CN112566911B - Photothermal reagent - Google Patents

Photothermal reagent Download PDF

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CN112566911B
CN112566911B CN201980040309.4A CN201980040309A CN112566911B CN 112566911 B CN112566911 B CN 112566911B CN 201980040309 A CN201980040309 A CN 201980040309A CN 112566911 B CN112566911 B CN 112566911B
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2tpe
photothermal
ndta
tumor
compound
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CN112566911A (en
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唐本忠
赵征
刘顺杰
丁丹
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Hong Kong University of Science and Technology HKUST
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Abstract

Photothermal agents may be used for both photoacoustic imaging (PAI) and photothermal therapy (PTT) applications. The photothermal agent may comprise small molecules, organic compounds, and/or polymers having absorption in the Near Infrared (NIR) interrogation window (700-900 nm). The compound may be a biocompatible Organic Nanoparticle (ONP). The photothermal agent may be used to locate a tumor site within a patient using in vivo imaging techniques. Once the tumor site is determined, the tumor site may be irradiated with near infrared light to prevent or inhibit tumor growth.

Description

Photothermal reagent
Technical Field
The subject of the present application is a series of small organic molecule compounds and conjugated polymers and their use in Photo Acoustic Imaging (PAI) and Photo Thermal Therapy (PTT).
Background
Among various light-triggered diagnosis/treatment techniques, photo-acoustic imaging (PAI) combined with photo-thermal treatment (PTT) has a good effect in accurately detecting a tumor location and effectively inhibiting tumor growth with minimal side effects on normal tissues. PAI is a very promising non-invasive imaging method combining deep tissue penetration in ultrasound imaging with high resolution and high contrast in optical imaging. The treatment technique typically accompanied by PAI is PTT, as PAI is primarily used to detect photothermal ultrasound signals. The most important prerequisite for PAI/PTT applications is the use of highly efficient contrast agents with strong absorption in the Near Infrared (NIR) interrogation window (700-900 nm), since NIR light is known to penetrate deeper tissues and to be less photodamaged to living subjects.
Among existing contrast agents, organic dyes are receiving a great deal of attention for their excellent biocompatibility, degradability, and processability. However, it has also been reported that the anticancer effect of organic contrast agents may be limited by their low photo-thermal properties. Most of the existing systems are only simple to construct strong donor (D) and acceptor (a) units into coplanar structures, as demonstrated by small molecules and semiconducting polymer nanoparticles. The strong intermolecular interactions within the Nanoparticles (NPs) may block other heat-generating channels.
Some previous studies have focused on exploring new approaches to further improve the photothermal properties. However, these studies are generally based on designing planar structures to enhance intermolecular interactions in aggregates. Furthermore, the complexity of the polymer structure is detrimental to a detailed study of the mechanism.
Recent studies revealed an excited state electron transfer process observed in small molecules, known as distorted intramolecular charge transfer (TICT) (org. Sensor actual B-Chem,2018,267,448). In this process, the dark tic state returns to the ground state after photoexcitation mainly by non-radiative relaxation, with concomitant red-shift emission. Notably, the preconditions for the formation of a tic state depend on active molecular rotation. In the TICT process, this sensitivity of the state is beneficial for various non-radiative quenching processes. Thus, small molecules with stronger tic properties may be beneficial for enhancing heat generation.
The ability to convert a low density source of optical radiant energy into thermal energy has led to a broad prospect in many advanced applications such as desalination of sea water, photoelectric and photo-thermal-mechanical converters, PAIs and PTT. In the biomedical field, PAI detection of photothermal generated ultrasound signals has recently received considerable attention because it exceeds the limit of light penetration capability, allowing for disease diagnosis of deeper tissues at higher spatial resolution. The PA effect of a material arises from the generation of heat, positively correlated to the non-radiative decay of the excited state. Among the numerous PAI agents, pi-conjugated small organic molecules or polymers based organic nanoparticles are receiving great attention due to their good biocompatibility, readily tunable band gap, and readily researched structure-property relationships. Some commonly used molecules, such as indocyanine green (ICG) and Methylene Blue (MB), have been approved for clinical use by the U.S. food and drug administration. However, these conventional planar organic dyes generally exhibit bright emissions in the solution state, while their non-radiative decay is strongly dependent on their aggregation state.
According to the exciton model of kasha, only strong face-to-face pi-pi stacking dyes, such as H-polymerization, exhibit efficient non-radiative decay, but this is not controllable. In most cases, the aggregates formed in the organic nanoparticles are randomly arranged and amorphous and thus exhibit inadequate radiative decay and non-radiative decay. Thus, they are not ideal reagents for both PAI and fluorescence imaging.
Therefore, it is necessary to develop photothermal agents that are effective for PAI/PTT.
Disclosure of Invention
The subject matter of the present application relates to a photothermal agent useful for photoacoustic imaging (PAI) and photothermal therapy (PTT) applications. According to some embodiments, the photothermal agent may comprise a small molecule organic compound having absorption in the Near Infrared (NIR) window (700-900 nm). Thus, certain useful compounds may be biocompatible Organic Nanoparticles (ONPs). The nanoparticle may exhibit intramolecular motion in the aggregated state. According to some embodiments, the photothermal agent may comprise a conjugated polymer.
The photothermal agent may be administered to a patient to locate a tumor site within the patient using photoacoustic imaging. Once the tumor site is identified, the tumor site may be irradiated with near infrared light, which when used in combination with existing compounds, may prevent or inhibit tumor growth.
In one embodiment, the photothermal agent comprises a compound having a donor-acceptor-donor structure:
D-A-D
each donor unit (D) is selected from the group consisting of:
the acceptor unit (a) is selected from the group consisting of:
wherein R is 1 Is hydrogen or an alkyl chain selected from the group consisting of straight chain C n H 2n+1 Alkyl chain and branching C n H 2n+1 Alkyl chains;
when the alkyl chain is straight, n is an integer from 4 to 12;
when the alkyl chain is branched, n is an integer from 6 to 24; and
R 2 selected from the group consisting of H, alkyl, unsaturated alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl, amino, sulfonic, alkylthio, alkoxy, alkyl-NCS, alkyl-N 3 alkyl-NH 2 And alkyl-Br.
In a further embodiment, the compound has one of the following structural formulas:
wherein R is
In one embodiment, the receptor is selected from the group consisting of:
wherein D is a donor group, and
wherein R is 1 Selected from the group consisting of:
in one embodiment, the compound has the following structural formula:
wherein R is selected from the group consisting of:
in one embodiment, the exemplary compound further comprises a poly (β -amino ester) conjugated thereto.
In another embodiment, the present subject matter relates to a photothermal agent comprising a conjugated polymer having a donor-acceptor-donor structure
D-A-D
Each donor unit (D) is selected from the group consisting of:
and is also provided with
The acceptor unit (a) is selected from the group consisting of:
wherein R is 1 Is hydrogen or an alkyl chain selected from the group consisting of straight chain C n H 2n+1 Alkyl chain and branching C n H 2n+1 Alkyl chains;
when the alkyl chain is straight, n is an integer from 4 to 12;
when the alkyl chain is branched, n is an integer from 6 to 24;
p is an integer of 2 to 1000, and
R 2 h.
Drawings
Various embodiments will now be described in detail with reference to the accompanying drawings.
FIG. 1 shows a 2TPE-NDTA 1 H NMR spectrum.
FIG. 2 shows a 2TPE-NDTA 13 C NMR spectrum.
FIG. 3 shows a high resolution mass spectrum (MALDI-TOF) of 2 TPE-NDTA.
FIG. 4 shows a 2TPE-2NDTA 1 H NMR spectrum.
FIG. 5 shows a 2TPE-2NDTA 13 C NMR spectrum.
FIG. 6 shows a mass spectrum of 2TPE-2 NDTA.
FIG. 7 shows Compound 2TPE-PDI-C 6 A kind of electronic device 1 H NMR spectrum。
FIG. 8 shows a 2TPE-PDI-C 6 A kind of electronic device 13 C NMR spectrum.
FIG. 9 shows a 2TPE-PDI-C 6 Is a high resolution mass spectrometry (MALDI-TOF).
FIG. 10 shows Compound 2TPE-PDI-C 16 In CDC l3 In (a) and (b) 1 H NMR spectrum.
FIG. 11 shows a 2TPE-PDI-C 16 In CDC l3 In (a) and (b) 13 C NMR spectrum.
FIG. 12 shows Compound 2TPE-PDI-C 16 In CDC l3 Is a high resolution mass spectrum of (a).
FIG. 13 shows the PL spectra of NDTA, 2TPE-NDTA and 2TPE-2NDTA in (a) THF solution, (b) encapsulated NPs and (c) water and film. Panel (b) shows a comparison of PL intensity of the THF solutions of NP and NDTA prepared in water. Panel (c) shows the PL intensity of the film versus that of the NDTA in THF.
Fig. 14 shows the uv-vis-nir absorption spectra of (a) NDTA (b) 2TPE-NDTA and (c) 2TPE-2NDTA in tetrahydrofuran solution, thin film and organic NP doped in water. The inset shows photographs of NDTA, 2TPE-NDTA, NP prepared by 2TPE-2NDTA in water.
FIG. 15 shows a schematic of (a) the chemical structure of a semiconducting polymer, poly (cyclopentadithiophene-alt-benzothiazole), and (b) Semiconducting Polymer Nanoparticles (SPNs).
Fig. 16 shows particle size distribution and morphology of (a) doped NDTA (b) doped 2TPE-NDTA and (c) doped 2TPE-2NDTA NPs studied by Dynamic Light Scattering (DLS) and Transmission Electron Microscopy (TEM).
Fig. 17 shows (a) the molar absorptivity of NDTA in a dilute tetrahydrofuran solution (b) the molar absorptivity of 2TPE-NDTA in a dilute tetrahydrofuran solution, and the molar absorptivity of 2TPE-2NDTA in a dilute tetrahydrofuran solution.
Fig. 18 shows (a) optimized molecular structure and (b) HOMO and LUMO orbital distributions, energy levels and bandgaps of NDTA, 2TPE-NDTA and 2TPE-2 NDTA.
FIG. 19 shows (a) a change in shaking and Contact Time (CT) at 5kHz 13 C CPMAS to specify 2TPE peak of TPE-NDTA, (b) 2TPE-NDTA 13 C relaxation measurement spectrum with relaxation time of about 5577 seconds and (C) 2TPE-NDTA and 2TPE-2NDTA 13 C relaxation measurement spectra with relaxation times of 10.5 seconds and 7.1 seconds, respectively.
FIG. 20 shows (a) a sample of the material exposed to 808nm (0.8W cm) -2 ) Infrared thermal images of various NPs in aqueous solution (100 μm based on repeat units of 2TPE-2NDTA, 2TPE-NDTA and semiconducting polymer) after laser irradiation for different times and (b) temperature changes of various NP solutions over time. The solution was irradiated with 808nm laser (0.8W cm) -2 ) Irradiated for 300s and then naturally cooled for 300s.
Fig. 21 shows (a) PA spectra of various NPs, (b) PA signal (stimulated by 680nm pulsed laser) comparisons of different agents at the same concentration of 100 μm based on repeat units of 2TPE-2NDTA, 2TPE-NDTA, MB and semiconductor polymer, (c) representative PA images of tumors of mice applied with 2TPE-2 NDTA-doped nanoparticles, and (d) PA intensity of tumors over time following intravenous injection of 2TPE-2 NDTA-doped nanoparticles. Error bars, mean ± standard deviation (n=3 mice). PA images were obtained by excitation at 730nm before (0 h) and within a specified time interval after intravenous injection of 2TPE-2NDTA doped nanoparticles (300 μm based on 2TPE-2 NDTA) into mice with xenograft 4T1 tumor.
FIG. 22 shows (a) molecular design and chemical structure of NIR12 and NIR6 of photo-acoustic guided PTT, (b) calculated HOMO and LUMO, (c) optimized ground state (S 0 ) Geometry, (d) schematic of tic state, (e) aggregated state and (f) PA imaging guided PTT of NIR12 and NIR 6. And (3) injection: r is R 1 =2-hexyldecyl, R 2 =1-hexyl.
FIG. 23 shows normalized absorption spectra in (a) tetrahydrofuran solvent, (b) lambda in different solvents for NIR12 and NIR6 em (c) relation of solvent parameters to Stokes shift, (d) relation of PL intensity to water fraction in tetrahydrofuran/water mixture, (e) relation of PL intensity to DMSO fraction in DMF/DMSO mixture, (f) PL spectrum of DSPE-PEG assembled nanoparticles, (g) powder XRD spectrum, (h) photo-thermal conversion behavior of NIR12, NIR6 and ICG NP in PBS solution of the same concentration (100. Mu.M)Is a comparison of (c).
FIG. 24 shows (a) infrared thermal imaging of NIR12 and ICG NP in PBS solution (100. Mu.M) at different times with laser irradiation at 808nm, (b) photo-thermal conversion behavior of NIR12 nanoparticles at different concentrations (5-100. Mu.M) under 808nm light irradiation, (c) photo-bleaching resistance of NIR12 and ICG nanoparticles (100. Mu.M) in five heat-cool cycles, (d) PA images of NIR12 and ICG nanoparticles after 780nm excitation at different concentrations, (e) PA amplitude versus 780nm for NIR12 and ICG nanoparticles.
FIG. 25 shows (a) NIR12 and ICG nanoparticles in PBS for various times (0.8W/cm 2 ) Post-photo and (b) I/I 0 Relationship to different illumination times, I and I 0 The maximum NIR absorption intensity of NIR12 and ICG nanoparticles in PBS solution before and after laser irradiation, respectively.
Fig. 26 shows a schematic of NIR12 nanoparticles based on the pH response properties of PAE to extend cycle time and cell uptake capacity.
Fig. 27 shows (a) cellular photoacoustic imaging, (b) photoacoustic intensity, (c) in vivo photoacoustic imaging, (d) tumor temperature, (e) tumor relative volume, and (f) mouse body weight of mice treated with PAE nanoparticles, PEG nanoparticles, or physiological saline.
FIG. 28 shows (a) tissue H & E, fluorescent TUNEL and PCNA staining of tumor sections after 16 days of treatment with different treatments and (b) tissue H & E staining of liver and spleen after 16 days of treatment with different treatments.
Detailed Description
The following definitions are provided to understand the subject matter of the present invention and to construct the appended claims.
Definition of the definition
It is to be understood that the drawings described above or below are for illustrative purposes only. The drawings are not necessarily to scale, emphasis instead generally being placed upon illustrating the principles of the teachings of the invention. The drawings are not intended to limit the scope of the invention in any way.
Throughout this application, where a composition is described as having, comprising, or including a particular component, or where a method is described as having, comprising, or including a particular method step, it is contemplated that a composition of the teachings of the present invention may also consist essentially of, or consist of, the recited component, and that a method of the teachings of the present invention may also consist essentially of, or consist of, the recited method step.
In the present application, where an element or component is referred to as being included in and/or selected from a list of enumerated elements or components, it should be understood that the element or component may be any one of the enumerated elements or components, or the element or component may be selected from the group consisting of two or more of the enumerated elements or components. Furthermore, it is to be understood that elements and/or features of the compositions, devices, or methods described herein may be combined in various ways, whether explicit or implicit, without departing from the spirit and scope of the present application.
The use of the terms "include," "contain," "have" or "possess" are generally understood to be open and non-limiting unless specifically stated otherwise.
The use of the singular in this application includes the plural (and vice versa) unless specifically stated otherwise. In addition, where the term "about" is used prior to a quantitative value, the present teachings also include the specific quantitative value itself, unless specifically stated otherwise. The term "about" as used herein, unless otherwise indicated or inferred, means that there is a + -10% change from the nominal value.
It should be understood that the order of steps or order of performing certain actions is not important so long as the present invention remains operable. Furthermore, two or more steps or actions may be performed simultaneously.
"heteroaryl" as used herein refers to an aromatic monocyclic system containing at least one ring heteroatom selected from oxygen (O), nitrogen (N), sulfur (S), silicon (Si) and selenium (Se), or a polycyclic system wherein at least one ring present in the ring system is an aromatic ring and contains at least one ring heteroatom. Polycyclic heteroaryl groups include two or more heteroaryl rings fused together and a monocyclic heteroaryl ring fused to one or more aromatic carbocyclic rings, non-aromatic carbocyclic rings, and/or non-aromatic cycloheteroalkyl rings. Heteroaryl groups as a whole may have, for example, 5 to 22 ring atoms and contain 1-5 ring heteroatoms (i.e., 5-20 membered heteroaryl groups). Heteroaryl groups may be attached to the defined chemical structure at any heteroatom or carbon atom that results in a stable structure. Typically, heteroaryl rings do not contain O-O, S-S or S-O linkages. However, one or more of the N or S atoms in the heteroaryl group may be oxidized (e.g., pyridine N-oxide, thiophene S, S-dioxide). Examples of heteroaryl groups include, for example, 5-membered monocyclic ring systems or 6-membered monocyclic ring systems and 5-6 bicyclic ring systems as shown below:
Wherein T is O, S, NH, N-alkyl, N-aryl, N- (arylalkyl) (e.g., N-benzyl), siH 2 SiH (alkyl), si (alkyl) 2 SiH (arylalkyl), si (arylalkyl) 2 Or Si (alkyl) (arylalkyl). Examples of such heteroaryl rings include pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, isothiazolyl, thiazolyl, thiadiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, quinolinyl, 2-methylquinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzotriazole, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzoxadiazolyl, benzoxazolyl, cinnolazinyl, 1H-indazolyl, 2H-indazolyl, indolizinyl, isobenzofuranyl, naphthyridinyl, phthalazinyl, pteridinyl, purinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyridinyl, furopyridinyl, thienopyridinyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, thienopyrazinyl, and the like. Other examples of heteroaryl groups include 4,5,6, 7-tetrahydroindolyl, tetrahydroquinolinyl, benzothieno-pyridyl, benzofuropyridinyl, and the like. In some embodiments, heteroaryl groups may be substituted as described herein.
"halo" or "halogen" as used herein refers to fluorine, chlorine, bromine and iodine.
As used herein, "alkyl" refers to a straight or branched saturated hydrocarbon group. Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, sec-butyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, -pentyl), hexyl, and the like. In various embodiments, the alkyl group may have 1-40 carbon atoms (i.e., C1-40 alkyl), such as 1-30 carbon atoms (i.e., C1-30 alkyl). In some embodiments, the alkyl group may have 1 to 6 carbon atoms, and may be referred to as "lower alkyl. Examples of lower alkyl groups include methyl, ethyl, propyl (e.g., n-propyl and isopropyl) and butyl (e.g., n-butyl, isobutyl, sec-butyl, tert-butyl). In some embodiments, alkyl groups may be substituted as described herein. The alkyl group is typically not substituted with another alkyl, alkenyl or alkynyl group.
"alkenyl" as used herein refers to a straight or branched chain alkyl group having one or more carbon-carbon double bonds. Examples of alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, and the like. The one or more carbon-carbon double bonds may be internal double bonds (e.g., double bonds in 2-butene) or terminal double bonds (e.g., double bonds in 1-butene). In various embodiments, alkenyl groups may have 2 to 40 carbon atoms (i.e., C2-40 alkenyl groups), for example, 2 to 20 carbon atoms (i.e., C2-20 alkenyl groups). In some embodiments, alkenyl groups may be substituted as described herein. Alkenyl is generally not substituted with another alkenyl, alkyl or alkynyl group.
As used herein, "fused ring" or "fused ring moiety" refers to a polycyclic ring system having at least two rings, wherein at least one ring is aromatic and such aromatic ring (carbocyclic or heterocyclic) has a bond in common with at least one other ring (which may be aromatic or non-aromatic and carbocyclic or heterocyclic). These polycyclic ring systems may be highly p-conjugated and optionally substituted as described herein.
As used herein, "heteroatom" refers to an atom of any element other than carbon or hydrogen and includes, for example, nitrogen, oxygen, silicon, sulfur, phosphorus, and selenium.
As used herein, "aryl" refers to an aromatic monocyclic hydrocarbon ring system or a polycyclic ring system in which two or more aromatic hydrocarbon rings are fused together (i.e., having a common bond) or at least one aromatic monocyclic hydrocarbon ring is fused to one or more cycloalkyl and/or cycloheteroalkyl rings. The aryl group can have 6-24 carbon atoms in its ring system (e.g., a C6-24 aryl group), which can include multiple fused rings. In some embodiments, the polycyclic aryl groups may have 8 to 24 carbon atoms. Any suitable ring position of the aryl group may be covalently linked to the defined chemical structure. Examples of aryl groups having only aromatic carbocycles include phenyl, 1-naphthyl (bicyclo), 2-naphthyl (bicyclo), anthryl (tricyclic), phenanthryl (tricyclic), fused-pentacenyl (pentacyclic), and the like. Examples of polycyclic ring systems in which at least one aromatic carbocyclic ring is fused to one or more cycloalkyl rings and/or cycloheteroalkyl rings include benzo derivatives of cyclopentane (i.e., indanyl, which is a 5, 6-bicyclic cycloalkyl/aromatic ring system), benzo derivatives of cyclohexane (i.e., tetrahydronaphthyl, which is a 6, 6-bicyclic cycloalkyl/aromatic ring system), benzo derivatives of imidazolines (i.e., benzimidazolinyl, which is a 5, 6-bicyclic cycloheteroalkyl/aromatic ring system), and benzo derivatives of pyran (i.e., benzopyranyl, which is a 6, 6-bicyclic cycloheteroalkyl/aromatic ring system). Other examples of aryl groups include benzodioxanyl, benzodioxolyl, chromanyl, indolinyl, and the like. In some embodiments, aryl groups may be substituted as described herein. In some embodiments, an aryl group may have one or more halogen substituents, and may be referred to as a "haloaryl. Perhaloaryl, i.e., aryl in which all hydrogen atoms are replaced with halogen atoms (e.g., -C6F 5), is included within the definition of "haloaryl". In certain embodiments, the aryl group is substituted with another aryl group and may be referred to as a biaryl group. Each aryl group in the biaryl group may be substituted as disclosed herein.
As used herein, a "donor" material refers to an organic material, e.g., an organic nanoparticle material, that has holes as the primary current or charge carrier.
As used herein, "acceptor" materials refer to organic materials, e.g., organic nanoparticle materials, that have electrons as the primary current or charge carrier.
As used herein, "photothermal agent" refers to an organic material, such as an organic nanoparticle material, that can convert optical radiation into heat and thereby provide ultrasonic emission.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the presently described subject matter belongs.
Where a range of values is provided, for example, a range of concentrations, a range of percentages, or a range of ratios, it is to be understood that each intervening value, to the tenth of the unit of the lower limit, and any other stated or intervening value in that stated range, is encompassed within the subject matter unless the context clearly dictates otherwise. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and embodiments are also included in the subject matter described, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of the limits included are also included in the subject matter described.
Throughout this application, the description of the various embodiments uses the expression "comprising. However, those skilled in the art will appreciate that in some particular instances, embodiments may alternatively be described using the expression "consisting essentially of.
For a better understanding of the teachings of the present application and in no way to limit the scope of the teachings of the present application, all numbers expressing quantities, percentages or proportions, and other values, used in the specification and claims, are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
Photothermal reagent
The subject matter of the present application is directed generally to photothermal agents, or agents capable of converting light energy into heat, thereby providing ultrasound imaging. Photothermal agents may be used for diagnostic and/or therapeutic purposes. According to some embodiments, the photothermal agents described herein may include small molecule organic compounds having absorption in the Near Infrared (NIR) interrogation window (700-900 nm). Such a compound may be an Organic Nanoparticle (ONP). In some embodiments, the photothermal agent may comprise a conjugated polymer. The photothermal agents described herein are capable of providing desirable contrast agents for photo-triggered diagnostic/therapeutic techniques, such as photo-acoustic imaging (PAI) associated with photothermal therapy (PTT).
In one embodiment, the compound is provided as a nanoparticle. In one embodiment, the compound is non-emissive in solution and in the solid state.
The compounds of the present application may include near infrared absorbing organic molecules having a donor-acceptor (D-a-D) structure and long alkyl side chains. The compounds of the application may include a molecular rotor and a large alkyl chain grafted onto the central D-a-D core to limit intermolecular interactions and enhance intramolecular movement of the aggregates. The enhanced molecular motion facilitates the formation of intramolecular charge transfer (tic) states that enhance photothermal properties by non-radiative decay of such states.
According to one embodiment, one or more polymers may be conjugated to certain compounds of the present application. In one embodiment, the compounds of the present application include poly (β -amino esters) conjugated thereto. In certain non-limiting embodiments, poly (cyclopentadithiophene-alt-benzothiazole).
In one embodiment, the photothermal agents of the application may include compounds having a donor-acceptor-donor structure:
D-A-D
each donor unit (D) is selected from the group consisting of:
the acceptor unit (a) is selected from the group consisting of:
Wherein R is 1 Is hydrogen or an alkyl chain selected from the group consisting of straight chain C n H 2n+1 Alkyl chain and branching C n H 2n+1 Alkyl chains;
when the alkyl chain is straight, n is an integer from 4 to 12;
when the alkyl chain is branched, n is an integer from 6 to 24; and
R 2 selected from the group consisting of H, alkyl, unsaturated alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl, amino, sulfonic, alkylthio, alkoxy, alkyl-NCS, alkyl-N 3 alkyl-NH 2 And alkyl-Br.
In one embodiment, R 1 C branched on the second carbon n H 2n+1 Alkyl chain, and n is 6 to 24. In another embodiment, R 1 Is straight chain C n H 2n+1 Alkyl chain, and n is 4 to 12.
In one embodiment, the compound has one of the following structural formulas:
wherein R is
These compounds may be referred to as 2TPE-NDTA and 2TPE-2NDTA, respectively.
In one embodiment, the receptor is selected from the group consisting of:
/>
wherein D is a donor group, and
wherein R is 1 Selected from the group consisting of:
in one embodiment, the compound has the following structural formula:
wherein R is selected from the group consisting of:
these compounds may be referred to as NIR12 and NIR6, respectively. In one embodiment, these compounds may further include a poly (β -amino ester) conjugated thereto, as described herein.
In another embodiment, the application relates to a photothermal agent comprising a compound having a donor-acceptor-donor structure:
D-A-D
each donor unit (D) is selected from the group consisting of:
the acceptor unit (a) is selected from the group consisting of:
wherein R is 1 Is hydrogen or an alkyl chain selected from the group consisting of straight chain C n H 2n+1 Alkyl chain and branching C n H 2n+1 Alkyl chains;
when the alkyl chain is straight, n is an integer from 4 to 12;
when the alkyl chain is branched, n is an integer from 6 to 24; and
R 2 is unsubstituted or substituted and is selected from the group consisting of H, alkyl, unsaturated alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, carboxyl, amino, sulfonic, alkylthio, alkoxy, alkyl-NCS, alkyl-N 3 alkyl-NH 2 And alkyl-Br.
In another embodiment, the subject of the application relates to a photothermal agent comprising a compound having a donor-acceptor-donor structure, each donor unit (D) being selected from the group consisting of:
and is also provided with
The acceptor unit (a) is selected from the group consisting of:
wherein R is 1 Is hydrogen or an alkyl chain selected from the group consisting of straight chain C n H 2n+1 Alkyl chain and branching C n H 2n+1 Alkyl chains;
when the alkyl chain is straight, n is an integer from 4 to 12;
When the alkyl chain is branched, n is an integer from 6 to 24; and is also provided with
R 2 H.
According to this embodiment, the photothermal agent may further comprise the poly (β -amino ester) conjugated thereon.
The compounds of the present application may include D-a-D structures having typical AIE units (compounds exhibiting aggregation-induced emission) as donor units and compounds having large pi-conjugation and strong electron withdrawing ability as acceptor units. Exemplary compounds include triphenylethylene and tetraphenylethylene derivatives as donor units, and NDI and/or PDI derivatives as acceptor units. For example, certain non-limiting embodiments of the present compounds include 2TPE-NDTA and 2TPE-2NDTA. The 2TPE-NDTA and 2TPE-2NDTA compounds include tetraphenyl ethylene (TPE). TPE is a prototype molecule with active excited state molecular motion. TPEs contain compounds with D-A or D-A-D structures that can cause distorted intramolecular charge transfer (TICT) that helps to undergo non-radiative decay with the aid of intramolecular motion. According to these embodiments, the acceptor comprises one or more naphthalimide fused 2- (1, 3-dithiol-2-ylidene) acetonitrile moieties (NDTA and 2 NDTA) that have large pi-conjugation and strong electron withdrawing capabilities. The receptor has long wavelength absorption, high molar absorptivity and strong tic effect. The long alkyl chains in the molecular backbone, when aggregated, provide steric isolation between the molecules, thereby creating the necessary space to promote free movement within the molecule. Based on this rational molecular design, 2TPE-NDTA and 2TPE-2NDTA can perform efficient intramolecular motion in solid and aggregated states within NPs, enhancing energy absorption of heat generation by enhancing non-radiative decay processes.
The 2TPE-2NDTA doped NPs exhibit superior ability to generate Photoacoustic (PA) signals compared to some established, high performance PA imaging agents, including semiconducting polymers NP and MB. As described herein, in vivo studies demonstrate that 2TPE-2 NDTA-doped NPs achieve superior performance in visualizing tumors by PA imaging in a high contrast manner.
According to some embodiments, the present compounds include a molecular rotor incorporated into a planar D-a based small molecule that both promotes molecular movement and stabilizes the dark tic state. In some embodiments, the compounds include long alkyl chains that can provide shielding units to inhibit intermolecular interactions, most importantly to maintain intramolecular rotation in the aggregate. In some embodiments, the compound comprises a low band gap benzo [1,2-c:4,5-c' ] bis ([ 1,2,5] thiadiazole) (BBTD) as acceptor, thiophene as pi conjugated unit and donor, triphenylamine (TPA) as molecular rotor and second donor, and long alkyl chain as shielding unit. We believe that the emission of AIE units is reduced by activating molecular movement in the aggregate while photothermal conversion is achieved due to the stability of dark-state tic and the limitation of fluorescence decay.
The presence of molecular rotors and long alkyl chains is important for the generation of the tic state in the aggregate. As described in detail herein, exemplary compound NIR12, having a long alkyl chain branching at the second carbon, exhibits enhanced photo-thermal properties when compared to compound NIR6, having a short linear alkyl chain, and the commercially available dye indocyanine green. Both in vitro and in vivo experiments have shown that NIR12 nanoparticles can be used as nanoagents for photoacoustic imaging guided photothermal therapy. Furthermore, charge reversal of poly (β -amino esters) causes NIR12 to accumulate specifically at tumor sites.
Recognizing tumor and preventing or inhibiting tumor growth
The compounds of the present application may be administered to a patient as contrast agents using in vivo imaging techniques, such as photoacoustic imaging, to locate a tumor site within the patient. For example, the compounds may be administered by intravenous injection. As elaborated herein, in vivo imaging studies have shown that this compound can be used as an effective probe for PAI in a high contrast manner. Once the tumor site is determined, the tumor site may be irradiated with near infrared light, which when used in combination with the compounds of the present application, may inhibit tumor growth.
In particular, in certain embodiments, the present methods relate to methods of locating a tumor in a patient, the methods comprising administering to the patient a photothermal agent as described herein; the tumor site is located using photoacoustic imaging.
In certain embodiments, the present methods relate to methods of preventing or inhibiting tumor growth in a patient comprising administering to a patient a photothermal agent as described herein; positioning a tumor site using photoacoustic imaging; when the photothermal agent is present at the tumor site, the tumor site is irradiated with light to inhibit the growth of the tumor. In some non-limiting embodiments, the light illumination may be near infrared light.
In certain embodiments, the photothermal agent is administered to the patient in Nanoparticle (NP) form when practicing the present methods.
According to some embodiments, the compounds of the invention may be co-precipitated with poly (β -amino esters) (PAEs) to extend circulation time in blood and enhance interaction with tumor cells. For example, NIR12 co-precipitated with poly (β -amino ester) (PAE) can rapidly and reversibly alter surface properties and provide effective imaging probes and tumor treatment. In general, manipulation of the tic properties using molecular rotors and alkyl chains may provide a useful platform for designing new photothermal agents.
The compounds of the application may show a rapid temperature increase at the tumor site under near infrared light irradiation, which results in heat-induced tumor suppression. For example, 2TPE-2NDTA doped nanoparticles exhibit better ability to generate photoacoustic signals than several recognized, high performance photoacoustic imaging agents (including semiconducting polymers NP and MB). As described herein, in vivo studies demonstrated that 2TPE-2NDTA doped nanoparticles have excellent performance in visualizing tumors in a high contrast manner by photoacoustic imaging.
These compounds have good photo-thermal/photo-acoustic properties, making them promising for in vivo diagnostic and therapeutic applications.
The present teachings are illustrated by the following examples.
Examples
Materials and instruments
All chemicals are commercially available without further purificationIs converted to a chemical form and is directly used. Deuterated solvent is available from J&K。TEP-B(OH) 2 Available from AIEgen Biotech limited. In at least some cases, the solvent used for the chemical reaction is distilled prior to use. Sodium is used as a drying agent, benzophenone is used as an indicator, and Tetrahydrofuran (THF) is dried by a distillation method. Benzo [1,2-c:4,5-c ]']Bis ([ 1,2, 5)]Thiadiazoles) were purchased from deluge Long Guang electric materials technology (Derthon Optoelectronic Materials Science Technology) limited. Poly (beta-amino ester) (PAE) was synthesized according to previous reports (chem. Commun.,2015,51,14985). All air and moisture sensitive reactions were carried out in flame-dried glassware under nitrogen atmosphere.
To characterize the 2TPE-NDTA and 2TPE-2NDTA derivatives, deuterated solvents were used as specific markers (lock) and tetramethylsilane (TMS; δ=0) was used as internal standard for recording on a Bruker ARX 400NMR spectrometer 1 H and 13 c NMR spectrum. High Resolution Mass Spectrometry (HRMS) was obtained on a Finnigan MAT TSQ 7000 mass spectrometer system operating in MALDI-TOF mode. The absorption spectrum was measured on a JASCO V-570 ultraviolet-visible-near infrared spectrophotometer. Steady state Photoluminescence (PL) spectra were recorded on an edinburgh FLS980 fluorescence spectrophotometer. Quantum yield is determined byAnd (5) measuring by an integrating sphere. Particle size analysis was performed using a ZetaPlus potentiometric analyzer (Brookhaven, zettaplus). Transmission Electron Microscopy (TEM) studies were performed on a JEOL-6390 instrument.
Femtosecond time resolved fluorescence (fs-TRF) experiments. The femtosecond time resolved fluorescence (fs-TRF) assay was performed on the same setup as fs-TA. The output 800nm laser pulse (200 mw) was used as a gate pulse, and the 400nm laser pulse (10 mw) (second harmonic) was used as a pump laser. Sample fluorescence is excited by a pump laser and then focused into a nonlinear crystal (BBO) mixed with the pulse of the AND gate, and a sum frequency signal is generated. Broadband fluorescence spectra were obtained by changing the crystal angle and detected with an air-cooled CCD. In this experiment, compound ND in THF solution was excited by 400nm pump light (800 nm-based second harmonic of the regenerative amplifier). Throughout the data collection, 1ml of the solution was studied in a cuvette of 2mm path length, with an absorbance at 400nm of 0.5.
To characterize NIR-12, NIR-6 and intermediate structures, recordings were made at room temperature on a Unity-400 NMR spectrometer 1 H and 13 c NMR spectra, using CDC l3 As solvent and with reference to Tetramethylsilane (TMS). UV-vis-NIR absorption spectroscopy was performed using a PerkinElmer Lambda 365 spectrophotometer. Mass Spectra (MS) were determined with a GCT professional CAB048 mass spectrometer in MALDI-TOF mode. Photoluminescence (PL) spectra were performed on a Horiba Fluorolog-3 spectrofluorimeter. Dynamic Light Scattering (DLS) was measured on a 90+ particle size analyzer. Transmission Electron Microscope (TEM) images were obtained from a JEM-2010F transmission electron microscope at an acceleration voltage of 200 kV. Laser confocal scanning microscope images were collected on a Zeiss laser scanning confocal microscope (LSM 7 DUO) and analyzed using ZEN 2009 software (Carl Zeiss).
For NIR-12, NIR-6 tests, all animal studies were conducted following guidelines set by the Tianjin laboratory animal use and Care Committee, all procedures approved by the university of south China animal ethics Committee. Female BALB/c mice of six weeks of age were purchased from Beijing Life river laboratory animal technology Co., ltd (Beijing, china). To establish a mouse model with xenograft 4T1 tumor-bearing, murine 4T1 breast cancer cells (1X 10) suspended in 50. Mu.L of RPMI-1640 medium 6 ) The right axillary space of the mice was injected subcutaneously. After about 10 days, a tumor volume of about 80-120mm was then applied 3 Is a mouse of (2).
Example 1
Femtosecond transient absorption (fs-TA) experiment
fs-TA experiments were completed using the experimental setup and methods detailed previously, only a brief description of which is provided herein. fs-TA measurements were performed using a 1000 hz femtosecond regenerative amplified titanium sapphire laser system (Maitai) whose amplifier emitted 120fs laser pulses from an oscillating laser system. The laser probe pulse was obtained by generating a white light continuum spectrum (430-750 nm) in the sapphire crystal using about 5% of the amplified 800nm laser pulse, and then splitting the probe beam into two parts, and then passing through the sample. One probe laser beam passes through the sample and the other probe laser beam enters a reference spectrometer to monitor fluctuations in probe laser beam intensity. In the experiments of the present application, the compounds in THF solution were excited by 400nm pump light (second harmonic of 800nm fundamental from the regenerative amplifier). Throughout the data collection, 1ml of the solution was studied in a cuvette of 2mm path length, with an absorbance at 400nm of 0.5.
Example 2
Solid state NMR experiments
NMR experiments were performed on a Varian Infinitplus-400wide-bore (89 mm) NMR spectrometer at room temperature (25 ℃ C.) and at a frequency of 399.72 and 100.52MHz, respectively 1 H and 13 nuclear magnetic resonance experiments of C. A sample having a volume of 52. Mu.L was placed in a zirconia PENCILE rotor using a T3 probe having a rotor diameter of 4 mm. The 90 pulse length is about 3 mus, corresponding to a Radio Frequency (RF) magnetic field strength of 83 kHz. The magic angle rotation at 5kHz is automatically controlled by a speed controller, and the rotation of the side bands is restrained by a side band total restraint (TOSS) sequence before signal acquisition. 13 Chemical shift of C with external HMB (hexamethylbenzene, 17.3ppm CH 3 ) Related to the following. 1 H- 13 The C-polarized transmission uses cross-section cross-polarization (CP) with CP contact times of 0.1ms and 1ms, respectively.
Example 3
Nanoparticle preparation
NDTA, 2TPE-NDTA, or 2TPE-2NDTA (1 mg) was dissolved in THF solution (1 mL). Then adding DSPE-PEG 2000 (2 mg) was dissolved in a THF solution. After this, the THF solution obtained was added to water (9 ml) and sonicated with a microprobe sonicator (XL 2000, misonix Incorporated, NY) and the mixture was then continued to sonicate for 60s. THF in the mixture was evaporated in a fume hood by stirring for 12 hours. The resulting NP suspension was purified by ultrafiltration (100 kDa cut-off) at 3000 Xg for 0.5 hours and then filtered using a 0.2 μm syringe-driven filter.
Example 4
Cell culture
Mouse 4T1 breast cancer cells were purchased from American Type Culture Collection (ATCC). 4T1 cancer cells were each at 37℃and 5% CO 2 Is cultured in Dulbecco's Modified Eagle's Medium (DMEM) containing 10% Fetal Bovine Serum (FBS) and 1% penicillin-streptomycin. Prior to the experiment, the cells were pre-cultured until the cells reached confluence.
Example 5
Animal and tumor-bearing mouse model
All animal studies were conducted in accordance with guidelines set by the Tianjin laboratory animal use and care committee, and all project protocols were approved by the university of south opening animal ethics committee. Female BALB/c mice (6 weeks old) were purchased from the laboratory animal center of the national academy of sciences of military medicine (Beijing, china). Xenograft 4T1 tumor-bearing mouse models were used in this study. To build animal models, it will contain 1X 10 6 mu.L of cell culture medium from murine 4T1 breast cancer cells was injected subcutaneously into the right armpit space of BALB/c mice. After about 10 days, a tumor volume of about 80-120mm is then applied 3 Is a mouse of (2).
Example 6
Photoacoustic imaging
The 4T1 tumor-bearing mice were first anesthetized with 2% isoflurane in oxygen and then 2TPE-2 NDTA-doped NP (300 μm based on 2TPE-2 NDTA) was intravenously injected via the tail vein with a microinjector (n=3 mice). In vivo tumor PA imaging was performed by a commercial small animal selective acoustic tomography system (MOST, iTheraMedical, germany). PA images were acquired at 730nm before and 4, 8, 16, 24h after administration.
The feasibility of implementing advanced practical applications of the concept MEPT was studied. PA imaging of MEPT NP was performed in vivo because PA effects depend on photothermal properties. PA performance of the reagents comprising 2TPE-2 NDTA-doped NP, 2 TPE-NDTA-doped NP, SPN and MB were measured and compared, respectively, prior to in vivo animal experiments. As shown in fig. 21A, their PA spectra in the 680-980nm region indicate that the maximum PA amplitude of the 2 TPE-NDTA-doped NPs, SPNs and MBs is at 680nm, while the 2TPE-2 NDTA-doped NPs have PA peaks at 735 nm. The PA signals of the different PA reagents were then compared under a pulsed laser at 680nm (fig. 21B). Under the same conditions, the PA intensity of the 2 TPE-NDTA-doped NPs is much higher than SPNs and MBs, while the signal of the 2TPE-2 NDTA-doped NPs is even higher than the 2 TPE-NDTA-doped NPs. Interestingly, 2TPE-2 NDTA-doped NPs had the highest PA intensity at 680nm, although 680nm was not the optimal excitation wavelength. The PA intensity of the 2TPE-2 NDTA-doped NPs was 1.6 and 2.1 times higher than SPN and MB, respectively. SPN is reported to be an excellent PA contrast agent with PA signaling even better than single-walled carbon nanotubes. Furthermore, MB is a star-shaped molecule for PA imaging. The comparative data shows that MEPT is an ideal platform for the development of advanced PA imaging probes, while active intramolecular motion in NP determines biomedical function and effectiveness.
In vivo PA imaging was then performed before and after administration of 2TPE-2 NDTA-doped NP to xenograft 4T1 tumor bearing mice via the tail vein. Figure 21C shows the time dependence of PA tumor imaging in mice injected with 2TPE-2 NDTA-doped NP. A strong PA signal was clearly observed at the tumor site 4h after injection of 2TPE-2 NDTA-doped NP compared to PA images before NP injection (0 h). PA intensity at 4h was 2.7 times higher than at 0h (fig. 26D). Such high contrast PA tumor imaging benefits not only from the excellent EPR effect of NP, but also from the significant PA effect of 2TPE-2NDTA (fig. 21A-21B). The superiority and importance of our design is highlighted by the excellent passive tumor targeting in EPR effects, enabling MEPT to occur in NP. The living animal experiment result shows that the MEPT NP can be used as an effective PA imaging probe for in vivo tumor diagnosis.
Example 7
6 16 Synthesis and characterization of 2TPE-NDTA, 2TPE-2NDTA, 2TPE-PDI-C and 2TPE-PDI-C
Typical reaction schemes for preparing 2TPE-NDTA and 2TPE-2NDTA are provided below:
synthesis of Compounds 2, 3 and 4. Under atmospheric conditions, the compounds NDTA (117 mg,0.1 mmol) and Br were combined 2 (160 mg,0.11 mmol) was dissolved in chloroform (8 ml) and reacted at room temperature for 0.5h. The reaction was terminated by adding water, extracted with methylene chloride, and then purified by silica gel column chromatography to obtain 73mg of compound 2 and 46mg of compound 3, respectively. Yield of compound 2: 55%, yield of compound 3: 37%.
Compound 2. 1 H NMR(400MHz,CDCl 3 ,25℃),δ(ppm):4.17(s,4H),2.04(br,2H),1.38-1.22(br,80H),0.87-0.84(m,12H). 13 C NMR(100MHz,CDCl 3 ,25℃),δ(ppm):162.0,161.9,161.6,147.5,147.4,145.4,145.2,125.0,124.7,124.5,116.5,116.1,114.1,71.2,46.2,36.4,32.0,31.530.1,29.7,29.4,26.3,22.7,14.1。
Compound 3. 1 H NMR(400MHz,CDCl 3 ,25℃),δ(ppm):5.67(s,1H),4.15(s,4H)1.99(br,2H),1.36-1.21(br,80H),0.88-0.84(m,12H). 13 C NMR(100MHz,CDCl 3 ,25℃),δ(ppm):164.5,162.3,162.1,161.8,147.5,147.4,147.3,147.2,146.9,146.8,144.7,125.02,124.8,124.7,116.6,116.2,115.6,114.3,85.8,71.2,46.2,46.1,36.6,36.5,32.0,31.6,31.5,30.2,30.1,29.8,29.7,29.5,26.5,26.4,22.8,14.2。
Synthesis of Compound 4. At N 2 Pd (PhCN) was added to a solution of compound 3 (200 mg,0.16 mmol) dissolved in anhydrous DMF (15 mL) and DMSO (3 mL) under an atmosphere 2 Cl 2 (3.1mg,0.008mmol)、AgNO 3 (81.6 mg,0.48 mmol) and KF (27.8 mg,0.48 mmol). At 120℃at N 2 The reaction mixture was stirred under an atmosphere for 8h. Cooled to room temperature, saturated NH was added to the mixture 4 Cl (aq), the precipitated product was filtered and collected. The crude product was purified by column chromatography (Hex/dcm=2/3) to give pure compound 4 (159 mg) in 80% yield. MS (MALDI-TOF): M/z: [ M ]]+C 136 H 196 Br 2 N 8 O 8 S 8 Is calculated by the following steps: 2487.4; actual measurement value: 2487.3. elemental analysis, calculated: 65.67 percent of C, 7.94 percent of H and 4.50 percent of N; actual measurement value: 65.39C％,H:7.82％,N:4.31％.
Synthesis of 2 TPE-NDTA. At N 2 To compound 2 (150 mg,0.11 mmol), TPE-B (OH) under protection 2 (213 mg,0.57 mmol) and K 2 CO 3 (125 mg,0.91 mmol) in THF (10 mL) and H 2 Pd (PPh) was added to a solution of O (4 mL) 3 ) 4 (13.1 mg,0.01 mmol). At N 2 The mixture was stirred overnight at 100℃under an atmosphere, after which it was stirred with CH 2 Cl 2 The mixture was extracted and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography to give pure 2TPE-NDTA (140 mg) in 70% yield. Melting point: 269-270 ℃. FIG. 1 shows a 2TPE-NDTA 1 H NMR spectrum. FIG. 2 shows a 2TPE-NDTA 13 C NMR spectrum. FIG. 3 shows a high resolution mass spectrum (MALDI-TOF) of 2 TPE-NDTA.
1 H NMR(400MHz,CDCl 3 ,25℃),δ(ppm):7.43-7.41(d,4H),7.18-7.17(m,36H),7.14-7.07(m,20H),4.18(s,2H),4.16(s,2H),2.03(br,2H),1.37-1.21(br,80H),0.88-0.83(m,12H). 13 C NMR(100MHz,CDCl 3 ,25℃),δ(ppm):162.3,162.2,157.2,147.4,147.3,146.0,145.9,145.1,143.5,143.3,143.2,142.6,139.9,132.4,131.6,131.5,131.4,131.0,128.1,128.0,127.8,127.1,126.9,126.8,126.7,115.8,115.5,101.7,46.1,36.4,32.0,31.5,30.2,29.8,29.7,29.5,26.5,26.4,22.8,14.2.HRMS(MALDI-TOF):m/z:[M]+C 120 H 136 N 4 O 4 S 4 Is calculated by the following steps: 1824.9444; actual measurement value: 1824.9493.
synthesis of 2TPE-2 NDTA. At N 2 Compound 4 (150 mg,0.06 mmol), TPE-B (OH) was reacted under atmospheric conditions 2 (113mg,0.3mmol)、K 2 CO 3 (66 mg,0.48 mmol) and Pd (PPh) 3 ) 4 (7 mg, 0.006mmol) in THF (10 mL) and deoxygenated H 2 O (3 mL). At N 2 The mixture was stirred overnight at 100 ℃ under an atmosphere. After cooling to room temperature, the mixture was cooled to room temperature with CH 2 Cl 2 The mixture was extracted and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography to give pure 2TPE-2NDTA (79 mg), yield: 44%. Melting point: 299.2-301.2 ℃. FIG. 4 shows a 2TPE-2NDTA 1 H NMR spectrum. FIG. 5 shows a 2TPE-2NDTA 13 C NMR spectrum. FIG. 6 shows a mass spectrum of 2TPE-2 NDTA.
1 H NMR(400MHz,CDCl 3 ,25℃),δ(ppm):7.46-7.43(m,4H),7.18-7.16(m,14H),7.14-7.07(m,20H),4.24(s,4H),4.15(s,4H),2.02(br,4H),1.24-1.18(br,H),0.88-0.83(m,24H). 13 C NMR(100MHz,CDCl 3 ,25℃),δ(ppm):162.3,162.2,157.2,147.4,147.3,146.0,145.9,145.1,143.5,143.3,143.2,142.6,139.9,132.4,131.6,131.5,131.4,131.0,128.1,128.0,127.8,127.1,126.9,126.8,126.7,115.8,115.5,101.7,46.1,36.4,32.0,31.5,30.2,29.8,29.7,29.5,26.5,26.4,22.8,14.2.MS(MALDI-TOF):m/z:[M]+C 188 H 234 N 8 O 8 S 8 Is calculated by the following steps: 2990.4; actual measurement value: 2990.2.
2TPE-PDI-C 6 is a synthesis of (a). At N 2 2TPE-PDI-C under atmosphere 6 (143mg,0.2mmol)、TPE-B(OH) 2 (188mg,0.5mmol)、K 2 CO 3 (221 mg,1.6 mmol) and Pd (PPh) 3 ) 4 A mixture of (23 mg, 0.006mmol) in THF (10 mL) and deoxygenated H 2 O (3 mL). At 100 ℃ under N 2 The mixture was stirred overnight under an atmosphere. After cooling to room temperature, the mixture was cooled to room temperature with CH 2 Cl 2 The mixture was extracted and the organic solvent was removed under reduced pressure. Purifying the crude product by column chromatography to obtain pure 2TPE-PDI-C 6 (160 mg), yield: 66%. FIG. 7 shows Compound 2TPE-PDI-C 6 A kind of electronic device 1 H NMR spectrum. FIG. 8 shows a 2TPE-PDI-C 6 A kind of electronic device 13 C NMR spectrum. FIG. 9 shows a 2TPE-PDI-C 6 High resolution mass spectrometry (MALDI-TOF).
1 H NMR(400MHz,CDCl 3 ,25℃),δ(ppm):8.52(s,2H),8.17-8.15(d,J＝8Hz,2H),7.80-7.78(d,J＝8Hz,2H),7.19-7.07(m,H),5.06-5.00(br,2H),2.61-2.53(m,4H),1.93-1.90(m,4H),1.77-1.74(m,6H),1.50-1.46(m,4H),1.39-1.33(m,2H). 13 C NMR(100MHz,CDCl 3 ,25℃),δ(ppm):144.5,143.6,143.4,143.3,142.0,140.7,140.1,135.0,134.4,133.1,132.1,131.4,131.3,129.9,129.0,128.4,128.0,127.9,127.7,127.5,127.0,126.8,126.7,122.6,122.2,54.0,29.1,26.6,25.5.HRMS(MALDI-TOF):m/z:[M]+C 88 H 66 N 2 O 4 Is calculated by the following steps: 1214.5023; actual measurement value: 1214.5033.
2TPE-PDI-C 16 is a synthesis of (a). At N 2 2TPE-PDI-C under atmosphere 6 (143mg,0.2mmol)、TPE-B(OH) 2 (188mg,0.5mmol)、K 2 CO 3 (221 mg,1.6 mmol) and Pd (PPh) 3 ) 4 A mixture of (23 mg, 0.006mmol) in THF (10 mL) and deoxygenated H 2 O (3 mL). At 100 ℃ under N 2 The mixture was stirred overnight under an atmosphere. After cooling to room temperature, the mixture was cooled to room temperature with CH 2 Cl 2 The mixture was extracted and the organic solvent was removed under reduced pressure. Purifying the crude product by column chromatography to obtain pure 2TPE-PDI-C 16 (160 mg), yield: 66%. FIG. 10 shows Compound 2TPE-PDI-C 16 In CDCl 3 In (a) and (b) 1 H NMR spectrum. FIG. 11 shows a 2TPE-PDI-C 16 In CDCl 3 In (a) and (b) 13 C NMR spectrum. FIG. 12 shows Compound 2TPE-PDI-C 16 In CDCl 3 Is a high resolution mass spectrum of (a).
1 H NMR(400MHz,CDCl 3 ,25℃),δ(ppm):8.47(s,1H),8.46(s,1H),8.03-8.01(d,J＝8Hz,2H),7.61-7.59(d,J＝8Hz,2H),7.30-7.29(br,6H),7.20-7.10(m,32H),4.16-4.15(br,4H),1.99(br,2H),1.26(m,50H),0.85-0.82(m,12H). 13 C NMR(100MHz,CDCl 3 ,25℃),δ(ppm):163.7,163.5,144.6,143.7,143.4,143.2,142.0,140.7,140.0,135.0,134.3,133.2,132.0,131.3,129.9,128.9,128.8,128.3,128.1,127.9,127.8,127.3,127.1,126.8,126.7,122.0,121.6,44.7,36.7,31.9,31.8,30.1,29.8,29.6,29.3,26.6,22.7,14.1.HRMS(MALDI-TOF):m/z:[M]+C 108 H 110 N 2 O 4 Is calculated by the following steps: 1498.8466; actual measurement value: 1498.8438.
example 8
Photophysical Properties
The optical properties of 2TPE-NDTA and 2TPE-2NDTA were characterized using Photoluminescence (PL) and ultraviolet-visible-near infrared spectra and compared to NDTA (FIGS. 13A-13C and 14A-14C). To evaluate the optical properties of the aggregate state, nano-precipitation was usedBy precipitation, 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [ methoxy- (polyethylene glycol) -2000 ](DSPE-PEG 2000 ) As an encapsulation matrix, these molecules were formulated into water-soluble NPs (fig. 15A-15B). The average diameters of the resulting NDTA-doped, 2 TPE-NDTA-doped and 2TPE-2 NDTA-doped NPs were about 125nm, 152nm and 156nm, respectively (FIGS. 16A-16C). As shown in fig. 13A, NDTA brightly emits light around 630nm in dilute tetrahydrofuran solution, however its NP and thin film show a substantial decrease in PL intensity but a large red shift of the emission peak (about 810 nm) (fig. 13B and 13C), indicating that aggregation of NDTA in the aggregated state leads to quenching (ACQ) and J-aggregation characteristics. This is reasonable because the large pi-conjugated structure and planar structure of NDTA favors strong pi-pi stacking. However, after coupling with TPE, neither dilute THF solution nor aggregates of 2TPE-NDTA and 2TPE-2NDTA (NPs and thin films) emitted, indicating that exciton relaxation of 2TPE-NDTA and 2TPE-2NDTA dominates the non-radiative relaxation process even in the solid state. This is in contrast to typical AIE molecular designs, where TPEs are typically introduced to convert ACQ molecules to AIE molecules.
In addition, the molar absorptivity of 2TPE-NDTA (50600) and 2TPE-2NDTA (67800) were comparable to NDTA (67822), showing their excellent light capturing ability (FIGS. 17A-17B). From solution to aggregates, the absorption profile and maximum peak of NDTA exhibit a large red shift, supporting its J-aggregate stacking mode. The absorption profile of 2TPE-NDTA was broadened compared to NDTA, with a slight change in the absorption maximum after aggregation, indicating that the introduction of TPE impeded the strong pi-pi accumulation of 2 TPE-NDTA. The absorption characteristics of 2TPE-2NDTA in solution were substantially identical to those of 2TPE-NDTA, indicating that 2TPE-2NDTA and 2TPE-NDTA have similar conjugation in solution. This is probably due to the twisted structure of 2NDTA, which impedes conjugation of the whole molecule. However, after aggregation, the molecular planarity of the 2TPE-2NDTA is significantly improved, resulting in a large red shift in the absorption spectrum. It is notable that the absorption range of 2TPE-2 NDTA-doped NPs can be extended to 750-880nm, and the absorption intensity at 808nm wavelength is stronger, and the absorption intensity is well matched with the excitation wavelength of a commercial near infrared laser source. These results further demonstrate that the compounds of the present application can play a role in PA imaging and photothermal applications.
Example 9
Theoretical calculation
The ground state (S) at the level of B3LYP/6-31G (d, p) was studied 0 ) To decrypt the change in optical properties of the molecule under study (fig. 18A-18B). NDTA exhibits a planar structure with the largest coefficients in the Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO) distributed along the entire pi skeleton and overlapping well with each other, which contributes to its emission in solution. However, 2TPE-NDTA exhibits a dumbbell-like molecular conformation due to the distorted structure of TPE, which is disadvantageous for strong intermolecular pi-pi stacking. In addition, according to the ICT effect, the HOMO of 2TPE-NDTA is distributed mainly over the TPE portion, while its LUMO is distributed over the NDTA portion. 2TPE-2NDTA shows an even more distorted conformation. In addition to the twisted TPE portion, the central acceptor unit of 2NDTA is also highly twisted at a dihedral angle of 120 °. The HOMO electron density distribution of 2TPE-2NDTA is located on one of the TPE parts, while its LUMO is distributed on the 2NDTA part, indicating ICT effects. The twisted structure and ICT effect of 2TPE-NDTA and 2TPE-2NDTA favors active movement within the molecule because they not only block pi-pi interactions between molecules, thereby promoting spatial isolation of molecules, but also enhance the tic effect, ultimately making non-radiative relaxation contributing excitons.
Example 10
Solid State Nuclear Magnetic Resonance (SSNMR)
Molecular motion behavior of 2TPE-NDTA and 2TPE-2NDTA in the solid state was studied using Solid State Nuclear Magnetic Resonance (SSNMR) (FIGS. 19A-19C). Since 2TPE-NDTA and 2TPE-2NDTA have no other aromatic hydrogen atoms except TPE, the process is carried out by 13 CCPMAS NMR spectrum allows easy identification of TPE parts 13 C signal and detect its intramolecular movement behavior 33 . As shown in fig. 19A, use is made of 13 C CPMAS NMR spectra were assigned to the TPE peak of 2TPE-NDTA at 5kHz as a function of shaking and Contact Time (CT). Then, record and plot the TPE part in 13 Relaxation of the C signal over time to provideRelaxation times of TPE fractions to assess the activity of intramolecular movements. Single TPE is a typical AIEgen with strong emission due to the inhibition of intramolecular motion. In fact, by 13 C CPMAS NMR the individual TPE molecules show a long relaxation time of about 5577 seconds in the solid state, demonstrating that their intramolecular movement is hindered. In contrast, the relaxation time of the TPE portion in 2TPE-NDTA was as short as 10.5s, indicating enhanced intramolecular motion. Likewise, the relaxation time of 2TPE-2NDTA is even shorter, indicating that the molecular motion of its TPE portion is more active. Notably, the relaxation time of the alkyl chain portion is shorter than that of the TPE portion, indicating that its flow characteristics favor molecular movement of the TPE portion. These data confirm that there is still effective intramolecular movement in both 2TPE-NDTA and 2TPE-2NDTA, even in the solid state.
After proving that intramolecular motion is the main cause of non-luminescence of the aggregated 2TPE-NDTA and 2TPE-2NDTA, long alkyl chains in these molecular backbones may play a decisive role in intermolecular steric isolation, thus creating some space allowing intramolecular free motion in NP and solid state. To elucidate the role of the long alkyl side chains, attempts to synthesize 2TPE-NDTA and 2TPE-2NDTA with shorter alkyl side chains have been unsuccessful. This attempt was unsuccessful due to solubility problems. Thus, analogs were synthesized to confirm this conjecture. Two TPE-substituted Perylene Diimides (PDIs) 2TPE-PDI-C with different alkyl side chain lengths were synthesized and characterized 6 And 2TPE-PDI-C 16 。2TPE-PDI-C 6 And 2TPE-PDI-C 16 The synthesis of the derivatives is shown below.
As expected, as the alkane chain length increases from cyclohexyl to 2-hexyloctyl, due to the solid state of 2TPE-PDI-C 16 Is more active in intramolecular movement, 2TPE-PDI-C in the film 16 (6%) Quantum yield ratio 2TPE-PDI-C 6 (17%) was significantly reduced. To confirm whether this hypothesis can be extended to other systems, triPE-3PDI was synthesized, reported withSemiconductors with different side chains and strong red emission were compared for their optical properties. The results show that the quantum yield (6%) of the TriPE-3PDI with the longer alkyl chain of 2-hexyl octyl was much lower in the film than the TriPE-3PDI with the shorter alkyl chain of 2-ethylhexyl (30%). Thus, the incorporation of long alkyl chains in the molecular rotor backbone is a popular and effective strategy to promote intramolecular movement and non-radiative relaxation of excitons in an aggregate. Since it has been determined that the photophysical mechanisms of fluorescence and photothermal show opposite properties, the absorbed light energy may reasonably be prone to heat generation with concomitant reduction in fluorescence.
Example 11
Photo-thermal conversion property
The photothermal conversion properties of 2 TPE-NDTA-doped and 2TPE-2 NDTA-doped NPs in water were investigated, as practical biomedical applications need to work in aqueous media. By DSPE-PEG 2000 As a positive control (fig. 15A-15B), a Semiconducting Polymer NP (SPN) prepared for a matrix and formulated with poly (cyclopentadithiophene-alt-benzothiazole), which was reported to be a high performance photothermal agent. When irradiated with 808nm laser (0.8W cm) -2 ) The aqueous solution temperature of the three NPs increased with time, reaching a maximum at 300s (FIGS. 25A-25B). As shown in fig. 20A-20B, the photothermal temperatures plateau for the 2TPE-2 NDTA-doped NP and the 2 TPE-NDTA-doped NP and SPN were 81.4 ℃, 69.6 ℃ and 57.5 ℃, respectively. According to literature, the photo-thermal conversion efficiency of SPN is as high as 27.5%. The photothermal conversion efficiencies of the 2TPE-2 NDTA-doped NP and the 2 TPE-NDTA-doped NP were as high as 54.9% and 43.0%, respectively, using the same calculation method, and were considered to be ultra high of the currently available photothermal agents. This excellent photo-thermal behavior can be attributed to the active movement within the molecule, which absorbs the absorbed light energy to generate heat. The results indicate that active intramolecular motion in NP is a highly efficient method of enhancing photothermal performance.
Example 12
Preparation of NIR12-PEG, NIR12-PAE nanoparticles
Will contain 1mg of NIR12 compound and 2mg of 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [ methoxy- (polyethylene glycol) -2000 (DSPE-PEG) 2000 ) To a solution of 10mL of deionized water in 1mL of THF. After this step, the sample was sonicated for 2 minutes with a microtip probe sonicator (XL 2000, misonix Incorporated, NY). The residual THF solvent was evaporated by vigorously stirring the suspension overnight in a fume hood to give a colloidal solution and used directly.
Will contain 1mg of NIR12 compound, 1mg of DSPE-PEG 2000 And 1mg of poly (β -amino ester) (PAE) in 1mL THF was poured into 10mL deionized water. After this step, the sample was sonicated for 2 minutes with a microtip probe sonicator (XL 2000, misonix Incorporated, NY). The residual THF solvent was evaporated by vigorously stirring the suspension overnight in a fume hood to give a colloidal solution and used directly (fig. 26).
Example 13
Photo-thermal stability study and photo-stability Properties (NIR 12-PEG NP and ICG NP)
For photo-thermal stability studies, a laser (0.8W/cm) 2 ) A PBS solution (pH 7.4) of NIR12-PEG NP and ICG NP was irradiated and the absorbance spectra were measured at different time points (FIGS. 23A-23H). For the anti-photobleaching study, the temperature of the sample solution was recorded in five cycles of the heating and cooling process. In one heating-cooling cycle, the NIR laser first irradiates the sample for 5 minutes to reach steady state, then the laser is removed, and then the sample is naturally cooled to ambient temperature within 6 minutes (FIGS. 24A-24E).
A PBS solution (pH 7.4) of NIR12-PEG NP and ICG NP was continuously exposed to 808nm NIR laser (0.8W/cm) 2 ) 5 minutes. The temperature was measured every 20 seconds and stopped until the temperature reached almost plateau. Corresponding infrared thermal images of the sample tubes were also recorded (fig. 25A-25B).
Example 14
In vivo photoacoustic imaging and in vivo photothermal therapy
Photoacoustic (PA) signals or images were acquired on a commercially available small animal photoacoustic tomography system (MOST, iTheraMedical, germany). Xenograft 4T1 tumor-bearing mice were anesthetized with 2% isoflurane-containing oxygen, and then NIR12-PAE and NIR12-PEG NP (150 μl,600 μΜ based on NIR 12) were injected into the tumor-bearing mice via tail vein using a microinjector (n=3). PA images were then acquired at 700nm at specified time intervals before administration and after NPs injection. Fig. 27A shows photoacoustic imaging in a cell. Fig. 27B is a graph showing photoacoustic intensities. Fig. 27C shows photoacoustic imaging in a living mouse. Fig. 27D is a graph depicting intratumoral temperature. Fig. 27E is a graph showing tumor volumes. Fig. 27F is a graph showing body weight of mice treated with PAE nanoparticles, PEG nanoparticles, or saline.
Xenograft 4T1 tumor-bearing mice were randomly divided into 6 groups (n=6 per group), named "saline only", "saline + laser", "NIR12-PEG NP + laser", "NIR12-PAE NP" and "NIR12-PAE NP + laser", respectively. On day 0, for the "saline only", "NIR12-PEG NP" and "NIR12-PAE NP" groups, saline, 150 μLNIR12-PEG NP and NIR12-PAE NP (600 μM based on NIR 12) were injected into 4T1 tumor-bearing mice via tail vein, respectively, without subsequent laser irradiation. For the "saline+laser", "NIR12-PEG NP+laser", and "NIR12-PAE NP+laser" groups, after intravenous saline, NIR12-PEG NP, and NIR12-PAE NP (150. Mu.L, 600. Mu.M, NIR 12-based) were each continued for 7 hours, followed by laser at 808nm (0.5 mW/cm) 2 ) Tumors of each group of mice were irradiated continuously for 5 minutes. At the same time, the temperature change of the tumor was recorded by a thermal infrared imager (Fluke Shanghai inc.) every 10 seconds. Tumor volumes and mouse weights were measured every other day for 16 days after various treatments. Tumor volumes were measured by calipers and calculated as follows: volume= (tumor length) × (tumor width) 2 /2. Calculated as V/V relative to tumor volume O (V O Is the initial tumor volume).
Example 15
Histological study
Sixteen days after photo-thermal treatment, the six groups of mice were sacrificed. Liver, spleen and tumor were excised, fixed in 4% formalin solution and cut to a thickness of 5 μm. After conventional H & E staining, the sections were examined with a digital microscope (Leica qwi in). Fluorescent Proliferating Cell Nuclear Antigen (PCNA) staining was performed following common immunohistochemical procedures. Fluorescent terminal deoxynucleotidyl transferase dUTP notch end labeling (TUNEL) staining was performed according to the instruction manual of the deaden fluorescent TUNEL system kit (Promega, usa). Nuclei were stained with a fixative solution containing "4', 6-diamidino-2-phenylindole (DAPI) (Dapi-fluoro-G, southern Biotech, UK) (FIGS. 28A-28B).
Example 16
Cell culture and cell uptake
Dulbecco's Modified Eagle's Medium (DMEM) containing 10% Fetal Bovine Serum (FBS) and 1% penicillin-streptomycin, respectively, in a 37% humid environment (5% CO in 2 ) Murine 4T1 breast cancer cells were cultured. Prior to the experiment, cells were pre-cultured until confluence was reached.
To intuitively investigate the cellular uptake of NIR12-PEG NP and NIR12-PAE NP, aggregation-induced emission (AIEgen) was incorporated into the core of the NP with NIR12 molecules in a 1:1 ratio, thereby rendering the NP fluorescent. Murine 4T1 breast cancer cells were treated at 1X 10 5 The density of cells was seeded in a confocal imaging chamber. After 24 hours incubation, the medium of each well was replaced with 1mL of fresh medium with different pH values (pH 7.4 and 6.5), and then PEG-NIR12-AIEgen NP and PAE-NIR12-AIEgen were added to each chamber. After a further 12 hours incubation, the cells were washed 3 times with 1x PBS buffer and fixed with 4% paraformaldehyde for 20 minutes at 0 ℃. Cellular uptake of NPs was observed after excitation at 405nm and collection of fluorescent signals above 580nm using confocal laser scanning microscopy (Zeiss LSM 710).
Example 17
Theoretical calculation of Density functional
All calculations were performed in the gas phase using the gaussian 09 procedure. The ground state structure was optimized using the B3LYP method and the 6-311G (d, p) basis set. Then, vertical excitation is performed based on the optimized structure in the same manner, thereby obtaining ground state molecular orbital energy.
Example 18
NIR-6 and NIR-12 Synthesis
Exemplary reaction schemes for preparing NIR12 and NIR6 are provided below:
compound 3a: dibromo-BBT 1 (0.1 g,0.28 mmol) and 2a (0.7 mmol), pd (PPh 3 ) 4 (20 mg,0.017 mmol) and 20mL of toluene were added to a two-necked flask. After refluxing the mixture for 24 hours, additional 2a (0.7 mmol) and Pd (PPh) 3 ) 4 (20 mg,0.017 mmol) was added to the reaction system. The solution was refluxed for an additional 24 hours. After cooling to room temperature, the solvent was removed by rotary evaporation. The crude product was purified by a silica gel column (hexane) to give the product (yield: 55%). 1 H NMR(400MHz,CDCl 3 ),δ(ppm):8.83(2H,s),7.28(2H,s),2.73(4H,d,J＝8Hz),1.77(2H,m),1.32(80H,m),0.9(12H,m).
Compound 3b: compound 3b was synthesized in a similar manner to compound 3 a. 1 H NMR(400MHz,CDCl 3 ),δ(ppm):8.85(2H,S),7.32(2H,S),2.79(4H,t,J＝8Hz),1.77(4H,m),1.32(12H,m),0.91(6H,m)。
Compound 4a: compound 3a (0.3 g,0.33 mmol) was dissolved in 10mL of CHCl under an argon atmosphere 3 And 10mL of acetic acid, NBS (117 mg,6.6 mmol) was slowly added to 5mL of CHCl at room temperature under light-shielding conditions over 30 minutes 3 And 5mL of acetic acid. The mixture was stirred overnight and then dried by condensing air. The crude product was purified by a silica gel column to give the product (yield: 80%). 1 H NMR(400MHz,CDCl 3 ),δ(ppm):8.73(2H,s),2.67(4H,d,J＝8Hz),1.84(2H,m),1.3(80H,m),0.89(12H,m)。
Compound 4b: compound 3b (0.3 g,0.57 mmol) was dissolved in an argon atmosphere10mL CHCl 3 And 10mL of acetic acid. 0.22g NBS (1.25 mmol) was slowly added to 5mL of CHCl over 30 minutes at room temperature under dark conditions 3 And 5mL of acetic acid. The mixture was stirred overnight and then dried by condensing air. The crude product was purified by silica gel column (hexane) to give the product (yield=80%). 1 H NMR(400MHz,CDCl 3 ),δ(ppm):8.76(2H,s),2.73(4H,t,J＝8Hz),1.76(4H,m),1.26(12H,m),0.9(6H,m).
Compound 5a (NIR 12): to a solution of compound 4a (50 mg,0.042 mmol) and tributyl (4- (diphenylamino) phenyl) stannane (80 mg,0.15 mmol) in toluene (10 mL) was added Pd (PPh) 3 ) 4 (4 mg). The mixture was stirred at 100℃for 48 hours. After cooling to room temperature, the mixture was poured into water and extracted with DCM. The organic layer was washed with saturated KF and brine, then over MgSO 4 Drying is performed. After evaporation of the solvent, the residue was purified by column chromatography on silica gel using DCM: hexane (1:5, v/v) as eluent to give the product (yield: 30%). 1 H NMR(400MHz,CDCl 3 ),δ(ppm):8.89(2H,s),7.46(4H,d,J＝8Hz),7.32-7.27(10H,m),7.18-7.13(10H,m),7.09-7.05(4H,m),2.79(4H,t),1.81(2H,m),1.21(80H,m),0.87(12H,m). 13 C NMR(100MHz,CDCl 3 ),δ(ppm):150.5,146.8,144.1,138.1,135.5,134.7,129.4,128.7,127.8,124.1,122.5,122.34,122.31,112.3,38.4,32.8,32.5,31.3,29.5,29.1,28.74,25.9,22.1,13.5.MS:m/z:[M] + Calculated values: c (C) 98 H 128 N 6 S 4 1518.3, measured values: 1518.2.
compound 5b (NIR 6): the synthesis of compound 5b was similar to that of 5a (yield: 10%). 1 H NMR(400MHz,CDCl 3 ),δ(ppm):8.93(2H,s),7.47(2H,d,J＝Hz),7.32-7.27(10H,m),7.18-7.12(10H,m),7.09-7.0(4H,m),2.87(4H,m),1.83(4H,m),1.26(12H,m),0.89(6H,m). 13 C NMR(100MHz,CDCl 3 ),δ(ppm):150.6,146.8,146.7,143.4,138.9,135.0,132.4,129.1,128.7,128.0,125.5,124.1,123.9,123.5,122.6,122.0,112.3,30.4,29.0,28.7,22.1,20.6,13.5,13.1.MS:m/z:[M] + Calculated values: c (C) 62 H 56 N 6 S 4 1012.3, measured values:1012.3.
FIG. 22 shows (a) molecular design and chemical structure of NIR12 and NIR6 of PAI-directed PTT, (b) calculated HOMO and LUMO, (c) optimized ground state (S 0 ) Geometry, (d) schematic of TICT state, (e) aggregation state and (f) PA imaging guided NIR12 and NIR6 PTT (R) 1 =2-hexyldecyl, R 2 =1-hexyl).
Having thus shown the subject matter, it will be apparent that the subject matter may be modified or varied in many ways. Such modifications and variations are not to be regarded as a departure from the spirit and scope of the present subject matter, and all such modifications and variations are intended to be included within the scope of the following claims.

Claims (12)

1. A photothermal agent comprising a compound having a donor-acceptor-donor structure:
D-A-D
each donor unit (D) is selected from the group consisting of:
the acceptor unit (a) is selected from the group consisting of:
wherein R is 1 Is an alkyl chain selected from the group consisting of straight chain C n H 2n+1 Alkyl chain and branching C n H 2n+1 Alkyl chains;
when the alkyl chain is straight, n is an integer from 4 to 12;
when the alkyl chain is branched, n is an integer from 6 to 24; and is also provided with
R 2 Selected from H or methoxy.
2. The photothermal reagent of claim 1, wherein R 1 Is straight-chain C n H 2n+1 Alkyl chain, and n is 4 to 12.
3. The photothermal reagent of claim 1, wherein R 1 C branched on a second carbon n H 2n+1 Alkyl chain, and n is 6 to 24.
4. The photothermal reagent of claim 1, wherein the compound is selected from the group consisting of:
wherein R is
5. The photothermal reagent of claim 1, wherein the compound is non-emissive in solution and in the solid state.
6. Use of a photothermal agent according to claim 1 for the preparation of a photoacoustic imaging agent for locating a tumor site in a patient.
7. The use of claim 6, wherein the photothermal agent is applied in nanoparticle form.
8. Use of a photothermal agent according to claim 1 for the preparation of a tumor suppressor for preventing or inhibiting tumor growth in a patient, wherein
Positioning a tumor site using photoacoustic imaging; and
the tumor site is irradiated with light while the compound is present at the tumor site to prevent or inhibit the growth of the tumor.
9. The use of claim 8, wherein the light is near infrared light.
10. A photothermal agent comprising the following compound having a donor-acceptor-donor structure and a poly (β -amino ester) conjugated to the compound:
D-A-D
each donor unit (D) is selected from the group consisting of:
the acceptor unit (a) is selected from the group consisting of:
wherein R is 1 Is an alkyl chain selected from the group consisting of straight chain C n H 2n+1 Alkyl chain and branching C n H 2n+1 Alkyl chains;
when the alkyl chain is straight, n is an integer from 4 to 12;
when the alkyl chain is branched, n is an integer from 6 to 24; and
R 2 is H or methoxy.
11. Use of a photothermal agent according to claim 10 in the preparation of a photoacoustic imaging agent for locating a tumor site in a patient.
12. The use of a photothermal agent according to claim 10, in the preparation of a tumor suppressor for preventing or inhibiting tumor growth in a patient,
positioning a tumor site using photoacoustic imaging; and
the photothermal agent is present at the tumor site while the tumor site is irradiated with light to prevent or inhibit the growth of the tumor.
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