharmaceutical composition concentration in A-431 cell
Column relational graph.
Fig. 6 is p-AKT, p-ERK, p-JNK and p- in A-431 cell after the processing of 400nM pharmaceutical composition gradient timetable
P38 relative expression quantity schematic diagram.
When Fig. 7 is that p-AKT, p-ERK, p-JNK and p-P38 relative expression quantity and pharmaceutical composition are handled in A-431 cell
Between column relational graph.
Fig. 8 is after the PDT of pharmaceutical composition processing, and different time sections nude mouse tumor is sliced Electronic Speculum observation schematic.
Fig. 9 is the different time sections nude mouse tumor situation of change schematic diagram after the PDT of pharmaceutical composition processing.
Figure 10 is that the A-431 cell by EtNBSe, pharmaceutical composition individually after irradiation is handled, through MTT analysis is living
Property figure.
Specific embodiment
Photosensitizer couplings treatment cutaneous squamous cell carcinoma effect is described in detail below with reference to experiment and attached drawing.
Embodiment 1: the preparation of pharmaceutical composition
The pharmaceutical composition of the present embodiment the preparation method is as follows:
(1) lanolin 5g, glycerin monostearate 2g, albolene 15g, atoleine 5g are taken, oily phase is mixed to get；It takes
Distilled water 30ml, glycerol 5g, ethylparaben 2g, are mixed to get water phase.Gained oil is mutually individually placed to water phase spare on one side.
(2) at room temperature, 0.01mol wortmannin and 0.01mol Sodium Hyaluronate are dissolved in 5ml ethylene glycol, sufficiently
Mixing, obtains hyaluronic acid.
(3) it sequentially adds 0.03mol chitosan and 0.01mol photosensitizer EtNBSe sufficiently reacts, with the ultrasound of 80kHz
Concussion continues 10min, then 5000r/min centrifugation 5min takes supernatant, dry as photosensitizer couplings at 5 DEG C.
(4) gained photosensitizer couplings are dispersed in oily phase obtained, 0.2g ethylenediamine tetra-acetic acid manganese disodium are taken, by it
Disperse in water phase obtained, water phase is added slowly in oily phase using magnetic heating stirrer, until generation milky creme is
It can.
Pharmaceutical composition manufactured in the present embodiment is used for following experiment and carries out effect assessment.
Application examples 1, pharmaceutical composition make squamous cell carcinoma generate autophagy embodiment
(1) experimental method
Squamous cell carcinoma A-431 cell line is incubated in the DMEM culture solution of 10% calf serum, adds the mould of 100IU/L
The streptomysin of element and 100mg/L is placed in 37 DEG C, and routine culture in the constant incubator of 5%CO2 is abandoned after cell covers with bottom of bottle
Falling culture solution, PBS liquid rinsed twice, then with 0.25% pancreatin and 0.02% EDTA digestion 5 minutes, by its sub-bottle culture, 2
Primary to passage in 3 days, logarithmic growth phase cell is for testing.
The A-431 cell of logarithmic growth phase is inoculated in six well culture plates after pancreatin digests, and is placed in 37 DEG C, 5%CO2
Constant incubator in routine culture, it is to be grown to 80%~90% Fusion Strain when, being separately added into concentration in every hole is
The photosensitizer couplings of 0nM, 100nM, 200nM, 400nM, 800nM use 20J/cm after being incubated for 1h2Red light irradiation 15min,
Acridine orange is used after 16h, there is a situation where autophagy for observation cell.
The A-431 cell of logarithmic growth phase is inoculated in six well culture plates after pancreatin digests, and is placed in 37 DEG C, 5%CO2
Constant incubator in routine culture, it is to be grown to 80%~90% Fusion Strain when, being separately added into concentration in every hole is
The photosensitizer couplings of 0nM, 100nM, 200nM, 400nM, 800nM use 20J/cm after being incubated for 1h2Red light irradiation 15min,
Cell extraction total protein is collected after 16h, with LC3b, the expression quantity of Lamp in Western Blot method detection cell.
(2) experimental result
Autophagosome staining conditions such as Fig. 1 institute that A-431 cell generates after graded doses pharmaceutical composition-PDT processing
Show, analysis result can obtain, the pass that the concentration gradient of the autophagy scale of construction and pharmaceutical composition that A-431 cell generates is positively correlated
System.
A-431 cell autophagy key protein LC3b after graded doses pharmaceutical composition-PDT processing, Lamp is with respect to table
It is as shown in Figure 2 up to amount.According to fig. 2, autophagy key protein LC3b, Lamp relative expression quantity and pharmaceutical composition concentration are made respectively
Column relational graph, as shown in figure 3, analysis result can show that the expression quantity of LC3b and Lamp is through pharmaceutical composition in A-431 cell
It obviously increases after object-PDT processing, and is positively correlated with the dosage of pharmaceutical composition.
Experiment shows that pharmaceutical composition-PDT can be obviously promoted squamous cancer cell system A-431 and autophagy, and facilitation occurs
Enhance as pharmaceutical composition concentration increases.
Application examples 2, pharmaceutical composition-PDT inhibit squamous cancer cell AKT and MAPK signal embodiment
(1) experimental method
Squamous cell carcinoma A-431 cell line is incubated in the DMEM culture solution of 10% calf serum, adds the mould of 100IU/L
The streptomysin of element and 100mg/L is placed in 37 DEG C, and routine culture in the constant incubator of 5%CO2 is abandoned after cell covers with bottom of bottle
Falling culture solution, PBS liquid rinsed twice, then with 0.25% pancreatin and 0.02% EDTA digestion 5 minutes, by its sub-bottle culture, 2
Primary to passage in 3 days, logarithmic growth phase cell is for testing.
The A-431 cell of logarithmic growth phase is inoculated in six well culture plates after pancreatin digests, and is placed in 37 DEG C, 5%CO2
Constant incubator in routine culture, it is to be grown to 80%~90% Fusion Strain when, being separately added into concentration in every hole is
The pharmaceutical composition of 0nM, 100nM, 200nM, 400nM, 800nM use 20J/cm after being incubated for 1h2Red light irradiation 15min, half
Cell extraction total protein is collected after hour, with p-AKT, p-ERK, p-JNK and p-P38 in Western Blot method detection cell
Expression quantity.
The A-431 cell of logarithmic growth phase is inoculated in culture dish after pancreatin digests, and is placed in 37 DEG C, the perseverance of 5%CO2
Routine culture in warm incubator, it is to be grown to 80%~90% Fusion Strain when, 400nM medicine group is added in each culture dish
Object is closed, after being incubated for 1h, uses 20J/cm2Red light irradiation 15min, respectively at pharmaceutical composition-PDT handle 0.5h, 1h, 2h, 8h
With collection cell extraction total protein after 16h, p-AKT, p-ERK, p-JNK and p-P38 in cell are detected with Western Blot method
Expression quantity.
(2) experimental result
A-431 cell its p-AKT, p-ERK, p-JNK and p-P38 phase after graded doses pharmaceutical composition-PDT processing
It is as shown in Figure 4 to expression quantity.According to Fig. 4, p-AKT, p-ERK, p-JNK and p-P38 relative expression quantity and medicine group are made respectively
Object concentration column relational graph is closed, as shown in Figure 5.Analysis result can obtain, through EtNBSe-PDT treated A-431 cell
In, p-AKT, p-JNK and p-P38 relative expression quantity is obviously increased as pharmaceutical composition dosage increases；P-ERK relative expression quantity
It obviously increases, but when pharmaceutical composition dosage reaches 400nM, reinforcing effect is gradually decreased.
A-431 cell its p-AKT, p-ERK, p-JNK and p- after the processing of 400nM pharmaceutical composition-PDT gradient timetable
P38 relative expression quantity is as shown in Figure 6.According to Fig. 6, make respectively p-AKT, p-ERK, p-JNK and p-P38 relative expression quantity with it is wet
Spoke-like relational graph when graceful penicillin-EtNBSe processing, as shown in Figure 7.Analysis result can obtain, at pharmaceutical composition-PDT
When managing 0.5h after A-431 cell, p-AKT, p-ERK, p-JNK and p-P38 relative expression quantity reach peak in cell, then by
Gradually it is returned to normal value.
Experiment shows that pharmaceutical composition-PDT has obvious inhibiting effect to squamous cancer cell AKT and MAPK signal path, and
When handling duration is 0.5 hour, inhibiting effect effect is the most obvious.
Application examples 3, pharmaceutical composition-PDT treat Skin Squamous Cell Carcinoma cytoma embodiment
(1) zoopery
Mouse squamous cytoma model, selection weight are 18-20g male nude mouse.When experiment, well-grown A-431 is taken
Cell, with sterile saline by tumor cell suspension, every mouse or so is made after 1:10 dilution proportion after pancreatin digests
Oxter portion is inoculated with 0.1ml tumor liquid.After tumor inoculation success, every nude mice right side tumor subcutaneous injection 1mM pharmaceutical composition is given
Object medicament, left side tumour are not handled as control, use 20J/cm2Red light irradiation 15min, respectively at pharmaceutical composition-PDT locate
Reason puts to death a nude mice and collects processing tumour and untreated tumor biopsy after 3 days, 7 days, 14 days and 21 days, Electronic Speculum observes tumour
Generate autophagy situation.
Separately take tumour subcutaneous injection 1mM pharmaceutical composition medicament on the left of nude mice, right side tumor do not handle as pair
According to using 20J/cm2Red light irradiation 15min, in 2 days, 4 days, 7 days, 12 days, 14 days, 17 days and 24 days observation tumor presences.
(2) experimental result
Different time collects nude mouse tumor production slice after pharmaceutical composition-PDT processing, and Electronic Speculum observes result such as Fig. 8 institute
Show.Result can obtain according to observations, and processing group generates a large amount of autophagosomes compared to untreated fish group, and cell passes through autophagy itself apoptosis, table
Bright pharmaceutical composition-PDT can promote tumor mass to generate autophagy.
Different time observes tumour situation of change after pharmaceutical composition-PDT processing, and observation nude mice result is as shown in Figure 9.According to
Observation result can obtain, with the passage of processing time, tumor mass is obvious downright bad after pharmaceutical composition-PDT processing and gradually contracts
It is small, show that pharmaceutical composition-PDT has good therapeutic effect to squamous cell tumor.
Application examples 4, pharmaceutical composition-PDT inhibit A-431 cell activity
(1) experimental method
Squamous cell carcinoma A-431 cell line is incubated in the culture solution containing 10% tire calf serum, it is outstanding to be made into individual cells
Liquid, with the standard of 1000-10000, every hole cell by the cell suspension inoculation in three 96 orifice plates, the volume in every hole is
200ul.Physiological saline, EtNBSe and pharmaceutical composition 400nmol are separately added into each hole of above three orifice plate, through laser
After irradiating 1min, the cell line is placed in 37 DEG C, routine culture 3 days in the constant incubator of 5%CO2.
After culture, the MTT solution 20ul that 5mg/ml is formulated by PBS is added into each hole of the orifice plate,
And continue to be incubated for 4 hours in the constant incubator containing 5%CO2, incubation temperature is 37 DEG C.It is incubated for after terminating, careful inhale abandons institute
The culture supernatant in hole is stated, after centrifugation, inhales the culture supernatant abandoned in hole again.Then, into each hole of the orifice plate
150ul DMSO is added, vibrates 10 minutes, after completely dissolution, the orifice plate is placed in enzyme linked immunological monitor for object to be crystallized,
To assess each boreliquid in the absorbance of 490nm, and record result.
(2) experimental result
Respectively through EtNBSe, pharmaceutical composition processing and with the cell activity after laser irradiation it is as shown in Figure 10.By in figure
As a result it is found that for compared with the control group, the A-431 cell activity of EtNBSe group and pharmaceutical composition group under illumination condition
Very low, however, described the two is in contrast, the cell lethality of pharmaceutical composition is higher, shows pharmaceutical composition of the present invention
The activity of A-431 cell can more be inhibited than EtNBSe.
Claims (6)
1. a kind of for treating the pharmaceutical composition of cutaneous squamous cell carcinoma, which is characterized in that the pharmaceutical composition includes auxiliary material
And active constituent, the active constituent include photosensitizer couplings and ethylenediamine tetra-acetic acid manganese disodium；Wherein ethylenediamine tetra-acetic acid
Manganese disodium and the mass ratio of photosensitizer couplings are 1:10-30；The photosensitizer couplings are compound by chitosan, hyaluronic acid
Object, photosensitizer are made by the molar ratio of 3:1:1；
Wherein, hyaluronic acid is the identical wortmannin of molar ratio and Sodium Hyaluronate is compound obtains；It is described photosensitive
The chemical structural formula of agent are as follows:Wherein Et indicates ethyl.
2. pharmaceutical composition as described in claim 1, which is characterized in that the pharmaceutical composition is creme, and auxiliary material is creme base
Matter.
3. pharmaceutical composition as claimed in claim 2, which is characterized in that the cream base is mutually emulsified with water phase by oily
It arrives, by weight, oil is mutually by 5-10 parts of lanolin, 1-10 parts of glycerin monostearate, 15-20 parts of albolene, atoleine
5-10 parts of compositions；Water phase is made of 30-50 parts of distilled water, 5-10 parts of glycerol, 2-4 parts of ethylparaben.
4. pharmaceutical composition as described in any one of claims 1-3, which is characterized in that wherein ethylenediamine tetra-acetic acid manganese disodium with
The mass ratio of photosensitizer couplings is 1:20.
5. a kind of preparation method of such as described in any item pharmaceutical compositions of claim 2-4, which is characterized in that including following step
It is rapid:
(1) wortmannin of equimolar ratio is mixed with Sodium Hyaluronate, obtains hyaluronic acid；
(2) chitosan, hyaluronic acid, photosensitizer are mixed by the molar ratio of 3:1:1, is dissolved in organic solvent, ultrasound
5-20min is shaken, then is centrifuged, supernatant is taken, obtains photosensitizer couplings after dry；
(3) photosensitizer couplings are dispersed in the oily phase of cream base, ethylenediamine tetra-acetic acid manganese disodium is dispersed in creme base
In the water phase of matter, then by it is oily mutually and water phase emulsifies to obtain described pharmaceutical composition.
6. preparation method as claimed in claim 5, which is characterized in that in step (2), the rate of centrifugation is 6000~8000r/
min。
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| WO2022237864A1 (en) * | 2021-05-14 | 2022-11-17 | The University Of Hong Kong | Compositions and methods of macropinocytosis inhibitors and photodynamic therapy to treat cancers |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022237864A1 (en) * | 2021-05-14 | 2022-11-17 | The University Of Hong Kong | Compositions and methods of macropinocytosis inhibitors and photodynamic therapy to treat cancers |
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