CN108926714B - High-molecular gel for delivering pharmacological active substances to bladder cancer in bladder perfusion targeted manner and preparation method of high-molecular gel - Google Patents
High-molecular gel for delivering pharmacological active substances to bladder cancer in bladder perfusion targeted manner and preparation method of high-molecular gel Download PDFInfo
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Abstract
The invention relates to a macromolecule gel for delivering pharmacological active substances by bladder perfusion and bladder cancer targeting and a preparation method thereof. The polymer gel mainly comprises dendrimer PAMAM capable of bearing pharmaceutical active substances and aldehyde polysaccharide which is targeted and adhered to bladder cancer. The invention also provides a macromolecule composite gel for targeted therapy of bladder cancer based on the macromolecule gel, and preferably, the macromolecule composite gel is loaded with a nano gold rod and gemcitabine. The composite gel has the following three advantages: firstly, the targeted sticking to the bladder cancer can slowly release the drug and prolong the action time of the drug, and meanwhile, the normal bladder epithelium drug has less retention and small side effect; secondly, the bladder cancer is treated by photo-heat, and tumor tissues can be killed and killed by the photo-heat ablation; thirdly, chemotherapy is combined with thermotherapy, and the tumor tissue killing effect of the chemotherapy is promoted through the thermotherapy. Meanwhile, compared with the traditional thermo-chemotherapy instrument, the device has low requirement on equipment and is easy to popularize.
Description
Technical Field
The invention relates to a macromolecule gel for delivering pharmacological active substances for targeting bladder cancer and a preparation method thereof, and also relates to a macromolecule composite gel medicinal preparation prepared by adding the pharmacological active substances into the macromolecule gel. The invention belongs to the technical field of medicines.
Background
The bladder perfusion drug therapy is a conventional auxiliary treatment means after the current non-muscle layer infiltration bladder cancer operation, and aims to kill tumor cells and tiny residual foci released in the operation process. However, the existing bladder perfusion drug formulation is a pure drug aqueous solution, the drugs cannot be effectively enriched in tumor tissues during bladder perfusion, and meanwhile, the drug duration is short (within two hours), so the curative effect of the drugs cannot be exerted to the maximum. Tumor cells that are still viable can be replanted in the bladder wall while residual cancer tissue is not completely killed, resulting in a 5-year recurrence rate of bladder cancer of up to 44.8% even with standard perfusion therapy [ Sylvester, et al.
In order to prolong the action time of the medicine and increase the penetrability of the medicine to tissues, one of the effective methods is to dissolve the medicine in a gel carrier so that the gel is attached to the surface of the bladder tissue for continuous administration, thereby achieving the purposes of prolonging the action time of the medicine and increasing the penetrability of the medicine and further better killing tumor tissues. This is reported in the relevant literature. Guhasarkar reported that the therapeutic effect is improved by using ion-excited gel as a carrier to wrap chemotherapeutic drug taxol for perfusion treatment of bladder [ Guhasarkar, et al. journal of Controlled Release,2017 ]. However, the current gel carrier can not effectively distinguish tumor tissues from normal bladder mucosa, and the wide and long-term attachment to the bladder mucosa can increase the stimulation of the drug to the normal tissues, thereby causing serious bladder stimulation symptoms.
Collagen is an important component of extracellular matrix and contains abundant amino groups. Tumor tissue, due to its exogenously growing nature, has more collagen than the normal urothelial surface. It has been reported in the literature that aldehyde groups can be tightly bound to the amino groups of collagen tissue by Schiff bases [ Oliva, et al, science comparative Medicine,2015,7(272):272ra11 ]. Therefore, the drug delivery system capable of specifically adhering amino groups can take collagen as a potential tumor target to distinguish tumor tissues from normal tissues, thereby achieving the purpose of targeted drug delivery.
In addition, the thermotherapy has obvious promotion effect on perfusion chemotherapy, and currently, a Synergo SB-TS101 system is clinically applied to carry out the thermotherapy on patients and strengthen the therapeutic effect of drugs on bladder perfusion [ Lammers, et al. However, current heating systems are bulky and expensive. Meanwhile, when the patient is subjected to hot infusion, a specific operation space and monitoring and measurement of medical care personnel are needed, the medical resource demand is high, and the hot infusion device cannot be effectively popularized.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The invention aims to provide a macromolecular gel for delivering a pharmacological active substance to bladder cancer by bladder perfusion and targeting and a preparation method thereof, so as to realize early isolation of free tumor cells; can be attached to the tumor residual focus in a targeted way, prolong the action time of the medicine and strengthen the aim of medicine penetration. By aiming at the two reasons of bladder cancer recurrence, tumor tissues are thoroughly killed, and the problem that the curative effect of the bladder perfusion medicine cannot be exerted to the maximum is solved.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention relates to a macromolecule gel for delivering pharmacological active substances to bladder cancer by bladder perfusion and targeting, which is prepared by the following steps:
1) preparing a PAMAM solution with the mass percentage concentration of 10% by using deionized water for the dendrimer PAMAM;
2) adding COOH-PEG-OH into the 10% PAMAM solution obtained in the step 1), and uniformly mixing;
3) mixing the aldehyde polysaccharide solution with the mass percentage concentration of 5% with the solution obtained in the step 2) to obtain the polymer gel.
Preferably, the dendrimer PAMAM in step 1) is a G5 generation dendrimer with an amino group at the end.
Wherein, the preferable mass ratio of the COOH-PEG-OH in the step 2) to the dendrimer PAMAM is 7: 1.
Preferably, the aldehydized polysaccharide in step 3) is prepared by oxidizing polysaccharide with potassium periodate, wherein the mass ratio of potassium periodate to polysaccharide is 19: 17.
Preferably, in the step 3), the solution of the aldehyde polysaccharide with the mass percentage concentration of 5% and the solution obtained in the step 2) are mixed according to the volume ratio of 1: 1.
Furthermore, the invention also provides application of the polymer gel in preparation of a pharmacological active substance carrier for bladder perfusion targeted bladder cancer delivery.
The polymer gel is prepared from drug-bearing dendrimer PAMAM and aldehyde polysaccharide specifically adhered to tumors. And COOH-PEG-OH is part of amino group for blocking PAMAM terminal, and is used for adjusting viscosity of final gel. Experiments prove that the preferable mass ratio of COOH-PEG-OH to PAMAM is 7:1, and the dendrimer PAMAM has a three-dimensional porous network structure and can effectively bear various pharmaceutical active substances. Meanwhile, the terminal amino group can form a reticular gel with the aldehyde group of the aldehyde polysaccharide through Schiff base action. And redundant aldehyde groups can specifically identify amino on the surface of the tumor tissue to carry out targeted adhesion and directionally release the active pharmaceutical substances in the gel.
When injected into the bladder, the polymer gel forms a layer of extensive protective film on the inner surface of the bladder to isolate floating tumor cells at early stage and prevent the tumor cells from being replanted in the bladder. Wherein the gel on the normal bladder mucosa can be degraded along with the washing of urine in a short time; the residual tumor surface expresses abundant collagen, and the gel can be specifically and continuously attached to the tumor surface, so that the aim of continuously delivering the medicine is fulfilled.
The second objective of the present invention is to provide a macromolecule composite gel for targeted therapy of bladder cancer, which is prepared by adding pharmacologically active substances into the macromolecule gel, wherein the pharmacologically active substances include but are not limited to gemcitabine, nanoparticles with therapeutic effect, doxorubicin, mitomycin, epirubicin and bcg, and one or more of the substances are used in combination.
Wherein, preferably, the pharmacological active substance is gemcitabine combined with a nano gold rod.
Wherein, preferably, the concentration of gemcitabine in the composite gel is 10mg/ml, and the concentration of gold nanorods is 50 mug/ml.
Preferably, the ultraviolet absorption peak of the nano gold rod is 760nm-800nm, the temperature can be raised to about 45 ℃ after the irradiation of near-infrared laser, the energy of the near-infrared laser is 1W, and the illumination time is 5 minutes.
Compared with the prior art, the invention has the beneficial effects that:
1. the polymer gel mainly comprises dendrimer PAMAM capable of bearing active substances of medicines and aldehyde polysaccharide targeted to be adhered to bladder cancer, and the polymer gel targeting tumor tissues is used as a medicine carrier to carry out targeted release, so that the retention time of medicines in the bladder is prolonged, the stimulation of the medicines to normal bladder tissues is reduced, and the side effect is further reduced.
2. The macromolecular composite gel for targeted therapy of bladder cancer can be prepared by adding a pharmacological active substance into the macromolecular gel, and taking the composite gel for targeted therapy of bladder cancer loaded with the gold nanorod and the gemcitabine as an example, the composite gel has the following three advantages: firstly, the targeted sticking to the bladder cancer can slowly release the drug and prolong the action time of the drug, and meanwhile, the normal bladder epithelium drug has less retention and small side effect; secondly, the photothermal effect of the nano gold rod can be used as thermal ablation to kill tumor tissues independently, and the provided thermal therapy effect can synergistically strengthen the chemotherapy effect of gemcitabine, promote the uptake of tumor cells to medicines and achieve the purpose of thermal chemotherapy. The bladder cancer can be treated by photo-heat, and tumor tissues can be killed and killed by the photo-heat ablation; thirdly, chemotherapy is combined with thermal therapy, the killing effect of the chemotherapy on tumor tissues is promoted through the thermal chemotherapy, and the applied photo-thermal equipment is only a near-infrared laser emitter, so that compared with the traditional thermal chemotherapy instrument, the manufacturing cost is relatively low, the application is simple and convenient, and the clinical popularization is easy.
Drawings
FIG. 1 is a graph showing the drug release profile of gemcitabine in a polymer gel with physiological saline;
FIG. 2 is the absorption peak and electron microscope image of the nano-gold rod;
FIG. 3 is a time-temperature graph of a polymer gel loaded with gold nanorods;
FIG. 4 is a diagram of a polymer composite gel targeting bladder cancer;
FIG. 5 is a graph showing the effect of complex gel, gemcitabine, saline on inhibiting cell seeding;
FIG. 6 is a graph showing the effect of complex gel, gemcitabine and saline on killing tumor tissue.
Detailed Description
The present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention in any way.
Example 1: preparation of macromolecule gel for targeted bladder cancer to deliver pharmacological active substances
(1) Dissolving G5 generation dendrimer PAMAM in deionized water to prepare a solution with the mass fraction of 10%.
(2) And adding the COOH-PEG-OH powder into the PAMAM solution to prepare a solution A, wherein the mass ratio of the COOH-PEG-OH powder to the solute PAMAM is 7: 1.
(3) Dissolving polysaccharide in deionized water to prepare a solution with the mass percent concentration of 5%. Potassium periodate powder was added to the polysaccharide solution, reacted overnight and dialyzed to prepare a 5% solution of an aldehydized polysaccharide, solution B. Wherein the mass ratio of the potassium periodate powder to the solute polysaccharide is 19: 17.
(4) And mixing the solution A and the solution B in equal volume to prepare the macromolecular gel capable of targeting bladder cancer to deliver the pharmacological active substance.
Example 2: preparing gemcitabine-loaded polymer gel.
Gemcitabine powder was dissolved in the polymer gel prepared in example 1 to prepare a gemcitabine-loaded targeting polymer gel. Wherein the gemcitabine is present at a concentration of 10 mg/ml.
To illustrate that the drug-loaded polymer gel in this example can be administered in a sustained release manner, the following experiments prove that:
dissolving gemcitabine in 1ml physiological saline solution and polymer gel solution respectively to prepare aqueous solution and gel solution with concentration of 10mg/ml, sealing in 1000DA dialysis bags, placing into two beakers filled with 500ml physiological saline respectively, and continuously stirring. Sampling according to different time points, detecting the gemcitabine concentration in the physiological saline of the two beakers by a high performance liquid chromatograph, and finally calculating and drawing the drug release curves of the two beakers. As shown in FIG. 1, the drug gemcitabine can be more effectively and slowly released from the polymer gel.
Example 3: preparation of polymer gel carrying nano gold rod
The nano gold rod with the diameter of about 40nm and the absorption peak between 760mm and 800nm is prepared by a seed growth method, as shown in figure 2. The gold nanorods were dissolved in the polymer gel prepared in example 1 to prepare a gold nanorod-loaded polymer gel having a concentration of 50. mu.g/ml.
To illustrate that the polymer gel loaded with the nano-gold rods in this example has a photothermal effect, the following experiment proves that:
1ml of the polymer gel carrying the gold nanorods at a concentration of 50. mu.g/ml was placed in an EP tube, irradiated with a near-infrared laser having a wavelength of 785nm at an energy of 0.5W, 1W, 1.5W, respectively, for 10 minutes, and a time-temperature curve was recorded with a thermal imaging camera. As a result, as shown in FIG. 3, the polymer gel loaded with the gold nanorods can reach a temperature of more than 50 ℃ under the irradiation of the near-infrared laser with the power of 1W, and can realize the effect of thermal therapy on tumor ablation.
Example 4: preparation of high-molecular composite gel loaded with gold nanorod and gemcitabine and used for targeting bladder cancer
The gold nanorods and gemcitabine were dissolved in the polymer composite gel prepared in example 1, respectively. The concentrations of the nano leaderboard and the gemcitabine are respectively 50 mu g/ml and 10 mg/ml. A polymer composite gel was prepared as shown in FIG. 4.
To illustrate the more effective tumor killing effect of the composite gel in this example, the following experiments prove that:
the compound gel inhibits the bladder cancer cell bladder from planting:
construction of a bladder cancer cell planting model: 30 BALB/c female nude mice, 5 weeks old, were randomly and evenly divided into A, B, C groups of 10 mice each. After the mice were anesthetized and sterilized, they were inserted into the urinary bladder of the mice through the urethra using a 24G indwelling needle. The electric knife was used to destroy the bladder intima by conducting electricity through the inner core of the indwelling needle to simulate the damage to the bladder by transurethral cystotomy of the tumor. The energy is 2.5W, and the action time is 1 second. Bladder cancer cells 5637 were prepared at a concentration of 1X 106A suspension in PBS/ml. 0.1ml of the bladder cancer cell suspension was injected into the bladder through an indwelling needle and left in the bladder for 60 minutes before being discharged.
And (3) medicine perfusion: group a was filled with the polymer composite gel loaded with the gold nanorods and gemcitabine prepared in this example; group B gemcitabine aqueous solution with the perfusion concentration of 10 mg/ml; group C was perfused with sterile saline. The mixture was retained in the bladder for 60 minutes and then discharged. Thereafter, the urinary bladder area of A, B, C three groups of mice were irradiated in vitro with a near infrared laser of 785nm wavelength and 1W energy for 5 minutes. After 30 days, the bladders of each group of mice are respectively taken and examined for the condition of tumor formation.
The experimental results are as follows: A. b, C the mice survived after drug infusion, 0 bladder tumor was detected in group A; 4 bladder tumors were detected in group B; bladder tumors were detected in group C in 9 cases. The tumor formation rates were 0%, 40%, and 90%, respectively, as shown in FIG. 5. Experimental results prove that the composite gel has the function of more effectively inhibiting the bladder cancer cell planting.
The composite gel can kill bladder cancer tissues:
construction of mouse orthotopic bladder cancer model: 15 BALB/c female nude mice, 5 weeks old, were randomly and evenly divided into A, B, C groups of 5 mice each. Establishing mouse in-situ bladder cancer model by cell perfusion method, and monitoring mouse tumor size with color ultrasound until tumor grows to 50mm3The next experiment was performed at size.
Single infusion treatment of bladder tumors: using a 24G indwelling needle to insert into the urinary bladder of a mouse through the urethra, and infusing the group A with the polymer composite gel loaded with the nano-gold rod and the gemcitabine prepared in the embodiment; group B gemcitabine aqueous solution with the perfusion concentration of 10 mg/ml; group C was perfused with sterile saline. The mixture was retained in the bladder for 60 minutes and then discharged. Thereafter, the urinary bladder area of A, B, C three groups of mice were irradiated in vitro with a near infrared laser of 785nm wavelength and 1W energy for 5 minutes. After 20 days, the bladders of each group of mice were individually removed and the tumor sizes were measured.
The experimental results are as follows: the tumor volume of the bladder in the group A is 0 +/-0 mm3(ii) a The tumor volume of the bladder in the group B is 43.28 +/-5.47 mm3(ii) a The tumor volume of the bladder in the group C is 78.36.28 +/-11.21 mm3As in fig. 6. The experimental result proves that the polymer composite gel group loaded with the nano gold rod and the gemcitabine has more obvious tumor killing effect.
Claims (7)
1. The application of the macromolecular composite gel in preparing the pharmacologically active substance carrier for bladder perfusion targeted bladder cancer delivery is characterized in that the macromolecular composite gel is prepared by adding a pharmacologically active substance into macromolecular gel;
the polymer gel is prepared by the following steps:
1) preparing a PAMAM solution with the mass percentage concentration of 10% by using deionized water for the dendrimer PAMAM;
2) adding COOH-PEG-OH into the 10% PAMAM solution obtained in the step 1), and uniformly mixing;
3) mixing the aldehyde polysaccharide solution with the mass percentage concentration of 5% with the solution obtained in the step 2) to obtain the polymer gel;
the aldehyde polysaccharide in the step 3) is prepared by oxidizing polysaccharide with potassium periodate, wherein the mass ratio of the potassium periodate to the polysaccharide is 19: 17;
in the step 3), mixing an aldehyde polysaccharide solution with the mass percentage concentration of 5% with the solution obtained in the step 2) according to the volume ratio of 1: 1;
the pharmacological active substance is gemcitabine combined with a nano gold rod, the concentration of the gemcitabine is 10mg/ml, and the concentration of the nano gold rod is 50 mu g/ml.
2. The use according to claim 1, wherein the dendrimer PAMAM of step 1) is a G5 generation dendrimer terminated with an amino group.
3. The use according to claim 1, wherein the mass ratio of COOH-PEG-OH and dendrimer PAMAM in step 2) is 7: 1.
4. A polymer composite gel for targeted therapy of bladder cancer, which is prepared by adding pharmacologically active substances into the polymer gel of claim 1, wherein the pharmacologically active substances comprise one or more of gemcitabine, nanoparticles with therapeutic effect, adriamycin, mitomycin, epirubicin and BCG.
5. The polymer composite gel of claim 4, wherein the pharmacologically active substance is gemcitabine in combination with gold nanorods.
6. The polymer composite gel of claim 5, wherein the gemcitabine concentration in the composite gel is 10mg/ml and the nano-gold rods concentration is 50 μ g/ml.
7. The polymer composite gel according to claim 5 or 6, wherein the nano gold rod has an ultraviolet absorption peak of 760nm to 800nm, and can be heated to about 45 ℃ after being irradiated by near-infrared laser, the energy of the near-infrared laser is 1W, and the illumination time is 5 minutes.
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