CN111454177A

CN111454177A - Photo-induced non-adiabatic fading type photo-thermal material and preparation method and application thereof

Info

Publication number: CN111454177A
Application number: CN202010275662.5A
Authority: CN
Inventors: 倪侦翔; 李凯; 张勋; 康天怿; 杨光
Original assignee: Southern University of Science and Technology
Current assignee: Southern University of Science and Technology
Priority date: 2020-04-09
Filing date: 2020-04-09
Publication date: 2020-07-28
Anticipated expiration: 2040-04-09
Also published as: CN111454177B

Abstract

The photo-thermal material is a compound shown in a formula I, shows good photo-thermal conversion efficiency and biological safety, cannot cause burn and/or necrosis of normal tissues near a tumor due to high temperature, can effectively reduce the dependence on temperature, and can achieve the functions of killing the tumor, protecting tissues and the like.

Description

Photo-induced non-adiabatic fading type photo-thermal material and preparation method and application thereof

Technical Field

The invention belongs to the technical field of biomedicine, and particularly relates to a photo-thermal material as well as a preparation method and application thereof, in particular to a photo-thermal material of a light-induced non-adiabatic fading type as well as a preparation method and application thereof.

Background

In recent years, the incidence of malignant tumor (malignant tumor) has been remarkably increasing. Radiotherapy (radiotherapy) and chemotherapy (chemotherapy), the main therapeutic approaches for malignant tumors, currently only have very low therapeutic effects, but are accompanied by high toxic and side effects, which maintain the cure rate of cancer at a very low level. Breaks through the existing thinking, and the photothermal therapy (PTT) is a new method for treating tumors and has great development potential. Photothermal therapy is an important therapeutic method in which a material having a high photothermal conversion efficiency (PTCE) is injected into the human body, and is focused near tumor tissue by using a targeting recognition technology, and light energy is converted into heat energy under the irradiation of external near infrared light (near infrared light), thereby killing cancer cells. An excellent photothermal agent (photothermal agents) should have the following three conditions: first, good photothermal conversion efficiency (PTCE) is the key to the application of such materials; secondly, the photo-thermal agent is nontoxic or low in biological toxicity, and is generally constructed by organic materials (organic materials) to be more favorable for the nontoxic application in vivo; third, it is easy to modify, functionalize and develop.

However, in general, photothermal therapy at high temperature (>50 ℃) is effective for treating tumors, but is also likely to cause side effects of burning and necrosis of normal tissues in the vicinity of tumors due to high temperature. Therefore, in the recent photothermal therapy, strategies such as genes, enzymes, Heat Shock Protein (HSP) inhibitors and the like are combined to resist the heat resistance mechanism generated after the cancer cells are irradiated by the laser light, the photothermal therapy is successfully carried out in a low-temperature region (41-45 ℃), the side effects or physiological lesions derived from the common high-temperature photothermal therapy are avoided, and the clinical transformation of the photothermal therapy is expected to be accelerated.

The characteristic of photoinduced non-adiabatic decay (PIND) is mainly that excited state molecules (excited state molecules) are subjected to a strong intramolecular torsional charge transfer (TICT) effect, so that the excited state molecules return to the ground state through cone intersections (cone intersections) mainly based on non-radiative decay (non-radiative decay), and a fluorescence manner mainly based on non-radiative decay (radiative decay) is adopted, so that the non-radiative decay manner is easily released in a thermal manner, and the efficient effect of converting light energy into heat energy is achieved, which is called the photoinduced non-adiabatic decay effect. The photothermal material constructed based on the mechanism of the light-induced non-adiabatic decay effect has higher photothermal conversion efficiency and is quite suitable for application of photothermal therapy in biomedicine. In addition, the synergistic effect of the heat shock protein 70(HSP70) inhibitor, such as Apoptozole (apo), can effectively break through the limitation of common high-temperature photothermal therapy, inhibit the anti-heat mechanism expressed by cancer cells in the treatment process under the low-temperature condition, and successfully realize the low-temperature photothermal therapy. The photo-thermal treatment of the tumor by the photo-induced non-adiabatic recession type photo-thermal material can effectively reduce the dependence on temperature, can achieve the functions of killing the tumor, protecting tissues and the like, and has important significance and value as the technical field of new generation of biological medicines.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide a light-induced non-adiabatic regression type photothermal material and a preparation method and application thereof, wherein the light-induced non-adiabatic regression type photothermal material has good photothermal conversion efficiency and bioactivity, does not cause burn and/or necrosis of normal tissues near a tumor due to high temperature, can effectively reduce the dependence on temperature, and can achieve the functions of killing the tumor, protecting tissues and the like.

In order to achieve the purpose, the invention adopts the following technical scheme:

in a first aspect, the present invention provides a photo-thermal material of a light-induced non-adiabatic decay type, wherein the photo-thermal material is a compound represented by formula I:

wherein Ar is₁The group is any one of substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, Ar₂And Ar₃The groups are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted Ar₁Any one of group, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, cycloalkyloxy, cycloalkylthio, acyl, ester group, amide group, aryl group, heterocyclic group, heteroaryl group, heterocycloalkyl group, monoalkylamino group or dialkylamino group, R₁The group is selected from any one of hydrogen, cyano, nitro, substituted or unsubstituted alkyl, alkenyl, alkynyl, halogen, hydroxyl, amino, ester group, amido, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, cycloalkyloxy, cycloalkylthio, acyl, ester group, amido, aryl, heterocyclic group, heteroaryl, heterocycloalkyl, monoalkylamino or dialkylamino.

Wherein, in R₁The number of substitution of the group on the phenyl ring of the compound of formula I may be 1 to the full substitution position, for example, 1, 2, 3 or 4.

Preferably, the substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, and substituted or unsubstituted Ar₁The substituents of the groups are respectively and independently selected from any one of halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, nitro, cyano, hydroxyl, C1-6 dialkylamino, piperidyl, N-methylpiperazinyl or morpholino.

Preferably, Ar is₁The group is selected from any one of the following units;

wherein R is₂Group selectionR is any one selected from hydrogen, cyano, nitro, substituted or unsubstituted alkyl, alkenyl, alkynyl, halogen, hydroxyl, amino, ester group, amido, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, cycloalkyloxy, cycloalkylthio, acyl, ester group, amido, aryl, heterocyclic group, heteroaryl, heterocycloalkyl, monoalkylamino or dialkylamino, R is₃The groups are independently selected from any one of hydrogen, substituted or unsubstituted alkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, cycloalkyloxy, cycloalkylthio, aryl, heterocyclyl, heteroaryl, heterocycloalkyl, monoalkylamino or dialkylamino.

Wherein, in R₂Group and R₃Radical in Ar₁The number of substitution of the group is independently selected from 1 to Ar₁The substitution position on the radical being occupied, e.g. Ar₁The radical is

When R is₂The number of substitution of the group may be 1, 2, 3, 4 or 5; for example Ar₁The radical is

When R is₂The number of substitution of the group may be 1, 2 or 3.

Preferably, said R is₂The group is selected from H, CF₃、CN、NO₂Halogen, C1-8 alkyl, C1-8 alkoxy, C1-8 alkylthio, C3-7 cycloalkyl, C3-7 cycloalkyloxy, aryl, heterocyclyl, heteroaryl, acyl, ester group, amide group, N-alkylpiperazinyl, morpholino or C1-6 dialkylamino, preferably H, C1-4 alkoxy, N-methylpiperazinyl, morpholino or C1-4 dialkylamino.

Preferably, said R is₃The group is selected from any one of H, substituted or unsubstituted C1-8 alkyl, C1-8 alkoxy, C1-8 alkynyl, C3-7 cycloalkyl or aryl.

Preferably, Ar is₁The group is selected from any one of the following units;

wherein R is₂The group is selected from any one of hydrogen, trifluoromethyl, substituted or unsubstituted alkyl, ester group, amide group, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, cycloalkyloxy, cycloalkylthio, acyl, ester group or amide group.

Preferably, Ar is₁The radicals being selected from

Wherein R is₂The group is selected from any one of hydrogen, substituted or unsubstituted alkyl, alkoxy, acyl, ester group or amide group.

Preferably, Ar is₂And Ar₃The groups are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted Ar₁Any one of the group, alkoxy, alkylthio, alkenyl, alkynyl or cycloalkyl.

Preferably, Ar is₂And Ar₃The groups are independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted Ar₁Any one of a group or an alkenyl group.

Preferably, said R is₁The group is selected from any one of hydrogen, trifluoromethyl, substituted or unsubstituted alkyl, ester group, amide group, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, cycloalkyloxy, cycloalkylthio, acyl, ester group or amide group.

Preferably, said R is₁The group is selected from any one of hydrogen, substituted or unsubstituted alkyl, alkoxy, acyl, ester group or amide group.

Preferably, said R is₁The group is selected from H, CF₃、CN、NO₂Halogen, C1-8 alkyl, C1-8 alkoxy, C1-8 alkylthio, C3-7 cycloalkyl, C3-7 cycloalkyloxy, aryl, heterocyclyl, heteroaryl, acyl, ester, amide, N-alkylpiperazino, morpholino, or C1-6 dialkylaminoAny one of the above.

Preferably, the photothermal material is a compound of formula I':

preferably, the photothermal material is selected from any one of the following structural formulas:

in a second aspect, the invention provides a method for preparing the photo-induced non-adiabatic fading type photo-thermal material according to the first aspect, wherein the method comprises a step of performing a polycondensation reaction between a compound of a structural formula shown in formula II and a compound of a formula III to obtain a compound of a formula I, and the reaction formula is as follows:

Preferably, the molar mass ratio of the compound of the structural formula shown in the formula II to the compound of the formula III is 1 (1-1.2), and may be, for example, 1:1, 1:1.1, 1:1.2, etc., preferably 1:1.

Preferably, the polycondensation reaction is carried out at a reaction temperature of 70 to 80 ℃, for example, 70 ℃, 72 ℃, 74 ℃, 76 ℃, 78 ℃, 80 ℃ or the like, and the polycondensation reaction is carried out for a period of 2 to 3 hours, for example, 2 hours, 2.2 hours, 2.4 hours, 2.6 hours, 2.8 hours, 3 hours or the like.

Preferably, the reaction solvent of the polycondensation reaction is ethanol.

Preferably, the mixture obtained after the polycondensation reaction is cooled to room temperature, the crude product obtained is concentrated under reduced pressure, and then washed with a cold (0-10 ℃) organic solvent (such as methanol), and then filtered to obtain the photothermal material (the compound represented by the formula I).

Preferably, the filtrate of the polycondensation reaction is subjected to vacuum concentration to obtain a crude product, the crude product is rapidly filtered on a filter plate filled with silica gel to obtain a crude product of the photothermal material, and the crude product is further recrystallized by dichloromethane-ethanol, and filtered to obtain the high-purity photothermal material.

In a third aspect, the invention provides a use of the photo-thermal material of the light-induced non-adiabatic fading type in the first aspect in preparing a tumor photo-thermal diagnosis and treatment agent.

The photothermal treatment of tumors comprises:

performing photothermal therapy on the cancer cells in vitro by near-infrared light irradiation, and detecting the anti-tumor killing effect by using a cell proliferation and toxicity detection kit (CCK-8 kit) and a flow cytometer;

an animal model of subcutaneous tumors in vivo was established, photothermal therapy was performed by near-infrared light irradiation, and the size of tumors at the treatment site was observed over time to evaluate the therapeutic effect.

The photothermal material has high photothermal conversion efficiency under near infrared light irradiation, is easy to synthesize, and is applied to photothermal treatment technology as a photothermal agent.

In a fourth aspect, the present invention provides a use of the photo-thermal material of the light-induced non-adiabatic degeneration type according to the first aspect in preparing a photo-thermal diagnosis and treatment device for tumor cells, bacteria or drug-resistant bacteria;

preferably, the photothermal diagnosis and treatment device comprises any one of a light emitting diode, a photoelectric amplifier, an optical information storage, a liquid crystal display, an optical waveguide material, a biosensor, a bio-logic gate, or a nondestructive bioprobe.

In a fifth aspect, the present invention provides a method of using the photothermal material of the first aspect, the method comprising the steps of:

A. treating tumor cells and/or cancer cells with the photothermal material of the first aspect;

B. performing photothermal therapy on tumor cells and/or cancer cells in vitro by near-infrared light irradiation, and detecting the killing effect of the photothermal material on the tumor cells and/or cancer cells by using a cell proliferation and toxicity detection kit (such as a CCK-8 kit) and a flow cytometer;

C. animal models of subcutaneous tumors and cancers in vivo are established, photothermal treatment is carried out through near-infrared light irradiation, and the change of the size of the treated tumors is observed along with time to evaluate the treatment effect.

Terms and definitions

The term "halogen" represents fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, further preferably fluorine.

The term "alkyl" represents a class of straight or branched alkyl groups containing only two atoms of carbon and hydrogen, for example C1-10 alkyl refers to straight or branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example any of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, 2-ethylbutyl, 2-ethylhexyl, or 2-butyloctyl. Preferably, the alkyl group contains 1, 2, 3 or 4 carbon atoms (C1-4 alkyl), for example any of methyl, ethyl, n-propyl or n-butyl.

The term "alkenyl" represents straight or branched chain alkenyl groups and contains 1 or at least two double bonds, e.g. C2-20 alkenyl means having 2, 4, 6, 8, 10, 12, 14, 16, 18, 20 carbon atoms, e.g. vinyl, propenyl or any of (E) -2-methylvinyl or (Z) -2-methylvinyl.

The term "alkynyl" represents straight or branched chain, containing 2 to 12 carbon atoms (which may for example be 2, 4, 6, 8, 10, 12) and containing 2 or at least two double bonds, for example any of ethynyl, propynyl, 2-butynyl or 2-pentynyl.

The term "alkoxy" represents a straight-chain or branched alkyl group bonded through an oxygen atom, wherein the term "alkyl" has the above definition, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, pentoxy or isomers thereof. Preferably, the alkoxy group contains 1 or 2 carbon atoms (C1-2 alkoxy), such as methoxy or ethoxy.

The term "alkylthio" represents a straight or branched chain alkyl group bonded through a sulfur atom.

The term "cycloalkyl" represents a saturated monocyclic hydrocarbon ring containing 3 to 8 carbon atoms, such as any one of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Preferably, the cycloalkyl group contains 5, 6 or 7 carbon atoms (C5-7 cycloalkyl), for example any of cyclopentyl, cyclohexyl or cycloheptyl.

The term "cycloalkyloxy" represents a straight-chain or branched cycloalkyl group bonded through an oxygen atom, wherein the term "cycloalkyl" has the definition as described above.

The term "cycloalkylthio" represents a straight-chain or branched cycloalkyl group bonded through a sulfur atom, wherein the term "cycloalkyl" has the definition as described above.

The term "aryl" generally means an aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring containing 6 to 14 carbon atoms, in particular a ring having 6 carbon atoms (e.g. phenylcyclyl or biphenylcyclyl), a ring having 9 carbon atoms (e.g. indenyl), a ring having 10 carbon atoms (e.g. dinaphthyl or naphthyl), a ring having 13 carbon atoms (e.g. fluorenyl) or a ring having 14 carbon atoms (e.g. onilyl). Preferably, aryl is a phenyl ring substituted with an "alkoxy" group containing 1 to 4 carbon atoms.

The term "heterocyclyl" represents a saturated or partially saturated monocyclic or bicyclic hydrocarbon ring containing 5 to 8 carbon atoms and containing 1 to 3 heteroatom-containing groups selected from oxygen, sulfur or nitrogen. Such as furyl, thienyl, pyrrolyl, thiazolyl, thiadiazolyl, oxazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl or pyranyl. Preferably, the heterocyclyl is thienyl, pyridyl or a heterocyclyl substituted therewith having 1 to 4 carbon atoms (C1-4 alkyl).

The term "heteroaryl" represents a group of compounds in which a benzene ring is fused with a heterocyclic ring, such as quinolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, indolyl or purinyl.

The term "heterocycloalkyl" denotes a heterocyclic group containing from 3 to 7 carbon atoms and from 1 to 3 oxygen, sulfur or nitrogen heteroatoms, such as piperidinyl, hydroxypiperidinyl, phenanthrolinyl, piperazinyl, N-methylpiperazinyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothienyl, morpholino or thiazinyl. Preferred heterocycloalkyl groups are piperidinyl, N-methylpiperazinyl or morpholino.

The term "monoalkylamino" represents an amino group (NH)₂) Wherein the term "alkyl" has the meaning as described above, is substituted for 1 hydrogen of (a). Such as methylamino, ethylamino, propylamino, butylamino or isomers thereof.

The term "dialkylamino" represents an amine group (NH)₂) Wherein the term "alkyl" has the meaning as described above. Such as dimethylamino, diethylamino, dipropylamino, dibutylamino or isomers thereof. Preferably, the dialkylamino group is a dimethylamino group or a diethylamino group.

The term "heteroatom" represents a compound containing 1 or more oxygen, sulfur or nitrogen atoms.

The term "substituted or unsubstituted" means that a hydrogen in the structure is substituted with the substituent or that the hydrogen is unsubstituted. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, or more than one (to the substitutable position on the substituted structure) position in the structure may be substituted.

As used herein, the numerical range "C1-10" and its included sub-ranges generally means having a defined number of 1-10 atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 atoms; "C1-10" and the sub-ranges contained therein, inclusive, of the number of carbon atoms, generally means a group having a defined number of 1-10 carbon atoms, i.e., a group containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.

Compared with the prior art, the invention has the following beneficial effects:

the photo-thermal material of the light-induced non-adiabatic fading type shows good photo-thermal conversion efficiency and biological safety, can not cause burn and/or necrosis of normal tissues near a tumor due to high temperature, can effectively reduce the dependence on the temperature, and can achieve the functions of killing the tumor, protecting tissues and the like.

Drawings

FIG. 1 is a schematic view of photothermal therapy of tumors using the photothermal material of the present invention;

FIG. 2 is a normalized UV-VIS-NIR absorption spectrum of C1TI and its nanoparticle C1TI NP in THF and aqueous solutions, respectively;

FIG. 3 is a normalized UV-VIS-NIR absorption spectrum of C2TI and its nanoparticle C2TI NP in THF and aqueous solutions, respectively;

FIG. 4 is a normalized UV-VIS-NIR absorption spectrum of C4TI and its nanoparticle C4TI NP in THF and aqueous solutions, respectively;

FIG. 5 is a normalized UV-VIS-NIR absorption spectrum of C6TI and its nanoparticle C6TI NP in THF and aqueous solutions, respectively;

FIG. 6 is a graph of a potential energy surface theoretical calculation for C1 TI;

FIG. 7 is a diagram of the highest occupied molecular orbital of C1TI in the ground state;

FIG. 8 is a diagram of the lowest unoccupied molecular orbital of C1TI in the ground state;

FIG. 9 is a diagram of the highest occupied molecular orbital of C1TI in the excited state;

FIG. 10 is a diagram of the lowest unoccupied molecular orbital of C1TI in the excited state;

FIG. 11 is a photo-thermal conversion graph of C1TI aggregates before and after exposure to 808nm NIR laser in a mixed solution of THF and water;

FIG. 12 is a photo-thermal conversion graph of C2TI aggregates before and after exposure to 808nm NIR laser in a mixed solution of THF and water;

FIG. 13 is a photo-thermal conversion graph of C4TI aggregates before and after exposure to 808nm NIR laser in a mixed solution of THF and water;

FIG. 14 is a photo-thermal conversion graph of a C6TI aggregate before and after exposure to 808nm NIR laser in a mixed solution of THF and water;

FIG. 15 is a plot of annealing process of C1TI aggregates in THF and water mixed solution after 808nm near-infrared laser irradiation as a function of time;

FIG. 16 is a plot of annealing process of C2TI aggregates in THF and water mixed solution after 808nm near-infrared laser irradiation as a function of time;

FIG. 17 is a plot of annealing process versus time for the aggregate of C4TI in a mixed solution of THF and water after 808nm NIR laser irradiation;

FIG. 18 is a plot of annealing process versus time for the aggregate C6TI in a mixed solution of THF and water after 808nm NIR laser irradiation;

FIG. 19 is a photo-thermal conversion chart of an aqueous solution of C6TI nanoparticles before and after 808nm NIR laser irradiation;

FIG. 20 is a functional diagram of the annealing process of the C6TI nano-particle aqueous solution irradiated by 808nm near-infrared laser and the relation of time;

FIG. 21 is a graph of photothermal conversion of an aqueous ICG aggregate solution before and after irradiation with 808nm near-infrared laser light;

FIG. 22 is a plot of the annealing process versus time for an aqueous ICG aggregate solution after 808nm NIR laser irradiation;

FIG. 23 is a photo-thermal conversion diagram of an aqueous solution of C6TI nanoparticles after irradiation with 808nm NIR laser light;

FIG. 24 is a graph of photothermal conversion of an aqueous solution of C6TI nanoparticles and ICG aggregates, before and after irradiation with 808nm near-infrared laser light;

FIG. 25 is a block diagram of bacterial activity after incubation of 4T1 cancer cells with different concentrations of C6TI-Tat, C6TI/Apo-Tat nanoparticle photothermal material and irradiation with 808nm near-infrared laser for 30 min;

FIG. 26 is a flow cytometric assay of 4T1 cancer cells in a phosphate buffer environment;

FIG. 27 is a flow cytometric image of 4T1 cancer cells after irradiation with 808nm near infrared laser in PBS environment of C6TI-Tat nanoparticles;

FIG. 28 is a flow cytometric image of 4T1 cancer cells after irradiation with 808nm near-infrared laser in PBS environment with C6TI/Apo-Tat nanoparticles;

FIG. 29 is a plot of relative tumor size of C6TI-Tat nanoparticles over time following hyperthermic photothermal therapy;

figure 30 is a graph of relative tumor size over time for the PBS blank control group following hyperthermic photothermal treatment;

FIG. 31 is a plot of relative tumor size of C6TI-Tat nanoparticles over time following hyperthermal photothermal therapy;

FIG. 32 is a graph of relative tumor size over time of subcutaneous tumors in vivo after treatment with low temperature photothermal therapy;

FIG. 33 is a graph of relative mouse body weight change over time following in vivo treatment of subcutaneous tumors via low temperature photothermal therapy;

FIG. 34 is a graph of the relative tumor size over time for the C6TI/Apo-Tat NPs light group following low temperature photothermal therapy;

FIG. 35 is a graph of relative tumor size over time for the C6TI-Tat NPs phototypeset following low temperature photothermal therapy;

FIG. 36 is a graph of relative tumor size over time for the C6TI/Apo-Tat NPs non-illuminated group following low temperature photothermal therapy;

FIG. 37 is a graph of relative tumor size over time for the C6TI-Tat NPs non-illuminated group following low temperature photothermal therapy;

FIG. 38 is a graph of relative tumor size over time for PBS light groups following low temperature photothermal therapy;

FIG. 39 is a graph of relative tumor size over time in the PBS non-illuminated group following low temperature photothermal therapy;

FIG. 40 is a photograph of a C6TI/Apo-Tat NPs erythrolysis assay;

FIG. 41 is a graph of the biochemical detection of blood at the alanine aminotransferase level for C6TI/Apo-Tat NPs;

FIG. 42 is a graph of the biochemical blood test of C6TI/Apo-Tat NPs for the aspartate aminotransferase indicator;

FIG. 43 is a graph of the total protein index for biochemical blood assays using C6TI/Apo-Tat NPs;

FIG. 44 is a graph of the blood biochemical assay for C6TI/Apo-Tat NPs in creatinine;

FIG. 45 is a graph of the blood biochemical assay for C6TI/Apo-Tat NPs in the determination of blood urea nitrogen;

FIG. 46 is a graph of a conventional blood test for C6TI/Apo-Tat NPs in a white blood cell marker;

FIG. 47 is a graph of a conventional blood test for C6TI/Apo-Tat NPs in red blood cells;

FIG. 48 is a graph of a conventional assay for blood platelet markers for C6TI/Apo-Tat NPs;

FIG. 49 is a graph of a conventional blood test of C6TI/Apo-Tat NPs on lymphocyte markers;

FIG. 50 is a graph of a routine blood test of C6TI/Apo-Tat NPs on hemoglobin markers;

FIG. 51 is a graph of a conventional assay for blood analysis of C6TI/Apo-Tat NPs in hematocrit indicators;

FIG. 52 is a graph of the blood routine measurements of C6TI/Apo-Tat NPs in mean corpuscular volume indicators;

FIG. 53 is a graph of a conventional blood test of C6TI/Apo-Tat NPs on the mean corpuscular hemoglobin index;

FIG. 54 is a graph of the blood routine measurements of C6TI/Apo-Tat NPs on a mean corpuscular hemoglobin concentration indicator;

FIG. 55 is a graph of the average platelet volume index for routine blood testing of C6TI/Apo-Tat NPs;

FIG. 56 is a hematoxylin-eosin staining analysis of untreated vital organ tissue sections from normal mice;

FIG. 57 is a hematoxylin-eosin staining analysis of vital organ tissue sections after low temperature photothermal treatment of the PBS control group;

FIG. 58 is a hematoxylin-eosin staining analysis of vital organ tissue sections after low temperature photothermal treatment of the C6TI-Tat NPs control group;

FIG. 59 is a hematoxylin-eosin staining analysis of vital organ tissue sections after low temperature photothermal treatment in the C6TI/Apo-Tat NPs treatment group.

Detailed Description

The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.

Fig. 1 is a schematic view of photothermal therapy of tumor by using the photothermal material of the present invention, and fig. 1 shows: the photo-thermal material constructed based on the light-induced non-adiabatic decay characteristic can show up to 90% of photo-thermal conversion efficiency under the irradiation of near infrared light, and is quite suitable for photo-thermal treatment research of tumors.

Example 1

Photo-thermal material and preparation of photo-thermal material nano particles

(1) Synthesis of photo-thermal material C1TI of light-induced non-adiabatic fading type

The synthetic route is as follows:

n, N-dimethyl-4-nitrosoaniline (N, N-dimethyl-4-nitrosaniline, C1P-NO; 1.5g, 10mmol), 2'- (1H-indene-1,3(2H) -diyl) dicarbonitrile (2,2' - (1H-indene-1,3(2H) -diimidene) diamononitrile, III-H; 2.42g, 10mmol) and ethanol (EtOH; 20m L) were put into a 100m L single-neck round-bottomed flask equipped with a condenser tube, and after heating and refluxing for more than two hours, the reaction was monitored with a silica gel plate (T L C) sheet, and after confirming completion of the reaction, the solvent was drained and purified by a column chromatography to give a deep purple green C1TI product with a yield of 71%.

¹H NMR(500MHz,DMSO-d₆),(ppm):8.40-8.38(m,1H),7.94-7.92(m,1H),7.55(br,1H),7.42(m,1H),7.21-7.17(m,2H),6.99(m,1H),6.79(m,1H),3.23(s,3H),2.96(s,3H).¹³CNMR(125MHz,DMSO-d₆),(ppm):158.60,155.59,153.32,151.48,144.92,142.44,142.15,139.85,138.09,136.92,134.60,132.73,131.27,128.40,126.35,124.98,124.10,120.01,116.80,114.71,113.87,113.63,113.54,113.11,71.68,71.52,59.39,40.41.MS(ESI):calculated for C₂₃H₁₄N₆[M+H]⁺375.1280；found 375.13503.

(2) Synthesis of photo-thermal material C2TI of light-induced non-adiabatic fading type

The synthetic route is as follows:

n, N-diethyl-4-nitrosoaniline (N, N-diethyl-4-nitrosaniline, C2P-NO; 1.78g, 10mmol), 2'- (1H-indene-1,3(2H) -diyl) dicarbonitrile (2,2' - (1H-indene-1,3(2H) -diimidene) diamononitrile, III-H; 2.42g, 10mmol) and ethanol (EtOH; 20m L) were put into a 100m L single-neck round-bottomed flask equipped with a condenser tube, and after heating and refluxing for more than two hours, the reaction was monitored with a silica gel plate (T L C) sheet, and after confirming that the reaction was complete, the solvent was drained off and purified by a column chromatography to give a deep purple green C2TI product with a yield of 92%.

¹H NMR(500MHz,DMSO-d₆),(ppm):8.38-8.36(m,2H),7.92-7.90(m,2H),7.43-7.40(m,2H),7.00-6.99(m,2H),3.63-3.62(m,4H),1.22-1.19(t,6H).¹³C NMR(125MHz,DMSO-d₆),(ppm):155.43,152.92,151.92,149.82,141.48,138.20,136.91,135.67,134.45,130.09,125.25,124.86,122.89,121.38,119.27,117.69,114.87,114.80,113.67,70.81,52.58,49.91,45.21,13.03,10.21.MS(ESI):calculated for C₂₅H₁₈N₆[M+H]⁺403.1593；found 403.16604.

(3) Synthesis of photo-thermal material C4TI of light-induced non-adiabatic fading type

The synthetic route is as follows:

n, N-di-N-butyl-4-nitrosoaniline (N, N-dibutyl-4-nitrosaniline, C4P-NO; 2.34g, 10mmol), 2'- (1H-indene-1,3(2H) -diyl) dicarbonitrile (2,2' - (1H-indene-1,3(2H) -diimidine) dimalono-nitrile, III-H; 2.42g, 10mmol) and ethanol (EtOH; 20m L) were charged into a 100m L single-neck round-bottomed flask equipped with a condenser tube, and after heating and refluxing for more than two hours, the reaction was monitored with a silica gel sheet (T L C), and after confirming completion of the reaction, the solvent was drained off and purified by column chromatography to give a deep purple green C4TI product in a yield of 95%.

¹H NMR(500MHz,DMSO-d₆),(ppm):8.39-8.37(m,2H),7.93-7.91(m,2H),7.42-7.41(m,2H),7.00-6.98(m,2H),3.58-3.55(m,4H),1.61-1.57(m,4H),1.39-1.34(m,4H),0.95-0.92(t,6H).¹³C NMR(125MHz,DMSO-d₆),(ppm):155.41,152.35,141.48,138.29,136.93,134.45,131.62,124.85,114.91,113.87,113.70,84.73,70.73,50.82,29.70,19.53,13.79.MS(ESI):calculated for C₂₉H₂₆N₆[M+H]⁺459.2219；found 459.22845.

(4) Synthesis of photo-thermal material C6TI of light-induced non-adiabatic fading type

The synthetic route is as follows:

n, N-di-N-hexyl-4-nitrosoaniline (N, N-dihexyl-4-nitrosoaniline, C6P-NO; 2.90g, 10mmol), 2'- (1H-indene-1,3(2H) -diyl) dicarbonitrile (2,2' - (1H-indene-1,3(2H) -diindidene) diamalono-nitrile, III-H; 2.42g, 10mmol) and ethanol (EtOH; 20m L) were charged in a 100m L single-neck round-bottomed flask equipped with a condenser, and after heating and refluxing for more than two hours, the reaction was monitored with a silica gel plate (T L C) sheet, and after confirming completion of the reaction, the solvent was drained off and purified by column chromatography to give a deep purple green C6TI product in a yield of 85%.

¹H NMR(500MHz,DMSO-d₆),(ppm):8.38-8.36(m,2H),7.92-7.90(m,2H),7.41-7.39(m,2H),6.99-6.97(m,2H),3.57-3.54(m,4H),1.63-1.57(m,4H),1.36-1.28(m,12H),0.89-0.87(m,6H).¹³C NMR(125MHz,DMSO-d₆),(ppm):155.36,152.52,152.40,141.43,140.62,138.32,136.91,134.42,129.64,124.92,124.82,114.90,113.87,113.69,70.67,50.98,31.04,27.58,25.88,22.10,13.91.MS(ESI):calculated for C₃₃H₃₄N₆[M+H]⁺515.2845；found 515.29110.

(5) Synthesis of C6TI photothermal nanoparticles

Prepared by a nano coprecipitation technology. Wherein the C6TI photothermal nanoparticles (C6TI-Tat NPs) are prepared as follows:

c6TI (1mg), DSPE-PEG2000-MA L (1mg) and DSPE-PEG2000(1mg) are ultrasonically dissolved in 1m L tetrahydrofuran solution, 9m L double distilled water is rapidly added, ultrasonic treatment is immediately carried out for 2min to prepare C6TI-MA L NPs, 15m L cell penetrating peptide is added into the solution, stirring is carried out overnight to obtain C6TI photo-thermal nano-particles (C6TI-Tat NPs) products, and other products (C1TI, C2TI and C4TI photo-thermal nano-particles) are similar and are not repeated in detail.

(6) Synthesis of C6TI photothermal nanoparticles containing HSP70 inhibitor

Prepared by a nano coprecipitation technology. The C6TI photothermal nanoparticles (C6TI/Apo-Tat NPs) containing HSP70 inhibitor therein were prepared as follows:

c6TI (1mg), Apo (0.1mg), DSPE-PEG2000-MA L (1mg) and DSPE-PEG2000(1mg) are ultrasonically dissolved in 1m L tetrahydrofuran solution, 9m L double distilled water is quickly added, and ultrasonic treatment is immediately carried out for 2min to prepare C6TI/Apo-MA L NPs, 15m L cell penetrating peptide is added into the solution, and stirring is carried out overnight to obtain C6TI photo-thermal nanoparticles (C6TI/Apo-Tat NPs) products containing HSP70 inhibitors, and other products (C1TI, C2TI and C4TI photo-thermal nanoparticles) are similar and are not detailed again.

Example 2

Research on optical and light-induced non-adiabatic fading and photo-thermal conversion efficiency of product

The optical properties, light-induced non-adiabatic degradation, and photothermal conversion efficiency characteristics of the photothermal materials were examined by taking 4 photo-induced non-adiabatic degradation type photothermal materials (C1TI, C2TI, C4TI, and C6TI) as examples.

(1) Investigation of optical Properties

Ultraviolet-visible-near infrared (UV-vis-NIR) absorption spectra of C1TI, C2TI, C4TI and C6TI and their nanoparticles (C1TI NP, C2TI NP, C4TI NP and C6TI NP) in Tetrahydrofuran (THF) and aqueous solutions, respectively, are shown in fig. 2-5. Fig. 2 is a normalized uv-vis-nir absorption spectrum of C1TI and its nanoparticles (C1TI NP) in THF and aqueous solutions, respectively, fig. 3 is a normalized uv-vis-nir absorption spectrum of C2TI and its nanoparticles (C2TI NP) in THF and aqueous solutions, respectively, fig. 4 is a normalized uv-vis-nir absorption spectrum of C4TI and its nanoparticles (C4TI NP) in THF and aqueous solutions, respectively, and fig. 5 is a normalized uv-vis-nir absorption spectrum of C6TI and its nanoparticles (C6TI NP) in THF and aqueous solutions, respectively.

The maximum absorption wavelengths of C1TI, C2TI, C4TI and C6TI in THF solution are all located between 740-765nm, but the absorption wavelengths of the nanoparticles (C1TI NP, C2TI NP, C4TI NP and C6TI NP) are respectively located at 587, 915, 757 and 765nm, mainly because of the stacking difference of the four photothermal materials of C1TI, C2TI, C4TI and C6TI in the nanoparticles, which results in the shift of the absorption spectrum. The absorption wave bands of the four products are matched with a near-infrared excitation light source with wavelength of 808nm commonly used in biological imaging, and the four products are quite favorable for serving as a photo-thermal material required by the biological medicine technology.

(2) Study of light-induced non-adiabatic decay characteristics

Theoretical calculation analysis of molecular orbital, potential energy surface and the like of C1TI molecules is carried out by a time-dependent density functional theory (TD-DFT) method of Gaussian software, and other product theories are not repeated in detail, as shown in FIGS. 6-10, FIG. 6 is a theoretical calculation graph of potential energy surface of C1TI (CI is cone intersection), FIG. 7 is a graph of Highest Occupied Molecular Orbital (HOMO) of C1TI in a ground state, FIG. 8 is a graph of lowest unoccupied molecular orbital (L UMO) of C1TI in a ground state, FIG. 9 is a graph of Highest Occupied Molecular Orbital (HOMO) of C1TI in an excited state, and FIG. 10 is a graph of lowest unoccupied molecular orbital (L UMO) of C1TI in an excited state.

It can be seen from fig. 6-10 that the C1TI molecule in the excited state returns to the ground state through a cone intersection, resulting in the release of a substantial portion of the excited state's energy in a non-radiative, i.e., thermal, manner, referred to herein as the light-induced non-adiabatic decay phenomenon. Compared with the traditional ICG material, the C1TI photo-thermal agent can release energy in a more complete conversion mode, and is quite suitable for the application of photo-thermal treatment on tumors in the biological treatment.

(3) Study of photothermal conversion efficiency (PTCE)

4 photo-thermal materials (C1TI, C2TI, C4TI and C6TI) of a light-induced non-adiabatic fading type were dispersed in a mixed solution of THF and water (volume ratio, 5/95), and the photo-thermal conversion efficiency of the product solution was tested by a near infrared laser (power density 1 watt per square centimeter) at 808 nm. As shown in fig. 11-18; fig. 11 is a photo-thermal conversion chart of C1TI aggregates in THF and water (volume ratio, 5/95) mixed solution before and after irradiation with 808nm near-infrared laser (laser intensity of 1 watt per square centimeter), fig. 12 is a photo-thermal conversion chart of C2TI aggregates in THF and water (volume ratio, 5/95) mixed solution before and after irradiation with 808nm near-infrared laser (laser intensity of 1 watt per square centimeter), fig. 13 is a photo-thermal conversion chart of C4TI aggregates in THF and water (volume ratio, 5/95) mixed solution before and after irradiation with 808nm near-infrared laser (laser intensity of 1 watt per square centimeter), fig. 14 is a photo-thermal conversion chart of C6TI aggregates in THF and water (volume ratio, 5/95) mixed solution before and after irradiation with 808nm near-infrared laser (laser intensity of 1 watt per square centimeter), fig. 15 is a chart of C1TI aggregates in THF and water (volume ratio, 5/95) mixed solution, defervescence process after 808nm near infrared laser irradiation and time, fig. 16 is a THF and water (volume ratio, 5/95) mixed solution of C2TI aggregate, defervescence process after 808nm near infrared laser irradiation and time, fig. 17 is a THF and water (volume ratio, 5/95) mixed solution of C4TI aggregate, defervescence process after 808nm near infrared laser irradiation and time, fig. 18 is a THF and water (volume ratio, 5/95) mixed solution of C6TI aggregate, defervescence process after 808nm near infrared laser irradiation and time.

The photothermal conversion efficiencies of C1TI, C2TI, C4TI, and C6TI in aqueous solution were calculated to be 57.1%, 62.9%, 58.2%, and 90.0%, respectively. Among them, the C6TI photothermal molecules have a long alkyl chain, which is favorable for the molecular motion in the aggregation state, and thus, higher photothermal conversion efficiency is obtained. The photo-thermal conversion efficiency of nanoparticles (C6TI NPs) constructed by C6TI was further tested, and 89.3% photo-thermal conversion efficiency was obtained under the conditions of near-infrared laser with 808nm, power density of 0.75W/sq cm and photo-thermal agent concentration of 10 micrograms/ml (FIG. 19 is a photo-thermal conversion graph (laser intensity of 0.75W/sq cm) before and after 808nm near-infrared laser irradiation of an aqueous solution of C6TI nanoparticles; and FIG. 20 is a plot of the relation of the annealing process to time after 808nm near-infrared laser irradiation of an aqueous solution of C6TI nanoparticles). Under the same conditions, the measured photothermal conversion efficiency of ICG was 32% (FIG. 21 is a photothermal conversion chart before and after 808nm near-infrared laser irradiation of an ICG aggregate aqueous solution (laser intensity of 0.75W/sq cm), and FIG. 22 is a diagram of the relationship between the annealing process and time of an ICG aggregate aqueous solution after 808nm near-infrared laser irradiation). In addition, the highest photothermal temperatures obtained for different concentrations (100, 50, 25, and 10 micrograms per milliliter) of C6TI nanoparticles were 76.4, 66.5, 55.8, and 43.9 ℃, respectively (fig. 23 is a photothermal conversion plot (laser intensity of 1 watt per square centimeter) of an aqueous solution of C6TI nanoparticles after irradiation with 808nm near-infrared laser). Compared with the stability test of ICG, the C6TI nanoparticles have higher photo-thermal stability (FIG. 24 is a photo-thermal conversion graph of the C6TI nanoparticles and ICG aggregate aqueous solution before and after 808nm near-infrared laser irradiation (laser intensity of 1 watt per square centimeter; concentration of 100 micrograms per milliliter)). The data show that the photothermal agent constructed based on the light-induced non-adiabatic decay characteristic not only has high photothermal conversion efficiency, but also has high photothermal stability, and has a great application prospect in the biological medicine for the photothermal treatment of tumors.

Example 3

Product for photothermal therapy of tumor

(1) In vitro antitumor Effect test

For in vitro photothermal antitumor experiments, photothermal materials of C6TI-Tat, C6TI/Apo nanoparticles (C6TI-Tat, C6TI/Apo-Tat NPs) at different concentrations in PBS solution (0, 25, 50 and 100 μ g/m L) were incubated with mouse breast cancer 4T1 cells in the dark at 37 ℃ for 1 hour, exposed to near infrared light at 808nm while controlling the temperature at 43 ℃ after irradiation for 30 minutes, and incubated back in the dark at 37 ℃ for 17 hours, then the biological activity of the nanoparticles at different concentrations was analyzed with a cell proliferation and toxicity detection kit (CCK-8 kit). The control group was placed in the dark and incubated at 37 ℃ for 24 hours, as shown in FIG. 25 (FIG. 25 is a block diagram showing that the effect of the photothermal and anti-tumor effects of HSP-Tat nanoparticles in the HSP-T photothermal material 4T TI-Tat 6324 cells were treated with different concentrations (0-100 μ g/m L) after irradiation for 30 minutes), and the photothermal effect of the HSP-Tat nanoparticle material was obtained as a heat-resistant therapeutic effect of the inhibitor (block diagram showing that the effect of the HSP photothermal and the HSP-Tat-T-4T-5-8 kit) was able to kill the cell killing effect of the HSP-HSP nanoparticles in the HSP photothermal material in the HSP-T-.

(2) Flow cytometry

Resuscitated mouse breast cancer 4T1 cells were cultured in a 37 ℃ carbon dioxide incubator 24 hours later and inoculated in 6-well plates, 11 × 10 per well⁶The number of cells, after 6 hours, the 6-well plate was added with culture medium containing C6TI-Tat, C6TI/Apo nanoparticles (C6TI-Tat, C6TI/Apo-Tat NPs) at a concentration of 100 μ g/m L, wherein the wells of experiment group 3 were treated with C6TI-Tat, C6TI/Apo-Tat NPs and normal cell culture medium, respectively, after the material was incubated for 6 hours, 1 × PBS washing was performed 2 times, fresh medium was added, heat shock was performed for 1 hour, the control group was added with normal cell culture medium, cultured in 37 ℃ carbon dioxide incubator, after completion of thermal shock in the experiment, cultured in 37 ℃ carbon dioxide incubator for 2 hours, Annexin V-FITC/PI double staining and flow cell assay were performed with Apoptosisdetection Kit from Vazyme Biotech, Inc. ApoptosisDetection Kit, the results of HSP70 inhibitor (Apo) (C6 NP24/Tat) showed that the nanoparticles can achieve the effect of anticancer by flow-through the anti-cell apoptosis mechanism of HSP70 inhibitor (Apo) and the nano-NP 26-NP 28-NP 2-NP, the heat-resistant effect of the cell-resistant map shows that the anti-cell-apoptosis effect of HSP70 inhibitor (C6) was achieved by the heat-resistant cell-resistant nano-phosphate-7) and the heat-resistant cell-Fig. 28 is a flow cytometric image of 4T1 cancer cells after 808nm near-infrared laser irradiation in PBS environment of C6TI/Apo-Tat nanoparticles (C6TI/Apo-Tat NPs). )

(3) In vivo hyperthermia photothermal therapy experiment

4T1 cells were randomly inoculated subcutaneously on the dorsal side of mice (2 × 10) using 6 week old, 10 BA L B/c Nude mice purchased from Guangzhou animal laboratories (Guangzhou)⁵Cell number per one), 5 days later, after 80-120 cubic millimeters of tumor size, photothermal treatment was performed, wherein 5 mice in the experimental group were injected caudally with C6TI-Tat NPs (200 microliters per one), the control group was injected with 1 × PBS (200 microliters per one), the experimental group was photothermal treated with 808nm near infrared laser (0.75 watts per square centimeter of irradiation 15 minutes) 8 hours after injection, the mice were weighed at

time points

0, 2, 4, 6, 8, 10, 12, 14, tumor size was measured, and data were recorded by photographing.

(4) In vivo low temperature photothermal therapy experiment

4T1 cells were randomly inoculated subcutaneously on the dorsal side of mice (2 × 10) using 6 week old, 10 BA L B/c Nude mice purchased from Guangzhou animal laboratories (Guangzhou)⁵Cell number per one), 5 days later, after the tumor size is 80-120 cubic millimeters, the tumor size is randomly divided into A, B, C, D, E and F groups, wherein experimental groups A and B are injected with C6TI/Apo-Tat NPs and C6TI-Tat NPs (200 microliters per one) in tail vein respectively, experimental control groups C and D are injected with C6TI/Apo-Tat NPs and C6TI-Tat NPs (200 microliters per one) respectively, and negative control groups E and F are injected with 1 × PBS (200 microliters per one) for 8 hours, then near-infrared light at 808 nanometers is used for irradiating the laserThe results show that the tumor can be cured significantly by photothermal therapy at a low temperature after the tumor is irradiated at 0, 2, 4, 6, 8, 10, 12, 14 time points, the tumor size is measured and the data is recorded by photographing, and the results show that the light-induced non-adiabatic regression type photothermal material can also exhibit a high efficacy in the general photothermal therapy (fig. 32-39: fig. 32 is a graph of the relative tumor size of the subcutaneous tumor after the low-temperature photothermal therapy with time; the PBS-irradiated group, the C6TI-Tat NPs-irradiated group, and the PBS, C6TI-Tat NPs, the Apo 6/Apo-Tat Apo-NPs-irradiated group all serve as experimental control groups; fig. 808nm near infrared laser (intensity is 0.5 square per centimeter), fig. 33 is a graph of the relative tumor size after the photothermal therapy with time; the Apo-irradiated at a low temperature after the photothermal therapy with light) of the tumor, the Apo-irradiated at a low temperature after the photothermal therapy with time; the Apo-irradiated at a graph of the PBS-irradiated at a low temperature after the Apo-irradiated at a low temperature, the Apo-p 6-p 5) and the Apo-p 35-p-s irradiated at a time point as experimental control group, the non-p-s as experimental control group, the p-p.

(5) Blood safety detection

The blood volume test chart of the normal blood cells of the normal blood volume test chart of the normal blood cells of the normal blood volume test chart of the normal blood cells of the normal blood volume test chart of the normal cells of the normal blood volume test chart of the normal cells of the normal blood cells of the normal cells of the blood volume test chart of the normal cells of the blood volume test chart of the normal cells of the blood volume test chart of the normal cells of the.

(6) Pathological examination

One mouse was randomly selected for low temperature photothermal therapy, and its heart, liver, spleen, lung and kidney were taken, fixed in 10% neutral formalin, dehydrated, paraffin-embedded, sectioned and stained with hematoxylin-eosin (H & E). Pathological changes were recorded by taking 20-fold pictures under the mirror. As shown in fig. 56-59: fig. 56 is hematoxylin-eosin (H & E) staining analysis of untreated vital organ tissue sections of normal mice, fig. 57 is hematoxylin-eosin (H & E) staining analysis of vital organ tissue sections after low-temperature photothermal treatment of the PBS control group, fig. 58 is hematoxylin-eosin (H & E) staining analysis of vital organ tissue sections after low-temperature photothermal treatment of the C6TI-Tat NPs control group, and fig. 59 is hematoxylin-eosin (H & E) staining analysis of vital organ tissue sections after low-temperature photothermal treatment of the C6TI/Apo-Tat NPs treatment group.

Compared with untreated data, the mice treated by various treatments have no great pathological difference in pathological examination, and the light-induced non-adiabatic fading photothermal material can not cause additional pathological changes to important organs of an individual while being treated.

Therefore, it can be concluded that the photo-thermal material of light-induced non-adiabatic regression type is not only suitable for general high-temperature anti-tumor photo-thermal therapy, but also can be applied to low-temperature anti-tumor photo-thermal therapy in combination with HSP70 inhibitor. In addition, the invention has the advantages of simple and easy preparation and high-efficiency photothermal conversion efficiency, and can highlight that the photothermal material has quite large competitiveness.

The present invention is exemplified by subcutaneous tumor inoculated with mouse breast cancer 4T1 cells, and it will be apparent to those skilled in the art that modifications and variations can be made in light of the above description, and all such modifications and variations are within the scope of the appended claims, including treatment of infection by other bacteria or resistant bacteria (E. coli, MRSA, VRE, CRE, MDR-TB, CD), photothermal treatment of tumor cells (e.g., MCF-7, He L a, MDA-MB-231 cells), or biological imaging and use of nanoprobes coated with such photothermal materials.

It will be apparent to those skilled in the art to which the invention relates that the invention may be varied from the precise details described without departing from the spirit and scope of the claims set out below. The present invention is not to be considered as limited in scope by the procedures, properties or compositions defined, since the preferred embodiments and other descriptions are intended only to illustrate specific aspects of the invention presently provided. Various modifications of the described modes for carrying out the invention which are obvious to those skilled in chemistry, biochemistry or related fields are intended to be within the scope of the following claims.

It will be understood that modifications and variations can be made by persons skilled in the art in light of the above teachings, and all such modifications and variations are intended to be included within the scope of the invention as defined in the appended claims.

Claims

1. A photo-thermal material of a light-induced non-adiabatic fading type, the photo-thermal material being a compound represented by formula I:

2. The photo-thermal material of claim 1, wherein Ar is selected from the group consisting of₁The group is selected from any one of the following units;

wherein R is₂The group is selected from hydrogen, cyano, nitro, substituted or unsubstituted alkyl, alkenyl, alkynyl, halogen, hydroxylAny one of amino, ester, amido, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, cycloalkyloxy, cycloalkylthio, acyl, ester, amido, aryl, heterocyclic, heteroaryl, heterocycloalkyl, monoalkylamino or dialkylamino, R₃The groups are independently selected from any one of hydrogen, substituted or unsubstituted alkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, cycloalkyloxy, cycloalkylthio, aryl, heterocyclyl, heteroaryl, heterocycloalkyl, monoalkylamino or dialkylamino.

3. The photo-thermal material of claim 1 or 2, wherein Ar is selected from the group consisting of₁The group is selected from any one of the following units;

wherein R is₂The group is selected from any one of hydrogen, trifluoromethyl, substituted or unsubstituted alkyl, ester group, amido, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, cycloalkyloxy, cycloalkylthio, acyl, ester group or amido;

preferably, Ar is₁The radicals being selected from

4. The photo-thermal material of any one of claims 1-3, wherein Ar is selected from the group consisting of₂And Ar₃The groups are independently selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted Ar₁Any one of a group, alkoxy, alkylthio, alkenyl, alkynyl or cycloalkyl;

5. The photo-thermal material of the light-induced non-adiabatic fading type as defined in any one of claims 1-4, wherein R is₁The group is selected from any one of hydrogen, trifluoromethyl, substituted or unsubstituted alkyl, ester group, amido, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, cycloalkyloxy, cycloalkylthio, acyl, ester group or amido;

6. The photo-thermal material of any one of claims 1-5, wherein the photo-thermal material is a compound of formula I':

7. the method for preparing the photo-induced non-adiabatic fading type photothermal material according to any one of claims 1-6, wherein the method comprises performing a polycondensation reaction between a compound of formula II and a compound of formula III to obtain a compound of formula I, wherein the reaction formula is as follows: .

8. The preparation method according to claim 7, wherein the molar mass ratio of the compound of the formula II to the compound of the formula III is 1 (1-1.2), preferably 1: 1;

preferably, the reaction temperature of the polycondensation reaction is 70-80 ℃, and the time of the polycondensation reaction is 2-3 h;

preferably, the reaction solvent of the polycondensation reaction is ethanol.

9. Use of the photo-thermal material according to any one of claims 1 to 6 for preparing a tumor photo-thermal diagnosis and treatment agent.

10. Use of the photo-thermal material according to any one of claims 1 to 6 for preparing a tumor cell, bacterial or drug-resistant bacterial photo-thermal diagnosis and treatment device;