Charge transfer compound pharmaceutical preparation based on biological thiol specific response and preparation method thereof

Abstract

The invention relates to a charge transfer compound pharmaceutical preparation based on biological thiol specific response, which is characterized in that a D-A precursor is formed by a clinical small molecule drug with electron donor property and a quinoid structure organic conjugated molecule with electron acceptor capability through a charge transfer effect; and coating with an amphiphilic polymer capable of forming micelles in an aqueous solution to form CTDC nanoparticles. According to the pharmaceutical preparation, firstly, photo-thermal and photo-acoustic signals of the pharmaceutical preparation can be used for disease diagnosis; secondly, an electron acceptor part can react with a biological thiol substance in a disease microenvironment to cause CTDC to be disassembled to release an electron donor drug to exert a drug effect, the drug release process can be accelerated by illumination, CTDC disassembly disappears along with a photoacoustic signal, and the CTDC is used for monitoring the drug release process. Through integration of real-time photoacoustic imaging, microenvironment response drug release, drug release monitoring and disease treatment, precise diagnosis and treatment integration based on clinical drugs is realized.

Description

Technical Field

[0001] The present invention belongs to the field of biomedical engineering technology and relates to a novel integrated diagnosis and treatment drug preparation based on the reconstruction of existing clinical drugs. The photoacoustic imaging and drug-responsive release and monitoring of drugs are achieved by constructing a charge transfer complex. Background Art

[0002] While advances in life sciences and biotechnology have provided new tools for drug development, the biological complexity of target validation, the physical and chemical constraints of molecular design, and the need for precise patient stratification in clinical translation remain key bottlenecks. Overcoming these obstacles requires integrating systems biology, translational medicine, and engineering strategies to build a more efficient pharmaceutical innovation ecosystem.

[0003] Small molecule drugs, as a core means of clinical treatment, account for more than 60% of the total number of FDA-approved drugs, but their development still faces multiple technical bottlenecks. First, about 90% of preclinical candidate compounds have significantly reduced bioavailability due to insufficient water solubility, which directly restricts the drug's drugability. Secondly, the toxicity risks caused by off-target effects, the shortened half-life caused by unstable metabolic pathways, and the lack of real-time integrated diagnosis and treatment functions further limit the therapeutic window and clinical transformation potential of existing small molecule drugs. In order to break through the above limitations, it is urgent to build a new generation of intelligent diagnostic and therapeutic small molecule drug platforms to achieve precise targeted delivery to reduce systemic toxicity, prodrug activation design to improve lesion selectivity, self-feedback drug release system to regulate blood drug concentration in real time, and integrated molecular imaging probes to achieve visual monitoring of treatment response. These technological leaps will promote the upgrade of drug therapy from a "passive intervention" to a "dynamic programmable" paradigm.

[0004] Nanotechnology-driven drug delivery systems offer a revolutionary strategy for addressing the inherent shortcomings of small-molecule drugs. Functionalized nanocarriers (such as liposomes and polymeric micelles) efficiently encapsulate poorly soluble drugs within their hydrophobic cores, increasing their water solubility by 10-100 times. Surface-modified targeting ligands (such as antibodies and aptamers) enable lesion-specific delivery, extending drug half-life by 3-5 times that of traditional formulations. More advanced designs integrate diagnostic and therapeutic modules—for example, by embedding near-infrared fluorescent probes or superparamagnetic iron oxide nanoparticles (SPIONs)—to simultaneously enable multimodal imaging monitoring of the treatment process (such as fluorescence imaging and MRI).

[0005] However, traditional nanoplatforms face two challenges: first, complex synthesis processes (such as multi-step emulsification, high-pressure homogenization, or chemical cross-linking) lead to batch-to-batch variability as high as 15-30%, severely restricting large-scale production; second, they are inert in their environmental responses. Over 80% of existing carriers are unable to sense pathological microenvironmental characteristics (such as low pH, high ROS, or specific enzyme expression at the tumor site), resulting in a lack of spatiotemporal controllability of drug release. Furthermore, drug release monitoring in existing systems often relies on in vitro sampling or terminal imaging, making it difficult to achieve dynamic visualization and tracking in vivo.

[0006] Charge transfer complexes (CTCs) are a class of complexes formed by the non-covalent or weakly covalent binding of an electron donor (D) and an electron acceptor (A). Their core characteristic is the partial delocalization of the electron cloud, resulting in a charge-separated state. Due to their unique spectral, electrical, and structural properties, CTCs have attracted considerable attention in recent years in materials science, analytical chemistry, and biomedicine.

[0007] The formation of charge transfer complexes does not require complete electron transfer, but is between covalent bonds and non-bonded interactions. This characteristic gives it unique dynamic regulation advantages and has led to significant progress in disease diagnosis, drug delivery and treatment, and biomolecule recognition.

[0008] However, charge transfer complexes still face core bottlenecks in drug development, such as poor stability, low in vivo delivery efficiency, imprecise targeting, high potential toxicity, complex preparation process and unclear mechanism of action, which restrict their clinical application transformation. Summary of the Invention

[0009] The purpose of the present invention is to provide a charge transfer complex drug preparation based on biothiol-specific response and a preparation method thereof, so as to solve the problems of poor water solubility, low bioavailability, off-target toxicity and inability to integrate diagnostic functions of current clinically used small molecule drug preparations.

[0010] To achieve the above-mentioned purpose of the invention, the present invention provides a charge transfer complex drug preparation (CTDC), which is formed by charge transfer interaction between clinical small molecule drugs with electron donor properties (D, Drug donors) and quinone-structured organic conjugated molecules with electron acceptor ability (A, Acceptors) to form DA precursors, and then the DA precursors are coated with amphiphilic polymers that can form micelles in aqueous solution through a nanoprecipitation method to form CTDC nanoparticles.

[0011] Furthermore, in the charge transfer complex pharmaceutical preparation, the molar ratio of the clinical small molecule drug to the quinone-structured organic conjugated molecule is 0.3 to 3:1.

[0012] Furthermore, the mass ratio of the DA precursor to the amphiphilic polymer is preferably 1:5-20.

[0013] Among them, the present invention has no special requirements for clinical small molecule drugs with electron donor properties. As long as they contain amino, hydroxyl, thiol, etc. with electron donating ability and have been used in clinical practice, various small molecule drug preparations, including but not limited to various chemotherapy drugs, immunomodulators, anti-infective drugs, anti-inflammatory drugs, etc., may be used in the present invention.

[0014] Furthermore, the quinone-structured organic conjugated molecule with electron acceptor capability may include, but is not limited to, any one or more of 7,7,8,8-tetracyanoquinodimethane, 2-fluoro-7,7,8,8-tetracyanoquinodimethane, 2,5-difluoro-7,7,8,8-tetracyanoquinodimethane, 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanodimethyl-p-benzoquinone, 2,5-dimethyl-7,7,8,8-tetracyanoquinodimethane, 11,11,12,12-tetracyanonaphthyl-2,6-quinolinemethane, 1,3,4,5,7,8-hexafluorotetracyanonaphthoquinodimethane, 2,2'-(benzo[1,2-B;4,5-B']dithiophene-4,8-diylidene)dimalononitrile, p-benzoquinone, tetrafluoro-p-benzoquinone, tetrabromo-p-benzoquinone, and tetrachloro-p-benzoquinone.

[0015] Furthermore, the amphiphilic polymer capable of forming micelles in an aqueous solution of the present invention is more preferably a polyethylene glycol-based amphiphilic polymer, including but not limited to any one of F127, PEG-PLGA, mPEG-PCL, mPEG-PLA, DSPE-PEG2000 and targeted modified derivatives thereof.

[0016] Furthermore, the DSPE-PEG2000 targeted modified derivative may include DSPE-PEG2000-biotin, DSPE-PEG2000-RGD peptide or DSPE-PEG2000-FA.

[0017] The charge transfer complex pharmaceutical preparation of the present invention can be used as a new type of integrated diagnosis and treatment pharmaceutical preparation. First, the complex can produce near-infrared absorption, has good photothermal properties and photoacoustic signals, and can be used for disease diagnosis; second, the electron acceptor part of the complex can react with biological thiol substances such as cysteine ​​and glutathione in the disease microenvironment and cause the complex to disassemble, and the clinical drug of the electron donor part can be precisely released at a specific point to exert the corresponding pharmacological effect, avoiding the off-target effect of the drug. The photothermal properties of the complex can also accelerate the release process of the drug under light; at the same time, the disassembly process of the complex is accompanied by the disappearance of the photoacoustic signal, which can be used to monitor the release process of the drug.

[0018] Therefore, the present invention provides a new drug formulation and its controlled release strategy, which adds a microenvironment-responsive drug release function on the basis of retaining the original medicinal effects of the clinical small molecule drugs contained therein, and can be used as a photothermal imaging and photoacoustic imaging diagnostic and therapeutic agent. By integrating real-time photoacoustic imaging, microenvironment-responsive drug release, drug release monitoring and disease treatment, it solves the current problems of poor water solubility, low bioavailability, off-target toxicity and inability to integrate diagnostic functions of clinical small molecule drugs. It can realize real-time photoacoustic imaging, drug-responsive release, drug release monitoring and disease treatment in a single nanoplatform, realizing the integrated application of precise diagnosis and treatment based on clinical drugs.

[0019] Furthermore, the present invention also provides a method for preparing the charge transfer complex pharmaceutical preparation based on the biothiol-specific response, which can be prepared, but not limited to, by the following method: 1) A clinical small molecule drug (D) with electron donor properties and a quinone-type organic conjugated molecule (A) with electron acceptor ability are dissolved in a good organic solvent to obtain an electron donor-acceptor complex (DA) precursor solution; 2) The electron donor-acceptor complex (DA) precursor solution is mixed with an aqueous solution of an amphiphilic polymer capable of forming micelles in an aqueous solution, and a CTDC nanoparticle aqueous solution is prepared by a nanoprecipitation method.

[0020] Specifically, the good organic solvent can be any organic solvent that has good solubility for the clinical small molecule drug and the organic conjugated molecule, including but not limited to any one of acetone, dichloromethane, tetrahydrofuran, dimethyl sulfoxide or acetonitrile or a mixture of any proportions thereof.

[0021] Furthermore, the present invention preferably assists with ultrasonic treatment to obtain a uniform electron donor-acceptor complex (DA) precursor solution. Furthermore, the ultrasonic treatment time is 5 to 20 minutes.

[0022] Furthermore, the electron donor-acceptor complex (DA) precursor solution of the present invention is mixed with an aqueous solution of an amphiphilic polymer and then rapidly stirred to react for 6 to 24 hours.

[0023] Furthermore, the preparation method of the present invention further comprises performing conventional dialysis treatment on the obtained CTDC nanoparticle aqueous solution to remove organic solvents and impurities.

[0024] The concentration of the CTDC nanoparticle aqueous solution finally obtained in the present invention is preferably 0.5 to 5 mmol / L.

[0025] The charge transfer complex pharmaceutical preparation based on the biothiol-specific response of the present invention uses clinically approved drugs as structural components, has a simple preparation method, does not require strict condition control, has low cost, is suitable for wide promotion and use, and improves the feasibility of clinical transformation.

[0026] Based on clinical small-molecule drugs, this invention constructs a charge-transfer complex drug formulation with a specific response to biothiols. By integrating a clinical small-molecule drug with electron-donating properties with a quinone-like organic conjugated molecule with electron-accepting capacity, a charge-transfer drug complex (CTDC) is synthesized. Its excellent photothermal and photoacoustic signals are used for disease diagnosis. Furthermore, its electron-accepting moiety reacts with biothiols such as cysteine ​​and glutathione in the disease microenvironment to trigger the dissociation of CTDC, leading to localized, specific drug release. Furthermore, the thermal effect generated by illumination accelerates the drug release process of CTDC, reducing off-target effects. Meanwhile, the disappearance of the photoacoustic signal accompanying the disassembly of CTDC can be used to monitor the drug release process in real time. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 The present invention is to prepare the charge transfer complex pharmaceutical preparation CTDC M , CTDC R , CTDC N and CTDC H Transmission electron micrograph of .

[0028] Figure 2 is the UV-visible-near-infrared absorption spectra of the prepared CTDC and its corresponding drug monomers (wherein MITO is mitoxantrone, R848 is resiquimod, NFX is norfloxacin, HCQ is hydroxychloroquine, EA1 is 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanodimethyl-p-benzoquinone, and EA2 is 7,7,8,8-tetracyanodimethyl-p-benzoquinone).

[0029] Figure 3 is the near-infrared photoacoustic signal of the prepared CTDC changing with concentration.

[0030] Figure 4 is the photothermal stability of the prepared CTDC under near-infrared light.

[0031] Figure 5 The UV-visible-near-infrared absorption spectrum of the prepared CTDC in response to biothiols changes with time at room temperature.

[0032] Figure 6 The UV-visible-near-infrared absorption spectrum changes of the prepared CTDC in response to biothiols at different temperatures.

[0033] Figure 7is the photoacoustic signal change of the prepared CTDC in response to biothiol.

[0034] Figure 8 The prepared CTDC M and CTDC R Cytotoxicity against normal cells L929 and tumor cells 4T1.

[0035] Figure 9 The prepared CTDC M and CTDC R Cytotoxicity against 4T1 tumor cells under near-infrared light irradiation and without light irradiation.

[0036] Figure 10 The prepared CTDC M and CTDC R Glutathione consumption levels in 4T1 tumor cells under near-infrared light irradiation and without light irradiation.

[0037] Figure 11 The prepared CTDC N The killing effect of its corresponding drug monomers on Klebsiella pneumoniae under near-infrared light and without light.

[0038] Figure 12 The prepared CTDC N and CTDC H and their mixtures (CTDC HN ) and the corresponding drug monomer mixture (DC HN ) on the level of glutathione consumption in Klebsiella pneumoniae. DETAILED DESCRIPTION

[0039] The specific embodiments of the present invention are further described in detail below with reference to the accompanying drawings and examples. The embodiments described below are only intended to more clearly illustrate the technical solutions of the present invention and are not intended to be exhaustive. They should not be construed as limiting the scope of the present invention. All other embodiments derived by persons of ordinary skill in the art based on the embodiments of the present invention without creative effort are intended to fall within the scope of protection of the present invention.

[0040] The names and abbreviations of the experimental methods, production processes, instruments and equipment involved in the embodiments and comparative examples of the present invention are conventional names in the field and are very clear and unambiguous in the relevant fields of use. Those skilled in the art can understand the conventional process steps and apply the corresponding equipment based on the names and implement them according to conventional conditions or the conditions recommended by the manufacturer.

[0041] The various raw materials or reagents used in the Examples and Comparative Examples of the present invention are not particularly limited in their sources and are all commercially available conventional products and can also be prepared according to conventional methods well known to those skilled in the art.

[0042] In the following examples of the present invention, the charge transfer complex pharmaceutical preparation with biothiol-specific response is formed by an electron donor (D) and an electron acceptor (A) interacting through charge transfer and then coated with an amphiphilic polymer that can form micelles in an aqueous solution.

[0043] Wherein, D is a clinical small molecule drug with electron-donating properties, in particular, a small molecule drug preparation containing amino, hydroxyl, thiol and the like with electron-donating ability that has been used in clinical practice.

[0044] More specifically, the clinical small molecule drugs with electron donor properties described in the present invention may include but are not limited to various chemotherapy drugs, such as DNA topoisomerase inhibitors mitoxantrone, doxorubicin, irinotecan, etc.; antimetabolite drugs lonidamine, genistein, etc.

[0045] More specifically, the clinical small molecule drugs with electron donor properties described in the present invention may also include, but are not limited to, various immunomodulators, such as TLR7 / 8 agonists resiquimod and imiquimod, and IDO inhibitors NLG919.

[0046] More specifically, the clinical small molecule drugs with electron donor properties described in the present invention may also include, but are not limited to, various anti-infective drugs, including quinolone drugs such as norfloxacin and levofloxacin; macrolide drugs such as azithromycin; sulfonamide drugs such as trimethoprim; and allylamine drugs such as terbinafine.

[0047] More specifically, the clinical small molecule drugs with electron donor properties described in the present invention may also include but are not limited to various anti-inflammatory drugs, such as the anti-malarial derivative compound hydroxychloroquine, the non-steroidal anti-inflammatory drug nabumetone, the flavonoid anti-inflammatory drug hangonine, etc.

[0048] Wherein, A is a quinone-type organic conjugated molecule with electron acceptor ability, including but not limited to any one or more of 7,7,8,8-tetracyanoquinodimethane, 2-fluoro-7,7,8,8-tetracyanoquinodimethane, 2,5-difluoro-7,7,8,8-tetracyanoquinodimethane, 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanodimethyl-p-benzoquinodimethane, 2,5-dimethyl-7,7,8,8-tetracyanoquinodimethane, 11,11,12,12-tetracyanonaphthyl-2,6-quinolinemethane, 1,3,4,5,7,8-hexafluorotetracyanonaphthoquinodimethane, 2,2'-(benzo[1,2-B;4,5-B']dithiophene-4,8-diylidene)dimalononitrile, p-benzoquinone, tetrafluoro-p-benzoquinone, tetrabromo-p-benzoquinone, and tetrachloro-p-benzoquinone.

[0049] In the following examples of the present invention, after D and A form a DA precursor, the DA precursor is coated with an amphiphilic polymer that can form micelles in an aqueous solution by a nanoprecipitation method, and impurities are removed by dialysis to finally obtain CTDC nanoparticles.

[0050] Specifically, the amphiphilic polymer capable of forming micelles in an aqueous solution according to the present invention is more preferably a polyethylene glycol-based amphiphilic polymer.

[0051] More specifically, the amphiphilic polymer comprises a hydrophilic segment and a hydrophobic segment, wherein: a) The hydrophilic segment is polyethylene glycol (PEG), with a molecular weight range of 1000-20000 Da, accounting for 30-80% of the total mass of the polymer; b) the hydrophobic segment is selected from polyoxypropylene (PPO), polylactic acid (PLA), polylactic-co-glycolic acid (PLGA), polycaprolactone (PCL) or distearoylphosphatidylethanolamine (DSPE); c) the polymer has a critical micelle concentration (CMC) of ≤0.1 mg / mL in an aqueous phase and can self-assemble into nanoparticles with an average particle size of 10 to 200 nm; d) Optionally, the terminal end of the polymer comprises a modifiable group selected from -COOH, -NH2, -MAL, biotin, RGD peptide or folic acid.

[0052] Furthermore, the amphiphilic polymer is preferably selected from any one of F127, PEG-PLGA, mPEG-PCL, mPEG-PLA, DSPE-PEG2000 and its targeted modified derivatives (DSPE-PEG2000-biotin, DSPE-PEG2000-RGD peptide, DSPE-PEG2000-FA). Example

[0053] Example 1

[0054] 4.44 mg (0.01 mmol) of mitoxantrone and 5.52 mg (0.02 mmol) of 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanodimethyl-p-benzoquinone were weighed and dissolved in 400 μL of a tetrahydrofuran / dimethyl sulfoxide mixture (the volume ratio of tetrahydrofuran to dimethyl sulfoxide was 1:1). The mixture was sonicated for 20 min until completely dissolved to obtain 400 μL of DA precursor solution.

[0055] The above DA precursor solution was added to 10 mL of aqueous solution containing 50 mg of F127, and the mixture was rapidly stirred for 24 h. The solution was dialyzed to remove organic solvents and impurities to obtain a CTDC nanoparticle solution based on clinical chemotherapy drugs. M .

[0056] Example 2

[0057] 3.14 mg (0.01 mmol) of R848 and 2.04 mg (0.01 mmol) of 7,7,8,8-tetracyanoquinodimethane were weighed and dissolved in 300 μL of a tetrahydrofuran / dimethyl sulfoxide mixed solution (the volume ratio of tetrahydrofuran to dimethyl sulfoxide was 1:1). The mixture was sonicated for 15 min until completely dissolved to obtain 300 μL of DA precursor solution.

[0058] The above DA precursor solution was added to 10 mL of aqueous solution containing 26 mg of F127 and rapidly stirred for 20 h. The solution was dialyzed to remove organic solvents and impurities to obtain a CTDC nanoparticle solution based on clinical immunotherapy drugs. R .

[0059] Example 3

[0060] 3.19 mg (0.01 mmol) of norfloxacin and 2.04 mg (0.01 mmol) of 7,7,8,8-tetracyanoquinodimethane were weighed and dissolved in 400 μL of a tetrahydrofuran / dimethyl sulfoxide mixed solution (the volume ratio of tetrahydrofuran to dimethyl sulfoxide was 1:1). The mixture was sonicated for 20 min until completely dissolved to obtain 400 μL of DA precursor solution.

[0061] The above DA precursor solution was added to 10 mL of aqueous solution containing 26 mg of F127 and rapidly stirred for 18 h. The solution was dialyzed to remove organic solvents and impurities to obtain a CTDC nanoparticle solution based on clinical antibacterial drugs. N .

[0062] Example 4

[0063] 3.36 mg (0.01 mmol) of hydroxychloroquine and 2.76 mg (0.01 mmol) of 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanodimethyl-p-benzoquinone were weighed and dissolved in 200 μL of a tetrahydrofuran / dimethyl sulfoxide mixed solution (the volume ratio of tetrahydrofuran to dimethyl sulfoxide was 1:1). The mixture was sonicated for 5 min until completely dissolved to obtain 200 μL of DA precursor solution.

[0064] The above DA precursor solution was added to 10 mL of aqueous solution containing 30 mg of F127, and the mixture was rapidly stirred for 12 h. The solution was dialyzed to remove organic solvents and impurities to obtain a CTDC nanoparticle solution based on clinical chemotherapy drugs. H .

[0065] Example 5

[0066] The physical and chemical properties of the CTDC nanoparticle solutions prepared in Examples 1 to 4 were tested.

[0067] Figure 1 1 is a transmission electron microscope image of the CTDC nanoparticles in each example. The particles are relatively uniform in size and have good monodispersity, with a particle size range of 30 to 50 nm.

[0068] The UV-visible-near infrared absorption spectra of the CTDC nanoparticle solutions prepared in Examples 1 to 4 were tested. The results are as follows: Figure 2 As shown in Figure 2, it can be seen that compared with their respective drug monomers, the absorption spectra of CTDC nanoparticles based on clinical drugs all show obvious near-infrared absorption peaks.

[0069] The photoacoustic signals of the CTDC nanoparticle solutions prepared in Examples 1 to 4 were tested respectively. The results are as follows: Figure 3 , different clinical drug-based CTDC nanoparticles all showed good photoacoustic signals in the near-infrared region, and their photoacoustic signal intensity was linearly dependent on concentration.

[0070] The photothermal properties of the CTDC nanoparticle solutions prepared in Examples 1 to 4 were tested, and the results were as follows: Figure 4 CTDC nanoparticles based on clinical drugs showed good photothermal effect under near-infrared light excitation, and their photothermal stability was good.

[0071] Cysteine ​​(Cys) was added to the CTDC nanoparticle solutions of Examples 1 to 4, respectively. Figure 5 As shown in the figure, with the extension of time, the near-infrared absorption peak of CTDC at long wavelength gradually decreases, while the characteristic absorption peak of the drug at short wavelength is significantly enhanced, indicating that CTDC can specifically respond to and degrade biothiols and gradually release drugs, confirming the biothiol-specific response drug release strategy of CTDC.

[0072] At the same time, the degradation and release experiments under different temperature conditions were carried out after adding Cys to the CTDC nanoparticle solutions of Examples 1 to 4. Figure 6 As shown in the figure, as the temperature increases, the near-infrared absorption peak of CTDC at long wavelengths decreases significantly, while the characteristic absorption peak of the drug at short wavelengths increases significantly, confirming that increasing temperature can accelerate the biothiol-specific response of CTDC to release drugs.

[0073] Photoacoustic signal measurements were performed before and after adding Cys to the CTDC nanoparticle solutions of Examples 1 to 4. The results are as follows: Figure 7 , after responding to Cys, the photoacoustic signal of CTDC disappeared, confirming that the photoacoustic signal can be used to monitor the drug release process in real time.

[0074] Example 6

[0075] This example uses CTDC (CTDC) constructed based on clinical chemotherapy drugs and immune drugs. M and CTDC R ), and its anti-tumor effect at the cellular level was evaluated through in vitro cell experiments.

[0076] L929 normal cell group and 4T1 tumor cell group were set up separately for evaluating CTDC M and CTDC R cytotoxicity.

[0077] CTDC M and CTDC R After incubation with cells for 24 h, CCK8 was added to evaluate cytotoxicity. Figure 8 As shown in Figure 2, tumor cells have higher redox levels than normal cells. Therefore, compared with normal cells, CTDC M and CTDC R It can respond to more biological thiols such as cysteine ​​and glutathione in tumor cells, thereby releasing chemotherapy drugs or immune drugs to exert their efficacy.

[0078] CTDC M and CTDC R 4T1 cells were treated under near-infrared light and without light, and CCK8 was added to evaluate cytotoxicity after incubation with the cells for 24 h.

[0079] Specific circumstances such as Figure 9 As shown in Figure 2, near-infrared light can cause CTDC to produce a thermal effect, thereby accelerating drug release. Therefore, compared with the non-light group, CTDC M and CTDC R The drug release is more complete and the killing effect on tumor cells is stronger.

[0080] PBS control group and CTDC control group were set up respectively. M Group and CTDC R The glutathione content in 4T1 tumor cells was evaluated by comparing the two groups, which were treated with near-infrared light and without light.

[0081] Specific circumstances such as Figure 10 As shown, CTDC M Group and CTDC R The glutathione content in 4T1 tumor cells was reduced after group treatment, and the glutathione content was further reduced after near-infrared light irradiation, confirming that CTDC can respond to biological thiols in tumor cells and that light irradiation can accelerate this response process.

[0082] Example 7

[0083] This example uses CTDC (CTDC) constructed based on clinical antibacterial drugs and anti-inflammatory drugs. N and CTDC H ), and its antibacterial effect was evaluated by in vitro antibacterial experiments.

[0084] The control group, the antibiotic monomer NFX group and the CTDC group were set up N The groups were treated with near-infrared light and without light, and the antibacterial ability of different treatment groups against Klebsiella pneumoniae (K.pn) was evaluated.

[0085] Specific circumstances such as Figure 11 As shown, when there is no light, CTDC N Compared with NFX, the antibacterial ability of CTDC is lower, but after near-infrared light irradiation, N It showed the same antibacterial ability as NFX, confirming the ability of near-infrared light to accelerate drug-responsive release.

[0086] Set up control group and CTDC H Group, CTDC N group, antibacterial and anti-inflammatory drug monomer mixed group (DC HN ) group and CTDC HN Group (CTDC H With CTDC N Mixed), and evaluated the glutathione levels in Klebsiella pneumoniae after different treatments.

[0087] Specific circumstances such as Figure 12 As shown in Figure 2, the glutathione level in Klebsiella pneumoniae treated with CTDC was compared with that in the control group and drug monomer mixed group (DC HN ) were all reduced, confirming that CTDC can respond to biological thiols in the bacterial microenvironment.

[0088] While the above describes specific embodiments of the present invention, those skilled in the art will appreciate that the foregoing is merely illustrative of the present invention, and that the scope of protection of the present invention is defined by the appended claims. Those skilled in the art may make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, and such changes and modifications are intended to fall within the scope of protection of the present invention.

Claims

1. A charge transfer complex drug formulation based on a biothiol-specific response, comprising a DA precursor formed by charge transfer interaction between a clinical small molecule drug with electron donor properties and a quinone-type organic conjugated molecule with electron acceptor ability. CTDC nanoparticles are then coated with an amphiphilic polymer that can form micelles in aqueous solution via a nanoprecipitation method.

2. The charge transfer complex pharmaceutical preparation according to claim 1, characterized in that The molar ratio of the clinical small molecule drug to the quinone-structured organic conjugated molecule is 0.3 to 3:

1.

3. The charge transfer complex pharmaceutical preparation according to claim 1, characterized in that The mass ratio of the DA precursor to the amphiphilic polymer is 1:5-20.

4. The charge transfer complex pharmaceutical preparation according to claim 1, characterized in that The clinical small molecule drug with electron donor properties is a small molecule chemotherapy drug, immunomodulator, anti-infective drug or anti-inflammatory drug containing amino, hydroxyl or sulfhydryl groups.

5. The charge transfer complex pharmaceutical preparation according to claim 1, characterized in that The quinone-type organic conjugated molecule with electron acceptor capability is any one or more of 7,7,8,8-tetracyanoquinodimethane, 2-fluoro-7,7,8,8-tetracyanoquinodimethane, 2,5-difluoro-7,7,8,8-tetracyanoquinodimethane, 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanodimethyl-p-benzoquinone, 2,5-dimethyl-7,7,8,8-tetracyanoquinodimethane, 11,11,12,12-tetracyanonaphthyl-2,6-quinolinemethane, 1,3,4,5,7,8-hexafluorotetracyanonaphthoquinodimethane, 2,2'-(benzo[1,2-B;4,5-B']dithiophene-4,8-diylidene)dimalononitrile, p-benzoquinone, tetrafluoro-p-benzoquinone, tetrabromo-p-benzoquinone, and tetrachloro-p-benzoquinone.

6. The charge transfer complex pharmaceutical preparation according to claim 1, characterized in that The amphiphilic polymer capable of forming micelles in an aqueous solution is a polyethylene glycol-based amphiphilic polymer, which is any one of F127, PEG-PLGA, mPEG-PCL, mPEG-PLA, DSPE-PEG2000 and targeted modified derivatives thereof.

7. A method for preparing the charge transfer complex pharmaceutical preparation according to claim 1, comprising: 1) Dissolving a clinical small molecule drug with electron donor properties and a quinone-type organic conjugated molecule with electron acceptor ability in a good organic solvent to obtain a DA precursor solution; 2) The DA precursor solution is mixed with an aqueous solution of an amphiphilic polymer that can form micelles in an aqueous solution, and a CTDC nanoparticle aqueous solution is prepared by a nanoprecipitation method.

8. The preparation method according to claim 7, wherein The good organic solvent is any one of acetone, dichloromethane, tetrahydrofuran, dimethyl sulfoxide or acetonitrile or a mixture of any proportions of the above.

9. The preparation method according to claim 7, wherein The method further comprises dialyzing the obtained CTDC nanoparticle aqueous solution to remove organic solvents and impurities.

10. The preparation method according to claim 7, characterized in that The DA precursor solution is mixed with the aqueous solution of the amphiphilic polymer and then rapidly stirred to react for 6 to 24 hours.

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