CN112168982A - Preparation and application of BODIPY-Gd conjugate nano diagnosis and treatment reagent - Google Patents
Preparation and application of BODIPY-Gd conjugate nano diagnosis and treatment reagent Download PDFInfo
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Abstract
The invention relates to a preparation method and application of a BODIPY-Gd (BD-Gd) conjugate nano diagnosis and treatment reagentPrepared from BD-Gd and polymer PEG113‑b‑PCL8(P) composition. First, a BODIPY molecule is contacted with a water-soluble Magnetic Resonance Imaging (MRI) contrast agentalk-DOTA-Gd covalent attachment to give a BD-Gd conjugate. Then, the polymer P and BD-Gd were co-assembled to form a nano-assembly which was stable in water and controllable in particle size. Compared with BD-Gd single molecules, the prepared nano assembly absorbs red shift of 138 nanometers, the molar extinction coefficient is increased by nearly 2 times, and the photo-thermal conversion efficiency reaches 71.5 percent, so that the nano assembly can be used for near-infrared photo-acoustic imaging and photo-thermal treatment; at the same time, compare withalkDOTA-Gd, the MRI signal of the nano assembly is enhanced by 1.4 times, and the enhanced MRI effect is realized. The nano diagnosis and treatment reagent prepared by the invention realizes enhanced photoacoustic and magnetic resonance bimodal imaging and good photothermal treatment effect in living tumor imaging and treatment application.
Description
Technical Field
The invention belongs to the field of chemical biology, and the research content is that a magnetic resonance imaging agent-based covalent modified BODIPY dye molecule is assembled with a high molecular polymer to form a nano structure for multi-modal imaging and photothermal therapy of tumors.
Background
The multi-modal imaging has important clinical application potential, can combine the advantages of different imaging modes, and can obtain various imaging information simultaneously, thereby improving the accuracy of clinical judgment. Magnetic Resonance (MR) imaging, the most commonly used technique for clinical diagnosis, has excellent tissue penetration depth, high soft tissue contrast and spatial-temporal resolution. However, MR imaging has its own drawbacks, such as relatively low sensitivity and long detection time. Photoacoustic (PA) imaging has the advantages of fast real-time scanning, high sensitivity and deep tissue penetration (max ≈ 5 cm). Thus, PA imaging can be combined with MR imaging, which can scan pre-and intra-operative macroscopic contours, while PA imaging can provide tissue structure and molecular information with high sensitivity and high resolution. Therefore, the dual-modality imaging system will integrate the advantages of PA and MR imaging, achieving imaging effects of high sensitivity and spatial resolution. In recent years, many PA and MR imaging systems have been reported. However, many nanocomposites are inorganic materials whose toxicity and clearance in living systems are often of concern. Meanwhile, in a multi-modal system composed of a plurality of organic materials, each component only completes the imaging function of the component, and the imaging functions can be improved mutually rarely among different components.
By controlling the organic chromophores to form J-aggregates in a sliding packing manner, improvements in photophysical properties other than monomers can be achieved, including significant red-shift in the absorption spectrum, enhancement of the molar extinction coefficient, and narrowing of the absorption spectrum. Therefore, J-aggregates are receiving increasing attention in the biomedical and optoelectronic device fields. In addition to these attractive optical properties, J-aggregation can drive the self-assembly of dyes into highly ordered structures, which have been extensively studied in the fields of supramolecular chemistry and living polymerization. In the biomedical field, most J-aggregate-based applications (e.g., bioimaging, biosensing, and phototherapy) utilize only their excellent photophysical properties. But the highly ordered structure induced by J-aggregation is rarely exploited to improve material properties or develop new functions. On the other hand, controlling the assembly or spatial distribution of functional groups such as catalysts, recognition units, fluorophores, Magnetic Resonance (MR) contrast agents, etc. by the supramolecular approach is an effective strategy to enhance the performance of nanomaterials.
BODIPY molecules, a common fluorescent dye, can form J aggregates by a simple method. But their use in living organisms is often limited due to their poor water solubility. Therefore, the contrast agent DOTA-Gd (III) commonly used for MR imaging is selected as a hydrophilic functional group and is combined with BODIPY through a covalent bond. After the BODIPY dye is covalently combined with hydrophilic Gd (III) chelate, a stable J aggregate nano structure can be formed in water, and further the MR signal enhancement and the photothermal property improvement are realized. The invention provides a new idea for the functional application of the J aggregate.
Disclosure of Invention
The invention relates to a preparation method and application of a BODIPY-Gd (BD-Gd) conjugate nano diagnosis and treatment reagent, wherein the diagnosis and treatment reagent consists of BD-Gd and a polymer PEG113-b-PCL8(P) composition. First, a fluoroboron dipyrrole molecule is covalently linked to a water-soluble Magnetic Resonance Imaging (MRI) contrast agent alk-DOTA-Gd to give a BD-Gd conjugate. Then, the polymer P and BD-Gd were co-assembled to form a nano-assembly which was stable in water and controllable in particle size. Compared with BD-Gd single molecules, the prepared nano assembly absorbs red shift of 138 nanometers, the molar extinction coefficient is increased by nearly 2 times, and the photo-thermal conversion efficiency reaches 71.5 percent, so that the nano assembly can be used for near-infrared photo-acoustic imaging and photo-thermal treatment; meanwhile, compared with alk-DOTA-Gd, the MRI signal of the nano assembly is enhanced by 1.4 times, and the enhanced MRI effect is realized. The nanometer diagnosis and treatment reagent prepared by the inventionIn the application of living tumor imaging and treatment, the enhanced photoacoustic and magnetic resonance bimodal imaging and good photothermal treatment effect are realized.
The structural formula of the BD-Gd molecule provided by the invention is shown in figure 1.
The present invention provides PEG113-b-PCL8(P) polymer molecules, the structural formula of which is shown in figure 2.
The technical scheme provided by the invention is as follows:
firstly, a BODIPY molecule which is easy to synthesize is synthesized to be used as a J aggregation module, and the J aggregation nano assembly is prepared under the action of a high molecular polymer P through covalent connection of a Click reaction and a hydrophilic magnetic resonance imaging agent DOTA-Gd.
Ultraviolet-visible absorption spectrum detection shows that: the maximum fine absorption of the prepared J aggregate nano assembly is 815 nm, and the red shift is 138 nm relative to the monomolecular maximum absorption 677 nm of the BODIPY dye. And detecting the morphology of the nano-sheet by a transmission electron microscope and an atomic force microscope. The nano-assembly is placed in pure water, PBS, DMEM (10% FBS) and other solutions for a week at 4 ℃, ultraviolet absorption does not change obviously, and the nano-assembly has good stability.
The preparation method of the J aggregate nano assembly comprises the following steps: 9.5 mL of the prepared 1 mg/mL aqueous solution of P was slowly added dropwise to a solution of BD-Gd (0.5 mL, 1 mg/mL) in DMF and stirred overnight at 900 RPM. Then heated at 95 ℃ for 10 min, cooled naturally to 20 ℃, transferred to an ultrafiltration tube (10K), centrifuged at 2000 RPM for 1 hour, the lower aqueous layer was discarded, and water was added to the upper layer to re-disperse the assembly, and centrifuged again. After repeating the operation three times, the assembly was filtered through a 0.22. mu.M filter and stored at 4 ℃ for further use.
For the J-aggregation nano-assembly proposed in the present invention, the following outstanding advantages are provided: (1) the hydrophobic BODIPY dye is covalently combined with hydrophilic DOTA-Gd, and the synthesized compound molecule forms a J aggregate in aqueous solution and has good stability; (2) the nano assembly has red shift of absorption spectrum into near infrared region, nearly doubled molar extinction coefficient, high photothermal conversion efficiency and high light stability; (3) the nano-assembly further enhances the magnetic resonance imaging effect of DOTA-Gd.
In conclusion, the preparation and application of the J aggregate nano-assembly provided by the invention have the following beneficial effects: the formed nano assembly has higher photo-thermal conversion efficiency and light stability; enhancement of magnetic resonance imaging is achieved by J-aggregation in water using BODIPY dyes; the stability of the aggregate in water is increased by the functional modification of the BODIPY dye.
And multi-modal imaging is realized by the functionalized modification of the BODIPY dye.
Drawings
FIG. 1 shows the molecular structure of the compound synthesized in the present invention.
FIG. 2 shows PEG provided by the present invention113-b-PCL8(P) the molecular structural formula of the polymer.
FIG. 3 shows the synthesis scheme of the molecule designed in the present invention.
FIG. 4 shows the absorption spectra of the nano-assembly prepared in the present invention in water and DMF, respectively.
FIG. 5 is a morphological characterization of the nano-assemblies prepared in the present invention.
FIG. 6 shows the stability of the nano-assembly prepared in the present invention in pure water, PBS, DMEM (10% FBS), respectively.
Fig. 7 is a graph showing the temperature change of the nano-assembly prepared in the present invention during five photo-thermal cycles.
FIG. 8 is a graph of photoacoustic signals at 820 nm for the nano-assembly prepared in the present invention.
FIG. 9 shows the change of the relaxation rate of the nano-assembly BD-Gd/P and the small molecule alk-DOTA-Gd prepared in the invention in the aqueous solution.
FIG. 10a is a graph of the change in tumor volume after a single intravenous treatment in tumor-bearing mice of different experimental groups; FIG. 10b is a photograph showing the tumor after the tumor-bearing mice in different groups are treated and dissected.
Detailed Description
The present invention is further illustrated by the following examples, which are intended to describe the present invention in detail, but the scope of the present invention is not limited to the following examples.
Example 1: the synthesis of amphiphilic BD-Gd molecules, the synthetic route is shown in figure 3: and (3) synthesizing a compound BD-Gd. The compound BD-Az (186.9 mg, 0.2 mmol) andalk-DOTA-Gd (59.6 mg, 0.1 mmol), sodium ascorbate (19.8 mg, 0.1 mmol) and anhydrous copper sulphate (8.0 mg, 0.05 mmol) were dissolved in a 10 mL tetrahydrofuran/water (4 mL/1 mL) solution. The reaction was stirred at room temperature for 48 h under nitrogen. After the reaction was completed, the solvent was removed by filtration and rotary evaporation, and the residue was purified by HPLC to obtain the black solid product BD-Gd (23.1 mg) in a yield of 15.1%. HRMS (ESI) corrected for C66H81BCl2F2GdN10O15 + [M+H]+ m/z 1530.4557; found 1530.4547。
Example 2. The preparation method of the BD-Gd/P nano assembly comprises the following steps: 0.5 mL of a DMF solution (1 mg/mL) of BD-Gd molecules was added dropwise slowly to 9.5 mL (1 mg/mL) of an aqueous P solution, and the mixture was stirred overnight at 900 RPM. Heating at 95 deg.C for 10 min, naturally cooling to 20 deg.C, transferring to ultrafiltration tube (10K), centrifuging at 2000 RPM for 1 h, discarding the lower aqueous layer, adding water to the upper layer and re-dispersing the assembly, and centrifuging again. After repeating the operation three times, the assembly was filtered using a 0.22. mu.M filter and stored at 4 ℃ for further use. (concentration 19.0 g/L P; 0.653 mM BD-Gd). The absorption spectra of the assembly BD-Gd/P in water and DMF are shown in FIG. 4.
Example 3. The photo-thermal conversion performance of the BD-Gd/P nano assembly is researched: the prepared BD-Gd/P (5. mu.M BD-Gd) nano assembly was irradiated on a sample (1W/cm) with a 808 nm laser2And 10 min), naturally cooling, repeatedly irradiating the sample for five times by taking the cycle as a cycle, and detecting the photo-thermal stability of the sample. As shown in figure 7, the BD-Gd/P nano assembly has stable photo-thermal conversion and good photo-bleaching resistance.
Example 4. The photoacoustic properties of the BD-Gd/P nano-assembly were studied: BD-Gd/P (0, 2.5, 5, 10, 20 mu M BD-Gd) nano assembly aqueous solutions with different concentrations are filled into a mold prepared by agarose gel, and a photoacoustic signal of the sample at 680-900 nm is detected by a photoacoustic imaging instrument. The photoacoustic imaging detection results are shown in fig. 8.
Example 5. The BD-Gd/P nano assembly magnetic resonance imaging was studied. Respectively taking BD-Gd/P and BD-Gd/P with different concentrationsalkDOTA-Gd sample solutions, their relaxation time changes being detected using a 1.2T magnetic resonance imaging system (T1). Taking the concentration of the sample as a horizontal coordinate and the reciprocal of the relaxation time as a vertical coordinate, performing curve fitting to solve the relaxation rate r1And (4) changing. As shown in fig. 9.
Example 6. The BD-Gd/P is applied to in-vivo anti-tumor research: the photothermal nano reagent BD-Gd/P prepared by the invention is injected through tail vein and undergoes photothermal (808 nm, 0.5W/cm)2And 10 min) can inhibit the growth of the tumor and realize the thermal ablation of the tumor, and the experimental result is shown in figure 10.
In the invention, the hydrophilic magnetic resonance imaging agent is covalently combined with the J aggregation dye, so that a formed nano assembly has good stability, high photothermal conversion efficiency and outstanding photobleaching resistance in water, and meanwhile, the aggregation of the BODIPY dye increases a magnetic resonance imaging signal.
Aggregates are co-assembled by polymers, and finally nano-assemblies with the size of more than 100 nanometers can be prepared.
The whole set of material preparation method provided by the invention opens up a new path for the research and development of J aggregation in multi-modal imaging.
Claims (10)
- The preparation method of the J aggregate nano assembly comprises the following steps: 0.5 mL of a DMF solution (1 mg/mL) of BD-Gd molecules is taken, 9.5 mL of a P aqueous solution (1 mg/mL) is slowly dropped into the solution, and the solution is stirred overnight under the condition of 900 RPM; heating at 95 deg.C for 10 min, naturally cooling to 20 deg.C, transferring to ultrafiltration tube (10K), centrifuging at 2000 RPM for 1 hr, discarding the lower layer water solution, adding water to the upper layer to disperse the assembly body weight, and centrifuging again; after repeating the operation three times, use 0.22μFiltering with M filter membrane, and storing at 4 deg.C.
- 2. The method according to claim 1, wherein the good solvent in which the BD-Gd molecule is soluble is: dimethylsulfoxide, N-dimethylformamide, and the like.
- 3. The method according to claim 1, wherein the J-aggregates are prepared by dissolving and dispersing a polymer which does not readily form an assembly in water, and then dropping the polymer into an organic solution containing BD-Gd dye molecules under stirring.
- 4. The method of claim 1, wherein the J-aggregate is initially prepared and further heated to cool to red-shift the absorption peak.
- 5. The method of preparing a nano-assembly according to claim 1, wherein the nano-assembly is prepared by using 0.22μThe shape of the M filter membrane is converted into a nano assembly with smaller volume by filtration, so that the material is more suitable for being applied to life bodies.
- 6. The ultrafiltration method of claim 1, wherein the prepared nano-assembly is concentrated by low-speed ultrafiltration and the organic solvent is removed.
- 7. The J aggregate nano-assembly obtained by the preparation method according to claim 1 realizes magnetic resonance imaging enhancement, has high photothermal conversion efficiency, and has excellent photoacoustic imaging effect.
- 8. The use of the J-aggregate photothermal nanomaterial of claims 1-7 for the photothermal treatment of tumors.
- 9. The J aggregate nano-assembly prepared by the preparation method of claim 1 is applied to photoacoustic and magnetic resonance imaging.
- 10. Dye molecule synthesis route.
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| CN110585449A (en) * | 2019-09-27 | 2019-12-20 | 南通市肿瘤医院 | Live cell probe construction method based on neutrophils |
| US20200101176A1 (en) * | 2018-09-13 | 2020-04-02 | The Regents Of The University Of Michigan | Small Highly Uniform Nanomedicine Compositions for Therapeutic, Imaging and Theranostic Applications |
| CN111053904A (en) * | 2020-01-09 | 2020-04-24 | 南开大学 | Preparation method and application of J aggregate photo-thermal nano-reagent constructed based on dye and polymer |
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| US20200101176A1 (en) * | 2018-09-13 | 2020-04-02 | The Regents Of The University Of Michigan | Small Highly Uniform Nanomedicine Compositions for Therapeutic, Imaging and Theranostic Applications |
| CN110585449A (en) * | 2019-09-27 | 2019-12-20 | 南通市肿瘤医院 | Live cell probe construction method based on neutrophils |
| CN111053904A (en) * | 2020-01-09 | 2020-04-24 | 南开大学 | Preparation method and application of J aggregate photo-thermal nano-reagent constructed based on dye and polymer |
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