CN102743759B - Phosphatase-regulated supramolecular nanosphere and preparation method thereof - Google Patents
Phosphatase-regulated supramolecular nanosphere and preparation method thereof Download PDFInfo
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- CN102743759B CN102743759B CN 201210249721 CN201210249721A CN102743759B CN 102743759 B CN102743759 B CN 102743759B CN 201210249721 CN201210249721 CN 201210249721 CN 201210249721 A CN201210249721 A CN 201210249721A CN 102743759 B CN102743759 B CN 102743759B
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Abstract
The invention discloses an enzyme-regulated supramolecular nanosphere and a preparation method thereof. Constitution unit of the nanosphere takes positively-charged amphoteric calix[4]arene (TAC4A) as host and adenosine triphosphate (ATP) as guest, and constitutes a supramolecular assembly through host-guest coordination interaction. The preparation method comprises the steps of (1) dissolving the positively-charged amphoteric calix[4]arene and ATP in water, and mixing; and (2) adding alkaline phosphatase. The supramolecular nanosphere is enzyme-regulated nanosphere based on binary supramolecular assembly of the amphoteric calix[4]arene (TAC4A) and the adenosine triphosphate. The supramolecular nanosphere has the advantages of good biocompatibility, rapid response to alkaline phosphatase, high selectivity, rapid de-polymerization at phosphatase target site, simple preparation method, and low consumption of host/guest materials; and has broad application prospect in loading, delivery and targeted release of drug for treating phosphatase-related cancer.
Description
[technical field]
The invention belongs to the Nanosized Supramolecular Materials Composed of Host technical field, particularly supermolecule nano ball of a kind of phosphatase regulation and control and preparation method thereof.
[background technology]
In recent years, the medicine transmission system of stimuli responsive becomes focus (C.J.F.Rijcken, the O.Soga of research due to its advantage that discharges at the specific site controllable high-efficiency, W.E.Hennink, C.F.van Nostrum.J.ControlledRelease2007,120,131 – 148.).Stimulus signal commonly used has (A.Almutairi, S.J.Guillaudeu, M.Y.Berezin, S.Achilefu, J.M.J.Fr é chet.J.Am.Chem.Soc.2008,130, the 444-445 such as temperature, light, magnetic field, ionic strength and pH; (2) Y.Bae, N.Nishiyama, K.Kataoka.Bioconjugate Chem.2007,18,1131 – 1139; (3) C.Wang, K.C.Tam, R.D.Jenkins, C.B.Tan.J.Phys.Chem.B2003,107,4667-4675; (4) S.Lecommandoux, O.Sandre, F.Checot, J.Rodriguez-Hernandez, R.Perzynski.Adv.Mater.2005,17,712 – 718; (5) D.Schmaljohann.Adv.Drug DeliveryRev.2006,58,1655 – 1670.).
The biostimulation signal, enzyme for example is because of its good biocompatibility and high selectivity, be significant and wide application prospect (M.D.Burke, J.O.Park, M.Srinivasarao, S.A.Khan.J.Controlled Release2005,104,141 – 153; (2) P.D.Thornton, G.McConnell, R.V.Ulijn.Chem.Commun.2005,5913 – 5915.).Numerous disease is all relevant with the improper activity of enzyme in addition, phosphatase that for example can the catalytic degradation liposome, overexpression in a variety of cancerous cell.Therefore, the assembly by the phosphatase stimuli responsive is having significant advantage (P.Meers.Adv.Drug Delivery Rev.2001,53,265-272 aspect drug delivery and treatment of cancer; (2) S.C.Davis, F.C.Szoka, Jr..Bioconjugate Chem.1998,9,783-792; (3) J.Davidsen, C.Vermehren, S.Frokjaer, O.G.Mouritsen, K.
Int.J.Pharm.2001,214,6769.).
The supermolecule self assembly is method (Y.Wang, H.Xu, X.Zhang.Adv.Mater.2009,21,28492864 that the another kind except the covalent bond means is constructed the stimuli responsive assembly; (2) X.Zhang, C.Wang.Chem.Soc.Rev.2011,40,94-101.).The stimuli responsive site can combine with the supermolecule nano assembly by non-covalent interaction, thereby has avoided the chemosynthesis of covalent bond.
[summary of the invention]
The objective of the invention is for above-mentioned technical Analysis, supermolecule nano ball of a kind of phosphatase regulation and control and preparation method thereof is provided, this supermolecule nano ball is based on the enzyme regulation and control nanosphere of the amphipathic cup of positive charge [4] aromatic hydrocarbons and adenosine triphosphate binary Supramolecular Assembling, good biocompatibility, to alkali phosphatase have the characteristic of quick response, with high selectivity and rapidly in phosphatase-targeting site depolymerization; And preparation method is easy, and is main, object raw material consumption is few.
Technical scheme of the present invention:
A kind of supermolecule nano ball of enzyme regulation and control, its construction unit take adenosine triphosphate (ATP) as object, is constructed super-molecule assembling body by the host-guest Coordination interaction take positive charge amphipathic cup [4] aromatic hydrocarbons (TAC4A) as main body.
A kind of preparation method of supermolecule nano ball of described enzyme regulation and control, step is as follows:
1) positive charge amphipathic cup [4] aromatic hydrocarbons and adenosine triphosphate are dissolved in the water, positive charge amphipathic cup [4] aromatic hydrocarbons and the concentration of adenosine triphosphate in water are 0.02mmol/L, get supermolecule nano ball solution after evenly mixing;
2) add alkali phosphatase in above-mentioned supermolecule nano ball solution, the concentration of alkali phosphatase in supermolecule nano ball solution is 0.15U/mL, can make the supermolecule nano ball of enzyme regulation and control.
This supermolecule nano ball is based on the enzyme regulation and control nanosphere of positive charge amphipathic cup [4] aromatic hydrocarbons and adenosine triphosphate binary Supramolecular Assembling, positive charge amphipathic cup [4] aromatic hydrocarbons and adenosine triphosphate can form supermolecule nano set of balls dress with the equivalent proportioning under low concentration under neutrallty condition.This nanosphere under alkali phosphatase exists, can be completed most of depolymerization in the short time in addition, thereby reaches the effect that targeting discharges.
Advantage of the present invention is: based on the supermolecule nano ball that the amphipathic cup of positive charge [4] aromatic hydrocarbons and adenosine triphosphate binary Supramolecular Assembling are constructed, preparation method is easy, and is main, object raw material consumption is few; This supermolecule nano ball good biocompatibility; This supermolecule nano ball has the characteristic of quick response to alkali phosphatase; This supermolecule nano ball can high selectivity and rapidly in phosphatase-targeting site depolymerization, and it has broad application prospects in the relevant cancer drug load for the treatment of phosphatase, transportation and targeting release field.
[description of drawings]
Fig. 1 is the process of the constructing schematic diagram of the supermolecule nano ball of these enzyme regulation and control.
Fig. 2 is the critical aggregate concentration figure under positive charge amphipathic cup [4] aromatic hydrocarbons and adenosine triphosphate equivalent proportioning.
Fig. 3 is the dynamic light scattering figure of the enzyme response nano ball of positive charge amphipathic cup [4] aromatic hydrocarbons and adenosine triphosphate Supramolecular Assembling.
Fig. 4 is the high resolution transmission electron microscopy image of the enzyme response nano ball of positive charge amphipathic cup [4] aromatic hydrocarbons and adenosine triphosphate Supramolecular Assembling.
Fig. 5 is the scanning electron microscope image of the enzyme response nano ball of positive charge amphipathic cup [4] aromatic hydrocarbons and adenosine triphosphate Supramolecular Assembling.
Fig. 6 is the atomic force microscope images of the enzyme response nano ball of positive charge amphipathic cup [4] aromatic hydrocarbons and adenosine triphosphate Supramolecular Assembling.
Fig. 7 is that the supermolecule nano spheroid of positive charge amphipathic cup [4] aromatic hydrocarbons and adenosine triphosphate assembling is dynamic light scattering light intensity time history plot, and adds alkali phosphatase and add the alkali phosphatase of inactivation to cause system dynamic light scattering light intensity time history plot in system.
Fig. 8 adds the variation diagram of alkali phosphatase system light scattering intensity and diameter after half an hour in being for the supermolecule nano spheroid toward the amphipathic cup of the positive charge of constructing [4] aromatic hydrocarbons and adenosine triphosphate assembling.
Fig. 9 is for adding the fluorescence intensity of trisulfonic acid hydroxyl pyrene in half an hour to change in the supermolecule nano spheroid system of the amphipathic cup of the positive charge of constructing [4] aromatic hydrocarbons and adenosine triphosphate assembling, and adds alkali phosphatase in the system again and add the alkali phosphatase of inactivation to cause the curve chart of system fluorescence intensity variation.
Figure 10 adds the transmission electron microscope image of alkali phosphatase system after half an hour in being for the supermolecule nano spheroid toward the amphipathic cup of the positive charge of constructing [4] aromatic hydrocarbons and adenosine triphosphate assembling.
[specific embodiment]
Embodiment:
A kind of preparation method of supermolecule nano ball of enzyme regulation and control, step is as follows:
1) positive charge amphipathic cup [4] aromatic hydrocarbons and adenosine triphosphate are dissolved in the water, positive charge amphipathic cup [4] aromatic hydrocarbons and the concentration of adenosine triphosphate in water are 0.02mmol/L, get supermolecule nano ball solution after evenly mixing, the process of constructing of the supermolecule nano ball of these enzyme regulation and control as shown in Figure 1;
2) add alkali phosphatase in above-mentioned supermolecule nano ball solution, the concentration of alkali phosphatase in supermolecule nano ball solution is 0.15U/mL, can make the supermolecule nano ball of enzyme regulation and control.
The detection analysis of this supermolecule nano ball:
1) particle diameter of this supermolecule nano ball and pattern:
At first determine the critical aggregate concentration of super-molecule assembling body in solution by measuring the solution light transmittance, Fig. 2 is the critical aggregate concentration figure under positive charge amphipathic cup [4] aromatic hydrocarbons and adenosine triphosphate equivalent proportioning, and critical aggregate concentration is 0.02mmol/L as shown in the figure.Then characterize by dynamic light scattering, high resolution transmission electron microscopy, scanning electron microscope and atomic force microscope respectively: Fig. 3 is the dynamic light scattering figure of the enzyme response nano ball of positive charge amphipathic cup [4] aromatic hydrocarbons and the assembling of adenosine triphosphate molecule, as shown in the figure, the particle size distribution of nanoparticle is homogeneous very, is 237.7nm; Fig. 4 is the high resolution transmission electron microscopy image of the enzyme response nano ball of positive charge amphipathic cup [4] aromatic hydrocarbons and adenosine triphosphate Supramolecular Assembling, Fig. 5 is the scanning electron microscope image of the enzyme response nano ball of positive charge amphipathic cup [4] aromatic hydrocarbons and adenosine triphosphate Supramolecular Assembling, and above two figure prove that all nanoparticle is spherical particle in solution; Fig. 6 is the atomic force microscope images of the enzyme response nano ball of positive charge amphipathic cup [4] aromatic hydrocarbons and adenosine triphosphate Supramolecular Assembling, and as shown in the figure, the height of nanosphere proves that much smaller than the particle diameter of nanosphere nanosphere is hollow-core construction.
2) experimental verification of the alkali phosphatase fast-response of this supermolecule nano ball:
Fig. 7 is that the supermolecule nano spheroid of positive charge amphipathic calixarene and adenosine triphosphate assembling is dynamic light scattering light intensity time history plot, and adds alkali phosphatase and add the alkali phosphatase of inactivation to cause system dynamic light scattering light intensity time history plot in system.As shown in the figure, after only adding alkali phosphatase in supermolecule nano ball solution, obvious decay has occured in the light scattering signal of solution, proved that the alkali phosphatase (0.15U/mL) that adds the normal physiological amount can make rapidly nanosphere generation depolymerization, and not enzyme-added and add the alkali phosphatase signal of same amount inactivation there is no significant change, prove that depolymerization is that catalyzing hydrolysis effect due to enzyme causes.Fig. 8 adds the variation diagram of alkali phosphatase system light scattering intensity and diameter after half an hour in being for the supermolecule nano spheroid toward the assembling of the positive charge amphipathic calixarene of constructing and adenosine triphosphate.As shown in the figure, add enzyme after half an hour, light scattering signal does not have enzyme-added nanometer set of balls that obvious decay has occured, and close with the light intensity of light scattering signal intensity of pure water, and nanosphere is described, and closely depolymerization is complete.Fig. 9 is for adding the fluorescence intensity of trisulfonic acid hydroxyl pyrene in half an hour to change in the supermolecule nano spheroid system of the amphipathic cup of the positive charge of constructing [4] aromatic hydrocarbons and adenosine triphosphate assembling, and adds alkali phosphatase in the system again and add the alkali phosphatase of inactivation to cause the curve chart of system fluorescence intensity variation.After adding alkali phosphatase, along with the hydrolysis of ATP, TAC4A can be with fluorescent probe (trisulfonic acid hydroxyl pyrene) thus effect reduces fluorescence intensity.Show in figure, add enzyme after fluorescence intensity obvious decline is arranged, and not enzyme-added and add fermentoid not have same phenomenon, this depolymerization that nanosphere has been described is equally caused by the alkali phosphatase hydrolysising ATP.Figure 10 adds the transmission electron microscope image of alkali phosphatase system after half an hour in being for the supermolecule nano spheroid toward the amphipathic cup of the positive charge of constructing [4] aromatic hydrocarbons and adenosine triphosphate assembling, as shown in the figure, nanosphere is depolymerization.
Claims (1)
1. the supermolecule nano ball of phosphatase regulation and control, it is characterized in that: construction unit take adenosine triphosphate as object, is constructed super-molecule assembling body by the host-guest Coordination interaction take the amphipathic cup of positive charge [4] aromatic hydrocarbons as main body; Its preparation process is as follows: positive charge amphipathic cup [4] aromatic hydrocarbons and adenosine triphosphate are dissolved in the water, and positive charge amphipathic cup [4] aromatic hydrocarbons and the concentration of adenosine triphosphate in water are 0.02mmol/L, get supermolecule nano ball solution after evenly mixing.
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| CN102258471A (en) * | 2011-04-22 | 2011-11-30 | 南开大学 | Preparation and application of sulfonated calix [4] arene-based nano supramolecular vesicles |
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| CN102258471A (en) * | 2011-04-22 | 2011-11-30 | 南开大学 | Preparation and application of sulfonated calix [4] arene-based nano supramolecular vesicles |
Non-Patent Citations (2)
| Title |
|---|
| 刘宇 等.杯芳烃的超分子化学研究(IV):对-叔丁基杯[4]芳烃对ATP的分子识别及液膜传输作用.《化学学报》.2002,第60卷(第06期),第1111-1115页. |
| 杯芳烃的超分子化学研究(IV):对-叔丁基杯[4]芳烃对ATP的分子识别及液膜传输作用;刘宇 等;《化学学报》;20021231;第60卷(第06期);第1111-1115页 * |
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