CN109846857B - Preparation method and application of active natural supramolecular photosensitizer - Google Patents
Preparation method and application of active natural supramolecular photosensitizer Download PDFInfo
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Abstract
The invention discloses a preparation method and application of an active natural supramolecular photosensitizer, wherein a sterol carrier nano particle is used as a carrier, and a chlorin photosensitizer Ce6 is used as a medicine to prepare the active supramolecular photosensitizer. The invention takes the natural product with anticancer activity as the nano-carrier to carry the photosensitizer, on one hand, the prepared nano-composite photosensitizer has obviously improved water solubility, enhanced stability, increased active oxygen yield and improved cell phagocytosis capacity, and ensures high-efficiency in vitro and in vivo anticancer activity; on the other hand, the combination of the sterol product with anticancer activity and the single photosensitizer has obvious synergistic anticancer effect, and meanwhile, the sterol substance has excellent biocompatibility and biodegradability, so that efficient and safe antitumor treatment is finally ensured.
Description
Technical Field
The invention belongs to the technical field of biomedical materials, and relates to a preparation method and application of an active natural supramolecular photosensitizer.
Background
Cancer is one of the important diseases that seriously threaten human health and life safety at present, and the search for novel, effective and safe anti-cancer drugs is always a focus of attention of researchers. Currently, among many anticancer approaches, photodynamic therapy has been widely reported and recognized as a novel tumor treatment mode with little invasiveness, low toxic and side effects, safety and high efficiency. The core of photodynamic therapy is photosensitizer, which is widely researched at present, namely chlorin photosensitizer with low toxicity, but the photosensitizer generally has the defects of low bioavailability, poor water solubility, easy aggregation under physiological conditions, low tumor targeting selectivity and the like, and limits the clinical practical application of the photosensitizer. Therefore, the development of a proper carrier for transportation has great significance for improving the water solubility of the photosensitizer, improving the tumor targeting property of the photosensitizer and enhancing the anticancer curative effect.
Supramolecular chemistry (intermolecular chemical reaction) generally refers to the binding of two or more substances by intermolecular non-covalent forces. Based on the weak acting force, the supermolecule photosensitizer has great advantages in photodynamic therapy, and most of the self-assembled or co-assembled novel photosensitizers have obvious anticancer effect. Based on the strategy, a plurality of substances with excellent biocompatibility, easy biodegradability and certain anticancer activity are used for constructing the carrier transport photosensitizer, and the defects of the traditional photodynamic therapy photosensitizer are overcome. However, it is important that these carriers do not have these excellent properties, and additional molecules with self-assembly ability are required to construct supramolecular photosensitizer, and the preparation process is relatively complicated. Therefore, it is necessary to develop a vector having the above-mentioned excellent properties. The natural product is derived from organisms and has good biocompatibility and biodegradability. The sterol substances have excellent physiological activity (such as anticancer), and can be used as a carrier to construct a supermolecular system for transporting a photosensitizer, so that on one hand, the defects of the photosensitizer can be overcome, on the other hand, the constructed nano system is expected to improve the tumor targeting of the medicine based on the enhanced permeability and retention Effect (EPR), and moreover, the substances with anticancer activity are expected to play the role of synergistically enhancing the anticancer curative effect, so that safe and efficient tumor physiotherapy is really realized.
Disclosure of Invention
In order to solve the defects of poor water solubility, low stability, low bioavailability caused by easy aggregation under physiological conditions, low anticancer activity caused by poor tumor targeting property and the like of the traditional chlorin photosensitizer (such as chlorin e6, Ce6 for short), the invention provides a preparation method and application of an active natural supramolecular photosensitizer. The invention takes sterol natural products with anticancer activity as a carrier to transport the photosensitizer, and achieves the purposes of enhancing the water solubility and tumor targeted aggregation capability of the single photosensitizer and synergistic anticancer curative effect.
The purpose of the invention is realized by the following technical scheme:
a preparation method of active natural supramolecular photosensitizer takes sterol carrier nano particles as a carrier and dihydroporphin photosensitizer Ce6 as a medicine to prepare the active supramolecular photosensitizer, and comprises the following steps:
(1) dissolving Ce6 dimethyl sulfoxide solution (less than or equal to 15 mg/mL) and sterols in organic solvent (carbon tetrachloride, dichloromethane, trichloromethane or acetone), then dropwise adding into 2.5% (mass/volume ratio) polyvinyl alcohol aqueous solution, vortex emulsifying for 0.25-2 min, controlling the mass ratio of Ce6 and sterols to be less than or equal to 15%, the volume ratio of the mass of sterols to the organic solvent to be less than or equal to 10, and the volume ratio of the organic solvent to the 2.5% polyvinyl alcohol aqueous solution to be 1: 1-5;
(2) emulsifying for 20-90 s by adopting an ultrasonic cell disruptor under an ice bath condition;
(3) quickly adding the emulsion obtained in the step (2) into 0.3% (mass/volume ratio) of polyvinyl alcohol aqueous solution, magnetically stirring and volatilizing the organic reagent at room temperature in a dark place, and controlling the volume ratio of the organic solvent to the 0.3% of polyvinyl alcohol aqueous solution to be 1: 20-50, and the magnetic stirring speed is 350-600 rpm;
(4) centrifuging to obtain active supermolecule photosensitizer, washing with secondary distilled water repeatedly, and freeze-drying for storage.
The active supermolecule photosensitizer prepared by the method can be used for anti-tumor treatment.
Compared with the prior art, the invention has the following advantages:
one of the main limiting factors of the traditional photodynamic therapy is that the photosensitizer has poor water solubility and is easy to aggregate under physiological conditions, so that the yield of active oxygen is reduced, and the aggregation of the photosensitizer medicine at tumor sites is reduced to a great extent, thereby limiting the clinical use of the photosensitizer medicine. Therefore, in order to overcome the defect, the invention uses natural products with anticancer activity as nano-carriers to carry photosensitizer, on one hand, the prepared nano-composite photosensitizer has obviously improved water solubility, enhanced stability, increased active oxygen yield and improved cell phagocytosis capacity, and ensures high-efficiency in vitro and in vivo anticancer activity; on the other hand, the combination of the sterol product with anticancer activity and the single photosensitizer has obvious synergistic anticancer effect, and meanwhile, the sterol substance has excellent biocompatibility and biodegradability, and finally ensures efficient and safe antitumor therapy (the in vitro mouse tumor inhibition rate is 86.4%).
Drawings
Fig. 1 is a Scanning Electron Microscope (SEM) picture of three nano drug-loaded systems, a: beta-sitosterol (Stio NPs), B: ergosterol (Ergo NPs), C: stigmasterol (Stigma NPs);
FIG. 2 is a graph of the anticancer toxicity of three individual vectors against 4T1 cells at different concentrations;
FIG. 3 is a graph of the anti-cancer toxicity of three individual vectors against MCF-7 cells at different concentrations;
FIG. 4 shows the in vitro phototoxicity results of three kinds of nano-photosensitizers, namely Ergo-Ce6 NPs, Stigma-Ce6 NPs and Stio-Ce6 NPs, with different concentrations on 4T1 cells;
FIG. 5 shows the in vitro phototoxicity results of three nano-photosensitizers, namely Ergo-Ce6 NPs, Stigma-Ce6 NPs and Stio-Ce6 NPs, with different concentrations on MCF-7 cells;
FIG. 6 is a UV-VIS spectrum of the single vector Ergo NPs, Ce6, Ergo-Ce6 NPs and Ergo NPs/Ce6 mixture;
FIG. 7 is a graph of relative tumor volume changes of mice treated three times with Ergo NPs, Ce6, Ergo-Ce6 NPs under light;
FIG. 8 is a graph of volume change during treatment of mouse cancer.
Detailed Description
The technical solution of the present invention is further described below with reference to the accompanying drawings, but not limited thereto, and any modification or equivalent replacement of the technical solution of the present invention without departing from the spirit and scope of the technical solution of the present invention shall be covered by the protection scope of the present invention.
The invention provides a preparation method of an active natural supramolecular photosensitizer, which comprises the following steps:
(1) preparation of sterol natural product carrier Nano Particles (NPs)
Mainly comprises three sterol carriers: ergosterol (Ergosterol, Ergo NPs), Stigmasterol (Stigmasterol, Stigma NPs), beta-sitosterol (beta-Stiosterol, Stio NPs), having the following structural formula:
the invention adopts an emulsion solvent volatilization method to prepare carrier nano particles, and the method comprises the following specific steps: 5 mg of sterols (ergosterol, stigmasterol, beta-sitosterol) were dissolved in 1mL of an organic solvent (carbon tetrachloride or methylene chloride), then dropwise added to 4 mL of a 2.5% (mass/volume ratio) aqueous polyvinyl alcohol solution, followed by vortex emulsification for 1 min, and further emulsified with an ultrasonic cell disruptor for 60s under ice bath conditions (frequency: 5s ultrasound, 5s rest, ultrasonic intensity: 40%). The obtained emulsion was quickly added to 40 ml of 0.3% aqueous polyvinyl alcohol solution, and the organic reagent was volatilized under magnetic stirring at 400 rpm in the dark at room temperature for 12 hours. Then, the Nanoparticles (NPs) were obtained by centrifugation at 12000 rpm, washed repeatedly 3 times with redistilled water, and then lyophilized for storage.
FIG. 1 is SEM pictures of nano materials prepared by three sterols. By adopting an emulsion solvent volatilization method, the three sterol substances can form nano particles with uniform appearance and excellent dispersibility. Wherein the beta-sitosterol and the ergosterol form rod-shaped nanoparticles, and the average particle size is 273 (l) × 113 (w) and 154 (l) × 95 (w) nm respectively. And stigmasterol can form rod-shaped nanoparticles with the average particle size of 585 (l) multiplied by 114 (w). This demonstrates that all three sterols can be used as a nanomaterial to transport photosensitizers or other drug molecules.
(2) Preparation of active supramolecular photosensitizers
The three natural sterol substances are respectively used as carriers, and the chlorin photosensitizer Ce6 is used as a medicine to prepare three supramolecular photosensitizers, namely Ergo-Ce6 NPs, Stigma-Ce6 NPs and Stio-Ce6 NPs.
mu.L of Ce6 dimethyl sulfoxide solution (. ltoreq.15 mg/mL) and 5 mg of sterol carrier (ergosterol, stigmasterol,. beta. -sitosterol) were dissolved in 1mL of organic solvent (carbon tetrachloride or methylene chloride), followed by dropwise addition to 4 mL of 2.5% (mass/volume) aqueous polyvinyl alcohol solution. Three drug-loaded supramolecular photosensitizers were obtained by strictly identical conditions for the preparation of vectors (Ergo NPs, Stigma NPs, Stio NPs).
Three supramolecular photosensitizers are dissolved by using dimethyl sulfoxide as a solvent, and the drug loading of Ce6 is detected by adopting a high performance liquid chromatography. The specific conditions are as follows: mobile phase: column temperature 30 ℃, mobile phase: 0.2% aqueous phosphoric acid/acetonitrile =40/60 (volume ratio), flow rate: 1mL/min, detection wavelength: 402 nm. Finally, determining the drug loading rates respectively as follows: Ergo-Ce6 NPs (3.4%), Stigma-Ce6 NPs (2.4%), Stio-Ce6 NPs (4.3%).
FIG. 2 is a graph showing the cell viability of 4T1 cells cultured with each of the three vectors. The results show that all three nanoparticles have concentration-dependent anticancer activity, and the cell survival rate is gradually reduced along with the increase of the drug concentration. Among them, Ergo NPs and Sito NPs are significantly more cytotoxic than Stigma NPs. Under the concentration of 25 mu g/mL, the tumor inhibition rates of Ergo NPs and Sito NPs are 48% and 39% respectively, which shows that the three nano-carriers have anticancer activity and are expected to realize the purpose of synergistic treatment with drugs.
FIG. 3 is a graph showing the survival rate of MCF-7 cells cultured with three vectors. The results also demonstrate that the three vectors are also cytotoxic to human MCF-7 breast cancer cells, and that at 25. mu.g/mL, the tumor inhibition rates of Ergo NPs and Sito NPs are 45% and 48%, respectively, which are also higher than Stigma NPs (37%).
The results of fig. 2 and 3 show that the natural product sterol substance has certain anticancer activity, and is expected to achieve the purposes of synergistic anticancer and curative effect enhancement after drug loading.
(3) Evaluation of three active supramolecular photosensitizers (Ergo-Ce 6 NPs, Stigma-Ce6 NPs, Stio-Ce6 NPs) in vitro anticancer activity
The anti-cancer activity of the drug under the illumination condition is detected by adopting a standard MTT method by taking murine 4T1 breast cancer cells and human MCF-7 breast cancer cells as cell strains respectively. The specific process is as follows: the method comprises the steps of inoculating tumor cells by using a 96-well plate, adding equivalent Ce6 medicines with different concentrations after the cells adhere to the wall for 24 hours, continuously culturing for 4 hours, then carrying out illumination treatment for 10 min under 675 +/-10 nm infrared light, and then detecting the cell survival rate by using an MTT method.
FIG. 4 shows the cell viability of 4T1 cells after incubation with three photosensitizers in combination with light. The results in the figure clearly show that under the concentration of the equivalent medicament Ce6, the three carriers show obviously increased cell inhibition rate after carrying the medicament, and the anticancer effect is obvious. Wherein, when the concentration of Ce6 is 1 mug/mL, the tumor cell inhibition rates of Ergo-Ce6 NPs and Sito-Ce6 NPs are respectively 70% and 68%, while the tumor cell inhibition rate of Stigma-Ce6 NPs is 82%, which is obviously higher than that of Ce6 alone (the cell inhibition rate is 42%). The result shows that the phototoxicity of the single drug to tumor cells is obviously increased after the three carriers carry the photosensitizer, and the single drug has obvious anticancer curative effect.
Fig. 5 shows that the cell survival rate of MCF-7 after incubation with three photosensitizers under illumination for 10 min shows concentration-dependent cell inhibition, and gradually decreases with increasing concentration of photosensitizers. Particularly, when the concentration of equivalent Ce6 is 0.5 mug/mL, the anti-cancer activity is remarkably increased compared with that of a free Ce6 drug (12% inhibition rate), and the cell inhibition rates of Ergo-Ce6 NPs, Stigma-Ce6 NPs and Stio-Ce6 NPs are respectively 94%, 94% and 72%.
The results of fig. 4 and 5 fully demonstrate that three vectors coated with the photosensitizer Ce6 exhibit significantly enhanced cellular activity, and this anticancer activity is derived from two aspects: 1) the carrier has activity, and the anticancer effect of the medicine is synergistically increased; 2) after the photosensitizer is loaded, the water solubility of the photosensitizer is increased by the nanoparticles prepared by an emulsification method, and the low phototoxicity caused by self-polymerization is reduced. The results fully show that: the three natural active carriers can be used as drug carriers to construct supramolecular photosensitizers.
(4) Using Ergo-Ce6 NPs as an example, the in vivo anticancer effect was examined.
Balb-c female white mice inoculated with 4T1 tumor cells are taken as tumor-bearing study objects, and the anticancer effect of the drug is studied by adopting a tail vein injection administration mode. The specific experiments were divided into two groups of 5 mice each: 1-blank control group: injection of 5% dextrose in water only; 2-vector group Ergo NPs alone; 3-administration group Ergo-Ce6 NPs: after 6h of Ergo-Ce6 NPs (equivalent Ce 64 mg/kg) injection via tail vein, rats were anesthetized and the tumors were exposed to light for 15min under infrared light. The rats were treated for 14 days on days 0, 3 and 6, respectively, during which the edema was recorded every two daysTumor volume and body weight. Mouse tumor volume calculation formula: v = (L × W)2)/2。
FIG. 6 shows the UV absorption of Ergo NPs, Ce6, Ergo-Ce6 NPs and mixture Ergo NPs/Ce 6. The single vector Ergo NPs only have four characteristic absorption peaks (264, 274, 285, 297 nm) in the ultraviolet region, and the drug Ce6 has distinct Soret peaks and Qy peaks, 406 nm and 668nm respectively. After the supermolecule photosensitizer Ergo-Ce6 NPs is constructed, ultraviolet absorption spectra of the supermolecule photosensitizer Ergo-Ce6 NPs show corresponding characteristic peaks of carriers Ergo NPs and Ce6, and the maximum absorption wavelength (Qy peak) shows obvious red shift to 672 nm, which indicates that the ergosterol molecules of the carriers and the photosensitizer Ce6 have pi-pi interaction, and the red shift phenomenon is promoted. Furthermore, the UV absorption spectrum of Ergo-Ce6 NPs is different from that of the mixture alone (Ergo NPs/Ce 6), and there is no distinguishable change in the peak of the absorption maximum wavelength Qy of Ce6 in the mixture. The above results indicate that Ce6 was successfully coated in nanoparticles formed by ergosterol as a carrier.
Fig. 7 is a graph showing the change in tumor volume of mice after treatment with the corresponding drug. The volume inhibition rates of the single medicines Ce6 and Ergo NPs after being treated under the illumination condition are respectively 61% and 52%, and the tumor inhibition rate of the medicine-carrying Ergo-Ce6 NPs reaches 86.4%, which is obviously higher than the anticancer effect of the single medicines when the medicines and the Ergo NPs are used separately, which shows that the Ce6 and the Ergo NPs have obvious synergistic anticancer effect, and the obvious anticancer curative effect of the supramolecular photosensitizer Ergo-Ce6 NPs further proves that after the active natural product carries the photosensitizer medicine, the synergistic anticancer purpose can be realized, and the clinical application is expected to be realized.
Fig. 8 is a graph showing the weight change of mice during different drug treatments, and it can be seen from the graph that the weight of the mice has not particularly obvious change, except the weight loss occurring in the second day of administration, the mice also return to normal in the subsequent treatment, which shows that the supramolecular photosensitizer Ergo-Ce6 NPs has good safety and biocompatibility, and has no obvious physiological toxicity. This further illustrates that the active natural product is a safe and effective carrier.
Claims (6)
1. A preparation method of active natural supramolecular photosensitizer is characterized in that sterol carrier nano particles are used as a carrier, and chlorin photosensitizer Ce6 is used as a medicine to prepare the active supramolecular photosensitizer, and the preparation method comprises the following specific steps:
(1) dissolving a Ce6 dimethyl sulfoxide solution and sterols into an organic solvent, dropwise adding the solution into a 2.5% mass/volume ratio polyvinyl alcohol aqueous solution, and performing vortex emulsification for 0.25-2 min, wherein the sterols are ergosterol, stigmasterol or beta-sitosterol;
(2) emulsifying for 20-90 s by adopting an ultrasonic cell disruptor under an ice bath condition;
(3) quickly adding the emulsion obtained in the step (2) into a polyvinyl alcohol aqueous solution with the mass/volume ratio of 0.3%, and magnetically stirring to volatilize the organic reagent at room temperature in a dark place;
(4) centrifuging to obtain active supermolecule photosensitizer, washing with secondary distilled water repeatedly, and freeze-drying for storage.
2. The method for the preparation of active natural supramolecular photosensitizers as claimed in claim 1, characterized in that said organic solvent is carbon tetrachloride, dichloromethane, trichloromethane or acetone.
3. The method for preparing active natural supramolecular photosensitizer according to claim 1, characterized in that the mass ratio of Ce6 and sterol is not more than 15%, the volume ratio of sterol to organic solvent is not more than 10, and the volume ratio of organic solvent to 2.5% polyvinyl alcohol aqueous solution is 1: 1 to 5.
4. The method for the preparation of active natural supramolecular photosensitizers as claimed in claim 1, characterized in that the volume ratio of organic solvent to 0.3% aqueous polyvinyl alcohol solution is 1: 25-40, and the magnetic stirring speed is 350-600 rpm.
5. The method for preparing active natural supramolecular photosensitizer as claimed in claim 1, characterized in that the concentration of Ce6 dimethyl sulfoxide solution is less than or equal to 15 mg/mL.
6. Use of the active supramolecular photosensitizers prepared by the process as claimed in any one of claims 1 to 5 for the preparation of medicaments for the treatment of tumors.
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