TW201317005A - Temperature-sensitive hydrogel that encloses radioisotopes and chemotherapeutic agent for application in cancer treatment and manufacturing method thereof - Google Patents

Abstract

The present invention relates to a temperature-sensitive hydrogel that encloses radioisotopes and chemotherapeutic agent for application in cancer treatment and manufacturing method thereof, in which cancer treatment agent, such as radio-therapeutic agent and chemotherapeutic agent, is uniformly enclosed in a hydrogel composed of polycaprolactone-polyethylene glycol-polycaprolactone. By taking advantage of the characteristic that the hydrogel is of a gel form at human body temperature and is a liquid as being preserved in low temperature, the cancer treatment agent can be smoothly injected to reach the location of tumor and is affected by human body temperature to keep in a gel form for realizing long term brachytherapy and greatly reducing the potential side effect caused by cancer treatment.

Description

Temperature-sensitive water gel coated with radioisotope and chemotherapeutic drug for cancer treatment and preparation method thereof

The invention relates to a cancer treatment temperature sensitive water gel and a preparation method thereof, in particular to a temperature sensitive water glue coated with a radioisotope and a chemotherapy drug and a preparation method thereof.

The three main methods of cancer treatment are surgery, chemotherapy and radiation therapy.
Among them, although surgery can remove most of the lesions through resection, there are application restrictions for cancers that are transferred or blood.
Chemotherapy uses chemical drugs to kill cancer cells. Different treatment plans can be made according to the patient's physical strength and the needs of the disease. The application time can be given before or after surgery, or combined with radiation therapy, or can be administered alone; Chemotherapy has cytotoxicity and serious side effects, often causing discomfort to the patient.
Radiation therapy uses a penetrating high-energy beam or particle beam to treat disease. These beams are called radiation. High-dose radiation can kill cells or prevent their growth and proliferation, because cancer cells grow and proliferate. It is faster than normal cells next to it, so radiation therapy can successfully treat many types of cancer; however, high doses of radiation used to destroy cancer cells can also damage nearby normal cells, so serious side effects can occur.
Therefore, the development of more effective treatment methods and better diagnostic methods has become an important topic in the current stage of cancer treatment. Among them, Brachytherapy is considered as a plan to place radioisotopes in or around the lesion. By reducing the exposure of the lesion to high doses of radiation, the damage to nearby normal tissue is reduced. In addition to the most commonly used proximal treatments for the mouth, neck, uterus, vagina, cervix, and prostate, in vivo radiation therapy for liver cancer is administered via the Transcatheter Arterial Embolization (TAE) model. Arterial embolization requires more difficult surgical techniques and expensive equipment.
Therefore, the present invention discloses a drug injection module for proximity treatment, which allows a high dose of radiation therapy or chemotherapy to reduce the damage of nearby normal tissues, and the required equipment is relatively simple and helps to promote The application range of this proximity treatment mode and indications.

The main object of the present invention is to provide a temperature-sensitive water gel coated with a radioisotope and a chemotherapeutic drug for cancer treatment, and a preparation method thereof, which is characterized in that a polymer water gel is coated on a nuclear medicine and a nanometer. The chemotherapeutic drug, through the difference between the storage temperature and the human body temperature, causes the water gel to be in an aqueous solution state before being injected into the human body, and after entering the human body, the phase state is transformed into a colloid, so that it can effectively stay fixed to the injected organ site, Will escape to other normal organizations.
A secondary object of the present invention is to provide a temperature-sensitive water gel coated with a radioisotope and a chemotherapeutic drug for cancer treatment and a preparation method thereof, which can concentrate radiation dose and chemical substance generated by radiotherapy and chemotherapy At the tumor site, reduce the impact on surrounding normal tissue.
Another object of the present invention is to provide a temperature-sensitive hydrogel coated with a radioisotope and a chemotherapeutic drug for cancer treatment and a preparation method thereof, which can be catabolized in the human body over time without causing sequelae.
Still another object of the present invention is to provide a temperature-sensitive water gel coated with a radioisotope and a chemotherapeutic drug for cancer treatment and a preparation method thereof, which have good biocompatibility and can reduce side effects suffered by a patient. And the risk of treatment.
In order to achieve the above object, the present invention discloses a cancer treatment temperature sensitive water gel, which comprises a hydrocolloid, which is a polymer compound composed of polycaprolactone-polyethylene glycol-polycaprolactone; A cancer therapeutic drug molecule encapsulated in the hydrocolloid. For the preparation method, the steps include: synthesizing a polymer compound of polycaprolactone-polyethylene glycol-polycaprolactone; preparing a drug molecule; and mixing the polymer compound and the drug molecule, during the mixing process The method of repeatedly raising and lowering the temperature.

In order to provide a better understanding and understanding of the features of the present invention and the efficacies achieved, the preferred embodiments and detailed descriptions are provided as follows:
In the cancer treatment method of the prior art, since the side effect is strong, or there is no way to concentrate the drug or radiation on the tumor of the lesion, the effect of the treatment is lowered, so the present invention is directed to the disadvantages, and the temperature-sensitive hydrocolloid is Cancer treatment drug coating materials to improve the benefits of proximity treatment.
First, please refer to the first figure, the cancer treatment temperature sensitive water gel of the present invention, which comprises a hydrocolloid composed of polycaprolactone-polyethylene glycol-polycaprolactone (Polycaprolactone - Polyethylene glycol - Polycaprolactone, PCL-PEG-PCL) is a polymer compound in which the number average molecular weight of the polymer compound is about 2,500, and the ratio of the number average molecular weight of PCL to PEG is 3 to 2.
The polymer compound is limited to this feature, because the ratio of PCL-PEG-PCL at a lower concentration allows the formed hydrocolloid to be colloidal under normal conditions of body temperature of 37 ° C. . Referring to the second figure, when the number average molecular weight of PCL-PEG-PCL is about 2,500, and the ratio of the average molecular weight of PCL to PEG is 3 to 2, the physical properties exhibited are in accordance with the foregoing conditions, and It further has the property of being a clear liquid at low temperatures, and is more suitable for use in subsequent mixing steps. In contrast, if the number average molecular weight of PCL-PEG-PCL is too large and the ratio of PCL to PEG composition is not 3 to 2, it is not applicable to the physical properties of the human body or the need to increase the concentration. Or even not appearing colloidal (not shown in the figure) due to changes in concentration and temperature, thus lacking in efficiency.
In addition to the water gel, the cancer treatment temperature sensitive water gel of the present invention further comprises a plurality of cancer therapeutic drug molecules. The cancer therapeutic drug molecules may be nuclear medicine or chemotherapeutic drugs, or they may be coated in a hydrocolloid at the same time as needed.
The term "nuclear drug" as used herein refers to a radioisotope, especially the length of the half-life, the ease of preparation, and the type and intensity of the radioactivity suitable for use in a radioisotope for in-situ radiotherapy. The radioisotope referred to in the present invention comprises 铼188 ( ¹⁸⁸ Re, half-life 16.9 hours), 铼186 ( ¹⁸⁶ Re, half-life 90 hours), 镏177 ( ¹⁷⁷ Lu, half-life 6.7 days), 钐153 ( ¹⁵³ Sm, half-life) 46.7 hours), iodine 131 ( ¹³¹ I, half-life 8 days), indium 111 ( ¹¹¹ In, half-life 67.9 hours), 钇90 ( ⁹⁰ Y, half-life 64 hours) and copper 64 ( ⁶⁴ Cu, half-life 12.8 hours).
As for the chemotherapeutic drug, a camptothecin derivative, a paclitaxel, a doxorubicin, and the like are included, and the chemotherapeutic drug has been nanotinized. Among them, the camptothecin derivative refers to 7-ethyl-10-hydroxycamptothecin (Sn-38) and has an action against tumor cells.
The cancer-sensing temperature-sensitive gelatin formed by coating a specific ratio of PCL-PEG-PCL coated with a nuclear drug or a chemotherapeutic drug is temperature-sensitive; as described above, when the hydrocolloid is at a low concentration It is colloidal under the normal conditions of body temperature of 37 ° C, but it is liquid at lower temperature. For example, referring to the second figure, when the concentration of PCL-PEG-PCL of the present invention is 10%, The liquid state of the aqueous solution is exhibited in an environment below 18 °C. Therefore, the present invention provides a temperature-dependent cooperation, so that PCL-PEG-PCL coated with a nuclear medicine or a chemotherapeutic drug exhibits an aqueous solution state in a catheter to facilitate local injection of tumor tissue or operation of liver cancer artery embolization. After being infused into the treatment area, since the body temperature of the human body is 37 ° C, the PCL-PEG-PCL of the present invention changes the phase state into a gelatinous solid under the condition of temperature increase, so that it can stay in the treatment area, and The nuclear medicine or the chemotherapeutic drug is locked in this part, and will not escape to other normal tissues, reducing the radiation dose or chemical dose absorbed by the normal tissue, and reducing side effects.
In such a fixed-stop colloidal state, the radioisotope used as a nuclear medicine will continue to emit radiation to the tumor until it gradually decays to background radiation; and as a chemical compound such as a chemotherapeutic drug, it can also be followed by PCL. - The decomposition of PEG-PCL is slowly released, which prolongs the residence time of the cancer therapeutic molecules and enhances the therapeutic effect.
The invention also discloses a method for preparing a temperature-sensitive water gel for cancer treatment, please refer to the third figure, and the steps thereof include:
Step S10: synthesizing a polymer compound of polycaprolactone-polyethylene glycol-polycaprolactone;
Step S20: preparing a drug molecule; and step S30: mixing the polymer compound and the drug molecule, and adopting a method of repeatedly raising and lowering temperature during the mixing process.
Step S10 is a method for synthesizing PCL-PEG-PCL, which is formed by using a polyethylene glycol (PEG) as a macroinitiator and ring-opening polymerization of cyclohexanolide (ε-Caprolactone). The molecular weight of PCL-PEG-PCL is required. Referring to FIG. 4A and FIG. 4B, the ring-opening polymerization cyclocaprolactone is heated by using stannous octoate (Sn(Oct) ₂ ) as a catalyst, and then the caprolactone after ring opening is polymerized with PEG, that is, The polymer compound of PCL-PEG-PCL is obtained; and the present invention is limited in the ratio of PCL to PEG in order to be temperature sensitive, so the number average molecular weight of the polymer compound is about 2,500, and the PCL and The number average molecular weight ratio of PEG is 3 to 2.
Step S20 is a step of preparing a drug molecule, which is a step of coating a temperature-sensitive water gel of the present invention with a nuclear medicine or a chemotherapy drug. The drug molecule refers to a radioisotope colloid or a nanocell drug, either of which can be coated with PCL-PEG-PCL alone or both.
If the coated drug molecule is a radioisotope colloid, further comprising a step S20A, please refer to the fifth figure, which is obtained by adding stannous chloride to a radioactive isotope eluting liquid to form the radioisotope colloid. The radioisotope is a radioisotope suitable for use in the treatment of brachytherapy in the body, and may be a nuclear species such as ¹⁸⁸ Re, ¹⁸⁶ Re, ¹⁷⁷ Lu, ¹⁵³ Sm, ¹³¹ I, ¹¹¹ In, ⁹⁰ Y and ⁶⁴ Cu.
If the coated drug molecule is a nano-cell drug, the method further comprises a step S20B, and then refer to the fifth figure, which is prepared by lyophilization and hydration, and the chemotherapeutic drug is prepared as a nanometer. a cytopharmaceutical; wherein the chemotherapeutic drug is selected from the group consisting of camptothecin derivatives, paclitaxel, and liposome. In addition, since the synthesis of PCL-PEG-PCL is accompanied by the production of mPEG-PCL, the side chain structure can suitably coat the nanopore drug.
After obtaining the applicable polymer compound and drug molecule, the two can be mixed. In step S30, the temperature is repeatedly raised to about 70 ° C or higher, and then the temperature is lowered to 4 ° C or less, so that the two can be uniformly mixed, so that the drug molecules can be more dispersedly mixed in the polymer compound to make the temperature sensitive. Cancer treatment temperature sensitive water gel.

The following is an actual operation example of the invention using ¹⁸⁸ Re as a drug molecule for cancer treatment:
Step S10: synthesizing one of polycaprolactone-polyethylene glycol-polycaprolactone polymer compound, taking 3.0 g of polyethylene glycol, heating to 120 ° C in a flask, and vacuuming and remaining in the polymer Moisture for four hours; take 2.0 grams of cyclocaprolactone and 0.02 grams of stannous octoate, add to the mixture, raise the temperature to 145 ° C, and continue to stir for 24 hours; the polymer synthesized by the reaction is in tetrahydrofuran (Tetrahydrofuran, The THF) was dissolved, then a precipitate was taken in an ice bath in diethyl ether. The precipitate was filtered and dried in vacuo.

Step S20: preparing a radioisotope colloid in a high purity ¹⁸⁸ Re perrhenate solution (having an activity of about 370 million Baker/ml), adding 5 to 45 mg of stannous chloride, heating to 50 ° C, Adjust the heating time by adding the amount of stannous chloride for 5 to 120 minutes; stop heating, cool to room temperature, centrifuge at 3000 rpm for 10 minutes, and then remove the supernatant, leaving the radioisotope colloid .

Step S30: mixing the polymer compound and the radioactive isotope colloid, and adopting a method of repeatedly raising and lowering temperature during the mixing process, after obtaining the polymer compound and the radioactive isotope colloid of the foregoing step, mixing the two, and repeatedly raising the temperature to about 70 ° C or higher Then, cool down to below 4 °C, so that the two can be evenly mixed.

After in vitro testing with tumor-bearing animals, the release of ¹⁸⁸ Re is shown to be quite slow. Please refer to the sixth graph. The release ratio of ¹⁸⁸ Re at the tumor site is quite low over time, especially in step S20A. When the concentration of stannous iron is 45 mg/ml, the lowest release ratio is obtained. Since the half-life of ¹⁸⁸ Re is 16.9 hours, supplemented by the sixth figure, after 3.5 half-lives, up to 90% of ¹⁸⁸ Re stays in the tumor site, and it is known that its intensity is half-life. The limit is reduced to 0.088 times the original intensity. Therefore, in the process of treating the temperature-sensitive water gel of the present invention, the anticancer drug can still stay at a high level in the process of isotope attenuation to the background, can enhance the therapeutic effect, can effectively prolong the survival period of the animal, and inhibit the growth of cancer.
A temperature sensitive water gel is formed by the hybrid coating of the present invention. With its temperature sensitivity, it will be possible to continuously apply radiation therapy to the tumor site of the patient, or to slowly release the chemotherapy drug, which not only has a high degree of concentration, but also prolongs the anticancer time of the drug, and is more capable of Naturally catabolized after treatment, it is a very effective anti-cancer application.
The above is only the preferred embodiment of the present invention, and is not intended to limit the scope of the present invention, and the variations, modifications, and modifications of the shapes, structures, features, and spirits described in the claims of the present invention. All should be included in the scope of the patent application of the present invention.
The invention is a novelty, progressive and available for industrial use, and should meet the requirements of the patent application stipulated in the Patent Law of China, and the invention patent application is filed according to law, and the prayer bureau will grant the patent as soon as possible. prayer.

No.

First: it is a schematic diagram of a composition of a preferred embodiment of the present invention;
Second: it is a comparison of characteristics of a preferred embodiment of the present invention;
Third: it is a preparation flow chart of a preferred embodiment of the present invention;
Figure 4A is a flow chart of a preferred embodiment of the present invention;
Figure 4B is a flow chart of a preferred embodiment of the present invention;
Figure 5 is a flow chart showing the preparation of a preferred embodiment of the present invention; and Figure 6 is an effect test chart of a preferred embodiment of the present invention.

no.

Claims (10)

A cancer treatment temperature sensitive water gel, the system comprising:
A hydrocolloid, which is a polymer compound composed of polycaprolactone-polyethylene glycol-polycaprolactone; and a plurality of cancer therapeutic drug molecules, coated in the hydrocolloid. The cancer treatment temperature sensitive water gel according to claim 1, wherein the polymer compound has a number average molecular weight of about 2,500, and the ratio of the number average molecular weight of the polycaprolactone to the polyethylene glycol is 3 ratio. 2. The cancer treatment temperature sensitive water gel according to claim 1, wherein the cancer therapeutic drug molecules are selected from at least one of the group consisting of nuclear medicines and chemotherapy drugs. The invention relates to a cancer treatment temperature sensitive water gel according to claim 3, wherein the nuclear medicine is a radioisotope. The cancer treatment temperature sensitive water gel according to claim 3, wherein the chemotherapeutic drug is selected from the group consisting of camptothecin derivatives, paclitaxel and liposome. The invention relates to a cancer treatment temperature sensitive water gel according to claim 4, wherein the radioisotope is selected from the group consisting of 铼188, 铼186, 镏177, 钐153, iodine131, indium 111, 钇90 and copper 64 One of the group consisting of. A method for preparing a temperature-sensitive water gel for treating cancer, the steps comprising:
Synthesizing a polymer compound of polycaprolactone-polyethylene glycol-polycaprolactone;
Preparing a drug molecule; and mixing the polymer compound and the drug molecule, and adopting a method of repeatedly raising and lowering temperature during the mixing process;
Wherein, the drug molecule is selected from at least one of the group consisting of a radioisotope colloid and a nanocell drug. The method for preparing a temperature-sensitive hydrogel for treating cancer according to the invention of claim 7, wherein the step of preparing a drug molecule further comprises:
Adding stannous chloride to a radioactive isotope washing liquid to form a radioisotope colloid;
The radioisotope is selected from the group consisting of 铼188, 铼186, 镏177, 钐153, iodine131, indium 111, 钇90, and copper 64. The method for preparing a temperature-sensitive hydrogel for treating cancer according to the invention of claim 7, wherein the step of preparing a drug molecule further comprises:
The lyophilized water is legally combined with ultrasonic waves, and the chemotherapeutic drug is prepared into a nano-cell drug;
Wherein the chemotherapeutic drug is selected from the group consisting of camptothecin derivatives, paclitaxel and liposome. The method for preparing a temperature-sensitive hydrogel for treating cancer according to claim 7, wherein the polymer compound has a number average molecular weight of about 2,500, and the ratio of the average molecular weight of the polycaprolactone to the polyethylene glycol is 3 to 2.