CN111481665A - Carrier-free nanoparticle with fluorescent molecular switch characteristic and preparation method and application thereof - Google Patents

Carrier-free nanoparticle with fluorescent molecular switch characteristic and preparation method and application thereof Download PDF

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CN111481665A
CN111481665A CN202010113367.XA CN202010113367A CN111481665A CN 111481665 A CN111481665 A CN 111481665A CN 202010113367 A CN202010113367 A CN 202010113367A CN 111481665 A CN111481665 A CN 111481665A
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carrier
fluorescent
free
free nanoparticle
nanoparticle
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柳文媛
曲玮
张仲涛
冯锋
王如意
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Institute Of Innovative Medicine China Pharmaceutical University Hangzhou
China Pharmaceutical University
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China Pharmaceutical University
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    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
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Abstract

The invention provides a carrier-free nanoparticle with fluorescent molecule switching characteristics and a preparation method and application thereof. The fluorescent 'off-on' characteristic of fluorescent molecules in the process of drug release can be used for monitoring the drug release condition in real time and providing guiding significance for adjusting the drug delivery time and the drug delivery dosage; provides a novel, safe and effective design idea and a preparation method for the visible diagnosis and treatment nanoparticles.

Description

Carrier-free nanoparticle with fluorescent molecular switch characteristic and preparation method and application thereof
Technical Field
The invention relates to a nanoparticle and a preparation method and application thereof, in particular to a carrier-free nanoparticle with fluorescent molecular switch characteristics and a preparation method thereof.
Background
Malignant tumors are a big killer threatening human health. Statistically, nearly 100 million people are diagnosed with cancer each year worldwide. Photodynamic therapy, as a novel anti-tumor mode, has the advantages of small treatment wound, small toxic and side effects and the like, and receives more and more attention since the photodynamic therapy is approved by the FDA in the United states for treating obstructive esophageal tumors in 1996. However, the photosensitizer, as an indispensable element of photodynamic therapy, often has the defects of poor water solubility, incapability of targeted delivery to tumor sites and the like, and the application of the photosensitizer in clinic is greatly limited. In recent years, the rapid development of nano drug delivery systems has provided opportunities to overcome these clinical drawbacks of photosensitizers. Research aiming at nano technologies such as liposome, micelle and the like has been reported, but photodynamic therapy is used as a light-triggered activation treatment mode, the distribution and the release of a photosensitizer are tracked in real time, and great help is provided for realizing space-time activation and accurate treatment of tumors for photodynamic therapy. The real-time tracking of the distribution of the photosensitizer by utilizing fluorescence imaging emitted by the photosensitizer itself is a non-invasive and non-toxic mode, but how to realize intelligent release of the photosensitizer and real-time monitoring of the release process still have great challenges. Currently, most of the strategies for monitoring the drug release process are to co-coat the fluorescent molecules and the drugs in the nano-carrier in a physical embedding manner, the fluorescent molecules do not have fluorescence due to quenching caused by aggregation, and the fluorescence is recovered when the fluorescent molecules are released from the nano-carrier. However, the preparation method is complex in preparation process, and the problems of low drug loading, poor stability, incapability of realizing response drug release of tumor parts and the like exist. Therefore, there is a need to develop more efficient and intelligent drug delivery systems for delivering photosensitizers while enabling real-time tracking of the in vivo distribution of photosensitizers, as well as real-time monitoring of drug release processes. Fluorescent molecules with a fluorescence quenching effect are prepared into small molecule prodrugs, and the photosensitizer is carried by utilizing the capability of self-assembling the fluorescent small molecule prodrugs to form nanoparticles, so that the related adverse reactions caused by the large-scale use of carrier materials are reduced or even avoided, and the drug loading rate is greatly improved.
The fluorescent small-molecule prodrug with Aggregation-induced fluorescence quenching (ACQ) effect generates fluorescence quenching after nanoparticles are formed, and the fluorescence is recovered after free fluorescent small molecules are released, so that the possibility of monitoring the drug release process is provided.
However, whether the conventional nano delivery strategy or the nano particle designed based on the small molecule prodrug strategy is adopted, the realization of the specific release of the target site has very important significance for improving the anti-tumor effect and reducing the toxic and side effects on normal tissues. The presence of high concentrations of ROS levels in tumor cells relative to normal cells can be used to design ROS-responsive drug delivery systems. For example, chemical bonds which are relatively sensitive to ROS, such as a single thioether bond, a disulfide bond, a single selenium bond, a diselenide bond or a spacing diselenide bond, a thioketal bond, an oxalate bond and the like, are introduced into the structure of the fluorescent small molecule prodrug. However, the expression level of ROS in tumor cells is still not enough to rapidly break the ROS sensitive bonds, so that rapid response drug release in tumor cells cannot be realized. The generated ROS can not only cause the apoptosis of tumor cells, but also serve as an ROS supplement to accelerate the release of fluorescent micromolecule prodrug, and the fluorescence emitted by the fluorescent micromolecules can reflect the real-time release condition of the photosensitizer, thereby providing guiding significance for adjusting the administration time and the administration dosage and further providing possibility for realizing accurate treatment of the anti-tumor. The carrier-free nanoparticle with the fluorescent molecular switch characteristic provided by the invention can be accumulated at a tumor part through an EPR effect, and the preparation method is simple and quick and has good clinical transformation application prospect.
Disclosure of Invention
The purpose of the invention is as follows: the first purpose of the invention is to provide a carrier-free nanoparticle with fluorescent molecular switch characteristics;
the second purpose of the invention is to provide a preparation method of the nanoparticle.
The third purpose of the invention is to provide the application of the nanoparticle.
The invention realizes the aim through the following technical scheme: the nano-particle is formed by coating photosensitizer by prodrug molecules through self-assembly, wherein the prodrug molecules are formed by connecting fluorescent molecules with aggregation fluorescence quenching characteristics with hydrophobic groups through ROS sensitive bonds.
Preferably, the fluorescent molecule with the aggregated fluorescence quenching characteristic is a coumarin molecule, a quinone molecule, a flavonoid molecule, an alkaloid molecule or a diphenylheptane molecule with an active hydroxyl group or an active carboxyl group.
Further, the fluorescent molecule with the aggregated fluorescence quenching property is curcumin, camptothecin, gambogic acid and quercetin.
Further, the fluorescent molecule with the aggregated fluorescence quenching property is curcumin.
Preferably, the ROS-sensitive bond is a monothioether bond, a disulfide bond, a monoselenium bond, a diselenium bond, a spacer diselenium bond or an oxalate-ester bond.
Further, the ROS sensitive bond is a monosulfide bond.
Preferably, the hydrophobic group is a compound containing an unsaturated group.
Further, the hydrophobic group is vitamin E, oleyl alcohol, oleic acid, linolenyl alcohol, linoleyl alcohol or all-trans retinoic acid.
Further, the hydrophobic group is oleyl alcohol.
Preferably, the photosensitizer is porphyrin or phthalocyanine.
Further, the photosensitizer is pyropheophorbide a, chlorin, zinc phthalocyanine, 5-aminolevulinic acid, hematoporphyrin monomethyl ether or chlorophyll derivatives.
Among them, chlorin is Ce6, and zinc phthalocyanine is ZnPc.
Preferably, the self-assembly package is that the prodrug molecule and the photosensitizer are combined through non-covalent interaction, the non-covalent interaction is pi-pi accumulation, hydrophobic interaction or intermolecular hydrogen bond, and the molar ratio of the prodrug molecule to the photosensitizer is 3: 1-1: 3.
The invention also provides a preparation method of the carrier-free nanoparticle with the fluorescent molecular switch characteristic, which comprises the following steps: dissolving a mixture of a fluorescent small molecule prodrug and a photosensitizer with a molar ratio of 3: 1-1: 3 into an organic solvent, then dropwise adding the mixture into water to form nanoparticles, and removing the organic solvent in the preparation by using a dialysis method to obtain the carrier-free nanoparticles; or adding a PEG modifier accounting for 15-50% of the weight of the fluorescent micromolecule prodrug into a mixture of the fluorescent micromolecule prodrug and the photosensitizer with the molar ratio of 3: 1-1: 3, dissolving the mixture into an organic solvent, dropwise adding the mixture into water to form nanoparticles, and removing the organic solvent in the preparation by using a dialysis method to obtain the carrier-free nanoparticles.
The fluorescent small molecule prodrug is a prodrug molecule formed by connecting a fluorescent molecule with ACQ characteristic with a hydrophobic group through an ROS sensitive bond.
Preferably, the fluorescent molecule with the ACQ characteristic is coumarin, quinone, flavonoid, alkaloid, diphenyl heptane and anthracycline compounds, such as curcumin, ROS sensitive bonds such as monothioether bonds, etc., the hydrophobic group is a compound containing an unsaturated group, such as oleyl alcohol, etc., and the photosensitizer is porphyrin and phthalocyanine, such as ZnPc, etc.
Preferably, the organic solvent is ethanol, tetrahydrofuran or dimethyl sulfoxide.
Further, the organic solvent is dimethyl sulfoxide.
Preferably, the PEG modifier is TPGS, DSPE-PEG, P L GA-PEG or PE-PEG, and the molecular weight is 1000, 2000 or 5000.
Further, the molecular weight of PEG in the PEG modifier is preferably 2000.
Specifically, ZnPc is selected as a photosensitizer mimic molecule, curcumin is selected as a fluorescent molecule mimic molecule with an aggregated fluorescence quenching characteristic, oleyl alcohol is used as a hydrophobic group, and the two molecules are connected by taking thiodiacetic acid (a monothio bond) as a connecting arm to construct a fluorescent small molecule prodrug (Cur-S-OA) with an ROS response characteristic. Meanwhile, curcumin and oleyl alcohol were bridged with glutaric acid to synthesize a control prodrug molecule (Cur-OA);
wherein the structural formula of Cur-S-OA is as follows:
Figure BDA0002390749890000041
the structural formula of Cur-OA is as follows:
Figure BDA0002390749890000042
the invention provides a synthesis method of the fluorescent molecule prodrug with the aggregation fluorescence quenching characteristic and a control prodrug, which comprises the following steps:
firstly, the oleyl alcohol reacts with dibasic acid to obtain an intermediate product. The intermediate product continues to react with curcumin to form an ester, and the final product is obtained.
The dibasic acid is selected from: thiodiacetic acid, selenodiacetic acid, 3 '-dithiodipropionic acid, 3' -diselenodipropionic acid, (ethylenedithio) diacetic acid, oxalic acid, glutaric acid.
Specifically, the invention provides a synthesis method of series curcumin-oleyl alcohol small molecule prodrugs, which comprises the following steps:
dissolving thiodiacetic acid, selenodiacetic acid, 3 '-dithiodipropionic acid, 3' -diselenodipropionic acid, (ethylenedithio) diacetic acid, oxalic acid and glutaric acid in dichloromethane, then adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), stirring and reacting Dimethylaminopyridine (DMAP) for 0.5h at room temperature, adding a certain amount of oleyl alcohol, continuing to stir and react for 2-5 h, monitoring the reaction degree by T L C, separating by column chromatography to obtain a monolaterial carboxyl substituted oleyl alcohol carboxylation product, then stirring and reacting the obtained alcohol carboxylation product, EDCI, DMAP, 1-Hydroxybenzotriazole (HOBT) and N, N-Diisopropylethylamine (DIPEA) for 0.5h at room temperature, adding curcumin, N2And (4) continuously stirring and reacting for 24 hours at room temperature under protection, and finally separating and purifying by column chromatography to obtain the product.
The curcumin can be replaced by other fluorescent molecules containing active hydroxyl, such as coumarins, quinones, flavonoids, alkaloids, other diphenylheptanes and anthracyclines.
The oleyl alcohol may be replaced by other groups containing unsaturated bonds, such as vitamin E, oleyl alcohol, oleic acid, linolenyl alcohol, linoleyl alcohol.
The photosensitizer may be replaced by other porphyrin or phthalocyanine photosensitizers, such as chlorin E6.
The invention also provides the curcumin-oleyl alcohol small molecule prodrug coated ZnPc self-assembled nanoparticles.
The preparation method of the curcumin-oleyl alcohol micromolecule prodrug coated ZnPc self-assembled nanoparticles provided by the invention comprises the following steps:
dissolving a certain amount of PEG modifier (TPGS, DSPE-PEG, P L GA-PEG or PE-PEG), fluorescent micromolecule prodrug and photosensitizer into a proper amount of organic solvent, slowly adding the organic solvent solution into water under vigorous stirring, and spontaneously forming uniform nanoparticles.
The organic solvent is ethanol, tetrahydrofuran or dimethyl sulfoxide;
furthermore, the invention provides a carrier-free nanoparticle with fluorescent molecular switching characteristics, which takes curcumin-oleyl alcohol and ZnPc co-assembled nanoparticles as a model.
Wherein the molar ratio of curcumin-oleyl alcohol to ZnPc is 3: 1-1: 3.
the preparation method of the curcumin-oleyl alcohol and ZnPc co-assembled nanoparticle comprises the following steps:
dissolving a certain amount of curcumin-oleyl alcohol, a PEG modifier and ZnPc in a proper amount of organic solvent, wherein the preferable organic solvent is ethanol and dimethyl sulfoxide, the concentration range of the curcumin-oleyl alcohol is 0.5-5 mg/ml, the concentration range of the ZnPc is 0.5-5 mg/ml, and the solution is slowly dripped into water under stirring to spontaneously form uniform nanoparticles, wherein the proportion of the PEG to the curcumin-oleyl alcohol is 0-30%, the preferable proportion is 30%, the used PEG modifier is TPGS, DSPE-PEG, P L GA-PEG or PE-PEG, and the like, the preferable PEG molecular weight is 1000, 2000, 5000, and the preferable PEG molecular weight is 2000.
The invention also provides application of the carrier-free nanoparticle with the fluorescent molecular switch characteristic in the drug release detection process, and the drug release process is monitored by the change of the fluorescent molecular fluorescence intensity from weak to strong in the depolymerization process of the nanoparticle.
Has the advantages that: (1) the carrier-free nanoparticle with the fluorescent molecule switching characteristic utilizes small-molecule fluorescent molecules of ROS sensitive drug release to wrap a photosensitizer in a non-covalent mode, so that the fluorescent molecules and the photosensitizer are synchronously delivered. The ROS generated by photodynamic therapy kills tumor cells and simultaneously causes the breakage of ROS sensitive bonds in the micromolecule fluorescent prodrug, so that the intelligent release of the fluorescent micromolecule and the photosensitizer under the light trigger is realized, the fluorescent micromolecule fluorescence is changed from 'off' to 'on', the fluorescent micromolecule fluorescence can be used for monitoring the drug release process in real time, and the guide is provided for adjusting the drug delivery time and the drug delivery dose;
(2) the nano-precipitation method is adopted for preparation, so that the method is simple and rapid, has a simple process, and is suitable for industrial production;
(3) the particle size is less than 200nm, the polydispersity is small, the particle size is uniform, the structure is stable; 3) the drug loading is high, and the toxicity caused by auxiliary materials can be avoided;
(4) the ROS response drug release characteristic is generated by light triggering, and the time-space response drug release of the tumor part can be realized;
(5) the fluorescent 'off-on' characteristic of fluorescent molecules in the process of drug release can be used for monitoring the drug release condition in real time and providing guiding significance for adjusting the drug delivery time and the drug delivery dosage; provides a novel, safe and effective design idea and a preparation method for the visible diagnosis and treatment nanoparticles.
Drawings
FIG. 1 is a 1H-NMR spectrum of a monothioether linked curcumin-oleyl alcohol prodrug (Cur-S-OA) of example 1 of the present invention;
FIG. 2 is an ESI-MS spectrum of a monothioether linked curcumin-oleyl alcohol prodrug (Cur-S-OA) of example 1 of the present invention;
FIG. 3 is a 1H-NMR spectrum of an ester-linked curcumin-oleyl alcohol prodrug (Cur-OA) of example 2 of the present invention;
FIG. 4 is an ESI-MS spectrum of a monothioether linked curcumin-oleyl alcohol prodrug (Cur-S-OA) of example 2 of the present invention;
FIG. 5 is a graph showing a fluorescence emission spectrum of Cur-S-OA or curcumin dispersed in water or THF in example 3 of the present invention;
fig. 6 is a transmission electron microscope image and a dynamic light scattering particle size distribution diagram of the self-assembled nanoparticles formed by coating ZnPc with the curcumin-oleyl alcohol prodrug of example 4 of the present invention;
FIG. 7 is a graph showing the particle size-storage time variation of the self-assembled nanoparticle (ZnPc @ Cur-S-OA) formed by coating ZnPc with the curcumin-oleyl alcohol prodrug containing a single thioether bond in example 4 of the present invention;
fig. 8 is a graph of an in vitro release experiment of self-assembled nanoparticles formed by coating ZnPc with curcumin-oleyl alcohol prodrug of example 6 of the present invention;
FIG. 9 is a graph showing the particle size change before and after laser irradiation of the self-assembled nanoparticle (ZnPc @ Cur-S-OA) formed by coating ZnPc with the curcumin-oleyl alcohol prodrug containing a single thioether bond in example 6 of the present invention;
FIG. 10 is an uptake map of cells in example 7 of the present invention;
FIG. 11 is the intracellular release profile of example 8 of the present invention;
FIG. 12 is a cytotoxicity plot of example 9 of the invention;
fig. 13 is an ex vivo organ distribution diagram of self-assembled nanoparticles formed by coating ZnPc with curcumin-oleyl alcohol prodrug of example 10 of the present invention;
FIG. 14 is a graph showing the change in tumor volume in the anti-tumor experiment of example 11;
FIG. 15 is a graph showing the body weight changes of tumor mice in the anti-tumor experiment of example 11;
Detailed Description
The technical solutions of the present invention are further described below with reference to specific embodiments, but the present invention is not limited to the scope of the embodiments.
Example 1
Synthesis of curcumin-oleyl alcohol prodrug (Cur-S-OA) linked by monothioether bond
Weighing a certain amount of thiodiacetic acid, dissolving in dichloromethane, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), adding a certain amount of oleyl alcohol, continuously stirring for reacting for 0.5H at room temperature, adding a certain amount of oleyl alcohol, continuously stirring for reacting for 2-5H, monitoring the degree of reaction progress by T L C, separating by column chromatography to obtain a unilateral carboxyl substituted oleyl alcohol carboxylation product, then continuously stirring the obtained oleyl alcohol carboxylation product, EDCI, DMAP, 1-Hydroxybenzotriazole (HOBT), and N, N-Diisopropylethylamine (DIPEA) for reacting for 0.5H at room temperature, adding curcumin, continuously stirring for reacting for 24H at room temperature under the protection of N2, and finally separating and purifying by column chromatography to obtain a product, determining the structure in example 1 by nuclear magnetic resonance hydrogen spectroscopy (1H-NMR), selecting a solvent as CDCl3, wherein the result is shown in figure 1, and the analysis result is as follows:
1H-NMR(400MHz,CDCl3,):0.89(t,J＝8.0Hz,3H,H-25),1.12～1.44(m,22H,H-10,11,12,13,14,19,20,21,22,23,24),1.52～1.67(m,2H,H-9),1.92～2.20(m,4H,H-15,18),3.46～3.53(s,2H,H-4),3.61～3.67(s,2H,H-2),3.83～3.89(s,3H,H-53),3.90～3.97(s,3H,H-52),4.11～4.17(t,J＝8.2Hz,2H,H-8),5.25～5.40(m,2H,H-16,17),6.45～6.59(m,2H,H-34,38),6.89～6.94(d,J＝8.3Hz,1H,H-29),7.02～7.17(m,5H,H-30,32,43,44,47),7.55～7.63(m,2H,H-33,39)。
the molecular weight of the prodrug structure of example 1 was determined by ESI-MS, and the results are shown in fig. 2, theoretical molecular weight 750.38, and [ M + H ] +: 751.3893.
example 2
Synthesis of ester-linked curcumin-oleyl alcohol prodrug (Cur-OA)
Weighing a certain amount of glutaric acid, dissolving in dichloromethane, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), adding Dimethylaminopyridine (DMAP), stirring at room temperature for 0.5H, adding a certain amount of oleyl alcohol, continuously stirring for 2-5H, monitoring the degree of reaction progress by T L C, performing column chromatography to obtain a unilateral carboxyl substituted oleyl alcohol carboxylation product, then stirring the obtained oleyl alcohol carboxylation product, EDCI, DMAP, 1-Hydroxybenzotriazole (HOBT) and N, N-Diisopropylethylamine (DIPEA) at room temperature for 0.5H, adding curcumin, continuously stirring for 24H at room temperature under the protection of N2, and finally performing column chromatography to obtain a purified product, determining the structure in example 2 by nuclear magnetic resonance hydrogen spectroscopy (1H-NMR), wherein the selected solvent is CDCl3, and the results are shown in figure 3, and the analysis results are as follows:
1H-NMR(400MHz,CDCl3,):0.89(t,J＝8.0Hz,3H,H-25),1.12～1.44(m,22H,H-10,11,12,13,14,19,20,21,22,23,24),1.52～1.67(m,4H,H-3,9),1.92～2.20(m,4H,H-15,18),2.44～2.54(t,J＝8.0Hz,2H,H-2),2.63～2.70(t,J＝8Hz,2H,H-4),3.82～3.89(s,3H,H-53),3.91～3.98(s,3H,H-51),4.05～4.13(t,J＝8.2Hz,2H,H-8),5.29～5.40(m,2H,H-16,17),6.44～6.62(m,2H,H-34,38),6.91～6.96(d,J＝8.3Hz,1H,H-29),7.03～7.19(m,5H,H-30,32,43,44,47),7.56～7.65(m,2H,H-33,39)。
the molecular weight of the prodrug structure of example 1 was determined by ESI-MS and the results are shown in fig. 4, theoretical molecular weight 732.42, where [ M + H ] +: 733.4305.
example 3
Aggregation-induced quenching phenomenon of curcumin-oleic acid prodrug (Cur-S-OA) containing single thioether bond
Equimolar amounts of Cur-S-OA and curcumin are respectively dissolved in THF to prepare equal molar concentrations of Cur-S-OA and curcumin solution, excitation is carried out by using 471nm excitation light, and fluorescence emission spectra at 450-800 nm are recorded. Taking equimolar amount of Cur-S-OA, ultrasonically dispersing into water with the same volume to form nanoparticles, exciting by using 471nm exciting light, and recording a fluorescence emission spectrum at 450-800 nm. As shown in FIG. 5, Cur-S-OA has fluorescence quenching phenomenon in water, the fluorescence intensity at about 520nm is very low, the fluorescence intensity is enhanced when the Cur-S-OA is dissolved in THF, and the curcumin with equimolar concentration is dissolved in THF and shows the strongest fluorescence intensity, so that the nanoparticles prepared by Cur-S-OA are accompanied with the enhancement of fluorescence in the depolymerization and hydrolysis process of the nanoparticles, and the nanoparticles can be used for monitoring the drug condition in real time.
Example 4
Preparation of self-assembled nanoparticles formed by wrapping ZnPc with curcumin-oleyl alcohol prodrug
The prodrugs prepared in examples 1 and 2 were precisely weighed to obtain 10mg, ZnPc 2mg, and TPGS 3mg, and dissolved in 1ml of dimethyl sulfoxide, and the dimethyl sulfoxide solution was slowly added dropwise to 4ml of ultrapure water under vigorous stirring, to obtain uniform nanoparticles (self-assembled nanoparticles ZnPc @ Cur-S-OA nanoparticles formed by ZnPc coated with curcumin-oleyl alcohol prodrug containing a single thioether bond and self-assembled nanoparticles ZnPc @ Cur-OA nanoparticles formed by ZnPc coated with curcumin-oleyl alcohol prodrug containing an ester bond). The appearance and morphology and particle size distribution of the nanoparticles prepared in example 4 were characterized by a transmission microscope and a malvern particle sizer. As a result, as shown in FIG. 6, the prepared nanoparticles have a particle size of about 100nm, a spherical appearance and a uniform particle size distribution.
Example 5
Stability investigation of ZnPc @ Cur-S-OA nanoparticles
The ZnPc @ Cur-S-OA nanoparticles prepared in example 4 were dispersed in PBS (pH 7.4) and FBS, respectively, to prepare 1mg/ml colloidal solutions, allowed to stand at 37 ℃ for 24 hours, and the change in particle size was measured at a predetermined time point by a Malvern particle sizer. The results are shown in FIG. 7. The self-assembled nanoparticles formed by wrapping ZnPc with the curcumin-oleyl alcohol prodrug have no obvious change in particle size within 24 hours, and show good stability.
Example 6
In-vitro release experiment of self-assembled nanoparticles formed by wrapping ZnPc with curcumin-oleyl alcohol prodrug and particle size change before and after laser irradiation
Taking a phosphate buffer solution containing 0.1% of Tween 80 as a release medium, and investigating the in-vitro release condition of the self-assembled nanoparticles formed by wrapping ZnPc with the curcumin-oleyl alcohol prodrug. The self-assembled nanoparticles formed by wrapping ZnPc with the curcumin-oleyl alcohol prodrug prepared in example 4 (the concentration of the curcumin-oleyl alcohol prodrug is 5mg/ml, and the concentration of ZnPc is 1mg/ml) are added into 10ml of release medium, samples are taken at set time points after irradiation is carried out for different times by 638nm laser (0.5W/cm2) at 37 ℃, the concentration of free curcumin is determined by high performance liquid chromatography, and the concentration of released ZnPc is determined by using an ultraviolet spectrophotometer.
The result is shown in fig. 8, as the illumination duration increases, the curcumin-oleyl alcohol prodrug containing the single sulfur bond wraps the self-assembled nanoparticles formed by ZnPc, the release speed of curcumin and ZnPc is accelerated, the obvious property of light triggering and accelerating drug release is shown, and compared with the single sulfur bond, the carbon bond has no ROS response drug release characteristic, so the release amount of curcumin and ZnPc24 h is very low.
Using ultrapure water to prepare 1mg/ml self-assembled nanoparticles formed by coating ZnPc with a curcumin-oleyl alcohol prodrug containing a single thioether bond, using 638nm (0.5W/cm2) laser to irradiate for 5min, and using a Malvern particle sizer to measure the change of particle size before and after irradiation, the result is shown in figure 9, after laser irradiation, the particle size of the nanoparticles becomes non-uniform, large agglomerates exceeding 1000nm appear, which means that after laser irradiation, the structure of the nanoparticles is destroyed, and the drug release under light trigger is successfully realized.
Example 7
Cellular uptake of ZnPc @ Cur-S-OA nanoparticles
B16F10 cells are inoculated into a confocal dish according to the density of 1 × 105 cells/hole, after the cells are cultured in a cell culture box for 24 hours, the curcumin-oleyl alcohol prodrug containing the monothioether bond prepared in the example 4 is coated on self-assembly nanoparticles ZnPc @ Cur-S-OA nanoparticles formed by ZnPc, and free ZnPc and B16F10 cells are incubated for 4 hours, the cells are washed by PBS, then fixed for 10 minutes by 4% paraformaldehyde, the cell nucleus is stained by adding DAPI, after 10 minutes, the cells are washed by PBS for three times, the cells are observed under a confocal microscope, ZnPc is excited by 638nm, a curcumin channel is excited by 472nm, and DAPI is excited by 405 nm.
The experimental result is shown in fig. 10, and in the same time, the cells incubated by the self-assembly nano-particle ZnPc @ Cur-S-OA nano-particle formed by wrapping ZnPc with the curcumin-oleyl alcohol prodrug containing the monothioether bond show higher intracellular fluorescence than the cells incubated by free ZnPc. Therefore, the self-assembled nanoparticles formed by wrapping ZnPc with the curcumin-oleyl alcohol prodrug with the single thioether bond prepared by the invention have higher cellular uptake efficiency than free ZnPc.
Example 8
Intracellular drug release of self-assembled nanoparticles formed by wrapping ZnPc with curcumin-oleyl alcohol prodrug
Co-incubating the nanoparticles prepared in example 4 with B16F10 cells for 4h, irradiating with 638nm laser for 30s or without irradiation, then continuing to incubate in a cell incubator for 2h, washing the cells with PBS, fixing with 4% paraformaldehyde for 10min, adding DAPI to stain the cell nucleus, washing the cells with PBS for three times after 10min, observing under a confocal microscope, exciting ZnPc at 638nm, exciting curcumin channels at 472nm, and exciting DAPI at 405 nm.
The result is shown in fig. 11, the self-assembled nanoparticle ZnPc @ Cur-S-OA formed by wrapping ZnPc with the curcumin-oleyl alcohol prodrug containing a single thioether bond can see significant fluorescence enhancement in the curcumin fluorescence channel after laser irradiation, which further confirms the phenomenon observed in example 3; the phenomenon that the self-assembly nanoparticle ZnPc @ Cur-OA formed by wrapping ZnPc by the ester bond-containing curcumin-oleyl alcohol prodrug is not observed before and after laser irradiation shows that the single thioether bond plays a key role in realizing accelerated drug release under light trigger, and fluorescence enhancement accompanied in the drug release process can be used for reflecting the drug release condition in real time.
Example 9
Cytotoxicity of ZnPc @ Cur-S-OA nanoparticles
The cytotoxicity of the ZnPc @ Cur-S-OA nanoparticles on B16F10 melanoma cells is examined by adopting an MTT method. B16F10 cells in a good state are inoculated into a 96-well plate at the density of 5000 cells per well, the plate is placed in an incubator to be incubated overnight, and when the cell density is up to 60 percent, the nanoparticles prepared in example 4 or the free photosensitizer ZnPc are added. Adding 100 mu l of test solution into each test hole, placing each test hole with the concentration of 5 parallel test holes into a cell incubator for 24 times of culture, taking out a 96-well plate, adding 10 mu l of 5ml of MTT solution into each test hole, removing liquid in the 96-well plate after 2 hours of culture in the cell incubator, adding 100 mu l of DMSO into each test hole, and measuring the absorbance value at 490nm by using a microplate reader.
The cytotoxic results are shown in figure 12. Compared with the free ZnPc group, the ZnPc @ Cur-S-OA nanoparticles have stronger cytotoxic effect, which is probably because the ZnPc can promote the cellular uptake after being prepared into the nanoparticles, thereby enhancing the cytotoxic effect.
Example 10
Distribution of ZnPc @ Cur-S-OA nanoparticles in mouse organs
B16F10 cells are inoculated in a BAB L/C mouse, when the tumor volume reaches 150mm3, the ZnPc @ Cur-S-OA nanoparticles prepared in example 4 and free ZnPc are injected into the tail vein, the administration dosage of the ZnPc is 2 mg/kg., because the ZnPc can emit strong near-infrared fluorescence and has strong penetrating power, the ZnPc @ Cur-S-OA nanoparticles can be used for observing the distribution of the drugs in real time, after 4, 12 or 24 hours of administration, the mouse is killed, the heart, the liver, the spleen, the lung, the kidney and the tumor are separated, and a small animal living body imaging system is used for analysis.
Example 11
In-vivo anti-tumor experiment of ZnPc @ Cur-S-OA nanoparticles
B16F10 melanoma cells were inoculated in the right axilla of mice, and when the tumor volume reached 150mm3, the mice were randomly grouped into 8 groups, each group was administered with physiological saline, free ZnPc, free curcumin, ZnPc @ Cur-S-OA nanoparticles prepared in example 4, once every other day for 3 times (ZnPc ═ 5mg/kg, Cur ═ 6.5mg/kg), laser-irradiated groups were irradiated with laser (638nm, 0.5mW/, 5min) 24 hours after administration, non-laser-irradiated groups were not irradiated with light, mouse body weight was recorded every day, and tumor volume was measured and recorded every other day. The results are shown in fig. 14, and the body weight of the mice of each treatment group does not change significantly in the treatment period, which indicates that the nanoparticles provided by the invention have good safety and biocompatibility. In addition, as shown in fig. 15, after the treatment period of the mice is over, the inhibition effect of the ZnPc @ Cur-S-OA nanoparticles on the tumors of the mice is most obvious compared with that of a single ZnPc treatment group or curcumin treatment group, which indicates that the nanoparticles prepared by the invention can significantly improve the photodynamic treatment effect of the photosensitizer. Therefore, the nanoparticles provided by the invention are a safe and effective anti-tumor preparation.

Claims (18)

1. A carrier-free nanoparticle with fluorescent molecular switching characteristics is characterized in that: the nanoparticle is formed by wrapping photosensitizer by prodrug molecules through self-assembly, wherein the prodrug molecules are formed by connecting fluorescent molecules with aggregated fluorescence quenching characteristics with hydrophobic groups through ROS sensitive bonds.
2. The carrier-free nanoparticle with fluorescent molecular switching properties of claim 1, wherein: the fluorescent molecule with the aggregated fluorescence quenching characteristic is coumarin, quinone, flavonoid, alkaloid and diphenylheptane molecules with active hydroxyl or active carboxyl.
3. The carrier-free nanoparticle with fluorescent molecular switching properties of claim 1, wherein: the fluorescent molecules with the aggregation fluorescence quenching characteristic are curcumin, camptothecin, gambogic acid and quercetin.
4. The carrier-free nanoparticle with fluorescent molecular switching properties of claim 3, wherein: the fluorescent molecule with the aggregated fluorescence quenching characteristic is curcumin.
5. The carrier-free nanoparticle with fluorescent molecular switching properties of claim 1, wherein: the ROS sensitive bond is a single thioether bond, a disulfide bond, a single selenium bond, a diselenide bond, an alternate diselenide bond or an oxalate bond.
6. The carrier-free nanoparticle with fluorescent molecular switching properties of claim 5, wherein: the ROS sensitive bond is a single thioether bond.
7. The carrier-free nanoparticle with fluorescent molecular switching properties of claim 1, wherein: the hydrophobic group is a compound containing an unsaturated group.
8. The carrier-free nanoparticle with fluorescent molecular switching properties of claim 7, wherein: the hydrophobic group is vitamin E, oleyl alcohol, oleic acid, linolenyl alcohol, linoleyl alcohol or all-trans retinoic acid.
9. The carrier-free nanoparticle with fluorescent molecular switching properties of claim 8, wherein: the hydrophobic group is oleyl alcohol.
10. The carrier-free nanoparticle with fluorescent molecular switching properties of claim 1, wherein: the photosensitizer is porphyrin or phthalocyanine.
11. The carrier-free nanoparticle with fluorescent molecular switching properties of claim 1, wherein: the photosensitizer is pyropheophorbide a, chlorin (Ce6), zinc phthalocyanine (ZnPc), 5-aminolevulinic acid, hematoporphyrin monomethyl ether or chlorophyll derivatives.
12. The carrier-free nanoparticle with fluorescent molecular switching properties of claim 1, wherein: the self-assembly coating is that the prodrug molecules and the photosensitizer are combined through non-covalent interaction, the non-covalent interaction is pi-pi accumulation, hydrophobic interaction or intermolecular hydrogen bond, and the molar ratio of the prodrug molecules to the photosensitizer is 3: 1-1: 3.
13. The method for preparing the carrier-free nanoparticle with fluorescent molecular switching characteristics according to any one of claims 1 to 12, wherein the carrier-free nanoparticle comprises: dissolving a mixture of a fluorescent small molecule prodrug and a photosensitizer with a molar ratio of 3: 1-1: 3 into an organic solvent, then dropwise adding the mixture into water to form nanoparticles, and removing the organic solvent in the preparation by using a dialysis method to obtain the carrier-free nanoparticles; or adding a PEG modifier accounting for 15-50% of the weight of the fluorescent micromolecule prodrug into a mixture of the fluorescent micromolecule prodrug and the photosensitizer with the molar ratio of 3: 1-1: 3, dissolving the mixture into an organic solvent, dropwise adding the mixture into water to form nanoparticles, and removing the organic solvent in the preparation by using a dialysis method to obtain the carrier-free nanoparticles.
14. The method for preparing the carrier-free nanoparticle with fluorescent molecular switching characteristics according to claim 13, wherein the carrier-free nanoparticle comprises: the organic solvent is ethanol, tetrahydrofuran and dimethyl sulfoxide.
15. The method for preparing the carrier-free nanoparticle with fluorescent molecular switching characteristics according to claim 14, wherein the carrier-free nanoparticle comprises: the organic solvent is dimethyl sulfoxide.
16. The method for preparing the non-carrier nanoparticle with fluorescent molecular switch characteristics according to claim 13, wherein the PEG modifier is TPGS, DSPE-PEG, P L GA-PEG or PE-PEG, and the molecular weight is 1000, 2000 or 5000.
17. The method for preparing the carrier-free nanoparticle with fluorescent molecular switching characteristics according to claim 16, wherein the carrier-free nanoparticle comprises: the PEG molecular weight of the PEG modifier is preferably 2000.
18. The use of the carrier-free nanoparticle with fluorescent molecular switching properties of claims 1-17 in detecting drug release, wherein: the monitoring of the drug release process is realized by the change of the fluorescence intensity of the fluorescent molecules from weak to strong in the depolymerization process of the nanoparticles.
CN202010113367.XA 2020-02-24 2020-02-24 Carrier-free nanoparticle with fluorescent molecular switch characteristic and preparation method and application thereof Pending CN111481665A (en)

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