CN115160496B - Glutathione activated polynorbornene photosensitizer as well as preparation method and application thereof - Google Patents
Glutathione activated polynorbornene photosensitizer as well as preparation method and application thereof Download PDFInfo
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- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 title claims abstract description 92
- 229960003180 glutathione Drugs 0.000 title claims abstract description 46
- 239000003504 photosensitizing agent Substances 0.000 title claims abstract description 45
- 229920000636 poly(norbornene) polymer Polymers 0.000 title claims abstract description 38
- 108010024636 Glutathione Proteins 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 239000002105 nanoparticle Substances 0.000 claims abstract description 24
- 239000000178 monomer Substances 0.000 claims abstract description 22
- 229920001577 copolymer Polymers 0.000 claims abstract description 9
- 239000004094 surface-active agent Substances 0.000 claims abstract description 5
- 238000007152 ring opening metathesis polymerisation reaction Methods 0.000 claims abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 150000001875 compounds Chemical class 0.000 claims description 19
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 17
- 238000003786 synthesis reaction Methods 0.000 claims description 14
- 230000015572 biosynthetic process Effects 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 229940126214 compound 3 Drugs 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- 229940125904 compound 1 Drugs 0.000 claims description 5
- 229940125782 compound 2 Drugs 0.000 claims description 5
- 229940125898 compound 5 Drugs 0.000 claims description 5
- 238000006116 polymerization reaction Methods 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
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- JFNLZVQOOSMTJK-KNVOCYPGSA-N norbornene Chemical compound C1[C@@H]2CC[C@H]1C=C2 JFNLZVQOOSMTJK-KNVOCYPGSA-N 0.000 claims 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 abstract description 14
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- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 abstract 1
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- 238000002474 experimental method Methods 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 210000004881 tumor cell Anatomy 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 4
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- 101100377855 Artemia franciscana ABDA gene Proteins 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010034972 Photosensitivity reaction Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
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- 239000012498 ultrapure water Substances 0.000 description 2
- IICCLYANAQEHCI-UHFFFAOYSA-N 4,5,6,7-tetrachloro-3',6'-dihydroxy-2',4',5',7'-tetraiodospiro[2-benzofuran-3,9'-xanthene]-1-one Chemical compound O1C(=O)C(C(=C(Cl)C(Cl)=C2Cl)Cl)=C2C21C1=CC(I)=C(O)C(I)=C1OC1=C(I)C(O)=C(I)C=C21 IICCLYANAQEHCI-UHFFFAOYSA-N 0.000 description 1
- 210000003771 C cell Anatomy 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- QYKIQEUNHZKYBP-UHFFFAOYSA-N Vinyl ether Chemical compound C=COC=C QYKIQEUNHZKYBP-UHFFFAOYSA-N 0.000 description 1
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- PNPBGYBHLCEVMK-UHFFFAOYSA-N benzylidene(dichloro)ruthenium;tricyclohexylphosphanium Chemical compound Cl[Ru](Cl)=CC1=CC=CC=C1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1 PNPBGYBHLCEVMK-UHFFFAOYSA-N 0.000 description 1
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- NJEVMKZODGWUQT-UHFFFAOYSA-N propane-1,1,3,3-tetracarboxylic acid Chemical compound OC(=O)C(C(O)=O)CC(C(O)=O)C(O)=O NJEVMKZODGWUQT-UHFFFAOYSA-N 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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- 229930187593 rose bengal Natural products 0.000 description 1
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- STRXNPAVPKGJQR-UHFFFAOYSA-N rose bengal A Natural products O1C(=O)C(C(=CC=C2Cl)Cl)=C2C21C1=CC(I)=C(O)C(I)=C1OC1=C(I)C(O)=C(I)C=C21 STRXNPAVPKGJQR-UHFFFAOYSA-N 0.000 description 1
- 238000001878 scanning electron micrograph Methods 0.000 description 1
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- 150000003384 small molecules Chemical class 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F232/00—Copolymers of cyclic compounds containing no unsaturated aliphatic radicals in a side chain, and having one or more carbon-to-carbon double bonds in a carbocyclic ring system
- C08F232/08—Copolymers of cyclic compounds containing no unsaturated aliphatic radicals in a side chain, and having one or more carbon-to-carbon double bonds in a carbocyclic ring system having condensed rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F236/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, at least one having two or more carbon-to-carbon double bonds
- C08F236/22—Copolymers of compounds having one or more unsaturated aliphatic radicals, at least one having two or more carbon-to-carbon double bonds the radical having three or more carbon-to-carbon double bonds
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
- G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
- G01N21/78—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator producing a change of colour
- G01N21/79—Photometric titration
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N2021/6417—Spectrofluorimetric devices
Abstract
The invention discloses a glutathione activated polynorbornene photosensitizer as well as a preparation method and application thereof. According to the invention, a monomer NB-SS-Py-Fc containing ferrocenyl groups and a monomer NB-TPE with near infrared emission are embedded into a polynorbornenyl skeleton by ROMP to obtain a copolymer P1. The water-soluble nano particles P1NPs with good biocompatibility are prepared by wrapping P1 in F-127 (polyoxypropylene polyoxyethylene copolymer) surfactant. The designed P1NPs show weak fluorescence under the action of fluorescence quenching groups ferrocene, and after being activated by GSH, the P1NPs generate near infrared emission of strong fluorescence and generate considerable singlet oxygen yield at the same time, thereby having excellent photodynamic treatment effect.
Description
Technical Field
The invention belongs to the fields of chemical synthesis and biological application, and particularly relates to a glutathione activated polynorbornene photosensitizer as well as a preparation method and application thereof.
Background
In recent years, cancer has gradually evolved into one of the major physiological diseases that are severely threatening human life, and thus it is of great importance to accurately diagnose and effectively treat cancer. To date, a number of treatments for cancer have been pursued, including conventional radiation, chemotherapy and surgical therapies. Novel therapeutic methods like gene therapy, biological therapy, immunotherapy, photodynamic therapy, etc. are also coming into our field of view and attracting great attention due to their novel therapeutic techniques and high therapeutic efficiency.
Currently, PDT (photodynamic therapy) has been successfully and effectively applied to clinical applications as a promising cancer treatment method. Compared with the traditional therapy, PDT has the advantages of high healing speed, small side effect, short treatment period and the like. The specific PDT process is to transfer the energy of PS (photosensitizer) to O surrounding the tumor 2 Promoting to haveCytotoxic activity 1 O 2 Can generate permanent damage to cancer cells and tissues, thereby achieving the therapeutic effect. However, there are numerous obstacles and challenges in photodynamic therapy, such as the selectivity of specific tumors, efficient singlet oxygen transfer, and lack of toxicity to normal tissues, which are all challenges to be addressed. It is therefore imperative to develop photosensitizers that activate responsive.
Typical tumor microenvironments have the following characteristics: hypoxia, high concentrations of ATP and GSH, low pH, DNA and protein overexpression, etc., all of which can be converted into factors that induce and activate effective PDT, thereby killing cancer cells. The data show that GSH concentrations in tumor cells can reach 1-10mM, far exceeding normal cells, making it the best trigger for activating photosensitizers. Traditional GSH-activated photosensitizers, such as phenothiazine porphyrin and derivatives of BODIPY, have been reported for use in efficient PDT processes. However, these photosensitizers inevitably generate aggregation-induced quenching (ACQ) in water due to their rigid planar structure, resulting in fluorescence loss and reduced singlet oxygen yield. Meanwhile, new GSH-activated photosensitizers for AIE have been developed gradually, with a strong fluorescence enhancement and singlet oxygen surge in response to GSH. However, most of them are small molecule photosensitizers, and GSH-activated polymeric photosensitizers with a huge potential AIE class are still rarely reported.
Disclosure of Invention
Aiming at the defects and the problems in the prior art, the invention aims to provide a glutathione activated polynorbornene photosensitizer as well as a preparation method and application thereof.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the invention provides a glutathione activated polynorbornene photosensitizer which can be used for photodynamic therapy aiming at specific tumor cells. The principle is that pyridine ferrocenyl with fluorescence quenching effect and near infrared emission TPE are introduced to the main chain of polynorbornene through copolymerization, and then quenching group is separated from polymer chain through shearing action of GSH on disulfide bond, thereby starting fluorescence response and generating singlet oxygen to guide photodynamic therapy. The chemical structural formula of the glutathione activated polynorbornene photosensitizer is shown as follows:
the invention also provides a preparation method of the polynorbornene photosensitizer, which comprises the following steps:
(1) Synthesis of precursor compound 3: dissolving the compound 1 and the compound 2 in a first solvent, adding dicyclohexylcarbodiimide and 4-dimethylaminopyridine, reacting at normal temperature, and separating and purifying after the reaction is finished to obtain a colorless liquid compound 3.
(2) Synthesis of monomer NB-SS-Py-Fc: dissolving the compound 3 and the compound 4 in a second solvent, adding a proper amount of potassium iodide, heating to a reflux state, and adding water for extraction, separation and purification after the reaction is completed to obtain a light brown solid compound NB-SS-Py-Fc.
(3) Synthesis of monomer NB-TPE: and dissolving the compound 5, the compound 6 and potassium iodide in a second solvent, heating to reflux under nitrogen atmosphere, cooling to room temperature after the reaction is completed, and separating and purifying to obtain a red solid compound NB-TPE.
(4) Synthesis of polynorbornene photosensitizer P1: and dissolving the monomer NB-SS-Py-Fc and the monomer NB-TPE in a first solvent, adding vinyl ethyl ether for end capping after polymerization, and purifying by recrystallization to obtain the copolymer P1.
Preferably, the molar ratio of compound 1 to compound 2 in step (1) is 1:1-2, wherein the molar ratio of the compound 3 to the compound 4 in the step (2) is 1:1-1.8, wherein the molar ratio of the compound 5 to the compound 6 in the step (3) is 1:1 to 1.5, wherein the molar ratio of the monomer NB-SS-Py-Fc to the monomer NB-TPE in the step (4) is 1:1-3.
Preferably, the first solvent is dichloromethane, and the second solvent is acetonitrile.
Preferably, the reaction time in the step (1) is 24-36h, the reaction time in the step (2) is 24-48h, and the reaction time in the step (4) is 30min.
Preferably, the purification techniques in the steps include washing, extraction, filtration, drying, recrystallization, and column chromatography.
The mechanism of action of the GSH activated polynorbornene photosensitizer of the invention is through a photo-induced charge transfer (PET) mechanism between molecules of two polymeric monomers. Fluorescence is very weak when GSH is absent, whereas fluorescence is enhanced when GSH is present. When GSH is absent, the active oxygen production efficiency is low, whereas when GSH is present, the active oxygen production efficiency is greatly improved. The photosensitizer belongs to aggregation-induced emission AIE type photosensitizers.
The invention also provides a glutathione activated polynorbornene nanoparticle photosensitizer, namely the nanoparticle of the polynorbornene photosensitizer, which is prepared by embedding the polynorbornene photosensitizer through a surfactant. The polynorbornene nanoparticle photosensitizer provided by the invention can be specifically started by GSH to respond in fluorescence, can generate considerable singlet oxygen under laser irradiation, can kill tumor cells efficiently, and has excellent biological application prospect.
The invention also provides a preparation method of the polynorbornene photosensitizer nanoparticle P1NPs, which comprises the following steps:
(1) The copolymer P1 was dissolved in an organic solvent to obtain a solution A, and the surfactant was dissolved in ultrapure water to obtain a solution B.
(2) And (3) rapidly dripping the solution A into the solution B, introducing nitrogen to remove the organic solvent after the reaction is completed, and evaporating the solvent to obtain the nanoparticle solution with the corresponding concentration.
Preferably, the organic solvent in the step (1) is tetrahydrofuran, and the surfactant is F-127 (polyoxypropylene polyoxyethylene copolymer).
Preferably, the reaction time of step (2) is 20 minutes.
Preferably, the particle size of the prepared nano particles is 158+/-4 nm.
The polynorbornene nanoparticle photosensitizer prepared by the invention has the advantages of cheap synthesis raw materials, simple synthesis process, easy separation procedure, high yield, stability, easy preservation and the like.
The polynorbornene nanoparticle photosensitizer provided by the invention can quantitatively detect GSH inside and outside organisms.
The polynorbornene nanoparticle photosensitizer provided by the invention can generate corresponding singlet oxygen under the induction of GSH, and can cause irreversible damage to tumor cells.
Compared with the prior art, the invention has the beneficial effects that:
the polynorbornene photosensitizer has the advantages of clear structure, simple synthesis, low raw material cost, convenient purification, stable property of the prepared nano particles, uniform dispersion and good water solubility and biocompatibility. Can achieve the specific recognition of GSH in vivo and in vitro and simultaneously generate singlet oxygen to kill tumor cells, and has considerable photodynamic treatment effect.
Drawings
FIG. 1 is a schematic diagram of the present invention;
FIG. 2 shows the nuclear magnetic resonance hydrogen spectrum (CDCl) of Compound 3 in example 1 3 )；
FIG. 3 shows the nuclear magnetic resonance hydrogen spectrum (CDCl) of the monomer NB-SS-Py-Fc of example 1 3 )；
FIG. 4 is a nuclear magnetic hydrogen spectrum (CDCl) of the monomer NB-TPE of example 1 3 )；
FIG. 5 shows the nuclear magnetic resonance hydrogen spectrum (CDCl) of copolymer P1 in example 1 3 )；
FIG. 6 is a graph showing the particle size distribution and SEM image after preparing nanoparticles from the copolymer P1 of example 2;
FIG. 7 is a graph showing fluorescence response of polynorbornene nanoparticles (P1 NPs) to GSH at various concentrations in example 3;
FIG. 8 is a graph of intracellular imaging of polynorbornene nanoparticles (P1 NPs) of example 3 for different concentrations of GSH;
FIG. 9 is a graph of singlet oxygen yield of polynorbornene nanoparticles (P1 NPs) before and after GSH addition in example 4;
FIG. 10 shows phototoxicity and darkness toxicity of polynorbornene nanoparticles (P1 NPs) to cells in example 5;
FIG. 11 is a live dead cell staining experiment of polynorbornene nanoparticles (P1 NPs) in example 5.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but embodiments of the present invention are not limited thereto.
Example 1
The synthesis method of the polynorbornene photosensitizer P1 comprises the following steps:
(1) Synthesis of precursor compound 3: compound 1 (0.40 g,1.82 mmol) and compound 2 (0.39 g,1.82 mmol) were dissolved in ultra-dry dichloromethane. Dicyclohexylcarbodiimide (0.45 g,2.18 mmol) and 4-dimethylaminopyridine (0.22 g,1.82 mmol) were then added to the system and reacted at room temperature under nitrogen atmosphere for 24h. After the completion of the reaction, the reaction solution was filtered and concentrated. Petroleum ether: dichloromethane (1:8) was used as an eluent, and 0.65g of colorless liquid compound 3 was obtained by column chromatography in 85% yield.
The colorless liquid compound obtained above was measured by a nuclear magnetic resonance apparatus (Varian instrument MHz), and the data were as follows:
1 H NMR(400MHz,CDCl 3 )δ(ppm):6.12(s,2H),4.35(t,J＝6.6Hz,2H),4.08(s,2H),3.59(t,J＝8.0Hz,2H),3.39(s,2H),3.36-3.31(m,2H),3.10-3.02(m,2H),2.90(t,J＝6.6Hz,2H),1.74(d,J＝1.8Hz,1H),1.55(d,J＝8.8Hz,1H).
(2) Synthesis of monomer NB-SS-Py-Fc: compound 3 (0.30 g,0.72 mmol), compound 4 (0.22 g,0.72 mmol) and potassium iodide (0.03 g,0.20 mmol) were dissolved in 20mL of ultra-dry acetonitrile, reacted at 80℃for 24 hours, and then the solvent was evaporated under reduced pressure. Dichloromethane: methanol (50:1) was used as eluent and the mixture was purified by silica gel chromatography to give 0.40g of pure pale brown solid compound NB-SS-Py-Fc in 76% yield.
The light brown solid compound NB-SS-Py-Fc obtained above was measured by nuclear magnetic resonance (Varian instrument MHz) and the data are shown below:
1 H NMR(400MHz,CDCl 3 )δ(ppm):10.26(s,1H),10.00(s,1H),9.54(d,J＝8.8Hz,1H),8.44(d,J＝5.9Hz,1H),7.89(t,J＝8.7Hz,1H),6.11(s,2H),5.35(s,2H),4.93(t,J＝6.4Hz,2H),4.51-4.49(m,2H),4.38(t,J＝6.0Hz,2H),4.30(s,5H),4.11(s,2H),3.43(t,J＝6.3Hz,2H),3.38(s,4H),2.99(t,J＝6.0Hz,2H),1.31(s,1H),1.26(d,J＝3.3Hz,1H).
(3) Synthesis of monomer NB-TPE: compound 5 (0.5 mmol), compound 6 (0.5 mmol) and potassium iodide (0.08 mmol) were sequentially dissolved in 15mL of anhydrous acetonitrile. Then heated to 80 ℃ and reacted under reflux for 24 hours. The solvent was removed using a rotary evaporator and the crude product was purified by silica gel chromatography (dichloromethane: methanol=18:1) to give 0.77g of compound NB-TPE as a red solid in 85% yield.
The red solid compound NB-TPE obtained above was measured by nuclear magnetic resonance (Varian instrument MHz) and the data are shown below:
1 H NMR(400MHz,CDCl 3 )δ(ppm):9.15(d,J＝6.3Hz,2H),7.93(d,J＝6.4Hz,2H),7.59(d,J＝16.1Hz,1H),7.34(d,J＝8.1Hz,2H),7.14-6.87(m,11H),6.62(t,J＝8.3Hz,4H),6.17(t,J＝4.3Hz,1H),5.87(dd,J＝6.0,3.0Hz,1H),4.90(t,J＝8.0Hz,2H),4.10(m,2H),3.72(s,6H),3.14(s,1H),2.93(dt,J＝8.6,3.9Hz,1H),2.88(s,1H),2.39(t,J＝7.2Hz,2H),1.41(d,J＝8.4Hz,1H),1.33(d,J＝11.2Hz,2H),1.25(d,J＝8.6Hz,2H).
(4) Synthesis of polynorbornene photosensitizer P1: NB-TPE (60 mg,0.08 mmol), NB-SS-Py-Fc (58 mg,0.08 mmol) and third generation Grubbs catalyst (8 mg,0.01 mmol) were dissolved in 10mL ultra-dry dichloromethane. The reaction was allowed to proceed under a nitrogen atmosphere for 30 minutes, and 2mL of vinyl ether was added dropwise thereto and stirred for 15 minutes to stop the polymerization reaction. Recrystallisation from methylene chloride and methanol several times gave 100mg of copolymer P1 in 80% yield.
The copolymer P1 obtained above was measured by a nuclear magnetic resonance apparatus (Varian instrument MHz), and the data are as follows:
1 H NMR(400MHz,CDCl 3 )δ(ppm):9.12,8.00,7.35,7.10,7.04,6.92,6.63,5.35,4.88,4.69,4.51,4.31,4.27,3.72,3.41,2.98,2.42,2.30,1.27.
example 2
The preparation method of polynorbornene photosensitizer nanoparticle P1NPs comprises the following steps:
4mg of copolymer P1 are dissolved in 3mL of tetrahydrofuran solution and the homogeneous and stable organic phase is obtained under ultrasound. The organic phase was then rapidly dropped into 5mL of ultrapure water containing 6mg of F-127 (polyoxypropylene polyoxyethylene copolymer). After complete dissolution, stirring was carried out for 30 minutes, and nitrogen was bubbled through the solution to eliminate THF. The desired nanoparticle concentration (2 mg/mL) was then achieved by evaporation of the aqueous solvent. As shown in FIG. 6, the obtained nanoparticles have stable and uniform properties, and the average diameter thereof is 158.+ -. 4nm, as shown by the particle size distribution and the scanning electron microscope.
Example 3
The nanoparticle solution obtained in example 2 was prepared into a 25. Mu.g/mL P1NPs test solution with PBS buffer (pH=7.4), and a fluorescence titration experiment was performed by adding GSH. As shown in FIG. 7, it was found that the fluorescence emission spectrum of P1NPs was changed with the addition of GSH, and its fluorescence emission peak at 615nm was increased with the increase of GSH concentration and reached saturation at 0.9mM, and the fluorescence intensity was increased 3.5 times as compared with that. Meanwhile, we also used P1NPs to monitor GSH concentration in vivo Hep-G2 cells, as shown in FIG. 8. The experiment was performed by three groups: group A was prepared by incubating Hep-G2 cells with P1NPs (25. Mu.g/mL) for 30min, and the cells showed strong fluorescence in the red emission channel (550-650 nm) under excitation of 405nm, indicating that P1NPs can permeate into the cells and disulfide bonds of P1NPs can be cleaved by endogenous GSH to restore the red fluorescence reaction. Group B were cells pretreated with NEM (0.5 mM) which is a biological thiol scavenger capable of reducing intracellular GSH concentration, and P1NPs (25. Mu.g/mL). Compared with the group A, the fluorescence of the cells in the group is obviously reduced, and the fluorescence intensity is reduced by 32%. Group C cells were pretreated with exogenous GSH (0.5 mM) and P1NPs (25. Mu.g/mL), and significant fluorescence emission occurred in the red channel and fluorescence intensity increased by 248%. Experiments show that the intracellular results are consistent with the phenomenon in PBS buffer solution, and the P1NPs have excellent monitoring capability on GSH inside and outside the cells.
Example 4
The nanoparticle solution P1NPs obtained in example 2 was tested for its singlet oxygen generating capacity. ABDA (9, 10-anthracenediacyl-bis (methylene) di-malonic acid) is an indicator of in vitro tracking of singlet oxygen. Rose Bengal (RB) was chosen as a standard photosensitizer with a singlet oxygen yield of 0.75 in aqueous solution. As shown in FIG. 9, the singlet oxygen yield of P1NPs and P1NPs treated with 0.9mM GSH under laser irradiation was represented by a decrease in absorbance of ABDA. Experiments find that only P1NPs 1 O 2 Quantum yield of 0.23, whereas GSH treated P1NPs 1 O 2 The quantum yield increased to 0.62, strongly demonstrating that singlet oxygen production of P1NPs can be activated by reaction with GSH, showing a significant photodynamic effect.
Example 5
The nanoparticle solution P1NPs obtained in example 2 was subjected to test experiments for its phototoxicity and dark toxicity to cells by the PTT method. As shown in FIG. 10, P1NPs were almost non-toxic to Huvec cells, both in the dark and under light. However, hep-G2 cells were unaffected by P1NPs concentration in the dark, but showed significant concentration-dependent cytotoxicity after 10 minutes of light. These properties fully meet the requirements of photosensitizers, namely superior biocompatibility in the dark and high cytotoxicity in light. In addition, we performed a live-dead cell staining experiment to evaluate the photodynamic therapy effect of P1NPs. As shown in FIG. 11, as a control group, cells not irradiated with P1NPs but treated with laser light or cells not irradiated with P1NPs but treated with laser light remained rather active. In contrast, when cells are treated with P1NPs and irradiated with laser light, a large number of dead cells appear. These results strongly support that P1NPs are excellent polymeric photosensitizers useful for efficient PDT of cancer cells.
The foregoing description of the preferred embodiments of the present invention has been presented only in terms of those specific and detailed descriptions, and is not, therefore, to be construed as limiting the scope of the invention. It should be noted that modifications, improvements and substitutions can be made by those skilled in the art without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (7)
1. A glutathione activated polynorbornene photosensitizer, characterized by the chemical structural formula:
the molar ratio of monomer NB-SS-Py-Fc to monomer NB-TPE is x:y=1: 1 to 3.
2. The method for preparing the glutathione activated polynorbornene photosensitizer according to claim 1, wherein two norbornene monomers NB-SS-Py-Fc and NB-TPE are dissolved in a pure solvent, and the polynorbornene photosensitizer is obtained through polymerization under the catalysis of a catalyst.
3. The method for preparing the glutathione-activated polynorbornene photosensitizer according to claim 2, wherein the solvent is ultra-dry dichloromethane, the catalyst is a three-generation catalyst of granbula, and the polymerization mode is ring opening metathesis polymerization.
4. The method for preparing the glutathione activated polynorbornene photosensitizer according to claim 2, comprising the steps of:
step 1, synthesis of precursor compound 3: dissolving a compound 1 and a compound 2 in a first solvent, adding dicyclohexylcarbodiimide and 4-dimethylaminopyridine, reacting at normal temperature, and separating and purifying after the reaction is finished to obtain a colorless liquid compound 3;
step 2, synthesis of monomer NB-SS-Py-Fc: dissolving a compound 3 and a compound 4 in a second solvent, adding a proper amount of potassium iodide, heating to a reflux state, and adding water for extraction, separation and purification after the reaction is completed to obtain a light brown solid compound NB-SS-Py-Fc;
step 3, synthesizing monomer NB-TPE: dissolving a compound 5, a compound 6 and potassium iodide in a second solvent, heating to reflux under nitrogen atmosphere, cooling to room temperature after the reaction is completed, and separating and purifying to obtain a red solid compound NB-TPE;
step 4, synthesizing polynorbornene photosensitizer P1: and dissolving the monomer NB-SS-Py-Fc and the monomer NB-TPE in a first solvent, adding vinyl ethyl ether for end capping after polymerization, and purifying by recrystallization to obtain the copolymer P1.
5. The method for preparing the glutathione activated polynorbornene photosensitizer according to claim 4, wherein the molar ratio of the compound 1 to the compound 2 in the step 1 is 1:1-2, the molar ratio of compound 3 to compound 4 described in step 2 is 1:1-1.8, the molar ratio of compound 5 to compound 6 described in step 3 is 1:1-1.5, the molar ratio of monomer NB-SS-Py-Fc to monomer NB-TPE described in step 4 is 1:1-3.
6. The method for preparing a glutathione activated polynorbornene photosensitizer of claim 4 wherein the first solvent is methylene chloride and the second solvent is acetonitrile.
7. A glutathione activated polynorbornene nanoparticle photosensitizer, characterized in that it is prepared by embedding the polynorbornene photosensitizer of claim 1 or obtained by the preparation method of any of claims 2-6 with a surfactant.
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| CN105343878A (en) * | 2015-11-30 | 2016-02-24 | 中国人民解放军第三军医大学第三附属医院 | Reduction-sensitive-type water-soluble molecularly-targeted photosensitizer and preparation method and application thereof |
| CN111233907A (en) * | 2020-01-17 | 2020-06-05 | 福州大学 | Glutathione-responsive BODIPY (BODIPY) anticancer photosensitizer and preparation and application thereof |
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| CN105343878A (en) * | 2015-11-30 | 2016-02-24 | 中国人民解放军第三军医大学第三附属医院 | Reduction-sensitive-type water-soluble molecularly-targeted photosensitizer and preparation method and application thereof |
| CN111233907A (en) * | 2020-01-17 | 2020-06-05 | 福州大学 | Glutathione-responsive BODIPY (BODIPY) anticancer photosensitizer and preparation and application thereof |
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