CN111012911A - Application of sodium alginate as antitumor drug targeting carrier - Google Patents
Application of sodium alginate as antitumor drug targeting carrier Download PDFInfo
- Publication number
- CN111012911A CN111012911A CN202010125433.5A CN202010125433A CN111012911A CN 111012911 A CN111012911 A CN 111012911A CN 202010125433 A CN202010125433 A CN 202010125433A CN 111012911 A CN111012911 A CN 111012911A
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- CN
- China
- Prior art keywords
- sodium alginate
- phthalocyanine
- conjugate
- targeting carrier
- tumor
- 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.)
- Granted
Links
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Abstract
The invention discloses an application of sodium alginate as an antitumor drug targeting carrier and a phthalocyanine-sodium alginate conjugate prepared based on the application. The invention utilizes the characteristic that scavenger receptors on the surfaces of macrophages related to tumor tissues have selectivity on sodium alginate, uses sodium alginate as a carrier, and generates the phthalocyanine-sodium alginate conjugate by coupling carboxyl on the sodium alginate and amino in a phthalocyanine compound through amido bonds.
Description
Technical Field
The invention belongs to the field of medicine preparation, and particularly relates to an application of sodium alginate as an antitumor medicine targeting carrier, and a phthalocyanine-sodium alginate conjugate prepared based on the application.
Background
Tumor-associated macrophages (TAMs) are abundant and widely present in various tumor tissues, and thus TAMs can be effective targets for antitumor therapy and diagnosis. TAMs express on their surface a variety of receptors associated with their ability to recognize phagocytic function, including lectins, mannose receptors, Scavenger Receptors (SRs), and the like.
Sodium alginate is a naturally occurring anionic polymer, usually obtained from brown seaweed, and is a linear copolymer formed by β -D-mannuronic acid (β -D-mannuronic, M) and α -L-guluronic acid (α -L-guluronic, G) connected through (1 → 4) glycosidic bonds.
Phthalocyanines are aromatic heterocycles consisting of a nitrogen atom bridging four isoindole rings. Phthalocyanine as a second generation photosensitizer in photodynamic therapyThere are many advantages in application: its maximum absorption band (lambda)max>670 nm) is positioned in a red light area with stronger tissue penetrating power, and simultaneously shows low absorption in a 400-600 nm area with the highest sunlight intensity, which is beneficial to treating deeper tumors and reducing the skin phototoxicity caused by sunlight; their chemical structures are easy to modify, and various central metal ions are easy to introduce, and make axial or peripheral modification. Thus, phthalocyanines are a very promising photosensitizer. However, the phthalocyanine complex with bioactivity reported at present still has defects, such as easy aggregation in physiological solution, poor biological selectivity and the like, and thus the clinical application of the phthalocyanine complex is limited. The development of an effective delivery system that contains a phthalocyanine drug and transfers it into a target tissue, addressing the key biological barrier of conventional phthalocyanine delivery, is one of the current directions in which novel phthalocyanines are developed.
Disclosure of Invention
The invention provides an application of sodium alginate as an antitumor drug targeting carrier by utilizing the characteristic that sodium alginate has targeting property on tumor-associated macrophages (TAM), and provides a phthalocyanine-sodium alginate conjugate and a preparation method thereof based on the application. The obtained conjugate shows good anti-tumor activity and extremely high photodynamic activity, has targeting property on tumor-related macrophages, and has remarkable advantages when being used as a photosensitizer or a therapeutic drug.
In order to achieve the purpose, the invention adopts the following technical scheme:
the application of sodium alginate as an antitumor drug targeting carrier can utilize the characteristic that scavenger receptor-A (SR-A) on the surface of macrophage related to tumor tissue has selectivity on sodium alginate, and the sodium alginate is used as the targeting carrier to prepare the tumor targeting drug.
Specifically, a method for using sodium alginate as an antitumor drug targeting carrier, which uses sodium alginate as the targeting carrier, and utilizes carboxyl on the sodium alginate and amino in a phthalocyanine compound to generate a phthalocyanine-sodium alginate conjugate through amido bond coupling, wherein the phthalocyanine-sodium alginate conjugate has targeting property on tumor-related macrophages; the chemical structural formula of the conjugate is as follows:
The preparation method of the phthalocyanine-sodium alginate conjugate comprises the steps of firstly using acidizing fluid to make sodium alginate in a carboxylate form (-COO)-) Converting into carboxylic acid (-COOH) form, and adding tetrabutylammonium hydroxide for neutralization to obtain tetrabutylammonium alginate; then using a phthalocyanine compound (A)
) And reacting with tetrabutylammonium alginate serving as a reaction raw material, dimethyl sulfoxide (DMSO) serving as a solvent, 2-chloro-1-methylpyridinium iodide (CMPI) serving as a condensation reagent and triethylamine serving as an acid-binding agent at 20-35 ℃ under the protection of nitrogen for 20 hours, adding a high-concentration NaCl solution to convert the tetrabutylammonium salt into sodium salt, and finally carrying out solvent precipitation, suction filtration, dialysis and freeze drying to obtain the phthalocyanine-sodium alginate conjugate.
The preparation method comprises the following specific steps:
1) dispersing sodium alginate in 70vol% formic acid/water solution or 1M hydrochloric acid/ethanol solution, stirring for 1h in ice water, transferring to 20-35 ℃, continuously stirring for 5 h, filtering, washing the obtained crude alginic acid with 70vol% to 100vol% ethanol water solution and acetone respectively, dispersing the alginic acid crude product in purified water after vacuum drying, slowly adding 10-40 wt% tetrabutylammonium hydroxide water solution to adjust the pH to be =8 +/-1, immediately freezing, and freeze-drying to obtain tetrabutylammonium alginate;
2) dissolving the obtained tetrabutylammonium alginate salt in DMSO, and stirring at 20-35 ℃ under the protection of nitrogen to completely dissolve the tetrabutylammonium alginate salt; then adding CMPI dissolved in DMSO, and activating for 1 h; and adding a phthalocyanine compound and triethylamine, continuing to react for 20 hours, finally adding 2.5M NaCl solution into the reaction solution, stirring for 10 minutes, pouring the reaction solution into 70-95 vol% ethanol water solution, violently stirring for 1 hour, standing for 30 minutes, performing suction filtration by using a sand core funnel, washing by using acetone, redissolving the obtained product in water, performing dialysis purification, and performing freeze-drying to obtain the phthalocyanine-sodium alginate conjugate.
The mass-volume ratio of the sodium alginate used in the step 1) to the acidizing fluid (70 vol% formic acid/water solution or 1M hydrochloric acid/ethanol solution) is 1: 20-200 g/mL, and the molecular weight of the sodium alginate is 1-2000 kDa.
The mol ratio of the phthalocyanine compound to the sodium alginate in the step 2) is 1: 20-200; the molar ratio of the CMPI to the phthalocyanine compound is 1: 2-20; the molar ratio of the triethylamine to the phthalocyanine compound is 1: 10-100.
The obtained phthalocyanine-sodium alginate conjugate can be used for preparing photodynamic medicaments, including photodynamic anti-cancer medicaments, photodynamic diagnostic agents and the like. The photodynamic therapy may be photodynamic therapy of malignant tumours, or photodynamic therapy of benign tumours, or photodynamic therapy of non-cancer diseases. The non-cancer disease can be bacterial infection, oral disease, macular degeneration eye disease, wound infection, skin disease or virus infection.
The phthalocyanine-sodium alginate conjugate provided by the invention is generated by coupling amino in a phthalocyanine compound and carboxyl on sodium alginate through amido bonds, so that the phthalocyanine-sodium alginate conjugate has the characteristics of phthalocyanine and sodium alginate. The surface potential of the conjugate is negative potential, and the property enables the conjugate to enter the interior of cells through SR-A on the surface of tumor-related macrophages, so that the conjugate can be enriched in tumor tissues, and simultaneously phthalocyanine in the conjugate generates photodynamic anti-cancer activity under the excitation of external red light. Therefore, the phthalocyanine-sodium alginate conjugate provided by the invention is a targeted anticancer drug with photodynamic therapy.
The application method comprises the following steps: dissolving the phthalocyanine-sodium alginate conjugate by using a mixed solution of water and other substances as a solvent to prepare a corresponding medicament (the concentration of the phthalocyanine-sodium alginate conjugate in the medicament is not higher than the saturated concentration); the prepared medicament can also be added with an antioxidant, a buffering agent and an isotonic agent so as to maintain the chemical stability and the biocompatibility of the photosensitive medicament.
The mass fraction of other substances in the mixed solution is not higher than 10%, and the other substances are one or more of castor oil derivatives, dimethyl sulfoxide, ethanol, glycerol, N-dimethylformamide, 300-3000 parts of polyethylene glycol, cyclodextrin, glucose, tween and polyethylene glycol monostearate.
The invention has the beneficial effects and outstanding advantages that:
(1) the invention adopts sodium alginate as the tumor drug targeting carrier, and has the advantages of rich source, low price and the like.
(2) The phthalocyanine-sodium alginate conjugate prepared by the invention not only keeps the photoactivity of pure amino zinc phthalocyanine, but also keeps the negative potential characteristic of the surface of sodium alginate.
(3) The phthalocyanine-sodium alginate conjugate prepared by the invention can be effectively positioned in tumor tissues by utilizing the selectivity of sodium alginate on tumor-related macrophages, namely, the phthalocyanine-sodium alginate conjugate has certain tumor targeting property, and pure phthalocyanine has no obvious positioning effect.
(4) The phthalocyanine-sodium alginate conjugate prepared by the invention can be directly dissolved in water for medicament preparation, and obviously improves the aggregation behavior of pure amino phthalocyanine in a water phase.
(5) The phthalocyanine-sodium alginate conjugate prepared by the invention has obvious anti-tumor effect and IC (integrated Circuit) of photodynamic inhibition macrophage J774A.150Can be as low as 0.5 mu M, lower than the corresponding value (IC) of pure amino zinc phthalocyanine50>3 mu M), the tumor inhibition rate reaches 86.9 percent in a mouse living body experiment.
Drawings
FIG. 1 is a graph showing the comparison of the electron absorption spectra of a phthalocyanine compound with (a) a phthalocyanine-sodium alginate conjugate (I) and (b) a phthalocyanine-sodium alginate conjugate (II) in water at the same phthalocyanine concentration.
FIG. 2 shows the dark toxicity and photodynamic activity of phthalocyanine compounds, phthalocyanine-sodium alginate conjugates (I) and phthalocyanine-sodium alginate conjugates (II) on HepG2 cells and J774A.1 cells, respectively.
FIG. 3 is a graph showing fluorescence images of (a) phthalocyanine-sodium alginate conjugate (I), (b) phthalocyanine-sodium alginate conjugate (II) and (c) phthalocyanine compound in mice.
FIG. 4 is a graph showing the change in tumor volume in each group of mice in tumor suppression experiments.
Detailed Description
A conjugate prepared by taking sodium alginate as a targeting carrier comprises the following steps:
1) dispersing sodium alginate in 70vol% formic acid/water solution or 1M hydrochloric acid/ethanol solution, stirring for 1h in ice water, transferring to 20-35 ℃, continuously stirring for 5 h, filtering, washing the obtained crude alginic acid with 70vol% to 95vol% ethanol water solution and acetone respectively, dispersing the alginic acid crude product in purified water after vacuum drying, slowly adding 10-40 wt% tetrabutylammonium hydroxide water solution to adjust the pH to be =8 +/-1, immediately freezing, and freeze-drying to obtain tetrabutylammonium alginate;
2) dissolving the obtained tetrabutylammonium alginate salt in DMSO, and stirring at 20-35 ℃ under the protection of nitrogen to completely dissolve the tetrabutylammonium alginate salt; then adding CMPI dissolved in DMSO, and activating for 1 h; and adding a phthalocyanine compound and triethylamine, continuing to react for 20 hours, finally adding 2.5M NaCl solution into the reaction solution, stirring for 10 minutes, pouring the reaction solution into 70-95 vol% ethanol water solution, violently stirring for 1 hour, standing for 30 minutes, performing suction filtration by using a sand core funnel, washing by using acetone, re-dissolving the obtained product in water, performing dialysis purification, and freeze-drying to obtain the phthalocyanine-sodium alginate conjugate.
The mass-volume ratio of the sodium alginate to the formic acid/water solution or hydrochloric acid/ethanol solution in the step 1) is 1: 20-200 g/mL, and the molecular weight of the sodium alginate is 1-2000 kDa.
The mol ratio of the phthalocyanine compound to the sodium alginate in the step 2) is 1: 20-200; the molar ratio of the CMPI to the phthalocyanine compound is 1: 2-20; the molar ratio of the triethylamine to the phthalocyanine compound is 1: 10-100.
The phthalocyanine-sodium alginate conjugate can be used for preparing photodynamic medicaments, including photodynamic anti-cancer medicaments, photodynamic diagnostic agents and the like. The photodynamic therapy may be photodynamic therapy of malignant tumours, or photodynamic therapy of benign tumours, or photodynamic therapy of non-cancer diseases. The non-cancer disease can be bacterial infection, oral disease, macular degeneration eye disease, wound infection, skin disease or virus infection.
The phthalocyanine-sodium alginate conjugate of the invention needs to be matched with a proper light source in the application of photodynamic therapy and photodynamic diagnosis, the proper light source can be provided by connecting a common light source with a proper optical filter or by laser with a specific wavelength, and the wavelength range of the light source is 600-800 nm, preferably 600-690 nm.
The specific application method comprises the following steps: dissolving the phthalocyanine-sodium alginate conjugate by using a mixed solution of water and other substances as a solvent to prepare a corresponding medicament (the concentration of the phthalocyanine-sodium alginate conjugate in the medicament is not higher than the saturated concentration); the prepared medicament can also be added with an antioxidant, a buffering agent and an isotonic agent so as to maintain the chemical stability and the biocompatibility of the photosensitive medicament.
The mass fraction of other substances in the mixed solution is not higher than 10%, and the other substances are one or more of castor oil derivatives, dimethyl sulfoxide, ethanol, glycerol, N-dimethylformamide, 300-3000 parts of polyethylene glycol, cyclodextrin, glucose, tween and polyethylene glycol monostearate.
For formulations for topical administration, the phthalocyanine-sodium alginate conjugate of the invention may be dissolved in water, or injected into an ointment, lotion or gel.
The invention is further illustrated by the following non-limiting examples.
Example 1
(1) Preparation of alginic acid
Dispersing 2g (9.1 mmol) of low molecular weight sodium alginate (MW =40kDa, the number of repeating units is 9.1 mmol) in 100mL of formic acid/water solution (7: 3, v/v) at 4 ℃, stirring for 1h in ice water, transferring to 20-35 ℃, continuing stirring for 5 hours, filtering, washing the obtained crude alginic acid with 300mL of absolute ethanol, then washing with 100mL of acetone, and drying in vacuum at 40 ℃ to obtain 1.44g of light yellow powdery solid, namely the alginic acid (1).
Characterization data of the product: ftir (atr):υ(OH) 3371 cm-1；υ as(CH) 2925 cm-1；υ(C=O inCOOH) 1723 cm-1；υ as(COO−) 1636 cm-1；υ s(COO-) 1402 cm-1；υ(C-O-C) 1232 cm-1；υ(C-OH)1029 cm-1。
(2) synthesis of tetrabutylammonium alginate
1g (5 mmol of a repeating unit) of alginic acid was dispersed in 200mL of purified water, then the pH was slowly adjusted to = 8. + -. 1 with 40wt% tetrabutylammonium hydroxide aqueous solution, then immediately placed in a refrigerator to be frozen to avoid absorption of carbon dioxide, and freeze-dried to obtain 2.06g of pale yellow sponge-like solid, i.e., tetrabutylammonium alginate (1).
Characterization data of the product: ftir (atr):υ(OH) 3382 cm-1；υ(CH) 2961cm-1，2935 cm−1and2875 cm−1；υ as(COO-) 1603cm-1；δ as(CH2and CH3) 1487 cm−1and 1465 cm−1；δ s(CH3) 1385cm−1；(C-O) 1315 cm−1and 1285 cm−1；(C-O-C) 1169 cm−1，1147 cm−1and 1099 cm−1，(C-OH) 1030 cm−1。
example 2
The molecular weight of sodium alginate in step (1) of example 1 was adjusted to 1230 kDa, and 1.51g of alginic acid (2) and 2.03g of tetrabutylammonium alginate (2) were obtained in the same manner as in example 1, except that the sodium alginate was washed with 300mL of an ethanol/water solution (7: 3, V: V) and then with 100mL of acetone.
Product characterization data were as follows:
alginic acid (2): ftir (atr):υ(OH) 3359 cm-1；υ as(CH) 2925 cm-1；υ(C=O in COOH) 1721cm-1；υ as(COO−) 1635 cm-1；υ s(COO-) 1394 cm-1；υ(C-O-C) 1236cm-1；υ(C-OH) 1028 cm-1。
tetrabutylammonium alginate salt (2): ftir (atr):υ(OH) 3384 cm-1；υ(CH) 2961cm-1，2935 cm−1and 2875 cm−1；υ as(COO-) 1603cm-1；δ as(CH2and CH3) 1487 cm−1and 1465 cm−1；δ s(CH3)1385 cm−1；(C-O) 1315 cm−1and 1285 cm−1；(C-O-C) 1171 cm−1，1147 cm−1and 1099 cm−1，(C-OH) 1031 cm−1。
example 3
220.0mg (0.4 mmol) of tetrabutylammonium alginate salt (1) are dissolved in 7 mL of DMSO and stirred overnight at 20-35 ℃ under nitrogen protection to completely dissolve. 25 mg of 2-chloro-1-methylpyridinium iodide (CMPI, 0.1 mM) was dissolved in 1mL of DMMSO and added dropwise to tetrabutylammonium alginate solution for 1h of activation. 7.2 mg (0.01 mM) of phthalocyanine compound and 0.65 mmol of triethylamine were added, and the reaction was continued for 20 hours. Adding 10 mL of 2.5M NaCl aqueous solution into the reaction solution to replace tetrabutyl cation by sodium ions, pouring the reaction solution into 120mL of 95vol% ethanol aqueous solution, stirring vigorously for 1h, standing for 30min, performing suction filtration by using a sand core funnel, washing by using acetone, performing vacuum drying at 40 ℃, re-dissolving the product in water, performing dialysis purification, and performing freeze-drying to obtain 87.3mg of phthalocyanine-sodium alginate conjugate (I). The phthalocyanine content of the conjugate was 2.07wt% as measured by uv-visible absorption spectroscopy. The surface potential of the conjugate was-42.9 mV, measured by dynamic light scattering.
The above tetrabutylammonium alginate (1) was adjusted to tetrabutylammonium alginate (2), and the same procedure was followed except that the reaction solution was poured into 120mL of 70vol% aqueous ethanol solution after replacing the cation, to give 88.4 mg of phthalocyanine-sodium alginate conjugate (II) having a phthalocyanine content of 1.36wt% and a surface potential of-44.8 mV.
Product characterization data were as follows:
phthalocyanine-alginic acidSodium conjugate (I): ftir (atr):υ(OH) 3306 cm-1；υ(CH) 2932 cm-1；υ as(COO-)1602 cm-1；υ s(COO-) 1409 cm-1；(C-O) 1298 cm−1；(C-O-C) 1119 cm−1and 1083 cm−1，(C-OH) 1028 cm−1。
phthalocyanine-sodium alginate conjugate (II): ftir (atr):υ(OH) 3347 cm-1；υ(CH) 2929 cm-1；υ as(COO-) 1604 cm-1；υ s(COO-) 1410 cm-1；(C-O) 1297 cm−1；(C-O-C) 1119 cm−1and 1084 cm−1，(C-OH) 1031 cm−1。
as can be seen from FIG. 1, compared with the electron absorption spectrum of a pure phthalocyanine compound in water at the same concentration of phthalocyanine, the peak height of the electron absorption spectrum of the conjugate obtained in the invention at 680nm (representing that the phthalocyanine exists as a monomer) is obviously higher than the peak height at 630nm (representing that the phthalocyanine exists as an aggregate), which indicates that the phthalocyanine exists mostly as a monomer in water, and proves that the phthalocyanine can obviously improve the aggregation behavior in water after being coupled with sodium alginate.
Example 4
The method for preparing the photodynamic medicament (namely the photosensitive medicament) by utilizing the phthalocyanine-sodium alginate conjugate comprises the following steps: dissolving the phthalocyanine-sodium alginate conjugate in a mixed solution of water and other substances as a solvent to prepare a medicament with uniform blue-green color (the concentration of phthalocyanine in the medicament is 1-100 mu M); the mass fraction of other substances in the medicament is not higher than 10%, and the other substances are one or more of castor oil derivatives, dimethyl sulfoxide, ethanol, glycerol, N-dimethylformamide, 300-3000 parts of polyethylene glycol, cyclodextrin, glucose, tween and polyethylene glycol monostearate. The prepared medicament can also be added with an antioxidant, a buffering agent and an isotonic agent so as to maintain the chemical stability and the biocompatibility of the photosensitive medicament.
The phthalocyanine-sodium alginate obtained by the invention can be dissolved in water to be used as a preparation for local administration.
Example 5
The application method of the photodynamic drug, the photosensitizer or the photosensitizer prepared by the invention in photodynamic anti-cancer and photodynamic diagnosis is the same as the application method of the photosensitizer or the photosensitizer prepared by applying phthalocyanine-sodium alginate in the prior art, but needs to be matched with a proper light source, the proper light source can be provided by connecting a common light source with a proper optical filter or by laser with a specific wavelength, and the wavelength range of the light source is 600-800 nm, preferably 620-690 nm.
Example 6
1. Dissolving the phthalocyanine-sodium alginate conjugate (I) and the phthalocyanine-sodium alginate conjugate (II) prepared in example 3 in water to prepare photosensitive agents of 120. mu.M and 50. mu.M (in terms of phthalocyanine), respectively; the phthalocyanine compound was dissolved in dimethyl sulfoxide to prepare a control drug at a concentration of 1 mM. These agents were filtered through 0.45 μm filters, respectively, and further diluted to appropriate concentrations with PBS or liquid medium. The fluorescent confocal method is adopted to test the drug uptake of the murine mononuclear macrophage J774A.1 cell and the liver cancer HepG2 cell.
The operation method comprises the following steps: HepG2 cells cultured in DMEM medium or J774A.1 cells cultured in RPMI1640 medium were seeded on confocal culture dishes at about 1X 10 cells per plate, respectively5Individual cells, 5% CO at 37 ℃2Incubate overnight. After aspirating the old medium with a pipette, 0.4mL of a medium containing a phthalocyanine compound, a conjugate (I) or a conjugate (II) (each at a concentration of 4. mu.M) was added, incubated under the same conditions for 2 hours, and then the cells were washed twice with PBS and observed with a Leica laser fluorescence confocal microscope, and fluorescence at 635nm and 750nm, 640-. Images were processed with SPE ROI fluorescence analysis software, counting 20 cells per sample, and calculating the mean intracellular fluorescence intensity. The experiment was repeated three times and the final results were averaged.
The uptake experiment result shows that the relative fluorescence intensity of the phthalocyanine-sodium alginate conjugate (I) in HepG2 cells and J774A.1 cells is 23.9 and 100 respectively, the relative fluorescence intensity of the phthalocyanine-sodium alginate conjugate (II) in HepG2 cells and J774A.1 cells is 24.3 and 58.6 respectively, and the two conjugates are obviously more taken up by the J774A.1 cells. For the phthalocyanine-sodium alginate conjugate (I), the intracellular fluorescence intensity of J774A.1 cells is increased by 4.2 times compared with HepG2 cells.
The uptake rate of the phthalocyanine compound in HepG2 cells was low (relative fluorescence intensity 2.6), which is probably caused by fluorescence quenching due to the severe aggregation of the phthalocyanine compound in the aqueous phase. The two sodium alginate-phthalocyanine conjugates have higher uptake rate, which shows that the phthalocyanine compound is coupled with the sodium alginate, the aggregation degree of the phthalocyanine compound in the water phase is reduced, and the uptake rate of HepG2 cells to the phthalocyanine compound is improved.
2. The murine mononuclear macrophage J774A.1 cell is selected as A model to study SR-A mediated endocytosis, and can be further verified by A competitive experiment of polyinosinic acid (poly I).
For the competitive inhibition experiment of J774A.1 cells, the operation method comprises the following steps: HepG2 cells cultured in DMEM medium or J774A.1 cells cultured in RPMI1640 medium were seeded on confocal culture dishes at about 1X 10 cells per plate, respectively5Individual cells, 5% CO at 37 ℃2Incubate overnight. After aspirating the old medium with a pipette, incubating the cells with poly I medium containing 100. mu.g/mL for half an hour, aspirating the old medium with a pipette, adding 0.4mL of medium containing phthalocyanine compound, conjugate (I) or conjugate (II) (both at 4. mu.M), incubating for 2h under the same conditions, washing the cells twice with PBS, observing with a Leica laser confocal microscope, exciting at 635nm and collecting the fluorescence of 640-. Images were processed with SPE ROI fluorescence analysis software, counting 20 cells per sample, and calculating the mean intracellular fluorescence intensity. The experiment was repeated three times and the final results were averaged.
Competitive experiment results show that after J774A.1 cells are incubated by using a culture medium containing poly I, the uptake of the phthalocyanine-sodium alginate conjugate (I) and the phthalocyanine-sodium alginate conjugate (II) by the J774A.1 cells is reduced (the relative fluorescence intensity is respectively 18.3 and 22.3), and the reduction times of the phthalocyanine-sodium alginate conjugate (I) and the phthalocyanine-sodium alginate conjugate (II) are respectively 5.5 and 2.6. However, uptake of phthalocyanine-sodium alginate conjugate (I) and phthalocyanine-sodium alginate conjugate (II) by HepG2 cells did not change significantly (relative fluorescence intensities of 26.8 and 23.5, respectively) for HepG2 cells, regardless of the presence of poly I. This is because HepG2 cells do not express SR-A receptors and do not exhibit SR-A mediated competitive inhibition.
The above results indicate that the obtained phthalocyanine-sodium alginate conjugate can be selectively taken up by tumor-associated macrophage J774A.1 cells through SR-A mediation, which is probably because polyanionic property of sodium alginate helps the drug selectively enter the tumor-associated macrophage. This demonstrates that sodium alginate has a role in targeting tumor-associated macrophages.
Example 7
Dissolving the phthalocyanine-sodium alginate conjugate (I) and the phthalocyanine-sodium alginate conjugate (II) prepared in example 3 in water to prepare photosensitive agents of 120. mu.M and 50. mu.M (in terms of phthalocyanine), respectively; the phthalocyanine compound was dissolved in dimethyl sulfoxide to prepare a control drug at a concentration of 1 mM. These agents were filtered through 0.45 μm filters, respectively, and further diluted to appropriate concentrations with PBS or liquid medium. The drugs were tested for dark toxicity and photodynamic activity on HepG2 cells or j774a.1 cells.
The cytotoxicity is measured by a 3- (4, 5-dimethylthiazole-2) -2, 5-diphenyl tetrazolium bromide (MTT) method. Each experiment was set with 4 control groups, blank, light, phototoxic and dark toxic, each set with 3 parallel groups.
The operation method comprises the following steps: HepG2 or J774A.1 in logarithmic growth phase was seeded into 96-well plates at approximately 1X 10 cells per well4At 37 deg.C, 5% CO2And culturing for 24 hours. The incubation was continued by replacing the blank control group with fresh medium. 0.1mL of dilution containing phthalocyanine compound or conjugate (I) or conjugate (II) with different concentrations is respectively added into the phototoxic group and the dark toxic group, so that the concentration of each drug in the culture solution is respectively 1, 2, 4 and 16 mu M (experiment group proliferation of conjugate (I) in J774A.1 cells)Set at this concentration of 0.5. mu.M) and incubated for 2h in a dark environment. Phototoxic group and dark toxic group after incubation, they were rinsed with PBS, and fresh DMEM medium or RPMI1640 medium was added according to the different cells. Then irradiating the control group and phototoxicity group with red light of more than 610nm at 150 W.m for 30min-2The light dose is 27J/cm2Then, the culture was continued for 24 hours. The blank control group and the dark toxicity group were cultured for 24 hours without light. After the culture, 20 mu L of 2.5 g/L3- (4, 5-dimethylthiazole-2) -2, 5-diphenyl tetrazolium bromide (MTT) is added into each well, the culture solution in a 96-well plate is removed after the culture is continued for 4h, 150 mu L of DMSO solution is added into each well, the vibration is carried out for 10min, the absorbance (A) value of each well is measured by a microplate reader (with the wavelength of 490 nm), and the average value of 3 wells in each group is taken as the average value A of each group. Cell viability was calculated according to the following formula: survival = aExperimental group/AControl groupX 100%. The experiment was repeated three times and the final results were averaged (the above red light with a wavelength of more than 610nm was provided by a 500W halogen lamp in conjunction with a thermally insulated water bath plus a filter of more than 610 nm).
As shown in the results of FIG. 2, when the concentration of the solution of the conjugate (I) and the conjugate (II) is as high as 16. mu.M, there is no killing and growth inhibition effect on HepG2 cells or J774A.1 cells without light irradiation, indicating that they have no dark toxicity. IC of conjugate (I) on HepG2 and J774A.1 cells under light conditions50(i.e., the concentration of drug required to kill 50% of the cells) was approximately 1.5. mu.M and 0.5. mu.M, respectively, and the IC of conjugate (II) on HepG2 cells and J774A.1 cells50Approximately 2.5. mu.M and 1.1. mu.M, respectively, and phthalocyanine compound on HepG2 cells and J774A.1 cells IC50The molecular weight of the phthalocyanine-sodium alginate conjugate is 2.3 mu M and 3.1 mu M respectively, which shows that the phthalocyanine-sodium alginate conjugate has higher photodynamic activity and certain cell selectivity.
Example 8
Dissolving the phthalocyanine-sodium alginate conjugate (I) and the phthalocyanine-sodium alginate conjugate (II) prepared in example 3 in water to prepare photosensitive agents of 120. mu.M and 50. mu.M (in terms of phthalocyanine), respectively; the phthalocyanine compound was dissolved in dimethyl sulfoxide to prepare a control drug at a concentration of 1 mM. These agents were separately filtered through 0.45 μm filters and further diluted to appropriate concentrations with PBS or liquid medium to test in vivo fluorescence imaging in drug-bearing tumor mice.
To construct a subcutaneous tumor model, H22 cells (200. mu.L, ca. 1X 10 cells) were used7Individual cells) were subcutaneously inoculated in the right hind limb of KM mice (20-25 g). When the tumor grows to 100-300 mm3In this case, a diluted solution of the phthalocyanine compound, a diluted solution of the conjugate (I) (100. mu.M, 100. mu.L) and a diluted solution of the conjugate (II) (50. mu.M, 200. mu.L) were injected into tumor-bearing mice via tail vein, respectively. Mice injected with phthalocyanine compound and conjugate were imaged for in vivo fluorescence at different time points using the IVIS spectroscopic in vivo imaging system (excitation at 605 nm), respectively. After 24 hours from the drug injection, KM mice were euthanized.
As shown in fig. 3, after the same dose of drug is injected via tail vein, for the mice treated with phthalocyanine-sodium alginate conjugate (i), strong fluorescence signals appear around the tumor site 1 hour after injection, and then diffuse throughout the body until the maximum distribution is reached 4-8 hours after injection. Thereafter, the fluorescence signals gradually decreased at sites other than the tumor site in the body and disappeared 24 hours after the injection; while the fluorescence intensity at the tumor site continuously increased and peaked around 8 hours, the tumor site still maintained a strong fluorescence signal even at 24 hours. The rapid elimination of other parts of the body, preferential accumulation of tumor parts and long-term retention demonstrate that the phthalocyanine-sodium alginate conjugate (I) has excellent tumor selectivity. The phthalocyanine-sodium alginate conjugate (II) with a larger molecular weight also showed similar properties. In contrast, over the entire observation period, the phthalocyanine compound-treated mice did not find selective aggregation of the phthalocyanine compound in tumor tissue, and the fluorescence signal was extremely weak, which is highly likely due to fluorescence quenching caused by aggregation of the phthalocyanine compound also in the physiological environment. All the results show that the prepared phthalocyanine-sodium alginate conjugate has good effect of targeting tumor tissues due to the targeting effect of the sodium alginate.
Example 9
The phthalocyanine-sodium alginate conjugate (I) prepared in example 3 was dissolved in water to prepare a photosensitizing agent at 120. mu.M (in terms of phthalocyanine). The drug was filtered through a 0.45 μm filter and then further diluted to an appropriate concentration with PBS or liquid medium to test the tumor inhibition rate of the drug.
20 KM mice (normal grade, female, about 20 g) were prepared and divided into phototoxic group, dark toxic group, blank control group and light control group. Inoculating mouse liver cancer H22 cells to the right hind limb of the mouse until the tumor grows to 60-100mm3In size, 100 μ L of phthalocyanine-sodium alginate conjugate (I) was injected into the tail vein of the first two groups of mice, the drug concentration was 100 μm, and 100 μ L of LPBS was injected into the tail vein of the second two groups of mice. Irradiating phototoxic group and irradiation control group with laser at wavelength of 685 + -4 nm and power density of 1400 W.m for 6 hr under FGZ-8B semiconductor laser-2And the illumination time is 5min (total illumination dose is 42J/cm)2). On day 5, the two doses were administered and the phototoxic and light control groups were irradiated, as before. The body weight of the mouse and the length and width of the tumor of the mouse are measured and recorded regularly for 12 days, and the tumor inhibition rate is calculated.
As shown in the results of FIG. 4, the tumor volumes of mice in the dark toxicity group, the blank control group and the light control group all increased with the growth time, which indicates that the tumor growth is not affected by the simple light or the simple administration of the phthalocyanine-sodium alginate conjugate (I). The tumor of the phototoxic mice is well inhibited, the tumor inhibition rate reaches 86.9 percent, and the result shows that the phthalocyanine-sodium alginate conjugate (I) has good tumor inhibition effect under illumination.
The above description is only a preferred embodiment of the present invention, and all equivalent changes and modifications made in accordance with the claims of the present invention should be covered by the present invention.
Claims (7)
1. The application of sodium alginate as an antitumor drug targeting carrier is characterized in that: the tumor targeting drug is prepared by utilizing the characteristic that scavenger receptors on the surfaces of macrophages related to tumor tissues have selectivity on sodium alginate and taking the sodium alginate as a targeting carrier.
2. A conjugate prepared by using sodium alginate as a targeting carrier is characterized in that: sodium alginate is used as a targeting carrier, and carboxyl on the sodium alginate and amino in a phthalocyanine compound are coupled through amido bonds to generate the phthalocyanine-sodium alginate conjugate with the tumor targeting effect.
3. The conjugate of claim 2, wherein: the surface potential of the conjugate is-30 to-60 mV.
4. A method of preparing a conjugate using sodium alginate as a targeting carrier as claimed in claim 2, wherein: the method comprises the following steps:
1) converting sodium alginate from a carboxylate form to a carboxylic acid form by using an acidification solution, and then adding tetrabutylammonium hydroxide to neutralize to obtain tetrabutylammonium alginate;
2) with phthalocyanine compounds
Reacting with tetrabutylammonium alginate serving as a reaction raw material, dimethyl sulfoxide serving as a solvent, 2-chloro-1-methylpyridinium iodide serving as a condensation reagent and triethylamine serving as an acid-binding agent at the temperature of 20-35 ℃ for 20 hours under the protection of nitrogen. And then adding a high-concentration NaCl solution, and then carrying out solvent precipitation, suction filtration, dialysis and freeze-drying to obtain the phthalocyanine-sodium alginate conjugate.
5. The method for preparing the conjugate by using sodium alginate as a targeting carrier according to claim 4, wherein the method comprises the following steps: the mass-to-volume ratio of the sodium alginate to the acidizing fluid in the step 1) is 1: 20-200 g/mL; the molecular weight of the sodium alginate is 1-2000 kDa, and the acidizing fluid is 70vol% formic acid/water solution or 1M hydrochloric acid/ethanol solution.
6. The method for preparing the conjugate by using sodium alginate as a targeting carrier according to claim 4, wherein the method comprises the following steps: pH =8 ± 1 of the solution after neutralization in step 1).
7. The method for preparing the conjugate by using sodium alginate as a targeting carrier according to claim 4, wherein the method comprises the following steps: the mol ratio of the phthalocyanine compound to the sodium alginate in the step 2) is 1: 20-200; the molar ratio of the 2-chloro-1-methylpyridinium iodide to the phthalocyanine compound is 1: 2-20; the molar ratio of the triethylamine to the phthalocyanine compound is 1: 10-100.
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