CN107469079A - A kind of light under T1 MRI imagings guiding moves therapeutic agent preparation method - Google Patents

A kind of light under T1 MRI imagings guiding moves therapeutic agent preparation method Download PDF

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CN107469079A
CN107469079A CN201710598438.8A CN201710598438A CN107469079A CN 107469079 A CN107469079 A CN 107469079A CN 201710598438 A CN201710598438 A CN 201710598438A CN 107469079 A CN107469079 A CN 107469079A
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solution
therapeutic agent
manganese
gadolinium
porphyrin
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CN107469079B (en
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徐祖顺
朱伟
王晶
阳哲
张力
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Hubei University
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Abstract

The invention discloses the light under a kind of T1 MRI imaging guiding to move therapeutic agent preparation method, prepares the nano-particle of gadolinium (manganese) porphyrin metal organic framework first；Protein/sulphadiazine compound is prepared again；Nano-particle and compound are mixed with bovine serum albumin/sulphadiazine gadolinium (manganese) porphyrin nano composite, it is that light moves therapeutic agent that light of the nano composite material under T1 MRI imaging guiding is moved into effect；Light under T1 MRI imaging guiding moves the preparation that therapeutic agent is specially protein/sulphadiazine gadolinium (manganese) porphyrin metal organic framework composite, obtained composite biocompatibility is preferable, cytotoxicity is low, MTT tests prove that this composite can trigger light under 660nm laser lights photograph and move effect, and kill tumour cell.Meanwhile obtained composite is good T1 MRI contrast agents, examination and the dynamic treatment of guiding light, this composite available for tumour have great potential using value in terms of the treatment of tumour.

Description

A kind of light under T1-MRI imagings guiding moves therapeutic agent preparation method
Technical field
The present invention relates to material science and biomedicine technical field, the light under specially a kind of T1-MRI imagings guiding moves Therapeutic agent preparation method.
Background technology
At present, malignant tumour, also referred to as cancer, one of disease for threatening human health maximum is had become.More early hair Existing tumour, is more advantageous to the treatment of tumour.Magnetic resonance imaging (MRI) is the most strong detection means of current clinical diagnosis tumour One of, it possesses high-resolution, without ionization radiation injury and the advantages that multi-parameter, multi-sequence im-aging.It is apparent in order to reach, more Accurately it is imaged, the contrast at imaging position is clinically improved usually using contrast agent, and obtains lesion more fully information. Therefore novel MRI contrast agent is developed to be particularly important.It can be used for MRI signal reinforcing agent with paramagnetic material, study More is the longitudinal relaxation contrast agent (T1 preparations) based on manganese complex with gadolinium.Tumour cell is due to possessing very high metabolism Ability, growth is vigorous, and easily shifts and threaten the life of patient.Therefore, the diagnosis and treatment examination of Clinics and Practices integration is developed Treatment of the agent for tumour has important Research Significance.
The dynamic treatment of light is simple and easy due to its traumatic small, less toxic side effect, the features such as repeating effect and can be used as swollen Knurl treats one of most promising therapeutic modality.It is to transfer energy to sensitizer using the illumination of specific wavelength and make shake-up Ambient oxygen produces the oxygen of substantial amounts of single ground state, makes tumour cell generating routine apoptosis.It is but main existing for the dynamic treatment of light Problem is the relatively low and pretherapy and post-treatment monitoring problem of oxygen accordance with tolerance is strong, sensitizer reaches tumor locus dosage and limits it Development.
Porphyrin Molecule due to its unique pi-electron and be the system of height conjugation and with to medical science light window (600- 1000nm) the broad absorption of light, while ambient oxygen can be triggered and produce single ground state oxygen, produce light and move effect.Utilize T1- The metal ion of MRI contrasting effects prepares the nano-particle of metal-organic framework, its nanoparticle with Porphyrin Molecule self assembly There is son T1-MRI radiographies and light to move the difunctional for the treatment of.Sulphadiazine be it is a kind of medically use more broad-spectrum antimicrobial, It can target the carbonic anhydrase of tumor locus overexpression simultaneously, there is provided for the ability of cancer target, can pass through suppression The activity of the carbonic anhydrase of tumor locus overexpression, so as to improve the state of tumor locus anoxic, can also improve light and move Therapeutic action.The biocompatibility of material is that protein is life entity as one of most important Consideration of medical material Material base, excellent pharmaceutical carrier can be served as.
The content of the invention
It is an object of the invention to provide the light under a kind of T1-MRI imaging guiding to move therapeutic agent preparation method, will prepare The nano composite material of protein/sulphadiazine-organic metal framework structure is moved as the light under a kind of T1-MRI imaging guiding The diagnosis and treatment agent for the treatment of, effective treatment for tumour have profound significance, to solve the problems mentioned in the above background technology.
To achieve the above object, the present invention provides following technical scheme：A kind of light dynamic treatment under T1-MRI imagings guiding Agent preparation method, comprises the following steps：
S1：Prepare the nano-particle of gadolinium (manganese)-porphyrin metal organic framework；
S2：Prepare protein/sulphadiazine compound；
S3：Prepare bovine serum albumin/sulphadiazine-gadolinium (manganese) porphyrin nano composite；
S4：It is that light moves therapeutic agent that light of the nano composite material under T1-MRI imaging guiding, which moves effect,.
Preferably, the specific preparation processes of the S1 are as follows：
S1.1：Prepare trivalent gadolinium ion solution (divalent manganesetion solution)：Weigh 3.72mg GdCl3·6H2O is dissolved in 10mL Organic solvent (1mmol/L), it is standby；1.98mg MnCl are weighed again2·4H2O is dissolved in 10mL organic solvent (1mmol/L), It is standby；
S1.2：Prepare porphyrin solution：Weigh 7.90mg mesos-four (4- carboxyl phenyls) porphines (TCPP, average molecular matter Amount=790g/mol) porphyrin is dissolved in 10mL organic solvent (1mmol/L), and it is standby；
S1.3：The above-mentioned 1mL GdCl prepared are taken respectively3·6H2O or MnCl2·4H2O, TCPP solution in 25mL three In mouth flask, 10mL organic solvent is added, and adds 0.4mL acetic acid, 2h is stirred at room temperature；
S1.4：System is warming up to 80-120 DEG C, reacts 24h, and be cooled to room temperature；
S1.5：Respectively with reaction dissolvent ethanol, deionized water centrifuge washing for several times, product is placed on to 60 DEG C of vacuum drying Case dries 24h, that is, prepares NMOFs nano-particles.
Preferably, the specific preparation processes of the S2 are as follows：
S2.1：Prepare bovine serum albumen solution (1 × 10-5mol/L)：Weigh 66.43mg (relative molecular mass= Bovine serum albumin 66.430kDa), 100mL deionized waters are dissolved in, it is standby；
S2.2：Prepare sulphadiazine solution (2 × 10-4mol/L)：Weigh sodium sulfadiazine 5.44mg (relative molecular masses =272g/mol), 100mL deionized waters are dissolved in, it is standby；
S2.3：The bovine serum albumen solution that 3mL has been prepared is taken in 0.8mL sulfanilamide (SN) solution blendings, magnetic agitation 12h, i.e., It is standby to obtain protein/sulphadiazine compound.
Preferably, the specific preparation processes of the S3 are as follows：
S3.1：Made gadolinium (manganese) the porphyrin metal organic framework nano-particle 10mg got ready in S1 is weighed to be scattered in In 10mL deionized waters, with 400W Ultrasound Instruments ultrasonic 2h repeatedly, it is uniformly dispersed in nano-particle in the aqueous solution；
S3.2：Add (1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides/n-hydroxysuccinimide) EDC/NHS carries out activation process to the NMOFs solution in S1；
S3.3：The protein prepared in S2/sulphadiazine complex solution is slowly added drop-wise in S3.2 at activation Gadolinium (manganese) porphyrin nano particle of reason, at room temperature ultrasonic 12h repeatedly；
S3.4：After the completion of reaction, abandon its supernatant with deionized water centrifuge washing for several times；
S3.5：Last product is scattered standby in aqueous, produces protein/sulphadiazine-gadolinium (manganese) porphyrin metal The Nanocomposite solution of organic framework.
Preferably, it is to the specific method of NMOFs solution progress activation process in the S3.2：1mL is added in the solution 4mg/mL EDC solutions, at room temperature after magnetic agitation 15min, add 1mL 3mg/mL NHS solution, at room temperature magnetic agitation 2h, after the completion of question response, with deionized water centrifuge washing after twice it is standby.
Preferably, described trivalent gadolinium salt is one kind in six chloride hydrate gadoliniums, Digadolinium trisulfate or nine nitric hydrate gadoliniums；Secondly Valency manganese salt is one kind in four chloride hydrate manganese, four nitric hydrate manganese, four nitric hydrate manganese manganese carbonates；Its derivatives of porphyrin is original One kind in porphyrin, meso-four (4- carboxyl phenyls) porphines；Described trivalent gadolinium salt and the mol ratio of derivatives of porphyrin are 1- 2:1。
Preferably, described organic solvent be DMF (DMF), DMA (DMAC), One or more in methanol.
Preferably, the bovine serum albumin in the S3 and sulphadiazine and gadolinium porphyrin mass ratio are 30-40:1:180-190.
Compared with prior art, the beneficial effects of the invention are as follows：
1st, the light under this T1-MRI imagings guiding moves therapeutic agent preparation method, and a kind of T1-MRI is prepared using simple method Light under imaging guiding moves therapeutic agent, and the cost of raw material is cheap and reaction condition is gentle, is easy to produce in enormous quantities.
2nd, the light under this T1-MRI imagings guiding moves therapeutic agent preparation method, under a kind of T1-MRI imaging guiding of preparation Light moves therapeutic agent, possesses T1-MRI imaging functions, is easy to the examination of tumour, can be used for pretherapy and post-treatment tumour observation, simultaneously Possess light to move effect and can treat in tumour, possess treatment and the function of diagnosing tumour, be also used as the novelty for tumour Diagnosis and treatment reagent.
3rd, the light under this T1-MRI imagings guiding moves therapeutic agent preparation method, under a kind of T1-MRI imaging guiding of preparation Its biocompatibility of the dynamic therapeutic agent of light is preferable, and cytotoxicity is low, can be used as potential bio-medical material.
4th, the light under this T1-MRI imagings guiding moves therapeutic agent preparation method, under a kind of T1-MRI imaging guiding of preparation Light moves therapeutic agent, has the targeting for tumor locus, it is possible to reduce the dosage of therapeutic reagent, reduce the poison of normal tissue Side effect, it also can preferably play its therapeutic action.
Brief description of the drawings
Fig. 1 is that spectrogram is studied in present protein and the fluorescent quenching of sulphadiazine interaction；
Fig. 2 is that present protein interacts with sulphadiazine, fluorescent quenching constant figure at different temperatures；
Fig. 3 is the UV-vis absorption spectrum of composite of the present invention；
Fig. 4 be present protein/sulphadiazine-metal-organic framework nano composite material cytotoxicity and Light moves therapeutic effect figure；
Fig. 5 is of the invention as sample concentration increases, the increasingly brighter external T1-MRI images of image.
Embodiment
Below in conjunction with the accompanying drawing in the embodiment of the present invention, the technical scheme in the embodiment of the present invention is carried out clear, complete Site preparation describes, it is clear that described embodiment is only part of the embodiment of the present invention, rather than whole embodiments.It is based on Embodiment in the present invention, those of ordinary skill in the art are obtained every other under the premise of creative work is not made Embodiment, belong to the scope of protection of the invention.
In the embodiment of the present invention：A kind of light under T1-MRI imagings guiding moves therapeutic agent preparation method, comprises the following steps：
The first step：Prepare the nano-particle of gadolinium (manganese)-porphyrin metal organic framework；Specific preparation method is as follows：
(1) trivalent gadolinium ion solution (divalent manganesetion solution) is prepared, its trivalent gadolinium salt is six chloride hydrate gadoliniums, Digadolinium trisulfate Or nine one kind in nitric hydrate gadolinium；Its manganous salt is four chloride hydrate manganese, four nitric hydrate manganese, four nitric hydrate manganese carbonic acid One kind in manganese；Specially weigh 3.72mg GdCl3·6H2O is dissolved in 10mL organic solvent (1mmol/L), standby；Weigh again 1.98mg MnCl2·4H2O is dissolved in 10mL organic solvent (1mmol/L), standby, and its organic solvent is N, N- dimethyl formyls One or more in amine (DMF), DMA (DMAC), methanol；
(2) porphyrin solution is prepared：Weigh 7.90mg mesos-four (4- carboxyl phenyls) porphines (TCPP, relative molecular mass =790g/mol) porphyrin is dissolved in above-mentioned 10mL organic solvent (1mmol/L), and it is standby；Its derivatives of porphyrin is protoporphyrin, interior disappeared Revolve one kind in-four (4- carboxyl phenyls) porphines；
(3) the above-mentioned 1mL GdCl prepared are taken respectively3·6H2O or MnCl2·4H2O, TCPP solution are in three mouthfuls of 25mL In flask, 10mL organic solvent is added, and adds 0.4mL acetic acid, 2h is stirred at room temperature；Its trivalent gadolinium salt and derivatives of porphyrin Mol ratio be 1-2:1；
(4) system is warming up to 80-120 DEG C, reacts 24h, and be cooled to room temperature；
(5) reaction dissolvent ethanol, deionized water centrifuge washing are used for several times respectively, product is placed on to 60 DEG C of vacuum drying chamber 24h is dried, that is, prepares NMOFs nano-particles.
Second step：Prepare protein/sulphadiazine compound；Specific preparation method is as follows：
(1) bovine serum albumen solution (1 × 10 is prepared-5mol/L)：Weigh 66.43mg (relative molecular mass= Bovine serum albumin 66.430kDa), 100mL deionized waters are dissolved in, it is standby；
(2) sulphadiazine solution (2 × 10 is prepared-4mol/L)：Weigh sodium sulfadiazine 5.44mg (relative molecular mass= 272g/mol), 100mL deionized waters are dissolved in, it is standby；
(3) bovine serum albumen solution that 3mL has been prepared is taken magnetic agitation 12h, to be produced in 0.8mL sulfanilamide (SN) solution blendings Protein/sulphadiazine compound is standby.
3rd step：Prepare bovine serum albumin/sulphadiazine-gadolinium (manganese) porphyrin nano composite；Specific preparation method is such as Under：
(1) made gadolinium (manganese) the porphyrin metal organic framework nano-particle 10mg got ready in step 1 is weighed to be scattered in In 10mL deionized waters, with 400W Ultrasound Instruments ultrasonic 2h repeatedly, it is uniformly dispersed in nano-particle in the aqueous solution；
(2) (1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides/n-hydroxysuccinimide) EDC/ is added NHS carries out activation process to the NMOFs solution in S1；Specific method is：1mL 4mg/mL EDC solutions are added in the solution, At room temperature after magnetic agitation 15min, 1mL 3mg/mL NHS solution is added, at room temperature magnetic agitation 2h, after the completion of question response, It is rear twice standby with deionized water centrifuge washing；
(3) protein prepared in step 2/sulphadiazine complex solution is slowly added drop-wise to above-mentioned at activation Gadolinium (manganese) porphyrin nano particle of reason, at room temperature ultrasonic 12h repeatedly；Its bovine serum albumin and sulphadiazine and gadolinium porphyrin quality Than for 30-40:1:180-190；
(4) after the completion of reacting, abandon its supernatant with deionized water centrifuge washing for several times；
(5) last product is scattered standby in aqueous, and producing protein/sulphadiazine-gadolinium (manganese) porphyrin metal has The Nanocomposite solution of machine frame structure；
4th step：It is that light moves therapeutic agent that light of the nano composite material under T1-MRI imaging guiding, which moves effect,.
In summary：Light under this T1-MRI imaging guiding moves therapeutic agent preparation method, protein/sulphadiazine-gadolinium (manganese) porphyrin metal organic framework nano composite material uniform particle diameter, Stability Analysis of Structures, synthesis condition is simple, biocompatibility Well, there is the light under T1-MRI imaging guiding to move effect, belong to the crossing domain of material and biological medicine, potentially should have With value.
Referring to Fig. 1, the fluorescent quenching research of protein understands that protein can be very good mutually with sulphadiazine molecule Effect.
Referring to Fig. 2, protein fluorescent quenching constant is studied under different temperatures, it was demonstrated that bovine serum albumin can with sulphadiazine Can happens is that static state, be dynamically quenched, based on being dynamically quenched, that is, interact and mainly acted on molecule hydrophobe.
Referring to Fig. 3, UV-vis absorption spectrum understands that protein/sulphadiazine gadolinium (manganese) porphyrin metal has machine frame Frame structural composite material has the absorption to ultraviolet/visible light/near infrared light broad-spectrum, also triggers composite wood for medical optics window Material produces the dynamic effect of light and provides possibility.
Referring to Fig. 5, external T1-MRI imagings, as sample concentration increases, image is more and more brighter.
Specific embodiment：The performance of protein/sulphadiazine gadolinium (manganese) porphyrin metal organic framework composite is surveyed Examination：
Embodiment one：
Cytotoxicity test：After prepared nano composite material and 4T1 cells are co-cultured into 24h, detected with mtt assay thin The relative survival rate of born of the same parents, it can be found that composite has good biocompatibility, under the Cmax of experiment, the phase of cell More than 80% can still be reached to survival rate.
Embodiment two：
The external dynamic treatment of light：After prepared nano composite material and 4T1 cells are co-cultured into 24h, existed with 660nm laser 60mW/cm210min is irradiated under power, after being placed on cell culture incubator culture 8h, the relative survival rate of cell, knot are detected with mtt assay Fruit shows that prepared nano composite material has good light to move therapeutic action to tumour cell.
Embodiment three：
External T1-MRI imaging tests：Load the aqueous solution of made nano composite material with 1.5mL centrifuge tubes, and by one The concentration of fixed composite prepares sample, sample is placed on to 3T medical MRI, has obtained difference with clear water as a control group The image of contrast, it was demonstrated that its nano composite material has T1-MRI imaging functions, and the concentration of imaging capability and composite It is directly proportional.
The foregoing is only a preferred embodiment of the present invention, but protection scope of the present invention be not limited thereto, Any one skilled in the art the invention discloses technical scope in, technique according to the invention scheme and its Inventive concept is subject to equivalent substitution or change, should all be included within the scope of the present invention.

Claims (8)

1. the light under a kind of T1-MRI imagings guiding moves therapeutic agent preparation method, it is characterised in that comprises the following steps：
S1：Prepare the nano-particle of gadolinium (manganese)-porphyrin metal organic framework；
S2：Prepare protein/sulphadiazine compound；
S3：Prepare bovine serum albumin/sulphadiazine-gadolinium (manganese) porphyrin nano composite；
S4：It is that light moves therapeutic agent that light of the nano composite material under T1-MRI imaging guiding, which moves effect,.
2. the light under a kind of T1-MRI imagings guiding as claimed in claim 1 moves therapeutic agent preparation method, it is characterised in that institute It is as follows to state the specific preparation processes of S1：
S1.1：Prepare trivalent gadolinium ion solution (divalent manganesetion solution)：Weigh 3.72mg GdCl3·6H2O is dissolved in having for 10mL Solvent (1mmol/L), it is standby；1.98mg MnCl are weighed again2·4H2O is dissolved in 10mL organic solvent (1mmol/L), standby；
S1.2：Prepare porphyrin solution：Weigh 7.90mg mesos-four (4- carboxyl phenyls) porphines (TCPP, relative molecular mass= 790g/mol) porphyrin is dissolved in 10mL organic solvent (1mmol/L), standby；
S1.3：The above-mentioned 1mL GdCl prepared are taken respectively3·6H2O or MnCl2·4H2O, TCPP solution are in 25mL three mouthfuls of burnings In bottle, 10mL organic solvent is added, and adds 0.4mL acetic acid, 2h is stirred at room temperature；
S1.4：System is warming up to 80-120 DEG C, reacts 24h, and be cooled to room temperature；
S1.5：Respectively with reaction dissolvent ethanol, deionized water centrifuge washing for several times, product is placed on to 60 DEG C of vacuum drying chamber and done Dry 24h, that is, prepare NMOFs nano-particles.
3. the light under a kind of T1-MRI imagings guiding as claimed in claim 1 moves therapeutic agent preparation method, it is characterised in that institute It is as follows to state the specific preparation processes of S2：
S2.1：Prepare bovine serum albumen solution (1 × 10-5mol/L)：Weigh 66.43mg (relative molecular mass=66.430kDa) Bovine serum albumin, be dissolved in 100mL deionized waters, it is standby；
S2.2：Prepare sulphadiazine solution (2 × 10-4mol/L)：Weigh sodium sulfadiazine 5.44mg (relative molecular mass= 272g/mol), 100mL deionized waters are dissolved in, it is standby；
S2.3：The bovine serum albumen solution that 3mL has been prepared is taken magnetic agitation 12h, to produce egg in 0.8mL sulfanilamide (SN) solution blendings White matter/sulphadiazine compound is standby.
4. the light under a kind of T1-MRI imagings guiding as claimed in claim 1 moves therapeutic agent preparation method, it is characterised in that institute It is as follows to state the specific preparation processes of S3：
S3.1：Weigh made gadolinium (manganese) the porphyrin metal organic framework nano-particle 10mg got ready in S1 and be scattered in 10mL In ionized water, with 400W Ultrasound Instruments ultrasonic 2h repeatedly, it is uniformly dispersed in nano-particle in the aqueous solution；
S3.2：Add (1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides/n-hydroxysuccinimide) EDC/ NHS carries out activation process to the NMOFs solution in S1；
S3.3：The protein prepared in S2/sulphadiazine complex solution is slowly added drop-wise in S3.2 activation process Gadolinium (manganese) porphyrin nano particle, at room temperature ultrasonic 12h repeatedly；
S3.4：After the completion of reaction, abandon its supernatant with deionized water centrifuge washing for several times；
S3.5：Last product is scattered standby in aqueous, and it is organic to produce protein/sulphadiazine-gadolinium (manganese) porphyrin metal The Nanocomposite solution of frame structure.
5. the light under a kind of T1-MRI imagings guiding as claimed in claim 4 moves therapeutic agent preparation method, it is characterised in that institute State in S3.2 and be to the specific method of NMOFs solution progress activation process：1mL 4mg/mL EDC solutions are added in the solution, At room temperature after magnetic agitation 15min, 1mL 3mg/mL NHS solution is added, at room temperature magnetic agitation 2h, after the completion of question response, It is rear twice standby with deionized water centrifuge washing.
6. the light under a kind of T1-MRI imagings guiding as claimed in claim 2 moves therapeutic agent preparation method, it is characterised in that institute The trivalent gadolinium salt stated is one kind in six chloride hydrate gadoliniums, Digadolinium trisulfate or nine nitric hydrate gadoliniums；Its manganous salt is four hydration chlorine Change one kind in manganese, four nitric hydrate manganese, four nitric hydrate manganese manganese carbonates；Its derivatives of porphyrin is protoporphyrin, meso-four One kind in (4- carboxyl phenyls) porphines；Described trivalent gadolinium salt and the mol ratio of derivatives of porphyrin are 1-2:1.
7. the light under a kind of T1-MRI imagings guiding as claimed in claim 2 moves therapeutic agent preparation method, it is characterised in that institute The organic solvent stated is DMF (DMF), DMA (DMAC), one kind in methanol or several Kind.
8. the light under a kind of T1-MRI imaging guiding as described in claim 1 or 4 moves therapeutic agent preparation method, its feature exists In bovine serum albumin and sulphadiazine and gadolinium porphyrin mass ratio in the S3 are 30-40:1:180-190.
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CN108939072A (en) * 2018-07-13 2018-12-07 湖北大学 A kind of nano-carrier and preparation method thereof for photodynamic therapy
CN110025596A (en) * 2019-04-25 2019-07-19 上海理工大学 A kind of Nano composite granules and preparation method thereof
CN113061260A (en) * 2021-03-19 2021-07-02 暨南大学 Rare earth metal porphyrin framework material and preparation method and application method thereof
CN113105641A (en) * 2021-03-29 2021-07-13 广东省第二人民医院（广东省卫生应急医院） Iron-manganese double-doped nano metal organic framework material and preparation method and application thereof
CN113105641B (en) * 2021-03-29 2022-12-23 广东省第二人民医院（广东省卫生应急医院） Iron-manganese double-doped nano metal organic framework material and preparation method and application thereof

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