CN112546025B - Preparation method of Ce6@CMCS-DSP-IPI549 anti-tumor nano-delivery system - Google Patents
Preparation method of Ce6@CMCS-DSP-IPI549 anti-tumor nano-delivery system Download PDFInfo
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- A61K47/6931—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
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- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Abstract
The invention discloses a Ce6@CMCS-DSP-IPI549 anti-tumor nano-delivery system and a preparation method thereof, which can adjust an action target point and control time, concentrate at tumor cells, effectively reduce toxic and side effects of a photosensitizer, improve solubility and reduce adverse reactions of organisms. Dissolving an amphiphilic prodrug CMCS-DSP-IPI549 bonded with an antitumor drug IPI-549 of immunotherapy and a disulfide bond group in deionized water, adding an organic solution containing a hydrophobic photosensitizer chlorin (Ce 6) through a dripping method, and obtaining the Ce6@CMCS-DSP-IPI549 antitumor nano-delivery system through ultrasonic crushing and dialysis self-assembly. The nano-delivery system synthesizes and encapsulates two drugs with different action mechanisms in one nanoparticle, adopts the dual-channel combination of immunotherapy and phototherapy to treat tumors, can release the two drugs in tumor microenvironment and specific near infrared illumination, and provides new methodology and theoretical basis for clinical tumor treatment.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a preparation method of a Ce6@CMCS-DSP-IPI549 antitumor nano-delivery system.
Background
A tumor is a highly specific disease in which each tumor is composed of cancer cells with different genetic backgrounds, and thus each tumor exhibits different responses to drugs. Once the cancer cells shed the organ tissues in the body, the free cancer cells can spread throughout the body along with blood or lymph fluid to form metastasis, thereby endangering life.
The traditional mode of treating tumors is chemotherapy, namely, antitumor drugs are orally taken or intravenous injected, and the drugs are delivered to focus positions through systemic circulation to kill tumor cells. However, most of the antitumor drugs have no selectivity on tumor cell tissues and normal cell tissues, and can cause unavoidable injury on normal cells, cause great injury on human bodies and cause great pain to patients. Secondly, because biological barriers (such as blood brain barriers) exist in the human body, only a small amount of medicine can reach focus areas, so that the bioavailability is low; in addition, long-term administration can cause organism drug resistance, and make tumor treatment more difficult. In order to solve the above problems, drug delivery systems using new dosage forms or new technologies are being vigorously developed.
Disclosure of Invention
Based on the defects of the prior art, the technical problem solved by the invention is to provide a Ce6@CMCS-DSP-IPI549 anti-tumor nano-delivery system and a preparation method thereof. The core-shell nanoparticle prepared by the method not only has good stability and tumor targeting, but also has good immunotherapeutic property and near infrared light responsiveness, can improve immunosuppressive cells in tumor microenvironment, and can regulate the action target point and action time of near infrared light to regulate and control the release of the photosensitizer.
In order to solve the technical problems, the invention provides a preparation method of a Ce6@CMCS-DSP-IPI549 anti-tumor nano-delivery system, which is characterized by comprising the following steps:
(1) Synthesis of DSP-IPI549 intermediate:
dissolving a certain DSP in DMSO, and stirring until the DSP is completely dissolved; dissolving IPI-549 in DMSO, slowly dripping into the DSP solution, magnetically stirring at room temperature in dark place for reaction for 24h, dialyzing with mixed solution of DMSO and deionized water and water, and freeze-drying to obtain DSP-IPI549 intermediate freeze-dried powder;
(2) Synthesis of CMCS-DSP-IPI549 prodrugs:
dissolving the DSP-IPI549 freeze-dried powder in DMSO to obtain a DSP-IPI549 solution; dissolving CMCS in deionized water, adjusting pH to 7.4, and performing ultrasonic treatment for 5min to obtain CMCS solution; slowly dripping the DSP-IPI549 solution into the CMCS solution, magnetically stirring at room temperature in a dark place for reaction for 24 hours, dialyzing with a mixed solution of DMSO and deionized water in a ratio of 7:3-3:7 and deionized water, and freeze-drying to obtain CMCS-DSP-IPI549 prodrug freeze-dried powder;
(3) Preparation of Ce6@CMCS-DSP-IPI549 anti-tumor nano-delivery system
Dissolving Ce6 in DMSO to prepare solution A, dissolving CMCS-DSP-IPI549 prodrug in deionized water to prepare solution B, dropwise adding the solution A into the solution B on a magnetic stirrer, stirring for 4 hours at room temperature and in the dark, performing low-temperature ultrasonic grinding to obtain Ce6@CMCS-DSP-IPI549 nanoparticle solution, dialyzing in deionized water for 4 hours, and performing freeze drying to obtain Ce6@CMCS-DSP-IPI549 nanoparticle freeze-dried powder, namely the Ce6@CMCS-DSP-IPI549 antitumor nano-delivery system.
As the optimization of the technical scheme, the preparation method of the Ce6@CMCS-DSP-IPI549 antitumor nano-delivery system provided by the invention further comprises part or all of the following technical characteristics:
as an improvement of the above technical solution, in the step (1), the molar ratio of DSP to IPI549 is 1:1; the mixed solution of DMSO and deionized water is a mixed solution with a volume ratio of DMSO to water of 1:9.
As an improvement to the above-described embodiment, in the step (2), the molar mass of CMCS is 1×10 4 And the carboxymethyl substitution degree is 85%; the mass ratio of CMCS to DSP-IPI549 in the step (2) is 1:1.3-3.3; the drug loading rate of the CMCS-DSP-IPI549 prodrug is 10.17% -13.63%. Wherein the drug loading rate is measured by ultraviolet photometry
As an improvement of the above technical scheme, in the step (3), the mass ratio of the CMCS-DSP-IPI549 prodrug to the photosensitizer Ce6 is 5:1-15:1.
As an improvement of the technical scheme, in the step (1), the molecular weight cut-off of the dialysis bag is 500Da, and in the steps (2) - (3), the molecular weight cut-off of the dialysis bag is 3500 Da.
As an improvement of the technical scheme, in the step (3), the low-temperature ultrasonic crushing is performed by using an ultrasonic cell crusher, and the probe is operated for 10min in a pulse mode with the power of 90w at the low temperature for 3.0s and intermittently for 2.0 s.
As an improvement of the technical scheme, the grain size of Ce6@CMCS-DSP-IPI549 nano-particles obtained in the step (3) is 141-396nm, the drug loading rate is 6.49% -10.92%, and the encapsulation rate is 55.68% -72.65%. Wherein the nanoparticles are drug loading and encapsulation rates measured using a Dynamic Light Scattering (DLS) method.
The Ce6@CMCS-DSP-IPI549 anti-tumor nano transfer system is prepared by any method.
The application of the Ce6@CMCS-DSP-IPI549 antitumor nano-delivery system is characterized in that: the two medicaments with different action mechanisms are synthesized and encapsulated in the same nanoparticle, and the two medicaments are released in the tumor microenvironment and specific near infrared illumination by adopting the combination of immunotherapy and phototherapy to treat tumors, so that the solubility of the medicaments is improved, the toxic and side effects are reduced, the targeting is increased, and a novel methodology and theoretical basis are provided for clinical tumor treatment
As the optimization of the technical scheme, the application of the Ce6@CMCS-DSP-IPI549 anti-tumor nano-delivery system provided by the invention further comprises part or all of the following technical characteristics:
as an improvement of the above technical solution, the near infrared light wavelength is 606nm.
IPI-549 as an immunological clinical candidate tumor drug was found during the optimization of the isoquinolone PI3K inhibitor, with selectivity over 100 times that of other lipid and protein kinases, and IC50 of 16nM. IPI-549 shows good pharmacokinetic properties and has an inhibitory effect on PI 3K-gamma mediated neutrophil migration, and the drug is currently in phase I clinical trials (subjects are patients with advanced solid tumors). In animal experiments (mice, rats, dogs and monkeys) IPI-549 was found to have excellent oral bioavailability, low clearance, short half-life (t 1/2 of 3.2, 4.4, 6.7, 4.3 hours respectively) and easy distribution into individual tissues (average distribution volume of 1.2L/kg). As a small molecule kinase inhibitor, IPI-549 is an ideal first-choice drug for combined treatment of tumors.
The nanometer medicine carrying system is one nanometer medicine transferring system prepared through physical embedding or chemical covalent coupling process to connect medicine and natural or synthetic polymer carrier. The system improves bioavailability of the medicine, reduces toxic and side effects of the medicine on organisms, can specifically identify focus areas, and controls medicine release. The system has targeting property, reduces the damage of the medicine to normal cells and tissues, and directionally conveys the medicine to a tumor area, thereby reducing the toxicity of the medicine.
Carboxymethyl chitosan (CMCS) is a polymer drug carrier with wider application, and has been widely applied in the field of medical biology because of its good biosafety and biocompatibility, multiple active groups and easy biodegradation. The active groups of CMCS can react with drugs to form covalent bonds and can exist stably in blood circulation, so CMCS has been developed as a carrier in a small molecule anti-tumor drug delivery system, which can improve the water solubility of small molecule drugs, prolong half-life, reduce toxic and side effects and improve targeting.
Glutathione (GSH) is a thiol-containing polypeptide protein present in humans, in body fluids or extracellular, where GSH concentrations are only micromolar (2-20 μm), whereas intracellular GSH concentrations generally reach millimolar (2-10 mM), resulting in GSH concentrations 4 times higher than normal cells due to the high degree of hypoxia within cancer cells, and disulfide bonds are susceptible to cleavage in this environment. The 3,3' -dithiodipropionic acid bis (N-hydroxysuccinimide ester) (DSP) containing disulfide bonds can be applied to an anti-tumor drug nano-delivery system, so that the steric hindrance of an anti-tumor drug and a carrier can be reduced, and the characteristics that the disulfide bonds are easily cracked by high-concentration GSH can be utilized to release the drug in tumor cells or tissues in a targeted manner.
Light therapy is an emerging tumor therapy that can be used to locally treat a specific target, by irradiating and exciting a photoactive drug accumulated in tumor cells or tissues with an ultraviolet or near infrared light source to generate local hyperthermia or Reactive Oxygen Species (ROS), thereby killing the tumor cells. The ultraviolet light has weak tissue penetrating ability and is easy to damage the organism, and the near infrared light has strong tissue penetrating ability which can reach the deep part of the tumor and has almost no damage to the organism, so a 650-950nm near infrared light source is generally used. The light therapy has the advantages of small wound, low discomfort of the patient body, high acceptance, controllable action site and time, low toxic and side effects and the like. Phototherapy is divided into photodynamic therapy (PDT) and photothermal therapy (PTT). Chlorin e6 (Ce 6), a second generation photosensitizer used in PDT treatment, belongs to chlorophyll derivatives and has been approved for use by the FDA. The Ce6 has the advantages of stronger penetrating power, higher ROS yield, fluorescence imaging capability and the like after excitation.
The photosensitizer Ce6 is added into an aqueous solution containing the CMCS-DSP-IPI549 prodrug through a dripping method, after being stirred and mixed uniformly, the Ce6@CMCS-DSP-IPI549 anti-tumor nano-delivery system is obtained through ultrasonic crushing and dialysis self-assembly, so that immune suppression cells in a tumor microenvironment can be improved, the ROS yield is improved, the action site and time are controlled, and a better anti-tumor treatment effect is exerted through the combination of immunotherapy and light therapy of two different action mechanisms.
Compared with the prior art, the technical scheme of the invention has the following beneficial effects:
1. the two medicaments with different action mechanisms are synthesized and encapsulated in the same nanoparticle, and the tumor is treated by combining immunotherapy and photodynamic therapy by adopting two paths, so that the two medicaments are released in the tumor microenvironment and specific near infrared illumination, the solubility of the medicaments is improved, the toxic and side effects are reduced, the targeting is increased, and a new methodology and theoretical basis are provided for clinical immunotherapy and phototherapy.
2. The near infrared light has no damage to organisms, and the release of the photosensitizer Ce6 can be controlled by adjusting the action part and the action time of the near infrared light outside to generate ROS to kill tumor cells or tissues.
3. By using the reduction sensitivity of disulfide bonds, ce6@CMCS-DSP-IPI549 nanoparticles increase the targeting property of the photosensitizer Ce6, improve the bioavailability of the medicine and reduce the toxic and side effects of the medicine on normal cells or tissues.
The foregoing description is only an overview of the present invention, and is intended to be implemented in accordance with the teachings of the present invention in order that the same may be more clearly understood and appreciated, as well as the other objects, features and advantages of the present invention, as described in detail below in connection with the preferred embodiments.
Drawings
In order to more clearly illustrate the technical solution of the embodiments of the present invention, the drawings of the embodiments will be briefly described below.
FIG. 1 is a transmission electron microscope image of Ce6@CMCS-DSP-IPI549 nanoparticles prepared in example 1 of the invention;
FIG. 2 is a graph showing the release profile of Ce6@CMCS-DSP-IPI549 nanoparticles prepared in example 1 of the present invention at different concentrations of GSH, wherein IPI-549 (A), ce6 (B);
FIG. 3 shows absorbance at 426nm of Ce6@CMCS-DSP-IPI549 nanoparticles prepared in example 1 of the present invention and a singlet oxygen probe (DPBF).
Detailed Description
The following detailed description of the invention, which is a part of this specification, illustrates the principles of the invention by way of example, and other aspects, features, and advantages of the invention will become apparent from the detailed description.
Example 1:
(1) Synthesis of DSP-IPI549 intermediate:
DSP 20mg was precisely weighed and dissolved in 4.2mL DMSO and stirred until completely dissolved. And accurately weighing 27mg of IPI-549, dissolving in 5.6mL of DMSO, slowly dripping into the DSP solution, magnetically stirring at room temperature in a dark place for reaction for 24h, transferring to a dialysis bag (with molecular weight cut-off of 500 Da), dialyzing for 48h by using a mixed solution of 1:9 DMSO and deionized water, and dialyzing for 24h by using deionized water. And freeze-drying to obtain the DSP-IPI549 intermediate freeze-dried powder.
(2) Synthesis of CMCS-DSP-IPI549 prodrugs:
precisely weighing 20mg of DSP-IPI549 freeze-dried powder, dissolving in 7mL of DMSO, precisely weighing 6mg of CMCS, dissolving in 70mL of deionized water, adjusting the pH value to 7.4, and carrying out ultrasonic treatment for 5min to obtain CMCS solution. Slowly dripping the DSP-IPI549 solution into the CMCS solution, magnetically stirring at room temperature in a dark place for reaction for 24 hours, transferring into a dialysis bag (the molecular weight cut-off is 3500 Da), dialyzing for 12 hours respectively by using a mixed solution of DMSO and deionized water in a ratio of 7:3/5:5/3:7, and dialyzing for 24 hours by using deionized water. Freeze-drying to obtain freeze-dried powder, dissolving the freeze-dried powder in 40mL of DMSO, performing ultrasonic treatment for 10min, filtering to remove the reactant dissolved in DMSO, and repeating the operation for 3 times. Dissolving the filter cake in deionized water, dialyzing with pure water in a dialysis bag for 24h, and freeze-drying to obtain CMCS-DSP-IPI549 prodrug freeze-dried powder.
(3) Preparation of Ce6@CMCS-DSP-IPI549 anti-tumor nano-delivery system
1mg of Ce6 is weighed and dissolved in 1mL of DMSO to prepare a solution of 1mg/mL, 10mg of CMCS-DSP-IPI549 is dissolved in 1mL of deionized water to prepare a solution of 10mg/mL, the Ce6 solution is dropwise added into the aqueous solution on a magnetic stirrer, the aqueous solution is stirred for 4 hours at room temperature and in a dark place, the aqueous solution is transferred to an ultrasonic cell grinder, a probe is subjected to ultrasonic treatment for 3.0s at low temperature, intermittent 2.0s and a pulse mode with the power of 90w is adopted for 10 minutes, thus obtaining a Ce6@CMCS-DSP-IPI549 nanoparticle solution, the Ce6@CMCS-DSP-IPI549 nanoparticle solution is transferred to a dialysis bag (the molecular weight cut-off is 3500 Da) and dialyzed for 4 hours, and freeze-dried is obtained, thus obtaining the Ce6@CMCS-DSP-IPI549 nanoparticle freeze-dried powder.
The Ce6@CMCS-DSP-IPI549 nanoparticle prepared in the embodiment has the drug loading rate of 8.05% and the encapsulation rate of 64.42%.
Example 2:
this embodiment differs from embodiment 1 in that: in the embodiment, 2mg of Ce6 is weighed in (3) and dissolved in 1mL of DMSO to prepare a solution of 2mg/mL, and other preparation raw material compositions and a Ce6@CMCS-DSP-IPI549 anti-tumor nano-delivery system are prepared in the same process as in the embodiment 1.
The Ce6@CMCS-DSP-IPI549 nanoparticle prepared in the embodiment has the drug loading rate of 10.92% and the encapsulation rate of 55.68%.
Example 3:
this embodiment differs from embodiment 1 in that: in this example, 15mg CMCS-DSP-IPI549 was weighed in (3) and dissolved in 1mL deionized water to prepare a 15mg/mL solution, and the composition of the other preparation materials and the preparation process of a Ce6@CMCS-DSP-IPI549 antitumor nano-delivery system were the same as in example 1.
The Ce6@CMCS-DSP-IPI549 nanoparticle prepared in the embodiment has the drug loading rate of 6.49% and the encapsulation rate of 72.65%.
Characterization of nanoparticles experiments:
in order to prove that the Ce6@CMCS-DSP-IPI549 prepared in the embodiment 1 can form core-shell nanoparticles by self-assembly in an aqueous solution, a transmission electron microscope is adopted for characterization (see figure 1), and the result shows that the Ce6@CMCS-DSP-IPI549 nanoparticles are spherical, regular in morphology and uniform in distribution; the nanoparticle was characterized by a dynamic light scattering instrument to have an average particle size of 218.8.+ -. 4.59nm.
To demonstrate that the Ce6@CMCS-DSP-IPI549 nano-delivery system prepared in example 1 has GSH responsiveness, we established 4 concentration gradients according to the concentration of GSH in normal cells and tumor cells, and prepared release curves of the Ce6@CMCS-DSP-IPI549 nano-delivery system at 267nm (IPI-549) and 402nm (Ce 6) (see FIG. 2).
Upon irradiation with near infrared light at 606nm, ce6 may excite the generated ROS to chemically react with a singlet oxygen probe (DPBF), resulting in a decrease in absorbance at 426nm, thereby reacting the ROS yield. To demonstrate that the Ce6@CMCS-DSP-IPI549 nano-delivery system prepared in example 1 produced ROS under irradiation of near infrared light, absorbance at 426nm was measured after various times of irradiation under near infrared light at 606nm (see FIG. 3).
The invention discloses a Ce6@CMCS-DSP-IPI549 anti-tumor nano-delivery system and a preparation method thereof, which can adjust an action target point and control time, concentrate at tumor cells, effectively reduce toxic and side effects of a photosensitizer, improve solubility and reduce adverse reactions of organisms, and provide new thought and theoretical basis for development of clinical anti-tumor medicaments. Dissolving an amphiphilic prodrug CMCS-DSP-IPI549 bonded with an antitumor drug IPI-549 of immunotherapy and a disulfide bond group in deionized water, adding an organic solution containing a hydrophobic photosensitizer chlorin (Ce 6) through a dripping method, and obtaining the Ce6@CMCS-DSP-IPI549 antitumor nano-delivery system through ultrasonic crushing and dialysis self-assembly. The nano-delivery system synthesizes and encapsulates two drugs with different action mechanisms in one nanoparticle, adopts the dual-channel combination of immunotherapy and phototherapy to treat tumors, can release the two drugs in tumor microenvironment and specific near infrared illumination, and provides new methodology and theoretical basis for clinical tumor treatment.
The present invention can be realized by the respective raw materials listed in the present invention, and the upper and lower limits and interval values of the respective raw materials, and the upper and lower limits and interval values of the process parameters (such as temperature, time, etc.), and examples are not listed here.
While the invention has been described with respect to the preferred embodiments, it will be understood that the invention is not limited thereto, but is capable of modification and variation without departing from the spirit of the invention, as will be apparent to those skilled in the art.
Claims (9)
1. The preparation method of the Ce6@CMCS-DSP-IPI549 anti-tumor nano transfer system is characterized by comprising the following steps:
(1) Synthesis of DSP-IPI549 intermediate:
dissolving a certain DSP in DMSO, and stirring until the DSP is completely dissolved; dissolving IPI-549 in DMSO, slowly dripping into the DSP solution, magnetically stirring at room temperature in dark for reaction 24h, dialyzing with mixed solution of DMSO and deionized water and water, and freeze-drying to obtain DSP-IPI549 intermediate lyophilized powder;
(2) Synthesis of CMCS-DSP-IPI549 prodrugs:
dissolving the DSP-IPI549 freeze-dried powder in DMSO to obtain a DSP-IPI549 solution; dissolving CMCS in deionized water, adjusting pH to 7.4, and performing ultrasonic treatment for 5min to obtain CMCS solution; slowly dripping the DSP-IPI549 solution into the CMCS solution, magnetically stirring at room temperature in a dark place for reaction 24h, dialyzing with a mixed solution of DMSO and deionized water 7:3-3:7 and deionized water, and freeze-drying to obtain CMCS-DSP-IPI549 prodrug freeze-dried powder;
(3) Preparation of Ce6@CMCS-DSP-IPI549 anti-tumor nano-delivery system
Dissolving Ce6 in DMSO to prepare solution A, dissolving CMCS-DSP-IPI549 prodrug in deionized water to prepare solution B, dropwise adding the solution A into the solution B on a magnetic stirrer, stirring for 4 hours at room temperature and in the dark, performing low-temperature ultrasonic crushing to obtain Ce6@CMCS-DSP-IPI549 nanoparticle solution, dialyzing in deionized water for 4 hours, and performing freeze drying to obtain Ce6@CMCS-DSP-IPI549 nanoparticle freeze-dried powder, namely the Ce6@CMCS-DSP-IPI549 antitumor nano-delivery system; the grain size of the Ce6@CMCS-DSP-IPI549 nanoparticle ranges from 141 to 396 and nm, the drug loading rate is 6.49 to 10.92 percent, and the encapsulation rate is 55.68 to 72.65 percent.
2. The method for preparing the Ce6@CMCS-DSP-IPI549 anti-tumor nano-delivery system, according to claim 1, which is characterized in that: in the step (1), the molar ratio of the DSP to the IPI549 is 1:1; the mixed solution of DMSO and deionized water is a mixed solution with a volume ratio of DMSO to water of 1:9.
3. The method for preparing the Ce6@CMCS-DSP-IPI549 anti-tumor nano-delivery system, according to claim 1, which is characterized in that: in the step (2), the molar mass of the CMCS is 1 multiplied by 10 4 And the carboxymethyl substitution degree is 85%; in the step (2), the mass ratio of the CMCS to the DSP-IPI549 is 1:1.3-3.3; the drug loading rate of the CMCS-DSP-IPI549 prodrug is 10.17% -13.63%.
4. The method for preparing the Ce6@CMCS-DSP-IPI549 anti-tumor nano-delivery system, according to claim 1, which is characterized in that: in the step (3), the mass ratio of the CMCS-DSP-IPI549 prodrug to the photosensitizer Ce6 is 5:1-15:1.
5. The method for preparing the Ce6@CMCS-DSP-IPI549 anti-tumor nano-delivery system, according to claim 1, which is characterized in that: in the step (1), the molecular weight cut-off of the dialysis bag is 500Da, and in the steps (2) - (3), the molecular weight cut-off of the dialysis bag is 3 Da.
6. The method for preparing the Ce6@CMCS-DSP-IPI549 anti-tumor nano-delivery system, according to claim 1, which is characterized in that: in the step (3), the low-temperature ultrasonic crushing is performed by using an ultrasonic cell crusher, and the probe is subjected to ultrasonic treatment at a low temperature for 3.0s, intermittent for 2.0s and a pulse mode with the power of 90w for 10min.
7. The Ce6@CMCS-DSP-IPI549 anti-tumor nano transfer system is characterized in that: the Ce6@CMCS-DSP-IPI549 anti-tumor nano transfer system is prepared by the method according to any one of claims 1-6.
8. Use of the ce6@cmcs-DSP-IPI549 antitumor nano-delivery system according to claim 7 for preparing antitumor drugs, characterized in that: the two medicaments with different action mechanisms are synthesized and encapsulated in the same nanoparticle, and the tumor is treated by adopting the combination of immunotherapy and phototherapy, so that the two medicaments are released in the tumor microenvironment and specific near infrared illumination, the solubility of the medicaments is improved, the toxic and side effects are reduced, the targeting is increased, and a new methodology and theoretical basis are provided for clinical tumor treatment.
9. The use of the ce6@cmcs-DSP-IPI549 antitumor nano-delivery system according to claim 8 for preparing antitumor drugs, wherein: the near infrared light wavelength is 606nm.
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