CN113209291A - Nano-carrier for combined treatment of tumor chemotherapy and photothermal therapy and preparation method and application thereof - Google Patents
Nano-carrier for combined treatment of tumor chemotherapy and photothermal therapy and preparation method and application thereof Download PDFInfo
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
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Abstract
The invention discloses a nano-carrier for tumor photothermal-chemotherapy combination therapy, which is formed by self-assembly of an amphiphilic copolymer, wherein a hydrophobic end of the amphiphilic copolymer is formed by oligomeric indocyanine green, a hydrophilic end of the amphiphilic copolymer is formed by polyethylene glycol, the hydrophilic end and the hydrophobic end of the amphiphilic copolymer are connected by a thermal response group, and the molecular weight of the amphiphilic copolymer is 1-20K Da; the response temperature of the thermal response group is 50-90 ℃. The nano-carrier provided by the invention has photothermal conversion capability, and can be used for chemotherapy and photothermal combined treatment without additionally coating a photothermal conversion material; the invention also discloses a preparation method of the nano-carrier and application of the nano-carrier in preparing nano-drugs for chemotherapy and photothermal combined treatment.
Description
Technical Field
The invention belongs to the technical field of biomedical materials, and particularly relates to a nano-carrier for combined treatment of tumor chemotherapy and photothermal therapy, a preparation method of the nano-carrier, and application of the nano-carrier in preparation of nano-drugs for combined treatment of chemotherapy and photothermal therapy.
Background
Cancer cases and deaths have increased rapidly over the past decade, with cancer being expected to be the leading cause of death worldwide in the 21 st century. Therefore, the development of highly effective anticancer strategies is urgently needed. Chemotherapy is a widely used treatment in the clinic, but due to the intolerable side effects and the complexity of tumor physiology brought by chemotherapeutic drugs, chemotherapy alone may not be sufficient to completely cure cancer. The combination therapy is a combined therapy system based on chemotherapy and other therapeutic means, which are mutually strengthened, and is an effective way to overcome the adverse factors.
Photothermal therapy (PTT), which generates heat by irradiation of laser light of a corresponding wavelength using a near-infrared light absorber and kills tumor cells at a predetermined location, is considered as one of the most promising minimally invasive tumor treatment methods. Low-energy near-infrared light is advantageous as a remotely activated light source in terms of spatial and temporal control due to its ease of focusing and switching. Meanwhile, the tissue is considered to be transparent due to the characteristic that the tissue is not easily absorbed by cells or tissues, so that the tissue penetration is better. Many clinical trials show that chemotherapy and thermotherapy produced by special means such as PTT and the like can greatly improve the control rate of tumors and the survival rate of patients. This is because the combination of hyperthermia and chemotherapy produces a synergistic response, on the one hand, hyperthermia alone kills tumor cells, and on the other hand, increases the flow and permeability of blood vessels by increasing the temperature of the tumor tissue, thereby enhancing the ability of the drug to enter the tumor tissue. It is predicted that the photothermal delivery of the PTT through the combination therapy system in tumor chemotherapy will maximize therapeutic efficacy and minimize side effects with precise controlled release.
Therefore, how to design nano-drugs to realize the combined use of chemotherapy and photothermal therapy is a key factor for improving the treatment effect.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a nano-carrier for combined treatment of tumor chemotherapy and photothermal therapy, the nano-carrier has photothermal conversion capability, and can be used for combined treatment of chemotherapy and photothermal therapy without additionally coating photothermal conversion materials; the invention also aims to provide a preparation method of the nano-carrier and application of the nano-carrier in preparation of nano-drugs for chemotherapy and photothermal combined therapy.
The invention is realized by the following technical scheme:
a nano-carrier for tumor photothermal-chemotherapy combination therapy is formed by self-assembly of amphiphilic copolymers, wherein a hydrophobic end is formed by oligomeric indocyanine green, a hydrophilic end is formed by polyethylene glycol, the hydrophilic end and the hydrophobic end are connected through a thermal response group, and the response temperature of the thermal response group is 50-90 ℃.
Further, the structural formula of the nano carrier is as follows:
the molecular weight of the nano-carrier is 1-20K Da.
The invention further improves the scheme as follows:
a preparation method of a nano-carrier for tumor photothermal-chemotherapy combination treatment comprises the following steps:
dissolving a first batch of HOOC-ICG-COOH in N, N-dimethylformamide, adding ethylenediamine, reacting at room temperature under the catalysis of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysulfosuccinimide (NHS), dialyzing, freeze-drying and purifying after the reaction is finished to obtain H2N-ICG-NH2(ii) a The obtained H2N-ICG-NH2Dissolving in N, N-dimethylformamide, adding a second batch of HOOC-ICG-COOH, reacting at room temperature under the catalysis of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysulfosuccinimide, and dialyzing, freeze-drying and purifying after the reaction to obtain HOOC-ICG-ICG-ICG-COOH, which is called PICG for short;
dissolving methoxy polyethylene glycol maleimide and 2-furanmethanamine in acetone, stirring, heating for reaction, and purifying after the reaction is finished to obtain mPEG-DA; dissolving the obtained mPEG-DA and the PICG prepared in the first step into N, N-dimethylformamide, reacting at room temperature under the catalysis of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysulfosuccinimide, and dialyzing, freeze-drying and purifying after the reaction is finished to obtain PEG-DA-PICG, namely the nano-carrier for the tumor photothermal-chemotherapy combination treatment;
the reaction equation is shown in FIG. 1.
Further, in the first step, the mole ratio of the first HOOC-ICG-COOH batch to the second HOOC-ICG-COOH batch is as follows: 1: (2-10): (2.5-4).
Further, in the second step, the molar ratio of methoxypolyethylene glycol maleimide to 2-furanmethanamine is 1: (0.9-1.4), wherein the temperature of the heating reaction is 40-70 ℃; the molar ratio of mPEG-DA to PICG is 1: (0.8 to 1.2).
The invention further improves the scheme as follows:
the application of the nano-carrier for tumor photothermal-chemotherapy combination therapy in preparing nano-drugs.
Further, the application of the nano-carrier in preparing nano-drugs comprises the following steps:
dissolving the nano-carrier and the active drug in dichloromethane, dripping the dissolved nano-carrier and the active drug into deionized water, removing the dichloromethane in a system by rotary evaporation after ultrasonic emulsification, centrifugally cleaning, and freeze-drying to obtain the nano-drug powder for the tumor photothermal-chemotherapy combined treatment.
Further, the mass ratio of the nano-carrier to the active drug is 10: 0.5 to 5; the volume ratio of the dichloromethane to the deionized water is 1: 10 to 25.
Further, the active drug is adriamycin, paclitaxel or camptothecin.
The reaction principle of the invention is seen in the following processes:
as shown in fig. 1, the first step: the trimer PICG is obtained through two reactions, wherein an amido bond is formed between carboxyl in HOOC-ICG-COOH and amino in ethylenediamine.
The second step is that: firstly, carrying out Diels-Alder reaction (Dies-Alder reaction) on methoxy polyethylene glycol maleimide (mPEG-Mal) and 2-aminofuran to form a group (DA group for short) with thermal response; and then the amino in mPEG-DA reacts with the carboxyl in PICG to form PEG-DA-PICG. The thermal response characteristics of PEG-DA-PICG are provided by the DA group: the DA group remains stable at normal temperature, however, it decomposes at temperatures above 50 ℃.
According to the PEG-DA-PICG prepared by the invention, under near-infrared illumination, the hydrophobic core PICG has photothermal conversion capacity and provides heat required by photothermal treatment; the PEG-DA-PICG prepared by the invention can be rapidly heated to 50 ℃ under the laser irradiation, and can well kill tumor cells at the temperature. In addition, at the temperature, the nano-carrier PEG-DA-PICG is decomposed, the nano-carrier is broken, the coated medicine is released, and photo-thermal medicine controlled release is realized. Therefore, when the nano-carrier PEG-DA-PICG is used for combined treatment of tumor photothermal-chemotherapy, the treatment effect can be obviously improved.
Compared with the prior art, the invention has the following beneficial effects: on one hand, the nano-carrier has photothermal conversion capability, and when chemotherapy and photothermal therapy are combined for use, no additional photothermal conversion material needs to be loaded, so that the preparation of the nano-carrier is simplified; on the other hand, the nano-carrier has a thermal response group, and under the action of the photothermal conversion performance of the nano-carrier, when the temperature is raised to 50 ℃, the thermal response group is decomposed, the nano-carrier is cracked, the coated medicine is released, and the photothermal medicine controlled release is realized. The invention realizes the coupling of the thermal response group and the photo-thermal conversion and endows the carrier with the photo-thermal controlled release characteristic.
Drawings
FIG. 1 reaction equation of the present invention;
FIG. 2 is a transmission electron microscope image of the nano-drug prepared in example 1;
as shown in FIG. 2, the nano-drug is spherical nano-particles with a particle size of about 150 nm;
FIG. 3 is a temperature rise curve of the nano-drug under near-infrared light irradiation;
figure 4 is the release profile of the nano-drug (. p < 0.001);
FIG. 5 is a graph of tumor volume versus time in tumor-bearing mice in different treatment groups.
Detailed Description
The invention is further illustrated by the following figures and examples.
Example 1: preparation of nano carrier and nano medicine
1) Dissolving 0.68 g HOOC-ICG-COOH in 50 mL of N, N-dimethylformamide, adding 0.7 mL of ethylenediamine, 0.2 g of EDC and 0.12 g of NHS, and reacting at room temperature overnight; dialyzing, freeze-drying and purifying to obtain H2N-ICG-NH2. Dissolving 50 mL of the mixture in N, N-dimethylformamide again, adding 1.7 g of HOOC-ICG-COOH, 0.5 g of EDC and 0.3 g of NHS, reacting overnight at room temperature, dialyzing, freeze-drying and purifying to obtain the PICG.
2) 0.2 g mPEG-Mal (molecular weight: 2 KDa) and 0.1 mL 2-furanmethanamine are dissolved in 20 mL acetone, heated to 50 ℃, stirred overnight, and purified to obtain mPEG-DA. Then, the mPEG-DA and 0.2 g PICG are dissolved in 20 mL of N, N-dimethylformamide, and react overnight at room temperature under the catalysis of 0.2 g of EDC and 0.12 g of NHS, and the PEG-DA-PICG is obtained after dialysis, freeze-drying and purification.
3) Dissolving 50 mg of PEG-DA-PICG and 5 mg of paclitaxel in 2 mL of dichloromethane, fully dissolving, dropwise adding into 40 mL of deionized water, ultrasonically emulsifying, removing dichloromethane in the system by rotary evaporation, centrifuging, cleaning, and lyophilizing to obtain nanometer medicinal powder composed of nanometer carrier used in combination with chemotherapy and photothermal therapy.
Example 2: preparation of nano carrier and nano medicine
1) Dissolving 0.68 g HOOC-ICG-COOH in 50 mL of N, N-dimethylformamide, adding 1.0 mL of ethylenediamine, 0.2 g of EDC and 0.12 g of NHS, and reacting at room temperature overnight; dialyzing, freeze-drying and purifying to obtain H2N-ICG-NH2. Dissolving 50 mL of the mixture in N, N-dimethylformamide again, adding 2.1 g of HOOC-ICG-COOH, 0.5 g of EDC and 0.3 g of NHS, reacting overnight at room temperature, dialyzing, freeze-drying and purifying to obtain the PICG.
2) 0.5 g mPEG-Mal (molecular weight: 5 KDa) and 0.12 mL 2-furanmethanamine are dissolved in 20 mL acetone, heated to 50 ℃, stirred overnight, and purified to obtain mPEG-DA. Then, the mPEG-DA and 0.2 g PICG are dissolved in 20 mL of N, N-dimethylformamide, and react overnight at room temperature under the catalysis of 0.2 g of EDC and 0.12 g of NHS, and the PEG-DA-PICG is obtained after dialysis, freeze-drying and purification.
3) Dissolving 50 mg of PEG-DA-PICG and 5 mg of adriamycin in 2 mL of dichloromethane, dropwise adding the mixture into 50 mL of deionized water after full dissolution, removing the dichloromethane in the system by rotary evaporation after ultrasonic emulsification, centrifugally cleaning, and freeze-drying to obtain nano-drug powder consisting of nano-carriers used in combination with chemotherapy and photothermal therapy.
Example 3: PEG-DA-PICG verification and photothermolysis capability verification
50 mg of PEG-DA-PICG prepared in example 1 were dissolved in 10 mL of ethanol and divided into two portions on average. One part was left untreated and one part was treated with a 808 nm laser (0.5W/cm)3) Irradiating for 10 min. Then dialyzed in deionized water using a dialysis bag having a molecular weight cut-off of 3.5 KDa, then lyophilized into a powder, and the molecular weights of both were measured using Gel Permeation Chromatography (GPC), with the results shown in table 1.The molecular weight of the PEG-DA-PICG which was not illuminated was 3870, close to the theoretical value, slightly less than the theoretical value, due to the small amount of unreacted PICG. The molecular weight measured value of PEG-DA-PICG after near infrared illumination is not 2150, and is close to the theoretical value of PICG connected with furyl, which shows that after near infrared illumination, the heat generated causes the DA group to crack, and mPEG-Mal is lost after dialysis. The above results indirectly demonstrate that PEG-DA-PICG was successfully prepared, and also demonstrate that PEG-DA-PICG has the ability to undergo photothermal cleavage.
TABLE 1 GPC measurement of molecular weight changes of PEG-DA-PICG under near Infrared illumination
Theoretically, after near infrared illumination, DA groups are broken, mPEG-Mal is lost after dialysis, and only PICG connected with furyl is left.
Example 4: morphology of the nanocarriers
20 mg of the nano-drug prepared in example 1 was dissolved in 4 mL of water to prepare a transmission electron microscope sample. It was then divided into two equal portions, one without treatment and one with a 808 nm laser (0.5W/cm)3) Irradiating for 10 min, and preparing transmission electron microscope samples respectively for 24 hours. As shown in FIG. 2, the prepared nano-drug is spherical nano-particles with a particle size of about 150 nm (FIG. 2A). After near infrared irradiation, the nano-drug was completely destroyed (fig. 2B), while the unirradiated nano-drug still maintained the original morphology at 24 h.
Example 5: verification of photothermal conversion Performance
10 mg of the nano-drug prepared in example 1 was dissolved in 2 mL of water using a 808 nm laser (0.5W/cm)3) Irradiating, and monitoring the temperature change of the solution in real time; the temperature change of 2 mL of deionized water under laser irradiation was tested in the same manner. The temperature was plotted against time as shown in fig. 3. It can be seen that the nano-drug solution was elevated by about 35 c within 5 min of laser irradiation, while the temperature of pure water was not much elevated. This shows that the nano-drug provided by the invention has photothermal conversion capability.
Example 6: verification of infrared light controlled release performance
100 mg of the nano-drug prepared as in example 1 was dissolved in 10 mL of deionized water, divided into two equal portions, packed in a dialysis bag, and then placed in a beaker containing 45 mL of water to prepare a drug release model (reference numerals 1, 2). Sample No. 1 was irradiated with 808 nm laser light before and at 6 hours, respectively, and sample No. 2 was not irradiated. At fixed time points, 3 100. mu.L of the solution was taken, and the absorbance of the solution at 227 nm was measured using a microplate reader to calculate the drug release amount. The results are shown in FIG. 4. It can be seen that the release rate of the nano-drug irradiated by laser is obviously higher than that of the nano-drug not irradiated by laser; and at 6h, the release rate of the nano-drug is remarkably improved by laser irradiation. The nano-drug provided by the invention has the near-infrared controlled release characteristic.
Example 7: synergistic treatment ability verification
When the tumor volume of the tumor-bearing mice (the in situ breast cancer formed by the 4T1 cell line) is as long as about 20 mm3At this time, they were divided equally into three groups of 5 pieces each. The first group was injected with 100 μ L of physiological saline as a control group; the second group was injected with 100. mu.L of the nano-drug solution (10 mg/mL) prepared in example 1 (chemotherapy only), and the third group was injected with 100. mu.L of the nano-drug solution (10 mg/mL) prepared in example 1 and irradiated with 808 nm laser for 10 min after 6h (chemotherapy and photothermal co-therapy). The above procedure was repeated on day 3. The maximum length (L) and minimum length (W) of the tumor in the mice were measured every three days in volume V = (L × W)2) The tumor volume was calculated and recorded as a function of time as shown in figure 5. It can be found that the tumor in the mice treated by the chemotherapy and photothermal synergistic treatment in the group (3) is inhibited to the maximum extent, and the effect is far higher than that of the control group (1) and the group (2) only treated by the chemotherapy, which indicates that the chemotherapy and photothermal synergistic treatment have better tumor treatment effect.
Claims (9)
1. The nano-carrier for tumor photothermal-chemotherapy combination therapy is characterized by being formed by self-assembly of amphiphilic copolymers, wherein the hydrophobic end of the nano-carrier is formed by oligomeric indocyanine green, the hydrophilic end of the nano-carrier is formed by polyethylene glycol, the hydrophilic end and the hydrophobic end are connected through a thermal response group, and the response temperature of the thermal response group is 50-90 ℃.
2. The nanocarrier for combined tumor photothermal-chemotherapy treatment according to claim 1, wherein: the structural formula of the nano carrier is as follows:
the molecular weight of the nano-carrier is 1-20K Da.
3. The method for preparing the nanocarrier for the combined tumor photothermal-chemotherapy treatment according to any one of claims 1 or 2, comprising the steps of:
step one, dissolving a first batch of HOOC-ICG-COOH in N, N-dimethylformamide, adding ethylenediamine, reacting at room temperature under the catalysis of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysulfosuccinimide, dialyzing, freeze-drying and purifying after the reaction is finished to obtain H2N-ICG-NH2(ii) a The obtained H2N-ICG-NH2Dissolving in N, N-dimethylformamide, adding a second batch of HOOC-ICG-COOH, reacting at room temperature under the catalysis of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysulfosuccinimide, and dialyzing, freeze-drying and purifying after the reaction to obtain HOOC-ICG-ICG-ICG-COOH, which is called PICG for short;
dissolving methoxy polyethylene glycol maleimide and 2-furanmethanamine in acetone, stirring, heating for reaction, and purifying after the reaction is finished to obtain mPEG-DA; and (3) dissolving the obtained mPEG-DA and the PICG prepared in the first step into N, N-dimethylformamide, reacting at room temperature under the catalysis of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and N-hydroxysulfosuccinimide, and dialyzing, freeze-drying and purifying after the reaction is finished to obtain the PEG-DA-PICG, namely the nano-carrier for the tumor photothermal-chemotherapy combined treatment.
4. The method for preparing the nanocarrier for the combined tumor photothermal-chemotherapy treatment according to claim 3, wherein: in the first step, the mole ratio of the first HOOC-ICG-COOH batch to the second HOOC-ICG-COOH batch is as follows: 1: (2-10): (2.5-4).
5. The method for preparing the nanocarrier for the combined tumor photothermal-chemotherapy treatment according to claim 3, wherein: in the second step, the molar ratio of the methoxy polyethylene glycol maleimide to the 2-furanmethanamine is 1: (0.9-1.4), wherein the temperature of the heating reaction is 40-70 ℃; the molar ratio of mPEG-DA to PICG is 1: (0.8 to 1.2).
6. Use of the nanocarrier according to any of claims 1 or 2 for photothermal-chemotherapeutic combination treatment of tumors for the preparation of a nano-drug.
7. The use of the nanocarrier for tumor photothermal-chemotherapy combination therapy according to claim 6 for preparing a nano-drug, wherein: the method comprises the following steps:
dissolving the nano-carrier and the active drug in dichloromethane, dripping the dissolved nano-carrier and the active drug into deionized water, removing the dichloromethane in a system by rotary evaporation after ultrasonic emulsification, centrifugally cleaning, and freeze-drying to obtain the nano-drug powder for the tumor photothermal-chemotherapy combined treatment.
8. The use of the nanocarrier for photothermal-chemotherapeutic combination treatment of tumor according to claim 7 for preparing a nano-drug, wherein: the mass ratio of the nano-carrier to the active drug is 10: 0.5 to 5; the volume ratio of the dichloromethane to the deionized water is 1: 10 to 25.
9. The use of the nanocarrier for tumor photothermal-chemotherapy combination therapy according to any one of claims 7 or 8 for preparing a nano-drug, wherein: the active drug is adriamycin, paclitaxel or camptothecin.
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